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Li S, Huang X, Zhao H, Liu S, Zhao S. Bariatric Surgery Impact on Women with Polycystic Ovary Syndrome: A Prospective Cohort Study. RESEARCH (WASHINGTON, D.C.) 2025; 8:0664. [PMID: 40207015 PMCID: PMC11979338 DOI: 10.34133/research.0664] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2025] [Revised: 03/09/2025] [Accepted: 03/15/2025] [Indexed: 04/11/2025]
Abstract
Bariatric surgery has emerged as a promising intervention for obese women with polycystic ovary syndrome (PCOS), a condition strongly associated with obesity and anovulatory infertility. While weight management is a key therapeutic strategy, the optimal approach remains uncertain. A recent randomized controlled trial evaluated the impact of bariatric surgery on ovulation rates in obese women with PCOS. However, methodological limitations, including baseline body mass index discrepancies and minimal weight loss in the medical management group, necessitate cautious interpretation of the findings. To further investigate this issue, we conducted a prospective cohort study involving 192 women with PCOS who had undergone bariatric surgery. We assessed 30 reproductive and metabolic parameters at baseline and at 3, 6, and 12 months postoperatively. Most metabolic parameters improved significantly by 3 months postsurgery but plateaued thereafter, with only triglycerides and high-density lipoprotein cholesterol showing continued improvement. Reproductive outcomes demonstrated sustained improvements in ovulatory dysfunction, coinciding with a reduction in luteinizing hormone levels. However, testosterone levels and polycystic ovarian morphology showed limited improvement, while anti-Müllerian hormone levels remained unchanged. Despite the total weight loss exceeding 30%, further weight reduction did not proportionally enhance outcomes. These findings suggest that while bariatric surgery effectively improves metabolic health and ovulation in PCOS, its long-term hormonal and ovarian effects remain unclear and require further investigation. Head-to-head comparisons with emerging therapies are also urgently needed to refine weight management strategies for this high-risk population.
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Affiliation(s)
- Shumin Li
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health,
Shandong University, Jinan 250012, China
| | - Xin Huang
- Division of Bariatric and Metabolic Surgery, Department of General Surgery,
Qilu Hospital of Shandong University, Jinan, China
| | - Han Zhao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health,
Shandong University, Jinan 250012, China
| | - Shaozhuang Liu
- Division of Bariatric and Metabolic Surgery, Department of General Surgery,
Qilu Hospital of Shandong University, Jinan, China
| | - Shigang Zhao
- State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health,
Shandong University, Jinan 250012, China
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Dwibedi C, Axelsson AS, Abrahamsson B, Fahey JW, Asplund O, Hansson O, Ahlqvist E, Tremaroli V, Bäckhed F, Rosengren AH. Effect of broccoli sprout extract and baseline gut microbiota on fasting blood glucose in prediabetes: a randomized, placebo-controlled trial. Nat Microbiol 2025; 10:681-693. [PMID: 39929977 PMCID: PMC11879859 DOI: 10.1038/s41564-025-01932-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 01/13/2025] [Indexed: 03/06/2025]
Abstract
More effective treatments are needed for impaired fasting glucose or glucose intolerance, known as prediabetes. Sulforaphane is an isothiocyanate that reduces hepatic gluconeogenesis in individuals with type 2 diabetes and is well tolerated when provided as a broccoli sprout extract (BSE). Here we report a randomized, double-blind, placebo-controlled trial in which drug-naive individuals with prediabetes were treated with BSE (n = 35) or placebo (n = 39) once daily for 12 weeks. The primary outcome was a 0.3 mmol l-1 reduction in fasting blood glucose compared with placebo from baseline to week 12. Gastro-intestinal side effects but no severe adverse events were observed in response to treatment. BSE did not meet the prespecified primary outcome, and the overall effect in individuals with prediabetes was a 0.2 mmol l-1 reduction in fasting blood glucose (95% confidence interval -0.44 to -0.01; P = 0.04). Exploratory analyses to identify subgroups revealed that individuals with mild obesity, low insulin resistance and reduced insulin secretion had a pronounced response (0.4 mmol l-1 reduction) and were consequently referred to as responders. Gut microbiota analysis further revealed an association between baseline gut microbiota and pathophysiology and that responders had a different gut microbiota composition. Genomic analyses confirmed that responders had a higher abundance of a Bacteroides-encoded transcriptional regulator required for the conversion of the inactive precursor to bioactive sulforaphane. The abundance of this gene operon correlated with sulforaphane serum concentration. These findings suggest a combined influence of host pathophysiology and gut microbiota on metabolic treatment response, and exploratory analyses need to be confirmed in future trials. ClinicalTrials.gov registration: NCT03763240 .
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Affiliation(s)
- Chinmay Dwibedi
- Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Department of Clinical Microbiology and Molecular Infection Medicine Sweden (MIMS), Umeå University, Umeå, Sweden
| | - Annika S Axelsson
- Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Birgitta Abrahamsson
- Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Jed W Fahey
- Departments of Medicine, Pharmacology and Molecular Sciences, and Psychiatry and Behavioral Sciences, Johns Hopkins University, Baltimore, MD, USA
| | - Olof Asplund
- Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Ola Hansson
- Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
- Institute for Molecular Medicine Finland, Helsinki University, Helsinki, Finland
| | - Emma Ahlqvist
- Department of Clinical Sciences, Lund University Diabetes Center, Lund University, Malmö, Sweden
| | - Valentina Tremaroli
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Fredrik Bäckhed
- The Wallenberg Laboratory, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Region Västra Götaland, Department of Clinical Physiology, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Anders H Rosengren
- Department of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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Carli F, Della Pepa G, Sabatini S, Vidal Puig A, Gastaldelli A. Lipid metabolism in MASLD and MASH: From mechanism to the clinic. JHEP Rep 2024; 6:101185. [PMID: 39583092 PMCID: PMC11582433 DOI: 10.1016/j.jhepr.2024.101185] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 11/26/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease/steatohepatitis (MASLD/MASH) is recognised as a metabolic disease characterised by excess intrahepatic lipid accumulation due to lipid overflow and synthesis, alongside impaired oxidation and/or export of these lipids. But where do these lipids come from? The main pathways related to hepatic lipid accumulation are de novo lipogenesis and excess fatty acid transport to the liver (due to increased lipolysis, adipose tissue insulin resistance, as well as excess dietary fatty acid intake, in particular of saturated fatty acids). Not only triglycerides but also other lipids are secreted by the liver and are associated with a worse histological profile in MASH, as shown by lipidomics. Herein, we review the role of lipid metabolism in MASLD/MASH and discuss the impact of weight loss (diet, bariatric surgery, GLP-1RAs) or other pharmacological treatments (PPAR or THRβ agonists) on hepatic lipid metabolism, lipidomics, and the resolution of MASH.
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Affiliation(s)
- Fabrizia Carli
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Giuseppe Della Pepa
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Silvia Sabatini
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
| | - Antonio Vidal Puig
- Metabolic Research Laboratories, Medical Research Council Institute of Metabolic Science University of Cambridge, Cambridge CB2 0QQ UK
- Centro de Investigacion Principe Felipe Valencia 46012 Spain
- Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, China
| | - Amalia Gastaldelli
- Cardiometabolic Risk Laboratory, Institute of Clinical Physiology (IFC), National Research Council (CNR), Pisa, Italy
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Sharma A, Godina Leiva E, Kalavalapalli S, Lomonaco R, Marangi SA, Valdez Saenz E, Gonzalez MA, Ortiz Rocha A, Cuervo Pardo N, Rosenberg J, Bedossa P, Bril F, Barb D, Cusi K. Obesity increases the risk of hepatic fibrosis in young adults with type 2 diabetes mellitus: the need to screen. Obesity (Silver Spring) 2024; 32:1967-1974. [PMID: 39315409 DOI: 10.1002/oby.24130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/18/2024] [Accepted: 07/03/2024] [Indexed: 09/25/2024]
Abstract
OBJECTIVE The objective of this study was to determine the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) in young compared with older adults. METHODS Individuals (n = 1420) with (63%) and without type 2 diabetes mellitus (T2D; 37%) who attended internal medicine clinics and did not have a known history of MASLD underwent laboratory evaluation and transient elastography to assess for hepatic steatosis and fibrosis. Magnetic resonance elastography and liver biopsy were recommended when indicated. RESULTS A total of 243 participants were ages <45 years, and 1177 were ages ≥45 years. Obesity, T2D, and metabolic syndrome were highly prevalent in young adults. Frequencies of steatosis and fibrosis were high in young adults (50.2% and 7.5% vs. older adults 52.7% and 9.9%, respectively) and were significantly higher in those with both obesity and T2D (71.1% and 15.7%, respectively; p < 0.01). In young adults, T2D and obesity were the strongest risk factors for hepatic fibrosis (odds ratios 4.33 [95% CI: 1.37-13.68] and 1.16 [95% CI: 1.07-1.25], respectively; p < 0.05). CONCLUSIONS There is a high prevalence of clinically significant hepatic fibrosis in young adults with cardiometabolic risk factors. Up to one in seven young adults with obesity and T2D had clinically significant hepatic fibrosis on elastography. This highlights the need to screen young adults with cardiometabolic risk factors for MASLD for early detection and intervention.
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Affiliation(s)
- Anu Sharma
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Eddison Godina Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Stephen A Marangi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Enrique Valdez Saenz
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Maria A Gonzalez
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Andrea Ortiz Rocha
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Nathaly Cuervo Pardo
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Jens Rosenberg
- Advanced Magnetic Resonance Imaging and Spectroscopy Facility, McKnight Brain Institute, University of Florida, Gainesville, Florida, USA
| | - Pierre Bedossa
- Department of Pathology, Hôpital Beaujon AP-HP, Clichy, France
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida College of Medicine, Gainesville, Florida, USA
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Sato M, Tamura Y, Kaga H, Yamasaki N, Kadowaki S, Sugimoto D, Nakagata T, Someya Y, Nishida Y, Kawamori R, Watada H. Adipose tissue insulin resistance in young Japanese women is associated with metabolic abnormalities and dehydroepiandrosterone-sulfate. Front Endocrinol (Lausanne) 2024; 15:1390778. [PMID: 39377071 PMCID: PMC11456452 DOI: 10.3389/fendo.2024.1390778] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/29/2024] [Indexed: 10/09/2024] Open
Abstract
Objective The proportion of young Japanese women who are underweight is exceptionally high. We previously showed that the prevalence of impaired glucose tolerance (IGT) was high in underweight young Japanese women, and that IGT was characterized by high free fatty acid levels and adipose tissue insulin resistance (ATIR). As the next step, this study aimed to explore factors associated with elevated ATIR in this population. Participants Ninety-eight young, healthy, underweight women participated in this study. Design To investigate the relationship between ATIR and metabolic parameters, participants were divided into three groups (Low, Medium, and High) according to ATIR level. Body composition examination, oral glucose tolerance testing, and blood biochemical analysis were performed; Adipo-IR and the Matsuda index were used as indices of ATIR and systemic insulin sensitivity, respectively. Results Participants in the High ATIR group had the highest prevalence of IGT (25%), and significantly higher body fat percentage, whole-body insulin resistance, and levels of insulin-like growth factor-1 and dehydroepiandrosterone sulfate (DHEA-S) than the other two groups. They were also significantly younger and had higher systolic blood pressure than the Low ATIR group. Multiple regression analysis showed that DHEA-S, which is known to enhance lipolysis in adipose tissue, was an independent correlate of ATIR. Conclusions Underweight Japanese women with high ATIR had impaired metabolism, a higher prevalence of IGT, higher systemic insulin resistance, and higher systolic blood pressure. DHEA-S was a determinant of high ATIR levels.
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Affiliation(s)
- Motonori Sato
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshifumi Tamura
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hideyoshi Kaga
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Nozomu Yamasaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Satoshi Kadowaki
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Daisuke Sugimoto
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Nakagata
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuki Someya
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuya Nishida
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Ryuzo Kawamori
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Hirotaka Watada
- Department of Metabolism and Endocrinology, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Sportology Center, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Therapeutic Innovations in Diabetes, Juntendo University Graduate School of Medicine, Tokyo, Japan
- Center for Identification of Diabetic Therapeutic Targets, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Wei Y, Li X, Cui R, Liu J, Wang G. Associations between sensitivity to thyroid hormones and insulin resistance in euthyroid adults with obesity. Front Endocrinol (Lausanne) 2024; 15:1366830. [PMID: 39175570 PMCID: PMC11338882 DOI: 10.3389/fendo.2024.1366830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2024] [Accepted: 07/10/2024] [Indexed: 08/24/2024] Open
Abstract
Background Impaired sensitivity to thyroid hormones (TH) was associated with metabolic syndrome. The study aimed to explore the association between central TH sensitivity indices and insulin resistance (IR) in euthyroid adults with obesity. Methods This cross-sectional study enrolled 293 euthyroid outpatients with obesity in Beijing Chao-Yang Hospital. We used the thyroid feedback quantile-based index (TFQI), thyroid stimulating hormone index (TSHI), and thyrotrophic T4 resistance index (TT4RI) to indicate central TH sensitivity. IR was assessed by homeostasis model assessment of insulin resistance (HOMA-IR), hepatic insulin resistance index (hepatic-IR), the Matsuda index, and the adipose tissue insulin resistance index (Adipo-IR). Participants were categorized according to tertiles of TH sensitivity indices. We used multiple linear regressions to explore the associations. Results There was a significant stepwise increase in HOMA-IR and Adipo-IR from the lowest to the highest tertiles of TH sensitivity indices (all P<0.05). After adjustment for age, sex, body mass index, hypertension, hyperlipidemia, and diabetes, only Adipo-IR was significantly associated with TH sensitivity indices. On average, each unit increased in TFQI, TSHI, and TT4RI was associated with 1.19 (P=0.053), 1.16 (P=0.04), and 1.01 (P=0.03) units increased in Adipo-IR, respectively. There was no significant association between TH sensitivity indices and HOMA-IR, hepatic-IR, and the Matsuda index after adjustment for other risk factors. Conclusions Reduced central TH sensitivity was associated with increased adipose tissue insulin resistance in euthyroid adults with obesity. The results further confirmed the importance of TH sensitivity on metabolic diseases.
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Affiliation(s)
| | | | | | - Jia Liu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
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Flores-Sierra JDJ, Muciño-Arellano MDR, Romo-Morales GDC, Sánchez-Palafox JE, Correa-Navarro VA, Colín-Castelán D, Pérez-Vázquez V, Rangel-Salazar R, Rivera-Bustamante R, de la Rocha C, Rodríguez-Ríos D, Trejo-Saavedra DL, Molina-Torres J, Ramírez-Chávez E, García-Rojas NS, Winkler R, Lund G, Zaina S. The DNA methyltransferase inhibitor decitabine blunts the response to a high-animal fat and protein diet in mice. J Lipid Res 2024; 65:100586. [PMID: 38942113 PMCID: PMC11325794 DOI: 10.1016/j.jlr.2024.100586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 06/30/2024] Open
Abstract
Increasing evidence hints that DNA hypermethylation may mediate the pathogenic response to cardiovascular risk factors. Here, we tested a corollary of that hypothesis, that is, that the DNA methyltransferase inhibitor decitabine (Dec) ameliorates the metabolic profile of mice fed a moderately high-animal fat and protein diet (HAFPD), a proxy of cardiovascular risk-associated Western-type diet. HAFPD-fed mice were exposed to Dec or vehicle for eight weeks (8W set, 4-32/group). To assess any memory of past exposure to Dec, we surveyed a second mice set treated as 8W but HAFPD-fed for further eight weeks without any Dec (16W set, 4-20/group). In 8W, Dec markedly reduced HAFPD-induced body weight gain in females, but marginally in males. Characterization of females revealed that Dec augmented skeletal muscle lipid content, while decreasing liver fat content and increasing plasma nonesterified fatty acids, adipose insulin resistance, and-although marginally-whole blood acylcarnitines, compared to HAFPD alone. Skeletal muscle mitochondrial DNA copy number was higher in 8W mice exposed to HAFPD and Dec, or in 16W mice fed HAFPD only, relative to 8W mice fed HAFPD only, but Dec induced a transcriptional profile indicative of ameliorated mitochondrial function. Memory of past Dec exposure was tissue-specific and sensitive to both duration of exposure to HAFPD and age. In conclusion, Dec redirected HAFPD-induced lipid accumulation toward the skeletal muscle, likely due to augmented mitochondrial functionality and increased lipid demand. As caveat, Dec induced adipose insulin resistance. Our findings may help identifying strategies for prevention and treatment of lipid dysmetabolism.
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Affiliation(s)
- José de Jesús Flores-Sierra
- Division of Health Sciences, Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico; Tecnológico Nacional de México/ITS de Purísima del Rincón, Purísima del Rincón, Guanajuato, Mexico
| | | | | | | | | | - Dannia Colín-Castelán
- Division of Health Sciences, Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
| | - Victoriano Pérez-Vázquez
- Division of Health Sciences, Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
| | - Rubén Rangel-Salazar
- Division of Health Sciences, Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico
| | | | - Carmen de la Rocha
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico
| | | | | | - Jorge Molina-Torres
- Department of Biotechnology and Biochemistry, CINVESTAV Irapuato Unit, Irapuato, Mexico
| | | | | | | | - Gertrud Lund
- Department of Genetic Engineering, CINVESTAV Irapuato Unit, Irapuato, Mexico.
| | - Silvio Zaina
- Division of Health Sciences, Department of Medical Sciences, Leon Campus, University of Guanajuato, Leon, Mexico.
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Singh S, Kumar A, Gupta S, Agrawal R. Curative role of natural PPARγ agonist in non-alcoholic fatty liver disease (NAFLD). Tissue Barriers 2024; 12:2289830. [PMID: 38050958 PMCID: PMC11262216 DOI: 10.1080/21688370.2023.2289830] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/15/2023] [Indexed: 12/07/2023] Open
Abstract
NAFLD is a condition that develops when the liver accumulates excess fat without alcohol consumption. This chronic liver ailment progresses along with insulin resistant and is typically not diagnosed until the patients have cirrhosis. Nuclear hormone receptor superfamily PPARs are essential for metabolism of fatty acids and glucose. In liver, lipid metabolism is regulated by nuclear receptors and PPARα, and PPARβ/δ encourages fatty acid β-oxidation. PPAR-γ, an energy-balanced receptor is a crucial regulator in NAFLD. The partial activation of PPAR-γ could lead to increased level of adiponectin and insulin sensitivity, thus improved NAFLD. Because of less side effects, natural compounds are emerged as potential therapeutic agents for NAFLD by PPARγ agonists. Although the results from preclinical studies are promising, further research is needed to determine the potential dosing and efficacy of mentioned compounds in human subjects. In this review, we summarize the effect of natural PPARγ agonist in the NAFLD.
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Affiliation(s)
- Swati Singh
- College of Pharmacy, JSS Academy of Technical Sciences, Noida, Uttar Pradesh, India
| | - Anit Kumar
- Department of Pharmacology, Divine College of Pharmacy, Bihar, India
| | - Suruchi Gupta
- School of Pharmacy, YBN University, Ranchi, Jharkhand, India
| | - Rohini Agrawal
- College of Pharmacy, JSS Academy of Technical Sciences, Noida, Uttar Pradesh, India
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Arner P, Viguerie N, Massier L, Rydén M, Astrup A, Blaak E, Langin D, Andersson DP. Sex differences in adipose insulin resistance are linked to obesity, lipolysis and insulin receptor substrate 1. Int J Obes (Lond) 2024; 48:934-940. [PMID: 38491191 PMCID: PMC11217000 DOI: 10.1038/s41366-024-01501-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 02/12/2024] [Accepted: 02/15/2024] [Indexed: 03/18/2024]
Abstract
BACKGROUND/OBJECTIVE Insulin resistance is more prominent in men than women. If this involves adipose tissue is unknown and was presently examined. SUBJECTS/METHODS AdipoIR (in vivo adipose insulin resistance index) was measured in 2344 women and 787 men. In 259 of the women and 54 of the men, insulin induced inhibition of lipolysis (acylglycerol breakdown) and stimulation of lipogenesis (glucose conversion to acylglycerols) were determined in subcutaneous adipocytes; in addition, basal (spontaneous) lipolysis was also determined in the fat cells. In 234 women and 115 men, RNAseq expression of canonical insulin signal genes were measured in subcutaneous adipose tissue. Messenger RNA transcripts of the most discriminant genes were quantified in 175 women and 109 men. RESULTS Men had higher AdipoIR values than women but only when obesity (body mass index 30 kg/m2 or more) was present (p < 0.0001). The latter sex dimorphism was found among physically active and sedentary people, in those with and without cardiometabolic disease and in people using nicotine or not (p = 0.0003 or less). In obesity, adipocyte insulin sensitivity (half maximum effective hormone concentration) and maximal antilipolytic effect were tenfold and 10% lower, respectively, in men than women (p = 0.005 or less). Basal rate of lipolysis was two times higher in men than women (p > 0.0001). Sensitivity and maximum effect of insulin on lipogenesis were similar in both sexes (p = 0.26 and p = 0.18, respectively). When corrected for multiple comparison only RNAseq expression of insulin receptor substrate 1 (IRS1) was lower in men than women (p < 0.0001). The mRNA transcript for IRS1 was 60% higher in women than men (p < 0.0001). CONCLUSIONS In obesity, adipose tissue insulin resistance is more pronounced in men than in women. The mechanism involves less efficient insulin-mediated inhibition of adipocyte lipolysis, increased basal rate of lipolysis and decreased adipose expression of a key element of insulin signaling, IRS1.
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Affiliation(s)
- Peter Arner
- Department of Medicine H7, Karolinska Institutet, Stockholm, Sweden.
| | - Nathalie Viguerie
- Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University - Paul Sabatier (UPS), Toulouse, France
| | - Lucas Massier
- Department of Medicine H7, Karolinska Institutet, Stockholm, Sweden
| | - Mikael Rydén
- Department of Medicine H7, Karolinska Institutet, Stockholm, Sweden
- Department of Endocrinology and Metabolism, Karolinska University Hospital, Stockholm, Sweden
| | - Arne Astrup
- Department of Obesity and Nutritional Sciences, Novo Nordisk Foundation, 2900, Hellerup, Denmark
| | - Ellen Blaak
- Department of Human Biology, NUTRIM, School of Nutrition and Translational Research in Metabolism, Faculty of Health, Medicine and Life Science, Maastricht University, 6200, MD, Maastricht, The Netherlands
| | - Dominique Langin
- Institute of Metabolic and Cardiovascular Diseases, I2MC, University of Toulouse, Inserm, Toulouse III University - Paul Sabatier (UPS), Toulouse, France
- Centre Hospitalier Universitaire de Toulouse, Toulouse, France
- Institut Universitaire de France (IUF), Paris, France
| | - Daniel Peter Andersson
- Department of Medicine H7, Karolinska Institutet, Stockholm, Sweden
- Department of Endocrinology and Metabolism, Karolinska University Hospital, Stockholm, Sweden
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11
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Peng Z, Zeng Y, Tan Q, He Q, Wang S, Wang J. 6-Gingerol alleviates ectopic lipid deposition in skeletal muscle by regulating CD36 translocation and mitochondrial function. Biochem Biophys Res Commun 2024; 708:149786. [PMID: 38493545 DOI: 10.1016/j.bbrc.2024.149786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 03/12/2024] [Indexed: 03/19/2024]
Abstract
Ectopic lipid deposition (ELD) and mitochondrial dysfunction are common causes of metabolic disorders in humans. Consuming too much fructose can result in mitochondrial dysfunction and metabolic disorders. 6-Gingerol, the main component of ginger (Zingiber officinale Roscoe), has been proven to alleviate metabolic disorders. This study seeks to examine the effects of 6-gingerol on metabolic disorders caused by fructose and uncover the underlying molecular mechanisms. In this study, the results showed that 6-Gingerol ameliorated high-fructose-induced metabolic disorders. Moreover, it inhibited CD36 membrane translocation, increased CD36 expression in the mitochondria, and decreased the O-GlcNAc modification of CD36 and OGT expression in vitro and vivo. In addition, 6-Gingerol enhanced the performance of mitochondria in the skeletal muscle and boosted the respiratory capability of L6 myotubes. This study provides a theoretical basis and new insights for the development of lipid-lowering drugs in clinical practice.
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Affiliation(s)
- Ze Peng
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Yan Zeng
- College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Qi Tan
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China
| | - Qifeng He
- College of Basic Medical Sciences, Chongqing Medical University, Chongqing, China
| | - Shang Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China.
| | - Jianwei Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing, China; Chongqing College of Traditional Chinese Medicine, Chongqing, China.
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12
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Cooreman MP, Butler J, Giugliano RP, Zannad F, Dzen L, Huot-Marchand P, Baudin M, Beard DR, Junien JL, Broqua P, Abdelmalek MF, Francque SM. The pan-PPAR agonist lanifibranor improves cardiometabolic health in patients with metabolic dysfunction-associated steatohepatitis. Nat Commun 2024; 15:3962. [PMID: 38730247 PMCID: PMC11087475 DOI: 10.1038/s41467-024-47919-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2023] [Accepted: 04/16/2024] [Indexed: 05/12/2024] Open
Abstract
Lanifibranor, a pan-PPAR agonist, improves liver histology in patients with metabolic dysfunction-associated steatohepatitis (MASH), who have poor cardiometabolic health (CMH) and cardiovascular events as major mortality cause. NATIVE trial secondary and exploratory outcomes (ClinicalTrials.gov NCT03008070) were analyzed for the effect of lanifibranor on IR, lipid and glucose metabolism, systemic inflammation, blood pressure (BP), hepatic steatosis (imaging and histological grading) for all patients of the original analysis. With lanifibranor, triglycerides, HDL-C, apolipoproteins, insulin, HOMA-IR, HbA1c, fasting glucose (FG), hs-CRP, ferritin, diastolic BP and steatosis improved significantly, independent of diabetes status: most patients with prediabetes returned to normal FG levels. Significant adiponectin increases correlated with hepatic and CMH marker improvement; patients had an average weight gain of 2.5 kg, with 49% gaining ≥2.5% weight. Therapeutic benefits were similar regardless of weight change. Here, we show that effects of lanifibranor on liver histology in MASH are accompanied with CMH improvement, indicative of potential cardiovascular clinical benefits.
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Affiliation(s)
- Michael P Cooreman
- Research and Development, Inventiva, New York, NY, USA.
- Research and Development, Inventiva, Daix, France.
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, TX, USA
| | - Robert P Giugliano
- Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Faiez Zannad
- Centre d'Investigations Cliniques Plurithématique 1433, Université de Lorraine, Nancy, France
| | - Lucile Dzen
- Research and Development, Inventiva, New York, NY, USA
- Research and Development, Inventiva, Daix, France
| | - Philippe Huot-Marchand
- Research and Development, Inventiva, New York, NY, USA
- Research and Development, Inventiva, Daix, France
| | - Martine Baudin
- Research and Development, Inventiva, New York, NY, USA
- Research and Development, Inventiva, Daix, France
| | | | - Jean-Louis Junien
- Research and Development, Inventiva, New York, NY, USA
- Research and Development, Inventiva, Daix, France
| | - Pierre Broqua
- Research and Development, Inventiva, New York, NY, USA
- Research and Development, Inventiva, Daix, France
| | - Manal F Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital and University of Antwerp, Antwerp, Belgium
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13
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Scoditti E, Sabatini S, Carli F, Gastaldelli A. Hepatic glucose metabolism in the steatotic liver. Nat Rev Gastroenterol Hepatol 2024; 21:319-334. [PMID: 38308003 DOI: 10.1038/s41575-023-00888-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/13/2023] [Indexed: 02/04/2024]
Abstract
The liver is central in regulating glucose homeostasis, being the major contributor to endogenous glucose production and the greatest reserve of glucose as glycogen. It is both a target and regulator of the action of glucoregulatory hormones. Hepatic metabolic functions are altered in and contribute to the highly prevalent steatotic liver disease (SLD), including metabolic dysfunction-associated SLD (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH). In this Review, we describe the dysregulation of hepatic glucose metabolism in MASLD and MASH and associated metabolic comorbidities, and how advances in techniques and models for the assessment of hepatic glucose fluxes in vivo have led to the identification of the mechanisms related to the alterations in glucose metabolism in MASLD and comorbidities. These fluxes can ultimately increase hepatic glucose production concomitantly with fat accumulation and alterations in the secretion and action of glucoregulatory hormones. No pharmacological treatment has yet been approved for MASLD or MASH, but some antihyperglycaemic drugs approved for treating type 2 diabetes have shown positive effects on hepatic glucose metabolism and hepatosteatosis. A deep understanding of how MASLD affects glucose metabolic fluxes and glucoregulatory hormones might assist in the early identification of at-risk individuals and the use or development of targeted therapies.
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Affiliation(s)
- Egeria Scoditti
- Institute of Clinical Physiology, National Research Council, Lecce, Italy
| | - Silvia Sabatini
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Fabrizia Carli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
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14
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Della Pepa G, Carli F, Sabatini S, Pezzica S, Russo M, Vitale M, Masulli M, Riccardi G, Rivellese AA, Vaccaro O, Bozzetto L, Gastaldelli A. Clusters of adipose tissue dysfunction in adults with type 2 diabetes identify those with worse lipidomic profile despite similar glycaemic control. Diabetes Metab Res Rev 2024; 40:e3798. [PMID: 38558269 DOI: 10.1002/dmrr.3798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Revised: 10/30/2023] [Accepted: 12/31/2023] [Indexed: 04/04/2024]
Abstract
AIMS To investigate clusters of adipose tissue dysfunction, that is, with adipose tissue insulin resistance (ADIPO-IR) and large waist circumference (WC), identify a worse lipidomic profile characterised by a high proportion of lipids rich in saturated fatty acids (SFA). MATERIALS AND METHODS Hierarchical clustering based on WC and ADIPO-IR (calculated as fasting plasma non-esterified fatty acids times fasting plasma insulin, FFA×INS), was performed in 192 adults with overweight/obesity and type 2 diabetes (T2D) treated with metformin (HbA1c = 7.8%). Free fatty acid composition and lipidomic profile were measured by mass spectrometry (GC-MS and LC-MSQTOF). Indexes of fatty acid desaturation (stearoyl-coA desaturase-1 activity, SCD116 = palmitoleic acid/palmitic acid and SCD118 = oleic acid/stearic acid) and of insulin resistance (HOMA-IR) were also calculated. RESULTS Three clusters were identified: CL1 (ADIPO-IR = 4.9 ± 2.4 and WC = 96±7 cm, mean ± SD), CL2 (ADIPO-IR = 6.5 ± 2.5 and WC = 114 ± 7 cm), and CL3 (ADIPO-IR = 15.0 ± 4.7 and WC = 107 ± 8 cm). Insulin concentrations, ADIPO-IR, and HOMA-IR significantly increased from CL1 to CL3 (all p < 0.001), while fasting glucose concentrations, HbA1c, dietary lipids and caloric intake were similar. Moreover, CL3 showed significantly higher concentrations of monounsaturated free fatty acids, oleic and palmitoleic acids, triglycerides (TAG) rich in saturated FA and associated with de novo lipogenesis (i.e., TAG 46-50), higher SCD116, SCD118, ceramide (d18:0/18:0), and phosphatidylcholine aa(36:5) compared with CL1/CL2 (all p < 0.005). CONCLUSIONS High ADIPO-IR and large WC identify a worse lipid profile in T2D characterised by complex lipids rich in SFA, likely due to de novo synthesis given higher plasma monounsaturated FFA and increased desaturase activity indexes. REGISTRATION NUMBER TRIAL ID NCT00700856 https://clinicaltrials.gov.
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Affiliation(s)
- Giuseppe Della Pepa
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Fabrizia Carli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Silvia Sabatini
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Samantha Pezzica
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Marco Russo
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
- Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
| | - Marilena Vitale
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Maria Masulli
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Gabriele Riccardi
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Angela A Rivellese
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Olga Vaccaro
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Lutgarda Bozzetto
- Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Amalia Gastaldelli
- Cardiometabolic Risk Unit, Institute of Clinical Physiology, National Research Council-CNR, Pisa, Italy
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15
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Ye RZ, Montastier E, Frisch F, Noll C, Allard-Chamard H, Gévry N, Tchernof A, Carpentier AC. Adipocyte hypertrophy associates with in vivo postprandial fatty acid metabolism and adipose single-cell transcriptional dynamics. iScience 2024; 27:108692. [PMID: 38226167 PMCID: PMC10788217 DOI: 10.1016/j.isci.2023.108692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/07/2023] [Accepted: 12/05/2023] [Indexed: 01/17/2024] Open
Abstract
Adipocyte hypertrophy is associated with metabolic complications independent of obesity. We aimed to determine: 1) the association between adipocyte size and postprandial fatty acid metabolism; 2) the potential mechanisms driving the obesity-independent, hypertrophy-associated dysmetabolism in vivo and at a single-cell resolution. Tracers with positron emission tomography were used to measure fatty acid metabolism in 40 men and women with normal or impaired glucose tolerance (NCT02808182), and single nuclei RNA-sequencing (snRNA-seq) to determine transcriptional dynamics of subcutaneous adipose tissue (AT) between individuals with AT hypertrophy vs. hyperplasia matched for sex, ethnicity, glucose-tolerance status, BMI, total and percent body fat, and waist circumference. Adipocyte size was associated with high postprandial total cardiac fatty acid uptake and higher visceral AT dietary fatty acid uptake, but lower lean tissue dietary fatty acid uptake. We found major shifts in cell transcriptomal dynamics with AT hypertrophy that were consistent with in vivo metabolic changes.
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Affiliation(s)
- Run Zhou Ye
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Emilie Montastier
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Frédérique Frisch
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Christophe Noll
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Hugues Allard-Chamard
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
| | - Nicolas Gévry
- Department of Biology, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada
| | - André Tchernof
- Québec Heart and Lung Research Institute, Laval University, Québec, QC G1V 4G5, Canada
| | - André C. Carpentier
- Division of Endocrinology, Department of Medicine, Centre de recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
- Department of Nuclear Medicine and Radiobiology, Centre de Recherche du CHUS, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada
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16
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Tiniakos DG, Anstee QM, Brunt EM, Burt AD. Fatty Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:330-401. [DOI: 10.1016/b978-0-7020-8228-3.00005-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Sandforth A, von Schwartzenberg RJ, Arreola EV, Hanson RL, Sancar G, Katzenstein S, Lange K, Preißl H, Dreher SI, Weigert C, Wagner R, Kantartzis K, Machann J, Schick F, Lehmann R, Peter A, Katsouli N, Ntziachristos V, Dannecker C, Fritsche L, Perakakis N, Heni M, Nawroth PP, Kopf S, Pfeiffer AFH, Kabisch S, Stumvoll M, Schwarz PEH, Hauner H, Lechner A, Seissler J, Yurchenko I, Icks A, Solimena M, Häring HU, Szendroedi J, Schürmann A, de Angelis MH, Blüher M, Roden M, Bornstein SR, Stefan N, Fritsche A, Birkenfeld AL. Mechanisms of weight loss-induced remission in people with prediabetes: a post-hoc analysis of the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS). Lancet Diabetes Endocrinol 2023; 11:798-810. [PMID: 37769677 DOI: 10.1016/s2213-8587(23)00235-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 08/02/2023] [Accepted: 08/04/2023] [Indexed: 10/03/2023]
Abstract
BACKGROUND Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes. METHODS In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models. FINDINGS Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m2 [SD 5·6] to mean at 12 months 29·0 kg/m2 [4·9] vs non-responders 32·1 kg/m2 [5·9] to 29·2 kg/m2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m2], SD 60 to mean at 12 months 378 mL/[min × m2], 56 vs 278 mL/[min × m2], 62, to 323 mL/[min × m2], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended. INTERPRETATION By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes. FUNDING German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation.
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Affiliation(s)
- Arvid Sandforth
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Reiner Jumpertz von Schwartzenberg
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Cluster of Excellence Controlling Microbes to Fight Infections, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Elsa Vazquez Arreola
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Robert L Hanson
- Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ, USA
| | - Gencer Sancar
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Sarah Katzenstein
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Karl Lange
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Hubert Preißl
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Simon I Dreher
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Cora Weigert
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Robert Wagner
- German Center for Diabetes Research, Neuherberg, Germany; Department of Endocrinology and Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Medical Faculty and University Hospital, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Kostantinos Kantartzis
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Jürgen Machann
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Department of Radiology, Section on Experimental Radiology, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Fritz Schick
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Department of Radiology, Section on Experimental Radiology, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Rainer Lehmann
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Andreas Peter
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Clinical Chemistry and Pathobiochemistry, Department for Diagnostic Laboratory Medicine, University Hospital of Tübingen, Tübingen, Germany
| | - Nikoletta Katsouli
- Central Institute for Translational Cancer Research, Technical University of Munich, Munich, Germany; Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Munich, Germany
| | - Vasilis Ntziachristos
- Central Institute for Translational Cancer Research, Technical University of Munich, Munich, Germany; Institute of Biological and Medical Imaging, Helmholtz Zentrum München, Munich, Germany
| | - Corinna Dannecker
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Louise Fritsche
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Nikolaos Perakakis
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine III, Technical University Dresden, Dresden, Germany
| | - Martin Heni
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Peter Paul Nawroth
- German Center for Diabetes Research, Neuherberg, Germany; Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany
| | - Stefan Kopf
- German Center for Diabetes Research, Neuherberg, Germany; Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany
| | - Andreas F H Pfeiffer
- German Center for Diabetes Research, Neuherberg, Germany; Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Kabisch
- German Center for Diabetes Research, Neuherberg, Germany; German Institute of Human Nutrition Potsdam-Rehbrücke, Brandenburg, Germany
| | - Michael Stumvoll
- German Center for Diabetes Research, Neuherberg, Germany; Department of Medicine, Endocrinology and Nephrology, Universität Leipzig, Leipzig, Germany
| | - Peter E H Schwarz
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine III, Technical University Dresden, Dresden, Germany
| | - Hans Hauner
- German Center for Diabetes Research, Neuherberg, Germany; Institute of Nutritional Medicine, Technical University of Munich, Munich, Germany
| | - Andreas Lechner
- German Center for Diabetes Research, Neuherberg, Germany; Diabetes Research Group, Medical Department, Ludwig-Maximilians University Munich, Munich, Germany
| | - Jochen Seissler
- German Center for Diabetes Research, Neuherberg, Germany; Diabetes Research Group, Medical Department, Ludwig-Maximilians University Munich, Munich, Germany
| | - Iryna Yurchenko
- German Center for Diabetes Research, Neuherberg, Germany; Medical Faculty and University Hospital, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Andrea Icks
- German Center for Diabetes Research, Neuherberg, Germany; Institute for Health Services Research and Health Economics, Centre for Health and Society, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Institute for Health Services Research and Health Economics, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Michele Solimena
- German Center for Diabetes Research, Neuherberg, Germany; Paul-Langerhans-Institut Dresden, Helmholtz Center Munich, University Clinic Carl Gustav Carus, Dresden, Germany
| | - Hans-Ulrich Häring
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Julia Szendroedi
- German Center for Diabetes Research, Neuherberg, Germany; Department of Medicine I and Clinical Chemistry, University Hospital of Heidelberg, Heidelberg, Germany
| | - Annette Schürmann
- German Center for Diabetes Research, Neuherberg, Germany; German Institute of Human Nutrition Potsdam-Rehbrücke, Brandenburg, Germany
| | - Martin Hrabé de Angelis
- German Center for Diabetes Research, Neuherberg, Germany; School of Medicine and School of Life Sciences Weihenstephan, Technical University of Munich, Munich, Germany; Institute of Experimental Genetics, Helmholtz Center Munich, Munich, Germany
| | - Matthias Blüher
- German Center for Diabetes Research, Neuherberg, Germany; Department of Medicine, Endocrinology and Nephrology, Universität Leipzig, Leipzig, Germany
| | - Michael Roden
- German Center for Diabetes Research, Neuherberg, Germany; Department of Endocrinology and Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Medical Faculty and University Hospital, Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Stefan R Bornstein
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine III, Technical University Dresden, Dresden, Germany; Department of Diabetes, Life Sciences and Medicine, Cardiovascular Medicine and Sciences, Kings College London, London, UK
| | - Norbert Stefan
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Andreas Fritsche
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Andreas L Birkenfeld
- German Center for Diabetes Research, Neuherberg, Germany; Department of Internal Medicine IV, Division of Diabetology, Endocrinology and Nephrology, Eberhard-Karls University of Tübingen, Tübingen, Germany; Institute for Diabetes Research and Metabolic Diseases, Helmholtz Center Munich, Eberhard-Karls University of Tübingen, Tübingen, Germany; Department of Diabetes, Life Sciences and Medicine, Cardiovascular Medicine and Sciences, Kings College London, London, UK.
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Wei Y, Liu J, Wang G, Wang Y. Sex differences in the association between adipose insulin resistance and non-alcoholic fatty liver disease in Chinese adults. Biol Sex Differ 2023; 14:69. [PMID: 37814297 PMCID: PMC10561490 DOI: 10.1186/s13293-023-00549-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 09/13/2023] [Indexed: 10/11/2023] Open
Abstract
BACKGROUND Adipose insulin resistance (Adipo-IR) is associated with multiple metabolic diseases, including non-alcoholic fatty liver disease (NAFLD). The study aimed to evaluate sex differences in the association between Adipo-IR and NAFLD, and further investigated other potential modifiers. METHODS This cross-sectional study enrolled adults without diabetes who underwent physical examinations in Beijing Chao-Yang Hospital. We calculated the Adipo-IR index as the product of the fasting insulin and free fatty acid concentration. We categorized Adipo-IR into four groups according to quartiles, using the first interquartile range (Q1) as the reference. Logistic regression was used stratified by the modifiers after adjustment for potential confounders. RESULTS There were 5586 participants in the study, 49.8% (n = 2781) of whom were women and 30.4% (n = 1698) with NAFLD. There was a graded positive association between Adipo-IR and NAFLD, with sex (P = 0.01) and hyperlipidemia (P = 0.02) modifying this association. In the hyperlipidemic women, for one unit increase in log-Adipo-IR, the odds of having NAFLD increased by 385% after adjustment for potential confounders (OR = 4.85, 95%CI 3.54-6.73, P < 0.001). However, it turned out that the odds of having NAFLD increased by 131% (OR = 2.31, 95%CI 1.74-3.11, P < 0.001), 216% (OR = 3.16, 95%CI 2.56-3.93, P < 0.001), 181% (OR = 2.81, 95%CI 1.88-4.28, P < 0.001) in normolipidemic men, hyperlipidemic men, and normolipidemic women, respectively. Similarly, the ORs for the association between Adipo-IR and NAFLD in women with age ≥ 50 years were higher than ORs in women with age < 50 years. CONCLUSIONS The positive correlation between Adipo-IR and NAFLD was stronger in hyperlipidemic women, compared with normolipidemic or hyperlipidemic men, or normolipidemic women. The association also strengthened for women over 50 years. Treatment strategies targeting Adipo-IR to alleviate NAFLD may be of value, especially in hyperlipidemic women after menopause.
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Affiliation(s)
- Ying Wei
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing, 100020, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing, 100020, China
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-Yang Hospital, Capital Medical University, No. 8, Gongti South Road, Chaoyang District, Beijing, 100020, China.
| | - Ying Wang
- Health Management Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
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19
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Ciccarelli G, Di Giuseppe G, Cinti F, Moffa S, Mezza T, Giaccari A. Why do some glucose-lowering agents improve non-alcoholic fatty liver disease whereas others do not? A narrative review in search of a unifying hypothesis. Diabetes Metab Res Rev 2023; 39:e3668. [PMID: 37309298 DOI: 10.1002/dmrr.3668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Revised: 04/04/2023] [Accepted: 04/15/2023] [Indexed: 06/14/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D) are metabolic disorders connected by common pathophysiological mechanisms. Since insulin resistance (IR) and metabolic alterations are common to both conditions, almost all glucose-lowering agents which improve IR have also been studied in patients with NAFLD. Some have shown great efficacy, others none. Thus, the mechanisms behind the efficacy of these drugs in improving hepatic steatosis, steatohepatitis, and eventually fibrosis remain controversial. Glycaemic control improves T2D, but probably has limited effects on NAFLD, as all glucose-lowering agents ameliorate glucose control but only a few improve NAFLD features. In contrast, drugs that either improve adipose tissue function, reduce lipid ingestion, or increase lipid oxidation are particularly effective in NAFLD. We therefore hypothesise that improved free fatty acid metabolism may be the unifying mechanism behind the efficacy of some glucose-lowering agents on NAFLD and may represent the key to NAFLD treatment.
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Affiliation(s)
- Gea Ciccarelli
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Gianfranco Di Giuseppe
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Francesca Cinti
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Simona Moffa
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Teresa Mezza
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
| | - Andrea Giaccari
- Centro per le Malattie Endocrine e Metaboliche, Fondazione Policlinico Universitario A. Gemelli IRCCS and Università Cattolica del Sacro Cuore, Rome, Italy
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20
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Tao M, Liu J, Chen X, Wang Q, He M, Chen W, Wang C, Zhang L. Correlation between serum uric acid and body fat distribution in patients with MAFLD. BMC Endocr Disord 2023; 23:204. [PMID: 37749567 PMCID: PMC10518962 DOI: 10.1186/s12902-023-01447-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 08/31/2023] [Indexed: 09/27/2023] Open
Abstract
BACKGROUND Metabolic dysfunction associated with fatty liver disease (MAFLD) is often correlated with obesity and hyperuricemia. The present study aimed to determine the association between serum uric acid (SUA) and central fat distribution in patients with MAFLD. METHODS A total of 485 patients were classified into the following groups: (1) controls without MAFLD and hyperuricemia (HUA), (2) MAFLD with normal SUA, and (3) MAFLD with HUA. DUALSCAN HDS-2000 was used to measure visceral fat (VAT) and subcutaneous fat (SAT). Dual-energy X-ray absorptiometry (DEXA) was used to measure body fat distribution. RESULTS MAFLD patients with HUA had remarkably higher BMI, fasting insulin, OGIRT AUC, ALT, AST, TG, VAT, SAT, Adipo-IR, trunk fat mass, android fat, and total body fat than MAFLD patients with normal SUA (all p < 0.05). The increase in VAT, SAT, CAP, Adipo-IR, upper limbs fat mass, trunk fat mass, and android fat, as well as the percentage of MAFLD, were significantly correlated with the increase in SUA. The percentage of MAFLD patients with HUA increased significantly with increasing VAT or SAT, as determined by the Cochran-Armitage trend test (all p < 0.05). Furthermore, VAT (OR = 1.01 CI: 1.00, 1.03; p < 0.05) and adipo-IR (OR = 1.09 CI: 1.00, 1.19; p < 0.05) were associated with circling SUA in MAFLD after adjusting for sex, age, TG, TC, HOMA-IR, and BMI. CONCLUSION Abdominal fat promotes the co-existence of HUA and MAFLD, while weight loss, especially, decreasing VAT, is of great importance to decrease SUA levels and manage MAFLD.
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Affiliation(s)
- Min Tao
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Jing Liu
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Xingyu Chen
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Qing Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Miao He
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Wenwen Chen
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China
| | - Cong Wang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
| | - Lili Zhang
- Department of Endocrinology, the Second Affiliated Hospital, Chongqing Medical University, Chongqing, 400010, China.
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Huang W, Shen B, Li X, Zhang T, Zhou X. Benefits of Combining Sonchus brachyotus DC. Extracts and Synbiotics in Alleviating Non-Alcoholic Fatty Liver Disease. Foods 2023; 12:3393. [PMID: 37761102 PMCID: PMC10530047 DOI: 10.3390/foods12183393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2023] [Revised: 09/04/2023] [Accepted: 09/05/2023] [Indexed: 09/29/2023] Open
Abstract
Non-alcoholic fatty liver disease, commonly abbreviated to NAFLD, is a pervasive ailment within the digestive system, exhibiting a rising prevalence, and impacting individuals at increasingly younger ages. Those afflicted by NAFLD face a heightened vulnerability to the onset of profound liver fibrosis, cardiovascular complications, and malignancies. Currently, NAFLD poses a significant threat to human health, and there is no approved therapeutic treatment for it. Recent studies have shown that synbiotics, which regulate intestinal microecology, can positively impact glucolipid metabolism, and improve NAFLD-related indicators. Sonchus brachyotus DC., a Chinese herb, exhibits hepatoprotective and potent antioxidant properties, suggesting its potential therapeutic use in NAFLD. Our preclinical animal model investigation suggests that the synergy between Sonchus brachyotus DC. extracts and synbiotics is significantly more effective in preventing and treating NAFLD, compared to the isolated use of either component. As a result, this combination holds the potential to introduce a fresh and encouraging therapeutic approach to addressing NAFLD.
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Affiliation(s)
- Wenwu Huang
- College of Life Sciences & Health, Wuhan University of Science & Technology, Wuhan 430065, China; (W.H.); (B.S.); (T.Z.)
| | - Boyuan Shen
- College of Life Sciences & Health, Wuhan University of Science & Technology, Wuhan 430065, China; (W.H.); (B.S.); (T.Z.)
| | - Xiumei Li
- Key Laboratory of Feed Biotechnology, Ministry of Agriculture and Rural Affairs, Institute of Feed Research of CAAS, Beijing 100000, China;
| | - Tongcun Zhang
- College of Life Sciences & Health, Wuhan University of Science & Technology, Wuhan 430065, China; (W.H.); (B.S.); (T.Z.)
| | - Xiang Zhou
- College of Life Sciences & Health, Wuhan University of Science & Technology, Wuhan 430065, China; (W.H.); (B.S.); (T.Z.)
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Engin B, Willis SA, Malaikah S, Sargeant JA, Biddle GJH, Razieh C, Argyridou S, Edwardson CL, Jelleyman C, Stensel DJ, Henson J, Rowlands AV, Davies MJ, Yates T, King JA. Sedentary Time Is Independently Related to Adipose Tissue Insulin Resistance in Adults With or at Risk of Type 2 Diabetes. Med Sci Sports Exerc 2023; 55:1548-1554. [PMID: 37093903 DOI: 10.1249/mss.0000000000003193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/25/2023]
Abstract
INTRODUCTION This cross-sectional study examined associations of device-measured sedentary time and moderate-to-vigorous physical activity (MVPA) with adipose tissue insulin resistance in people with or at high risk of type 2 diabetes (T2DM). METHOD Data were combined from six previous experimental studies (within our group) involving patients with T2DM or primary risk factors (median (interquartile range) age, 66.2 (66.0-70.8) yr; body mass index (BMI), 31.1 (28.0-34.4) kg·m -2 ; 62% male; n = 179). Adipose tissue insulin resistance was calculated as the product of fasted circulating insulin and nonesterified fatty acids (ADIPO-IR), whereas sedentary time and MVPA were determined from wrist-worn accelerometery. Generalized linear models examined associations of sedentary time and MVPA with ADIPO-IR with interaction terms added to explore the moderating influence of ethnicity (White European vs South Asian), BMI, age, and sex. RESULTS In finally adjusted models, sedentary time was positively associated with ADIPO-IR, with every 30 min of sedentary time associated with a 1.80-unit (95% confidence interval, 0.51-3.06; P = 0.006) higher ADIPO-IR. This relationship strengthened as BMI increased ( β = 3.48 (95% confidence interval, 1.50-5.46), P = 0.005 in the upper BMI tertile (≥33.2 kg·m -2 )). MVPA was unrelated to ADIPO-IR. These results were consistent in sensitivity analyses that excluded participants taking statins and/or metformin ( n = 126) and when separated into the participants with T2DM ( n = 32) and those at high risk ( n = 147). CONCLUSIONS Sedentary time is positively related to adipose tissue insulin sensitivity in people with or at high risk of T2DM. This relationship strengthens as BMI increases and may help explain established relationships between greater sedentary time, ectopic lipid, and hyperglycemia.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Charlotte Jelleyman
- Human Potential Centre, School of Sport and Recreation, Auckland University of Technology, Auckland, NEW ZEALAND
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Jorge-Galarza E, Medina-Urrutia A, Reyes-Barrera J, Torres-Tamayo M, Montaño-Estrada LF, Páez-Arenas A, Massó-Rojas F, Juárez-Rojas JG. Adipose tissue dysfunction serum markers are associated with high density lipoprotein size and glycation in the early stages of type 2 diabetes. Lipids Health Dis 2023; 22:89. [PMID: 37391843 DOI: 10.1186/s12944-023-01847-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 06/12/2023] [Indexed: 07/02/2023] Open
Abstract
BACKGROUND High-density lipoproteins (HDLs) have antiatherogenic properties related to their chemical structure. Adipose tissue (AT) influences HDL reverse cholesterol transport and plasma HDL cholesterol levels. However, whether AT dysfunction affects HDL subpopulations and their glycation in early type 2 diabetes (T2D) is still unknown. OBJECTIVE To investigate the association of inflammation and AT dysfunction serum markers with the size and glycation of HDLs in normoglycemic, prediabetes, and T2D subjects. METHODS We assessed HDL particle size and advanced glycation end-product (AGE) content in HDLs isolated from normoglycemic (n = 17), prediabetes (n = 17), and recently T2D-diagnosed (n = 18) subjects. Insulin, adiponectin, and plasminogen activator inhibitor 1 (PAI-1) were determined using the Bio-Rad Multiplex Platform, and free fatty acids (FFAs) and high sensitivity C-reactive protein (hs-CRP) were determined by standard procedures. The AT insulin resistance (ATIR) index and ATIR/adiponectin and adiponectin/leptin ratios were calculated. RESULTS HDL was progressively smaller (nm) and enriched with AGE (mg-BSA-AGE/mg protein) according to the glucose categories: 8.49 and 7.5 in normoglycemic subjects, 8.44 and 12.4 in prediabetic subjects, and 8.32 and 14.3 in T2D subjects (P = 0.033 and P = 0.009 for size and AGE, respectively). In multivariable regression analysis, the ATIR/adiponectin ratio was inversely associated with HDL size (β = -0.257, P = 0.046), and the ATIR ratio was directly associated with HDL glycation (β = 0.387, P = 0.036). In contrast, adiponectin and the adiponectin/leptin ratio were not associated with alterations in HDL particles. Furthermore, HDL size was associated with resistin (β = -0.348, P = 0.007) and PAI-1 (β = -0.324, P = 0.004). HDL and AGE were related to insulin concentrations (β = 0.458, P = 0.015). Analyses were adjusted for age, sex, body mass index, triglycerides, and HDL-cholesterol. CONCLUSION HDL size was significantly associated with the ATIR/adiponectin ratio and inflammation, whereas glycation was more strongly related to the ATIR index. These findings have important implications for the management and prevention of cardiovascular disease in T2D patients.
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Affiliation(s)
- Esteban Jorge-Galarza
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Aida Medina-Urrutia
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Juan Reyes-Barrera
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Margarita Torres-Tamayo
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Luis Felipe Montaño-Estrada
- Laboratorio de Inmunobiología, Departamento de Biología Celular y Tisular, Facultad de Medicina, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico
| | - Araceli Páez-Arenas
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Felipe Massó-Rojas
- Laboratorio de Medicina Traslacional, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Juan Gabriel Juárez-Rojas
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico.
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Kutoh E, Kuto AN, Akiyama M, Ozawa E, Kurihara R. Alogliptin: a DPP-4 inhibitor modulating adipose tissue insulin resistance and atherogenic lipid. Eur J Clin Pharmacol 2023:10.1007/s00228-023-03506-3. [PMID: 37193913 DOI: 10.1007/s00228-023-03506-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 05/08/2023] [Indexed: 05/18/2023]
Abstract
AIMS The purpose of this study is to investigate the regulation of adipose tissue insulin resistance with DPP-4 inhibitors in treatment-naive subjects with T2DM and to examine its relation to other diabetic parameters. SUBJECTS AND METHODS A total of 147 subjects were treated with alogliptin 12.5-25 mg/day (n = 55), sitagliptin 25-50 mg/day (n = 49), or teneligliptin 10-20 mg/day (n = 43) monotherapy for 3 months. Changes in adipo-IR, a mathematical model used to evaluate adipose tissue insulin resistance, and various diabetic parameters were analyzed in this prospective, non-randomized observational study. RESULTS Among these three drugs, only alogliptin significantly reduced adipo-IR (-25.9%, p < 0.004) and some lipid parameters, such as LDL-C, T-C/HDL-C, log(TG)/HDL-C, non-HDL-C/HDL-C, and LDL-C/HDL-C. Subjects in the alogliptin group were divided into two groups with distinct changes in adipo-IR. Group A had a significant decrease in adipo-IR (-56.5%, p < 0.00001, n = 28), whereas group B had an insignificant increase (19.1%, p = 0.055, n = 27). Significant reductions in FBG or HbA1c were observed in groups A and B, respectively. Group A also showed significant reductions in HOMA-R, T-C/HDL-C, TG, log(TG)/HDL-C, non-HDL-C/HDL-C, LDL-C/HDL-C, and FFA, as well as increases in QUICKI or HDL-C. In contrast, group B showed significant reductions in QUICKI or LDL-C, and increases in HOMA-R, insulin, HOMA-B, C-peptide, or CPR-index. CONCLUSIONS In contrast to other tested DPP-4 inhibitors, alogliptin demonstrated the ability to down-regulate insulin resistance in adipose tissue, as well as certain atherogenic lipids. This study provides the initial evidence of a DPP-4 inhibitor's potential to regulate adipose tissue insulin resistance. Furthermore, adipo-IR is associated with non-LDL-C lipid parameters instead of glycemic control in those receiving alogliptin.
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Affiliation(s)
- Eiji Kutoh
- Biomedical Center, 1-5-8-613 Komatsugawa, Edogawa-ku, Tokyo, 132-0034, Japan.
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan.
- Division of Diabetes, Department of Internal Medicine, Kumagaya Surgical Hospital, Kumagaya, Saitama, Japan.
| | - Alexandra N Kuto
- Biomedical Center, 1-5-8-613 Komatsugawa, Edogawa-ku, Tokyo, 132-0034, Japan
| | - Midori Akiyama
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan
| | - Eri Ozawa
- Division of Diabetes, Department of Internal Medicine, Kumagaya Surgical Hospital, Kumagaya, Saitama, Japan
| | - Rumi Kurihara
- Division of Diabetes and Endocrinology, Department of Internal Medicine, Gyoda General Hospital, Saitama, Japan
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Francque S, Ratziu V. Future Treatment Options and Regimens for Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2023; 27:429-449. [PMID: 37024217 DOI: 10.1016/j.cld.2023.01.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Recent progress in our understanding of the pathogenic mechanisms that drive progression of nonalcoholic steatohepatitis as well as lessons learned from several clinical trials that have been conducted over the past 15 years guide our current regulatory framework and trial design. Targeting the metabolic drivers should probably be the backbone of therapy in most of the patients, with some requiring more specific intrahepatic antiinflammatory and antifibrotic actions to achieve success. New and innovative targets and approaches as well as combination therapies are currently explored, while awaiting a better understanding of disease heterogeneity that should allow for future individualized medicine.
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Affiliation(s)
- Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; InflaMed Centre of Excellence, University of Antwerp, Antwerp, Belgium; Translational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Antwerp University Hospital, Drie Eikenstraat 665, Edegem B-2650, Belgium.
| | - Vlad Ratziu
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, Paris Cedex 13 75651, France; INSERM UMRS 1138 CRC, Paris, France.
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Patel AH, Peddu D, Amin S, Elsaid MI, Minacapelli CD, Chandler TM, Catalano C, Rustgi VK. Nonalcoholic Fatty Liver Disease in Lean/Nonobese and Obese Individuals: A Comprehensive Review on Prevalence, Pathogenesis, Clinical Outcomes, and Treatment. J Clin Transl Hepatol 2023; 11:502-515. [PMID: 36643037 PMCID: PMC9817050 DOI: 10.14218/jcth.2022.00204] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 08/09/2022] [Accepted: 08/12/2022] [Indexed: 12/24/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide, with an estimated prevalence of 25% globally. NAFLD is closely associated with metabolic syndrome, which are both becoming increasingly more common with increasing rates of insulin resistance, dyslipidemia, and hypertension. Although NAFLD is strongly associated with obesity, lean or nonobese NAFLD is a relatively new phenotype and occurs in patients without increased waist circumference and with or without visceral fat. Currently, there is limited literature comparing and illustrating the differences between lean/nonobese and obese NAFLD patients with regard to risk factors, pathophysiology, and clinical outcomes. In this review, we aim to define and further delineate different phenotypes of NAFLD and present a comprehensive review on the prevalence, incidence, risk factors, genetic predisposition, and pathophysiology. Furthermore, we discuss and compare the clinical outcomes, such as insulin resistance, dyslipidemia, hypertension, coronary artery disease, mortality, and progression to nonalcoholic steatohepatitis, among lean/nonobese and obese NAFLD patients. Finally, we summarize the most up to date current management of NAFLD, including lifestyle interventions, pharmacologic therapies, and surgical options.
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Affiliation(s)
- Ankoor H. Patel
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Dhiraj Peddu
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Sahil Amin
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Mohamed I. Elsaid
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, Columbus, OH, USA
- Secondary Data Core, Center for Biostatistics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Carlos D. Minacapelli
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Toni-Marie Chandler
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Carolyn Catalano
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
| | - Vinod K. Rustgi
- Department of Medicine, Division of Gastroenterology and Hepatology, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
- Center for Liver Diseases and Masses, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA
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Antonio-Villa NE, Juárez-Rojas JG, Posadas-Sánchez R, Reyes-Barrera J, Medina-Urrutia A. Visceral adipose tissue is an independent predictor and mediator of the progression of coronary calcification: a prospective sub-analysis of the GEA study. Cardiovasc Diabetol 2023; 22:81. [PMID: 37013573 PMCID: PMC10071707 DOI: 10.1186/s12933-023-01807-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Accepted: 03/19/2023] [Indexed: 04/05/2023] Open
Abstract
BACKGROUND Coronary artery calcium (CAC) improves cardiovascular event prediction. Visceral adipose tissue (VAT) is a cardiometabolic risk factor that may directly or through its related comorbidities determine the obesity-related risk. A clinical VAT estimator could allow an efficient evaluation of obesity-related risk. We aimed to analyze the effect of VAT and its related cardiometabolic risk factors on CAC progression. METHODS CAC was quantified at baseline and after 5 years by computed tomography (CT), determining its progression. VAT and pericardial fat were measured by CT and estimated by a clinical surrogate (METS-VF). Considered cardiometabolic risk factors were: peripheral insulin resistance (IR), HOMA-IR, adipose tissue IR (ADIPO-IR), and adiponectin. Factors independently associated to CAC progression were analyzed by adjusted Cox proportional hazard models, including statin use and ASCVD risk score as covariates. We performed interaction and mediation models to propose possible pathways for CAC progression. RESULTS The study included 862 adults (53 ± 9 years, 53% women), incidence CAC progression rate: 30.2 (95% CI 25.3-35.8)/1000 person-years. VAT (HR: 1.004, 95% CI 1.001-1.007, p < 0.01) and METS-VF (HR: 1.001, 95% CI 1.0-1.001, p < 0.05) independently predicted CAC progression. VAT-associated CAC progression risk was evident among low-risk ASCVD subjects, and attenuated among medium-high-risk subjects, suggesting that traditional risk factors overcome adiposity in the latter. VAT mediates 51.8% (95% CI 44.5-58.8%) of the effect attributable to IR together with adipose tissue dysfunction on CAC progression. CONCLUSIONS This study supports the hypothesis that VAT is a mediator of the risk conferred by subcutaneous adipose tissue dysfunction. METS-VF is an efficient clinical surrogate that could facilitate the identification of at-risk adiposity subjects in daily clinical practice.
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Affiliation(s)
- Neftali Eduardo Antonio-Villa
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Sección XVI, C.P. 14080, Ciudad de Mexico, Tlalpan, México
| | - Juan Gabriel Juárez-Rojas
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Sección XVI, C.P. 14080, Ciudad de Mexico, Tlalpan, México
| | - Rosalinda Posadas-Sánchez
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Sección XVI, C.P. 14080, Ciudad de Mexico, Tlalpan, México
| | - Juan Reyes-Barrera
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Sección XVI, C.P. 14080, Ciudad de Mexico, Tlalpan, México
| | - Aida Medina-Urrutia
- Departamento de Endocrinología, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Col. Sección XVI, C.P. 14080, Ciudad de Mexico, Tlalpan, México.
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Wang Z, Du H, Zhao Y, Ren Y, Ma C, Chen H, Li M, Tian J, Xue C, Long G, Xu M, Jiang Y. Response to pioglitazone in non-alcoholic fatty liver disease patients with vs. without type 2 diabetes: A meta-analysis of randomized controlled trials. Front Endocrinol (Lausanne) 2023; 14:1111430. [PMID: 37065735 PMCID: PMC10091905 DOI: 10.3389/fendo.2023.1111430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Accepted: 02/13/2023] [Indexed: 03/31/2023] Open
Abstract
Background Pioglitazone is considered a potential therapy for non-alcoholic fatty liver disease (NAFLD). However, different effects of pioglitazone on NAFLD have been demonstrated in diabetic and non-diabetic patients. Herein, a meta-analysis of randomized, placebo-controlled trials was carried out to indirectly compare pioglitazone in NAFLD patients with vs. without type 2 diabetes. Methods Randomized controlled trials (RCTs) of pioglitazone vs. placebo involving NAFLD patients with or without type 2 diabetes/prediabetes collected from databases were enrolled into this analysis. Methodological quality was employed to evaluate the domains recommended by the Cochrane Collaboration. The analysis covered the changes in histology (fibrosis, hepatocellular ballooning, inflammation, steatosis), liver enzymes, blood lipids, fasting blood glucose (FBS), homeostasis model assessment-IR (HOMA-IR), weight and body mass index (BMI) before and after treatment, and adverse events. Results The review covered seven articles, with 614 patients in total, of which three were non-diabetic RCTs. No difference was found in patients with vs. without type 2 diabetes in histology, liver enzymes, blood lipids, HOMA-IR, weight, BMI, and FBS. Moreover, no significant difference was revealed in adverse effects between NAFLD patients with diabetes and without DM, except the incidence of edema that was found to be higher in the pioglitazone group than in the placebo group in NAFLD patients with diabetes. Conclusions Pioglitazone could exert a certain effect on alleviating NAFLD, which was consistent between non-diabetic NAFLD patients and diabetic NAFLD patients in improving histopathology, liver enzymes, and HOMA-IR and reducing blood lipids. Furthermore, there were no adverse effects, except the incidence of edema which is higher in the pioglitazone group in NAFLD patients with diabetes. However, large sample sizes and well-designed RCTs are required to further confirm these conclusions.
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Affiliation(s)
- Zeyu Wang
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Huiqing Du
- Department of Gastroenterology, Xingtai People’s Hospital, Xingtai, China
| | - Ying Zhao
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Yadi Ren
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Cuihua Ma
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Hongyu Chen
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Man Li
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Jiageng Tian
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
| | - Caihong Xue
- Department of Pediatric Ophthalmology and Strabismus, Tianjin Eye Hospital, Tianjin, China
| | - Guangfeng Long
- Department of Clinical Laboratory, Children’s Hospital of Nanjing Medical University, Nanjing, China
| | - Meidong Xu
- Endoscopy Center, Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Yong Jiang
- Department of Gastroenterology, The Second Hospital of Tianjin Medical University, Tianjin, China
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Chen H, Tan H, Wan J, Zeng Y, Wang J, Wang H, Lu X. PPAR-γ signaling in nonalcoholic fatty liver disease: Pathogenesis and therapeutic targets. Pharmacol Ther 2023; 245:108391. [PMID: 36963510 DOI: 10.1016/j.pharmthera.2023.108391] [Citation(s) in RCA: 90] [Impact Index Per Article: 45.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/20/2023] [Accepted: 03/20/2023] [Indexed: 03/26/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD), currently the leading cause of global chronic liver disease, has emerged as a major public health problem, more efficient therapeutics of which are thus urgently needed. Peroxisome proliferator-activated receptor γ (PPAR-γ), ligand-activated transcription factors of the nuclear hormone receptor superfamily, is considered a crucial metabolic regulator of hepatic lipid metabolism and inflammation. The role of PPAR-γ in the pathogenesis of NAFLD is gradually being recognized. Here, we outline the involvement of PPAR-γ in the pathogenesis of NAFLD through adipogenesis, insulin resistance, inflammation, oxidative stress, endoplasmic reticulum stress, and fibrosis. In addition, the evidence for PPAR-γ- targeted therapy for NAFLD are summarized. Altogether, PPAR-γ is a promising therapeutic target for NAFLD, and the development of drugs that can balance the beneficial and undesirable effects of PPAR-γ will bring new light to NAFLD patients.
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Affiliation(s)
- Hao Chen
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, China
| | - Juan Wan
- West China Center of Excellence for Pancreatitis, Institute of Integrated Traditional Chinese and Western Medicine / West China School of Nursing, Sichuan University, Chengdu, China
| | - Yong Zeng
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China
| | - Jincheng Wang
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
| | - Haichuan Wang
- Department of Liver Surgery and Laboratory of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China; Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA.
| | - Xiaojie Lu
- Department of General Surgery, Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
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Harrison SA, Thang C, Bolze S, Dewitt S, Hallakou-Bozec S, Dubourg J, Bedossa P, Cusi K, Ratziu V, Grouin JM, Moller DE, Fouqueray P. Evaluation of PXL065 - deuterium-stabilized (R)-pioglitazone in patients with NASH: A phase II randomized placebo-controlled trial (DESTINY-1). J Hepatol 2023; 78:914-925. [PMID: 36804402 DOI: 10.1016/j.jhep.2023.02.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/19/2023] [Accepted: 02/01/2023] [Indexed: 02/23/2023]
Abstract
BACKGROUND & AIMS Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH. METHODS Patients (≥8% liver fat, NAFLD activity score [NAS] ≥4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed. RESULTS One hundred and seventeen patients were evaluated. All PXL065 groups met the primary endpoint (-21 to (-25% LFC, p = 0.008-0.02 vs. placebo); 40% (22.5 mg) achieved a ≥30% LFC reduction. Favorable trends in non-invasive tests including reductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a ≥2 point NAS improvement without fibrosis worsening vs. 30% with placebo. Metabolic improvements included: HbA1c (-0.41% p = 0.003) and insulin sensitivity (HOMA-IR, p = 0.04; Adipo-IR, p = 0.002). Adiponectin increased (+114%, 22.5 mg, p <0.0001) vs. placebo. There was no dose-dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. Pharmacokinetics confirmed dose-proportional and higher steady state R- vs. S-Pio exposure. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease. CONCLUSIONS PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. IMPACT AND IMPLICATIONS Pioglitazone (Pio) is an approved diabetes medicine with proven efficacy in non-alcoholic steatohepatitis (NASH); PXL065 is a novel related oral agent which has been shown to retain Pio's efficacy in preclinical NASH models, with reduced potential for PPARγ-driven side effects. Results of this phase II study are important as PXL065 improved several key NASH disease features with a favorable safety profile - these findings can be applied by researchers seeking to understand pathophysiology and to develop new therapies. These results also indicate that PXL065 warrants further clinical testing in a pivotal NASH trial. Other implications include the potential future availability of a distinct oral therapy for NASH that may be relevant for patients, providers and caregivers seeking to prevent the progression and complications of this disease.
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Affiliation(s)
| | | | | | | | | | | | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Vlad Ratziu
- Sorbonne Université, ICAN, Hospital Pitié-Salpêtrière, INSERM UMRS 1138 CRC, Paris, France
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Lee E, Korf H, Vidal-Puig A. An adipocentric perspective on the development and progression of non-alcoholic fatty liver disease. J Hepatol 2023; 78:1048-1062. [PMID: 36740049 DOI: 10.1016/j.jhep.2023.01.024] [Citation(s) in RCA: 85] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 12/20/2022] [Accepted: 01/19/2023] [Indexed: 02/07/2023]
Abstract
Alongside the liver, white adipose tissue (WAT) is critical in regulating systemic energy homeostasis. Although each organ has its specialised functions, they must work coordinately to regulate whole-body metabolism. Adipose tissues and the liver are relatively resilient and can adapt to an energy surplus by facilitating triglyceride (TG) storage up to a certain threshold level without significant metabolic disturbances. However, lipid storage in WAT beyond a "personalised" adiposity threshold becomes dysfunctional, leading to metabolic inflexibility, progressive inflammation, and aberrant adipokine secretion. Moreover, the failure of adipose tissue to store and mobilise lipids results in systemic knock-on lipid overload, particularly in the liver. Factors contributing to hepatic lipid overload include lipids released from WAT, dietary fat intake, and enhanced de novo lipogenesis. In contrast, extrahepatic mechanisms counteracting toxic hepatic lipid overload entail coordinated compensation through oxidation of surplus fatty acids in brown adipose tissue and storage of fatty acids as TGs in WAT. Failure of these integrated homeostatic mechanisms leads to quantitative increases and qualitative alterations to the lipidome of the liver. Initially, hepatocytes preferentially accumulate TG species leading to a relatively "benign" non-alcoholic fatty liver. However, with time, inflammatory responses ensue, progressing into more severe conditions such as non-alcoholic steatohepatitis, cirrhosis, and hepatocellular carcinoma, in some individuals (often without an early prognostic clue). Herein, we highlight the pathogenic importance of obesity-induced "adipose tissue failure", resulting in decreased adipose tissue functionality (i.e. fat storage capacity and metabolic flexibility), in the development and progression of NAFL/NASH.
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Affiliation(s)
- Eunyoung Lee
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Department of Medical Physiology, Chiba University, Graduate School of Medicine, Chiba, Japan
| | - Hannelie Korf
- Laboratory of Hepatology, CHROMETA Department, KU Leuven, Leuven, Belgium.
| | - Antonio Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK; Centro de Innvestigacion Principe Felipe, Valencia, Spain; Cambridge University Nanjing Centre of Technology and Innovation, Nanjing, China.
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Mankieva E, Kukhareva E. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus. DOKAZATEL'NAYA GASTROENTEROLOGIYA 2023; 12:103. [DOI: 10.17116/dokgastro202312041103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Dumesic DA, Winnett C, Lu G, Grogan TR, Abbott DH, Naik R, Chazenbalk GD. Randomized clinical trial: effect of low-dose flutamide on abdominal adipogenic function in normal-weight women with polycystic ovary syndrome. Fertil Steril 2023; 119:116-126. [PMID: 36400597 PMCID: PMC12036725 DOI: 10.1016/j.fertnstert.2022.09.324] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 09/17/2022] [Accepted: 09/26/2022] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To examine whether low-dose flutamide administration to normal-weight women with polycystic ovary syndrome (PCOS) reduces abdominal fat deposition, attenuates accelerated lipid accumulation in newly formed adipocytes derived from subcutaneous (SC) abdominal adipose stem cells (ASCs), and/or alters glucose-lipid metabolism. DESIGN A double-blind, placebo-controlled randomized clinical trial. SETTING An academic medical center. PATIENT(S) Twelve normal-weight women with PCOS and 12 age- and body mass index-matched controls. INTERVENTION(S) Women underwent circulating hormonal and metabolic determinations, intravenous glucose tolerance testing, total body dual-energy roentgenogram absorptiometry, and SC abdominal fat biopsy. Interventions were repeated in women with PCOS after 6-month administration of flutamide (125 mg orally daily) vs. placebo. MAIN OUTCOME MEASURE(S) Clinical parameters and lipid accumulation in newly formed adipocytes derived from SC abdominal ASCs in vitro were compared between controls and the women with PCOS receiving flutamide vs. placebo. RESULTS Serum luteinizing hormone and androgen levels as well as lipid accumulation in newly formed SC abdominal adipocytes were greater in the women with PCOS than controls. Flutamide vs. placebo reduced percent android fat, lowered serum log low-density lipoprotein and log non-high-density lipoprotein levels, and increased fasting circulating glucose levels. In all women with PCOS, changes in percent android fat positively correlated with serum log non-high-density lipoprotein and log low-density lipoprotein levels, with correlations influenced by serum free testosterone levels. Flutamide vs. placebo also attenuated lipid accumulation in newly-formed PCOS SC abdominal adipocytes in vitro relative to controls, which was unrelated to serum lipid levels. CONCLUSION Low-dose flutamide administration to normal-weight PCOS women reduces preferential abdominal fat deposition, attenuates accelerated lipid accumulation in newly-formed adipocytes derived from SC abdominal ASCs in vitro, and alters glucose-lipid homeostasis. CLINICAL TRIAL REGISTRATION NUMBER NCT01889199 (URL, clinicaltrials.gov; date of registration, 6/28/2013; enrollment date of first subject, 6/28/2013).
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Affiliation(s)
- Daniel A Dumesic
- Department of Obstetrics and Gynecology, University of California, Los Angeles, California.
| | - Chloe Winnett
- Department of Obstetrics and Gynecology, University of California, Los Angeles, California
| | - Gwyneth Lu
- Department of Obstetrics and Gynecology, University of California, Los Angeles, California
| | - Tristan R Grogan
- Department of Medicine Statistics Core, University of California, Los Angeles, California
| | - David H Abbott
- Department of Obstetrics and Gynecology, Wisconsin National Primate Research Center, University of Wisconsin, Madison, Wisconsin
| | - Rajanigandha Naik
- Department of Obstetrics and Gynecology, University of California, Los Angeles, California
| | - Gregorio D Chazenbalk
- Department of Obstetrics and Gynecology, University of California, Los Angeles, California
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Kalavalapalli S, Leiva EG, Lomonaco R, Chi X, Shrestha S, Dillard R, Budd J, Romero JP, Li C, Bril F, Samraj G, Pennington J, Townsend P, Orlando F, Shetty S, Mansour L, Silva-Sombra LR, Bedossa P, Malaty J, Barb D, Gurka MJ, Cusi K. Adipose Tissue Insulin Resistance Predicts the Severity of Liver Fibrosis in Patients with Type 2 Diabetes and NAFLD. J Clin Endocrinol Metab 2022; 108:1192-1201. [PMID: 36378995 DOI: 10.1210/clinem/dgac660] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/10/2022] [Accepted: 11/11/2022] [Indexed: 11/16/2022]
Abstract
CONTEXT While T2D is a risk factor for liver fibrosis in NAFLD, the specific contribution of insulin resistance (IR) relative to other factors is unknown. OBJECTIVE Assess the impact on liver fibrosis in NAFLD of adipose tissue (Adipo-IR) and liver (HOMA-IR) IR in people with T2D and NAFLD. DESIGN Participants were screened by elastography in the outpatient clinics for hepatic steatosis and fibrosis, including routine metabolites, cytokeratin-18 (marker of hepatocyte apoptosis/steatohepatitis), and HOMA-IR/Adipo-IR. SETTING University ambulatory care practice. PARTICIPANTS 483 participants with T2D. INTERVENTION Screening for steatosis and fibrosis with elastography. MAIN OUTCOME MEASURES Liver steatosis (CAP) and fibrosis (LSM) and measurements of IR (Adipo-IR, HOMA-IR) and fibrosis (cytokeratin-18). RESULTS Clinically significant liver fibrosis (stage F ≥ 2= LSM ≥8.0 kPa) was found in 11%, having more features of the metabolic syndrome, lower adiponectin, and higher AST, ALT, liver fat and cytokeratin-18 (p < 0.05-0.01). In multivariable analysis including just clinical variables (model 1), obesity (BMI) had the strongest association with fibrosis (OR: 2.56, CI:1.87-3.50; p < 0.01). When metabolic measurements and cytokeratin-18 were included (model 2), only BMI, AST and liver fat remained significant. When fibrosis stage was adjusted for BMI, AST, and steatosis (model 3), only adipo-IR remained strongly associated with fibrosis (OR: 1.51, CI:1.05-2.16; p = 0.03), but not BMI, hepatic IR or steatosis. CONCLUSIONS These findings pinpoint to the central role of dysfunctional, insulin-resistant adipose tissue to advanced fibrosis in T2D, beyond simply BMI or steatosis. The clinical implication is that targeting adipose tissue should be the priority of treatment in NAFLD.
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Affiliation(s)
- Srilaxmi Kalavalapalli
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Eddison Godinez Leiva
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Romina Lomonaco
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Xiaofei Chi
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Sulav Shrestha
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Rachel Dillard
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Jeffery Budd
- Division of General Internal Medicine, University of Florida, Gainesville, FL, USA
| | | | - Christina Li
- Division of General Internal Medicine, University of Florida, Gainesville, FL, USA
| | - Fernando Bril
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - George Samraj
- Department of Family Medicine, University of Florida, Gainesville, FL, USA
| | - John Pennington
- Department of Family Medicine, University of Florida, Gainesville, FL, USA
| | - Petra Townsend
- Department of Family Medicine, University of Florida, Gainesville, FL, USA
| | - Frank Orlando
- Department of Family Medicine, University of Florida, Gainesville, FL, USA
| | - Shwetha Shetty
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Lydia Mansour
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | | | - Pierre Bedossa
- Publique-Hôpitaux de Paris, Beaujon Hospital, Pathology Department and University Paris-Diderot, Paris, France
| | - John Malaty
- Department of Family Medicine, University of Florida, Gainesville, FL, USA
| | - Diana Barb
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
| | - Matthew J Gurka
- Department of Pediatrics, University of Florida, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes and Metabolism, University of Florida, Gainesville, FL, USA
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Lactation alters the relationship between liver lipid synthesis and hepatic fat stores in the postpartum period. J Lipid Res 2022; 63:100288. [PMID: 36162520 PMCID: PMC9619182 DOI: 10.1016/j.jlr.2022.100288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 09/14/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022] Open
Abstract
In mothers who are nursing their infants, increased clearance of plasma metabolites into the mammary gland may reduce ectopic lipid in the liver. No study to date has investigated the role of lactation on liver lipid synthesis in humans, and we hypothesized that lactation would modify fatty acid and glucose handling to support liver metabolism in a manner synchronized with the demands of milk production. Lactating (n = 18) and formula-feeding women (n = 10) underwent metabolic testing at 6-week postpartum to determine whether lactation modified intrahepatic triacylglycerols (IHTGs), measured by proton magnetic resonance spectroscopy. Subjects ingested oral deuterated water to measure fractional de novo lipogenesis (DNL) in VLDL-TG during fasting and during an isotope-labeled clamp at an insulin infusion rate of 10 mU/m2/min. Compared with formula-feeding women, we found that lactating women exhibited lower plasma VLDL-TG concentrations, similar IHTG content and similar contribution of DNL to total VLDL-TG production. These findings suggest that lactation lowers plasma VLDL-TG concentrations for reasons that are unrelated to IHTG and DNL. Surprisingly, we determined that the rate of appearance of nonesterified fatty acids was not related to IHTG in either group, and the expected positive association between DNL and IHTG was only significant in formula-feeding women. Further, in lactating women only, the higher the prolactin concentration, the lower the IHTG, while greater DNL strongly associated with elevations in VLDL-TG. In conclusion, we suggest that future studies should investigate the role of lactation and prolactin in liver lipid secretion and metabolism.
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Baboota RK, Rawshani A, Bonnet L, Li X, Yang H, Mardinoglu A, Tchkonia T, Kirkland JL, Hoffmann A, Dietrich A, Boucher J, Blüher M, Smith U. BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH. Nat Metab 2022; 4:1007-1021. [PMID: 35995996 PMCID: PMC9398907 DOI: 10.1038/s42255-022-00620-x] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 07/13/2022] [Indexed: 11/09/2022]
Abstract
The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.
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Affiliation(s)
- Ritesh K Baboota
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Aidin Rawshani
- Wallenberg Laboratory for Cardiovascular and Metabolic Research, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Laurianne Bonnet
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Hong Yang
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
| | - Tamar Tchkonia
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - James L Kirkland
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Anne Hoffmann
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Arne Dietrich
- Department of Visceral, Transplantation, Thoracic and Vascular Surgery, Section of Bariatric Surgery, University Hospital Leipzig, Leipzig, Germany
| | - Jeremie Boucher
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
- Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Gothenburg, Sweden
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Ulf Smith
- Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
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Singh PK, Naithani M, Pathania M, Mirza AA, Saha S. An Insight Into the Association of Sclerostin With Insulin Sensitivity and Glycemic Parameters in Male Indian Prediabetic and Diabetic Population. Cureus 2022; 14:e27123. [PMID: 36004027 PMCID: PMC9392653 DOI: 10.7759/cureus.27123] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2022] [Indexed: 11/07/2022] Open
Abstract
Background Type 2 diabetes (T2D) is increasing day by day and creating a huge financial and social burden on the Indian population. Insulin resistance results in hyperglycemia, a condition that eventually causes prediabetes and Type 2 diabetes. The etiopathogenesis of T2D is still not clearly defined. Wnt signaling pathway is involved in pancreas development, islet function, insulin production, and secretion. Recent studies show that sclerostin, a Wnt signaling inhibitor, is associated with diabetes. The sclerostin level is altered as a function of race and ethnicity. However, no study has been conducted to observe the sclerostin level in prediabetic and diabetic individuals in the Indian population. Objectives The main objectives of the study are: to determine whether sclerostin is associated with glycemic parameters, serum insulin levels, insulin resistance/ sensitivity, beta-cell function, and adipose tissue insulin resistance (Adipo-IR). Methods This observational study was carried out at a tertiary care hospital, in Rishikesh, Uttarakhand, India. Individuals with T2D and prediabetes and healthy references were included in this study. Sclerostin and free fatty acids (FFA) were measured with the enzyme-linked immunosorbent assay (ELISA), and blood sugar, insulin, and glycated haemoglobin (HbA1c) were measured by the hexokinase, chemiluminescent, and chromatography methods, respectively. Messenger RNA (mRNA) was quantified by real-time polymerase chain reaction (PCR) using the SYBR Green protocol. Adipo-IR, homeostasis model assessment-estimated insulin resistance (HOMA-IR), homeostasis model assessment of β-cell function (HOMA-B), quantitative insulin sensitivity check index (QUICKI), and single point insulin sensitivity estimator (SPISE) indices were calculated. Results A total of 171 study participants were enrolled in type 2 diabetes, prediabetes, and controls groups, having 57 each in the group. There was a gradual increase in sclerostin levels from healthy [242.12(158.44)] to prediabetes [256.06(299.65)] and diabetes [465.76 (735.71)] with a significant (<0.001) difference from healthy reference. Sclerostin showed a significant positive correlation with fasting blood sugar (r=0.200; p=0.009), HbA1c (r=0.394; p<0.001) and free fatty acids (r=0.205; p=0.007) in total study participants. The SPISE index showed a significant positive correlation (r=0.269, p=0.043) in the prediabetic group. SOST, GLUT4, and insulin receptor (IR) mRNA expression all corroborate with the glycemic status. Conclusion Significantly higher expression of sclerostin (both protein and gene) in newly diagnosed T2D and prediabetes male patients, as well as significant association with SPISE index, suggest that sclerostin might be an indicator of pathophysiology related to insulin resistance, which is a characteristic feature of diabetes mellitus. However, the identification of causal relationships would warrant a large-scale prospective cohort study.
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Rieger TR, Allen RJ, Musante CJ. A Quantitative Systems Pharmacology Model of Liver Lipid Metabolism for Investigation of Non-Alcoholic Fatty Liver Disease. Front Pharmacol 2022; 13:910789. [PMID: 35928268 PMCID: PMC9343875 DOI: 10.3389/fphar.2022.910789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Accepted: 06/21/2022] [Indexed: 12/05/2022] Open
Abstract
Non-alcoholic fatty liver disease is a metabolic and inflammatory disease that afflicts many people worldwide and presently has few treatment options. To enhance the preclinical to clinical translation and the design of early clinical trials for novel therapeutics, we developed a Quantitative Systems Pharmacology model of human hepatocyte lipid metabolism. The intended application of the model is for simulating anti-steatotic therapies for reversing fatty liver. We parameterized the model using literature data from humans with both normal and elevated liver fat. We assessed that the model construct was sufficient to generate a virtual population of NAFLD patients that matched relevant statistics of a published clinical cohort, and then validated the model response to treatment by simulating pioglitazone and diet intervention in the virtual population. Finally, a sensitivity analysis was performed to determine the best points of intervention for reducing hepatic steatosis. Analysis of the model suggests the most potent method for reducing hepatic steatosis is by limiting non-esterified fatty acid flux from the adipose to the liver.
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Affiliation(s)
- Theodore R. Rieger
- Quantitative Systems Pharmacology, Early Clinical Development, Pfizer Inc, Cambridge, MA, United States
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39
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Engin B, Willis SA, Malaikah S, Sargeant JA, Yates T, Gray LJ, Aithal GP, Stensel DJ, King JA. The effect of exercise training on adipose tissue insulin sensitivity: A systematic review and meta-analysis. Obes Rev 2022; 23:e13445. [PMID: 35319136 DOI: 10.1111/obr.13445] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 02/07/2022] [Accepted: 03/08/2022] [Indexed: 11/28/2022]
Abstract
This systematic review and meta-analysis determined the impact of exercise training on adipose tissue insulin sensitivity in adults. Its scope extended to studies measuring whole-body and localized subcutaneous adipose tissue insulin sensitivity using validated techniques. Consensus from four studies demonstrates that exercise training improved whole-body adipose tissue insulin sensitivity when measured via stable-isotope lipid tracers (rate of appearance suppression in response to hyperinsulinemia). Meta-analysis of 20 studies (26 intervention arms) employing the adipose tissue insulin resistance index (ADIPO-IR) supported these findings (-10.63 [-14.12 to -7.15] pmol·L-1 × mmol·L-1 ). With ADIPO-IR, this response was greater in studies documenting weight loss and shorter sampling time (≤48 h) post-training. Overall, exercise training did not affect whole-body adipose tissue insulin sensitivity in seven studies (11 intervention arms) measuring the suppression of circulating non-esterified fatty acids in response to insulin infusion (1.51 [-0.12 to 3.14]%); however, subgroup analysis identified an enhanced suppression post-training in trials reporting weight loss. From four microdialysis studies, consensus indicates no effect of exercise training on localized (abdominal/femoral) adipose tissue insulin sensitivity, potentially suggesting that enhanced whole-body responses are related to improvements in central adipose depots. However, heterogeneity within microdialysis protocols dictates that findings must be viewed with caution.
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Affiliation(s)
- Buket Engin
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Scott A Willis
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - Sundus Malaikah
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Clinical Nutrition Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Jack A Sargeant
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Thomas Yates
- NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK.,Diabetes Research Centre, University of Leicester, Leicester, UK
| | - Laura J Gray
- Department of Health Sciences, University of Leicester, Leicester, UK
| | - Guruprasad P Aithal
- Nottingham Digestive Diseases Centre, School of Medicine, University of Nottingham, Nottingham, UK.,NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and The University of Nottingham, Nottingham, UK
| | - David J Stensel
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
| | - James A King
- National Centre for Sport and Exercise Medicine, School of Sport, Exercise and Health Sciences, Loughborough University, Loughborough, UK.,NIHR Leicester Biomedical Research Centre, University Hospitals of Leicester NHS Trust and University of Leicester, Leicester, UK
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Abdollahi A, Dowden BN, Buhman KK, Zembroski AS, Henderson GC. Albumin knockout mice exhibit reduced plasma free fatty acid concentration and enhanced insulin sensitivity. Physiol Rep 2022; 10:e15161. [PMID: 35238481 PMCID: PMC8892599 DOI: 10.14814/phy2.15161] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 04/15/2023] Open
Abstract
Circulating albumin is expected to play a significant role in the trafficking of plasma free fatty acids (FFA) between tissues, such as FFA transfer from adipose tissue to the liver. However, it was not yet known how disrupting FFA binding to albumin in circulation would alter lipid metabolism and any resulting impacts upon control of glycemia. To improve understanding of metabolic control, we aimed to determine whether lack of serum albumin would decrease plasma FFA, hepatic lipid storage, whole body substrate oxidation, and glucose metabolism. Male and female homozygous albumin knockout mice and C57BL/6J wild type controls, each on a standard diet containing a moderate fat content, were studied at 6-8 weeks of age. Indirect calorimetry, glucose tolerance testing, insulin tolerance testing, exercise performance, plasma proteome, and tissue analyses were performed. In both sexes of albumin knockout mice compared to the wild type mice, significant reductions (p < 0.05) were observed for plasma FFA concentration, hepatic triacylglycerol and diacylglycerol content, blood glucose during the glucose tolerance test, and blood glucose during the insulin tolerance test. Albumin deficiency did not reduce whole body fat oxidation over a 24-h period and did not alter exercise performance in an incremental treadmill test. The system-level phenotypic changes in lipid and glucose metabolism were accompanied by reduced hepatic perilipin-2 expression (p < 0.05), as well as increased expression of adiponectin (p < 0.05) and glucose transporter-4 (p < 0.05) in adipose tissue. The results indicate an important role of albumin and plasma FFA concentration in lipid metabolism and glucoregulation.
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Affiliation(s)
- Afsoun Abdollahi
- Department of Nutrition SciencePurdue UniversityWest LafayetteIndianaUSA
| | - Brianna N. Dowden
- Department of Nutrition SciencePurdue UniversityWest LafayetteIndianaUSA
| | - Kimberly K. Buhman
- Department of Nutrition SciencePurdue UniversityWest LafayetteIndianaUSA
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Mocciaro G, Gastaldelli A. Obesity-Related Insulin Resistance: The Central Role of Adipose Tissue Dysfunction. Handb Exp Pharmacol 2022; 274:145-164. [PMID: 35192055 DOI: 10.1007/164_2021_573] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Obesity is a key player in the onset and progression of insulin resistance (IR), a state by which insulin-sensitive cells fail to adequately respond to insulin action. IR is a reversible condition, but if untreated leads to type 2 diabetes alongside increasing cardiovascular risk. The link between obesity and IR has been widely investigated; however, some aspects are still not fully characterized.In this chapter, we introduce key aspects of the pathophysiology of IR and its intimate connection with obesity. Specifically, we focus on the role of adipose tissue dysfunction (quantity, quality, and distribution) as a driver of whole-body IR. Furthermore, we discuss the obesity-related lipidomic remodeling occurring in adipose tissue, liver, and skeletal muscle. Key mechanisms linking lipotoxicity to IR in different tissues and metabolic alterations (i.e., fatty liver and diabetes) and the effect of weight loss on IR are also reported while highlighting knowledge gaps.
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Affiliation(s)
- Gabriele Mocciaro
- Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Amalia Gastaldelli
- Institute of Clinical Physiology, National Research Council, Pisa, Italy.
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Monti LD, Genzano CB, Fontana B, Galluccio E, Spadoni S, Magistro A, Bosi E, Piatti P. Association between new markers of cardiovascular risk and hepatic insulin resistance in those at high risk of developing type 2 diabetes. Endocrine 2022; 75:409-417. [PMID: 34546488 DOI: 10.1007/s12020-021-02868-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 09/04/2021] [Indexed: 12/20/2022]
Abstract
AIM/HYPOTHESIS Hepatic insulin resistance (HIR) is considered to be an independent predictor of metabolic disorders and plays an important role in systemic inflammation, which contributes to abnormalities in cardiovascular disease (CVD) risk factors. The aim of this study was to investigate the relationship between HIR and new markers of cardiovascular risks, including leptin/adiponectin ratio (L/A), lipoprotein(a) [Lp(a)], and tumor necrosis factor alpha (TNF-α), at comparable whole body insulin sensitivity in non-diabetic individuals with or without CVD and at high risk of developing type 2 diabetes. METHODS The HIR index, L/A, Lp(a), and TNF-α were measured in 50 participants with CVD and in 200 without CVD (1:4 ratio). These were also matched for the homeostatic model assessment for insulin resistance (HOMA-IR) and Matsuda-insulin sensitivity index (ISI) in an observational study design. RESULTS The HIR index (1.52 ± 0.14 vs. 1.45 ± 0.17, p < 0.02), L/A (3.22 ± 3.10 vs. 2.09 ± 2.27, p < 0.004), and levels of Lp(a) (66.6 ± 49.5 vs. 37.9 ± 3 6.8 mg/dL, p < 0.0001) and TNF-α (18.9 ± 21.8 vs. 5.4 ± 7.1 pg/mL, p < 0.0001) were higher in those with CVD than those without CVD. HOMA-IR and ISI were not significantly different (p = 0.88 and p = 0.35, respectively). The HIR index was directly correlated with L/A (r = 0.41, p < 0.0001), Lp(a) (r = 0.20, p < 0.002), TNF- α (r = 0.14, p < 0.03), and diastolic blood pressure (DBP) (r = 0.13, p < 0.03). The stepwise model analysis showed that L/A, Lp(a), and TNF-α explained about 20% of the variation in the HIR indices of all the participants (p < 0.02). CONCLUSIONS/INTERPRETATIONS Our results suggest a positive association between HIR and new markers of cardiovascular risk [L/A, Lp(a), and TNF- α] at comparable whole body insulin sensitivity in those with or without CVD and at high risk of developing type 2 diabetes.
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Affiliation(s)
- Lucilla D Monti
- Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan, MI, Italy.
- Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan MI, Italy.
| | - Camillo Bechi Genzano
- Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan, MI, Italy
| | - Barbara Fontana
- Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan MI, Italy
| | - Elena Galluccio
- Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan MI, Italy
| | - Serena Spadoni
- Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan MI, Italy
| | - Andrea Magistro
- Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan, MI, Italy
| | - Emanuele Bosi
- Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan, MI, Italy
- Cardio-Diabetes and Core Lab Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan MI, Italy
| | - Piermarco Piatti
- Cardio-Metabolism and Clinical Trials Unit, Diabetes Research Institute, Department of Internal Medicine, IRCCS San Raffaele Institute, Via Olgettina 60, 20132 Milan, MI, Italy
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Albhaisi S, Sanyal AJ. Pharmacology of NASH. COMPREHENSIVE PHARMACOLOGY 2022:214-238. [DOI: 10.1016/b978-0-12-820472-6.00121-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Nunez Lopez YO, Casu A, Kovacova Z, Petrilli AM, Sideleva O, Tharp WG, Pratley RE. Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes. Front Endocrinol (Lausanne) 2022; 13:955593. [PMID: 36120427 PMCID: PMC9471675 DOI: 10.3389/fendo.2022.955593] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/15/2022] [Indexed: 11/13/2022] Open
Abstract
UNLABELLED Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues and PPARγ agonism has been shown to alter cancer derived extracellular vesicle (EV)-miRNAs. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived EVs to alter interorgan crosstalk in people with diabetes. We tested our hypothesis in a 3-month trial in which 24 subjects with T2D were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs using low density TaqMan arrays. Levels of differentially expressed EV-miRNAs and their most relevant target genes were also measure in adipose tissue from the same participants, using individual TaqMan assays. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. The opposite occurred for miR-195-5p in subcutaneous AT. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a downregulation trend in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of pioglitazone are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, identifier NCT00656864.
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Affiliation(s)
- Yury O. Nunez Lopez
- Diabetes Program, Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Anna Casu
- Diabetes Program, Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Zuzana Kovacova
- Diabetes Program, Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Alejandra M. Petrilli
- Diabetes Program, Translational Research Institute, AdventHealth, Orlando, FL, United States
| | - Olga Sideleva
- Department of Medicine, Larner College of Medicine, University of Vermont, Burlington, VT, United States
| | - William G. Tharp
- Department of Anesthesiology, University of Vermont Medical Center, University of Vermont Larner College of Medicine, Burlington, VT, United States
| | - Richard E. Pratley
- Diabetes Program, Translational Research Institute, AdventHealth, Orlando, FL, United States
- *Correspondence: Richard E. Pratley,
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Sun H, Chang X, Bian N, An Y, Liu J, Leng S, Wang G. Adipose Tissue Insulin Resistance Is Positively Associated With Serum Uric Acid Levels and Hyperuricemia in Northern Chinese Adults. Front Endocrinol (Lausanne) 2022; 13:835154. [PMID: 35757425 PMCID: PMC9226335 DOI: 10.3389/fendo.2022.835154] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 05/04/2022] [Indexed: 01/23/2023] Open
Abstract
OBJECTIVE Adipose tissue plays a crucial role in serum uric acid (UA) metabolism, but the relative contribution of adipose tissue insulin resistance (IR) to serum UA levels and hyperuricemia have not explicitly been illustrated. Herein, we aimed to investigate the association between the adipose tissue insulin resistance index (Adipo-IR) and hyperuricemia in this cross-sectional study. The homeostasis model assessment of insulin resistance (HOMA-IR) index, another widely applied marker to determine systemic IR, was also explored. METHODS A total of 5821 adults were included in this study. The relationship between Adipo-IR or HOMA-IR and serum UA levels was assessed by multivariate linear regression. Binary logistic regression analyses were applied to determine the sex-specific association of the Adipo-IR tertiles and HOMA-IR tertiles with hyperuricemia. Participants were then divided into normal BMI (18.5 ≤ BMI < 24) and elevated BMI (BMI ≥ 24) groups for further analysis. RESULTS Both Adipo-IR and HOMA-IR were positively correlated with serum UA (P < 0.001). Compared with the lowest tertile, the risks of hyperuricemia increased across Adipo-IR tertiles (middle tertile: OR 1.52, 95%CI 1.24-1.88; highest tertile: OR 2.10, 95%CI 1.67-2.63) in men after full adjustment (P for trend < 0.001). In women, only the highest tertile (OR 2.09, 95%CI 1.52-2.87) was significantly associated with hyperuricemia. Those associations remained significant in participants with normal BMI status. As for HOMA-IR, only the highest tertile showed positive relationships with hyperuricemia in both genders after full adjustment (P for trend < 0.001). The association between HOMA-IR and hyperuricemia disappeared in men with normal BMI status. CONCLUSIONS Adipo-IR was strongly associated with serum UA and hyperuricemia regardless of BMI classification. In men with normal BMI, Adipo-IR, rather than HOMA-IR, was closely associated with hyperuricemia. Altogether, our finding highlights a critical role of adipose tissue IR on serum UA metabolism and hyperuricemia.
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Affiliation(s)
- Honglin Sun
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Xiaona Chang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Nannan Bian
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Yu An
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Jia Liu
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
| | - Song Leng
- Health Management Center, The Second Hospital of Dalian Medical University, Dalian, China
- *Correspondence: Guang Wang, ; Song Leng,
| | - Guang Wang
- Department of Endocrinology, Beijing Chao-yang Hospital, Capital Medical University, Beijing, China
- *Correspondence: Guang Wang, ; Song Leng,
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Foss-Freitas MC, Akinci B, Neidert A, Bartlett VJ, Hurh E, Karwatowska-Prokopczuk E, Oral EA. Selective targeting of angiopoietin-like 3 (ANGPTL3) with vupanorsen for the treatment of patients with familial partial lipodystrophy (FPLD): results of a proof-of-concept study. Lipids Health Dis 2021; 20:174. [PMID: 34865644 PMCID: PMC8647384 DOI: 10.1186/s12944-021-01589-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 10/27/2021] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. METHODS This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). RESULTS Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. CONCLUSIONS Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.
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Affiliation(s)
- Maria C Foss-Freitas
- Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, MI, Ann Arbor, USA
- Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, MI, 48109-2800, Ann Arbor, USA
| | - Baris Akinci
- Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, MI, Ann Arbor, USA
- Dokuz Eylul University, İzmir, Turkey
- Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, MI, 48109-2800, Ann Arbor, USA
| | - Adam Neidert
- Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, MI, Ann Arbor, USA
- Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, MI, 48109-2800, Ann Arbor, USA
| | | | - Eunju Hurh
- Akcea Therapeutics, Inc, MA, Boston, USA
| | | | - Elif A Oral
- Division of Metabolism, Endocrinology & Diabetes and Caswell Diabetes Institute, University of Michigan, MI, Ann Arbor, USA.
- Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, Michigan Medicine, University of Michigan, Caswell Diabetes Institute, 2800 Plymouth Road, North Campus Research Complex, 25-3696, MI, 48109-2800, Ann Arbor, USA.
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Masoodi M, Gastaldelli A, Hyötyläinen T, Arretxe E, Alonso C, Gaggini M, Brosnan J, Anstee QM, Millet O, Ortiz P, Mato JM, Dufour JF, Orešič M. Metabolomics and lipidomics in NAFLD: biomarkers and non-invasive diagnostic tests. Nat Rev Gastroenterol Hepatol 2021; 18:835-856. [PMID: 34508238 DOI: 10.1038/s41575-021-00502-9] [Citation(s) in RCA: 247] [Impact Index Per Article: 61.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/15/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide and is often associated with aspects of metabolic syndrome. Despite its prevalence and the importance of early diagnosis, there is a lack of robustly validated biomarkers for diagnosis, prognosis and monitoring of disease progression in response to a given treatment. In this Review, we provide an overview of the contribution of metabolomics and lipidomics in clinical studies to identify biomarkers associated with NAFLD and nonalcoholic steatohepatitis (NASH). In addition, we highlight the key metabolic pathways in NAFLD and NASH that have been identified by metabolomics and lipidomics approaches and could potentially be used as biomarkers for non-invasive diagnostic tests. Overall, the studies demonstrated alterations in amino acid metabolism and several aspects of lipid metabolism including circulating fatty acids, triglycerides, phospholipids and bile acids. Although we report several studies that identified potential biomarkers, few have been validated.
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Affiliation(s)
- Mojgan Masoodi
- Institute of Clinical Chemistry, Bern University Hospital, Bern, Switzerland.
| | | | - Tuulia Hyötyläinen
- School of Natural Sciences and Technology, Örebro University, Örebro, Sweden
| | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | | | | | | | - Quentin M Anstee
- Clinical & Translational Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
| | - Oscar Millet
- Precision Medicine & Metabolism, CIC bioGUNE, CIBERehd, BRTA, Bizkaia Technology Park, Derio, Spain
| | - Pablo Ortiz
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | - Jose M Mato
- Precision Medicine & Metabolism, CIC bioGUNE, CIBERehd, BRTA, Bizkaia Technology Park, Derio, Spain
| | - Jean-Francois Dufour
- University Clinic of Visceral Surgery and Medicine, Inselspital Bern, Bern, Switzerland.,Hepatology, Department of BioMedical Research, University of Bern, Bern, Switzerland
| | - Matej Orešič
- School of Medical Sciences, Örebro University, Örebro, Sweden. .,Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
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Wang TZ, Zuo GW, Yao L, Yuan CL, Li HF, Lai Y, Chen ZW, Zhang J, Jin YQ, Yamahara J, Wang JW. Ursolic acid ameliorates adipose tissue insulin resistance in aged rats via activating the Akt-glucose transporter 4 signaling pathway and inhibiting inflammation. Exp Ther Med 2021; 22:1466. [PMID: 34737806 DOI: 10.3892/etm.2021.10901] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 04/07/2021] [Indexed: 11/06/2022] Open
Abstract
Ageing often results in insulin resistance (IR) and chronic inflammation, and adipose is one of the tissues in which inflammation and IR occur earliest during this process. The present study investigated the effect and underlying mechanisms of ursolic acid (UA) on adipose IR and inflammation in ageing rats. Specific pathogen-free male Sprague-Dawley rats were randomly divided into 4 groups: i) Young normal (young); ii) untreated ageing (aged); and groups supplemented with UA either iii) low-UA 10 mg/kg (UA-L) or iv) high-50 mg/kg (UA-H). Animals in the UA-treated groups received 10 or 50 mg/kg UA (suspended in 5% Gum Arabic solution). The rats in the corresponding aged group and young groups received vehicle (5% Gum Arabic) alone. All rats were intragastrically treated once daily by oral gavage for 7 weeks. The day before the experiment terminated, overnight fasting blood (~700 µl) was collected and plasma was prepared to measure biochemical indicators; western blotting was performed to analyze the expression of insulin signaling proteins [(insulin receptor substrate 1 (IRS-1), phosphorylated (p)-IRS-1, PI3K, glucose transporter 4 (GLUT4), Akt and p-Akt)] and inflammatory factors (NF-κB, IL-6 and IL-1β) in the epididymis white adipose tissue (eWAT). The results revealed that treatment with UA-H decreased eWAT weight, the ratio of eWAT weight/body weight, fasted insulin and triglyceride levels, the homeostasis model assessment of insulin resistance and adipose tissue insulin resistance index in ageing rats, indicating the amelioration of systemic and adipose tissue IR, compared with the aged group. Mechanistically, UA-H administration upregulated p-protein kinase B, the ratio of p-Akt to protein kinase B and total and cellular membrane GLUT4 protein levels in eWAT of ageing rats. Conversely, UA inhibited the increase in NF-κB expression and proinflammatory cytokines IL-6 and IL-1β. However, these alterations were not observed in the rats of the aged group. Taken together, the findings of the present study indicated that UA may ameliorate adipose IR, which is associated with activation of the Akt-GLUT4 signaling pathway and inhibition of inflammation in ageing rats. These data provide a basis for the development of effective and safe drugs or functional substances, such as UA, for the prevention and treatment of metabolic diseases.
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Affiliation(s)
- Tong-Zhuang Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Guo-Wei Zuo
- Laboratory of Medical Tests, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ling Yao
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chun-Lin Yuan
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Hai-Fei Li
- Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ying Lai
- Institute of Life Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Zhi-Wei Chen
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Jun Zhang
- Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ya-Qian Jin
- Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, P.R. China
| | | | - Jian-Wei Wang
- Chongqing Key Laboratory of Traditional Chinese Medicine for Prevention and Cure of Metabolic Diseases, College of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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Dumesic DA, Tulberg A, McNamara M, Grogan TR, Abbott DH, Naik R, Lu G, Chazenbalk GD. Serum Testosterone to Androstenedione Ratio Predicts Metabolic Health in Normal-Weight Polycystic Ovary Syndrome Women. J Endocr Soc 2021; 5:bvab158. [PMID: 34661039 PMCID: PMC8513761 DOI: 10.1210/jendso/bvab158] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Indexed: 11/19/2022] Open
Abstract
Context Increased aldo-keto reductase 1C3 (AKR1C3)-mediated conversion of androstenedione (A4) to testosterone (T) promotes lipid storage in subcutaneous (SC) abdominal adipose in overweight/obese polycystic ovary syndrome (PCOS) women. Objective This work examines whether an elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts metabolic function in normal-weight PCOS women. Methods This prospective cohort study took place in an academic center and comprised 19 normal-weight PCOS women and 21 age- and body mass index–matched controls. Interventions included circulating hormone/metabolic determinations, intravenous glucose tolerance testing, total body dual-energy x-ray absorptiometry, and SC abdominal fat biopsy. Serum T/A4 ratios, hormone/metabolic measures, and AKR1C3 expression of adipocytes matured in vitro were compared between female types; serum T/A4 ratios were correlated with serum lipids, adipose insulin resistance (adipose-IR), homeostatic model assessment of insulin resistance (HOMA-IR) and insulin sensitivity (Si). Results Increased serum T/A4 ratios (P = .040) and log adipose-IR values (P = .002) in PCOS women vs controls were accompanied by AKR1C3 messenger RNA overexpression of PCOS adipocytes matured in vitro (P = .016). Serum T/A4 ratios in PCOS women, but not controls, negatively correlated with log triglycerides (TGs: R = –0.65, P = .002) and the TG index (R = –0.57, P = .011). Adjusting for serum free T, serum T/A4 ratios in PCOS women remained negatively correlated with log TG (R = –0.57, P = .013) and TG index (R = –0.50, P = .036), respectively, without significant relationships with other metabolic measures. Conclusion An elevated serum T/A4 ratio, as a marker of enhanced AKR1C3 activity in SC abdominal adipose, predicts healthy metabolic function in normal-weight PCOS women.
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Affiliation(s)
- Daniel A Dumesic
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Ayli Tulberg
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Megan McNamara
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Tristan R Grogan
- Department of Medicine Statistics Core, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - David H Abbott
- OB/GYN, Wisconsin National Primate Research Center, University of Wisconsin, Madison, Madison, Wisconsin 53715, USA
| | - Rajanigandha Naik
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Gwyneth Lu
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
| | - Gregorio D Chazenbalk
- Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, California 90095, USA
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Gastaldelli A, Sabatini S, Carli F, Gaggini M, Bril F, Belfort‐DeAguiar R, Positano V, Barb D, Kadiyala S, Harrison S, Cusi K. PPAR-γ-induced changes in visceral fat and adiponectin levels are associated with improvement of steatohepatitis in patients with NASH. Liver Int 2021; 41:2659-2670. [PMID: 34219361 PMCID: PMC9290929 DOI: 10.1111/liv.15005] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Peroxisome proliferator-activated receptor (PPAR)-γ agonists decrease hepatic/visceral fat (VF) and improve necroinflammation despite subcutaneous (SC) fat weight-gain. Understanding the impact of changes in VF, VF-to-SC fat distribution (VF/SC) and adiponectin (ADPN) levels in relation to histological improvement after weight-loss or pioglitazone is relevant as novel PPAR-γ agonists are being developed for treating non-alcoholic steatohepatitis (NASH). METHODS Fifty-five patients with NASH received a -500 kcal/d hypocaloric diet and were randomized (double-blind) to pioglitazone (45 mg/d) or placebo for 6-months. Before and after treatment patients underwent a liver biopsy and measurement of hepatic/peripheral glucose fluxes, hepatic/adipose tissue-IR and, in 35 patients, hepatic and VF/SC-fat was measured by magnetic resonance spectroscopy/imaging. Data were examined by multivariable statistical analyses combined with machine-learning techniques (partial least square discriminant analysis [PLS-DA]). RESULTS Both pioglitazone (despite weight-gain) and placebo (if weight-loss) reduced steatosis but only pioglitazone ameliorated necroinflammation. Using machine-learning PLS-DA showed that the treatment differences induced by a PPAR-γ agonist vs placebo on metabolic variables and liver histology could be best explained by the increase in ADPN and a decrease in VF/SC, and to a lesser degree, improvement in oral glucose tolerance test-glucose concentrations and ALT. Decrease in steatosis and disease activity score (ballooning plus lobular inflammation) kept a close relationship with an increase in ADPN (r = -.71 and r = -.44, P < .007, respectively) and reduction in VF/SC fat (r = .41 and r = .37, P < .03 respectively). CONCLUSIONS Reduction in VF and improved VF/SC-distribution, combined with an increase in ADPN, mediate the histological benefits of PPAR-γ action, highlighting the central role of fat metabolism and its distribution on steatohepatitis disease activity in patients with NASH.
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Affiliation(s)
- Amalia Gastaldelli
- Diabetes DivisionThe University of Texas Health Science Center at San AntonioSan AntonioTXUSA,Institute of Clinical PhysiologyNational Research CouncilCNRPisaItaly
| | - Silvia Sabatini
- Institute of Clinical PhysiologyNational Research CouncilCNRPisaItaly,Università degli Studi di SienaSienaItaly
| | - Fabrizia Carli
- Institute of Clinical PhysiologyNational Research CouncilCNRPisaItaly
| | - Melania Gaggini
- Institute of Clinical PhysiologyNational Research CouncilCNRPisaItaly
| | - Fernando Bril
- Division of Endocrinology, Diabetes and MetabolismUniversity of FloridaGainesvilleFLUSA
| | - Renata Belfort‐DeAguiar
- Department of Internal Medicine and EndocrinologyYale University School of MedicineNew HavenCTUSA
| | | | - Diana Barb
- Division of Endocrinology, Diabetes and MetabolismUniversity of FloridaGainesvilleFLUSA
| | - Sushma Kadiyala
- Division of Endocrinology, Diabetes and MetabolismUniversity of FloridaGainesvilleFLUSA,Division of Endocrinology, Diabetes and MetabolismMalcom Randall Veteran Administration Medical Center at GainesvilleGainesvilleFLUSA
| | | | - Kenneth Cusi
- Division of Endocrinology, Diabetes and MetabolismUniversity of FloridaGainesvilleFLUSA,Division of Endocrinology, Diabetes and MetabolismMalcom Randall Veteran Administration Medical Center at GainesvilleGainesvilleFLUSA
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