|
1
|
Hong Z, Huang L, Zhou Q, Wu Y, Lin X, Wei Y, Wei Q, Deng G, Zhang Z. Plasma amino acid profiles and gestational diabetes mellitus risk: A case-control study. Clin Nutr 2025; 48:90-100. [PMID: 40174443 DOI: 10.1016/j.clnu.2025.03.008] [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: 10/08/2024] [Revised: 03/07/2025] [Accepted: 03/08/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND & AIMS Gestational diabetes mellitus (GDM) is a prevalent pregnancy complication associated with adverse short-term and long-term health outcomes for both mother and child. This study aimed to investigate the association between plasma amino acid concentrations and the incidence of GDM from 2019 to 2021. METHODS Plasma levels of 37 amino acids were precisely measured using triple quadrupole mass spectrometry. The principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) models identified metabolic differences between GDM and non-GDM groups. Conditional logistic regression, generalized linear model, and quantile g-computation were employed to assess the associations between individual or combined amino acids and GDM risk/blood glucose levels. The discriminatory power of various factors associated with the risk of GDM was evaluated using the area under the receiver operating characteristic curve (AUC-ROC). RESULTS A total of 969 pregnant women were included in this case-control study. OPLS-DA model identified 16 biomarkers that differentiated the GDM and non-GDM groups. After adjusting for potential covariates and correcting for multiple testing, conditional logistic regression analysis revealed that certain key amino acids, such as valine and isoleucine, were positively associated with the incidence of GDM, while glycine and serine were negatively associated with GDM risk (OR = 0.753-1.671, Pfdr = <0.001-0.001). Generalized linear model analysis showed that specific amino acids, including alpha-aminoadipic acid and arginine, were positively associated with blood glucose levels, while glycine and serine were negatively associated (β = -0.211-0.365, Pfdr = <0.001-0.045). Additionally, mixtures of the identified amino acids were significantly associated with an increased risk of GDM (P < 0.001). The combination of selected amino acids showed the highest ability to identify GDM in comparison with traditional risk factors and specific amino acids (AUC-ROC = 0.761, 95 % CI: 0.729-0.792). The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis identified two metabolic pathways related to GDM risk: "Glycine, Serine, and Threonine Metabolism" and "Arginine biosynthesis". CONCLUSIONS The overall amino acid profile, rather than disturbances in specific amino acids, may serve as a more important prevention or therapeutic target for GDM.
Collapse
Affiliation(s)
- Zhen Hong
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Lan Huang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Qinwen Zhou
- Department of Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Yulin Wu
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Xiaoping Lin
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Yuanhuan Wei
- Department of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, Shenzhen 518000, China
| | - Qinzhi Wei
- Department of Food Safety and Health Research Center, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China
| | - Guifang Deng
- Department of Clinical Nutrition, Union Shenzhen Hospital of Huazhong University of Science and Technology, Shenzhen 518000, China.
| | - Zheqing Zhang
- Department of Nutrition and Food Hygiene, Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou 510515, China.
| |
Collapse
|
|
2
|
Gawlik-Kotelnicka O, Czarnecka-Chrebelska K, Margulska A, Pikus E, Wasiak J, Skowrońska A, Brzeziańska-Lasota E, Strzelecki D. Associations between intestinal fatty-acid binding protein and clinical and metabolic characteristics of depression. Prog Neuropsychopharmacol Biol Psychiatry 2025; 136:111170. [PMID: 39393435 DOI: 10.1016/j.pnpbp.2024.111170] [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: 02/20/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024]
Abstract
INTRODUCTION The topic of increased intestinal permeability is associated with disruption of the intestinal barrier, leading to the "leaky gut" syndrome. Depressive disorders often coexist with abdominal obesity, metabolic syndrome, or its components and complications. Intestinal permeability has been proven to relate to all of the above. METHODS In this cross-sectional study, we aimed to assess the "leaky gut" blood biomarker - intestinal fatty acid-binding protein (I-FABP) - in 114 adult patients diagnosed with depressive disorders depending on abdominal obesity comorbidity, depression, anxiety, and stress level, or antidepressant use. The corrected p-value was set at 0.02. We analyzed patients' mental state, diet, anthropometric parameters, metabolic laboratory markers and I-FABP. RESULTS There was no difference in circulating I-FABP levels between obese and non-obese patients with depressive disorders (p = 0.648). Similarly, I-FABP levels were not different in patients with different emotional symptoms severity (p = 0.829 for self-assessed depression, p = 0.164 for anxiety, and p = 0.543 for stress). But, I-FABP levels differed significantly between patients treated and not treated with antidepressants (p = 0.011). In general linear model analysis treatment with antidepressants, anxiety severity level, their interaction, along with smoking status, drinks intake, and using dietary supplements were shown to significantly explain I-FABP variance (p < 0.001, R2adj = 0.261). CONCLUSIONS Comorbid obesity did not increase intestinal permeability circulating marker, I-FABP, in the population of patients with depressive disorders. Treatment with antidepressants may be connected to higher I-FABP levels. Using dietary supplements, drinks intake, smoking status, or anxiety level may serve as explanatory factors.
Collapse
Affiliation(s)
- Oliwia Gawlik-Kotelnicka
- Department of Affective and Psychotic Disorders, Medical University of Lodz, Czechosłowacka 8/10, 92-216 Lodz, Poland.
| | | | - Aleksandra Margulska
- Department of Child and Adolescent Psychiatry, Medical University of Lodz, Czechosłowacka 8/10, 92-216 Lodz, Poland.
| | - Ewa Pikus
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland.
| | - Jakub Wasiak
- Faculty of Medicine, Medical University of Lodz, Kościuszki 4, 90-419 Lodz, Poland.
| | - Anna Skowrońska
- Department of Affective and Psychotic Disorders, Medical University of Lodz, Czechosłowacka 8/10, 92-216 Lodz, Poland
| | - Ewa Brzeziańska-Lasota
- Department of Biomedicine and Genetics, Medical University of Lodz, 92-213 Lodz, Poland.
| | - Dominik Strzelecki
- Department of Affective and Psychotic Disorders, Medical University of Lodz, Czechosłowacka 8/10, 92-216 Lodz, Poland.
| |
Collapse
|
|
3
|
Aydin MA, Aykal G, Gunduz UR, Dincer A, Turker A, Turkoglu F, Guler M. Type 2 diabetes mellitus remission in sleeve gastrectomy patients: Role of enteroendocrine response and serum citrulline and I-FABP levels. Am J Surg 2024; 236:115782. [PMID: 38821725 DOI: 10.1016/j.amjsurg.2024.115782] [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: 03/07/2024] [Revised: 05/06/2024] [Accepted: 05/27/2024] [Indexed: 06/02/2024]
Abstract
INTRODUCTION This prospective cohort study examines the relationship between post-sleeve gastrectomy (SG) weight loss and serum citrulline, I-FABP levels, and the I-FABP/citrulline ratio in obese patients, alongside the correlation with type 2 diabetes mellitus (T2DM) remission. METHODS 88 participants were enrolled, including 48 undergoing SG and 21 with T2DM. 40 healthy individuals served as controls. Preoperative and 1-year postoperative assessments included citrulline, I-FABP, glucose, insulin, HbA1c, and C peptide levels. RESULTS Significant weight loss and T2DM remission (11/21) were observed post-SG. Preoperatively, patients had low citrulline and high I-FABP levels, which normalized postoperatively. A positive correlation was found between the I-FABP/citrulline ratio and weight, BMI, glucose, insulin, and C peptide levels. CONCLUSION SG not only induces enterocyte dysfunction and mass recovery but also may facilitate T2DM remission and alleviate obesity-related effects on the enteroendocrine system. These findings highlight the potential beneficial effects of SG on enteroendocrine function in obese patients.
Collapse
Affiliation(s)
- Muhammed Ali Aydin
- Antalya Training and Research Hospital, Department of Biochemistry, Antalya, Turkey.
| | - Guzin Aykal
- Antalya Training and Research Hospital, Department of Biochemistry, Antalya, Turkey.
| | - Umut Riza Gunduz
- Antalya Training and Research Hospital, Department of General Surgery, Antalya, Turkey.
| | - Aydin Dincer
- Antalya Training and Research Hospital, Department of General Surgery, Antalya, Turkey.
| | - Alper Turker
- Antalya Training and Research Hospital, Department of General Surgery, Antalya, Turkey.
| | - Furkan Turkoglu
- Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey.
| | - Mert Guler
- Istanbul Training and Research Hospital, Department of General Surgery, Istanbul, Turkey.
| |
Collapse
|
|
4
|
Boškoski I, Gualtieri L, Matteo MV. Small Bowel Therapies for Metabolic Disease and Obesity. Gastrointest Endosc Clin N Am 2024; 34:715-732. [PMID: 39277300 DOI: 10.1016/j.giec.2024.06.002] [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] [Indexed: 09/17/2024]
Abstract
The small bowel has a crucial role in metabolic homeostasis. Small bowel endoscopic bariatric metabolic treatments (EBMTs) include several devices aimed at providing minimally invasive approaches for the management of metabolic disorders. The aim of this review is to provide an updated and exhaustive overview of the EBMTs targeting the small bowel developed to date, including the duodenal mucosa resurfacing, the duodenal-jejunal bypass liners, gastro-jejunal bypass sleeve, and the incisioneless magnetic anastomosis system, as well as to mention the future perspectives in the field.
Collapse
Affiliation(s)
- Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Loredana Gualtieri
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy
| | - Maria Valeria Matteo
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo A. Gemelli 8, 00168, Roma, Italy; Università Cattolica del Sacro Cuore, Roma 00168, Italy.
| |
Collapse
|
|
5
|
Busch CBE, Meiring S, van Baar ACG, Gastaldelli A, DeFronzo R, Mingrone G, Hagen M, White K, Rajagopalan H, Nieuwdorp M, Bergman JJGHM. Insulin sensitivity and beta cell function after duodenal mucosal resurfacing: an open-label, mechanistic, pilot study. Gastrointest Endosc 2024; 100:473-480.e1. [PMID: 38280531 DOI: 10.1016/j.gie.2024.01.031] [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] [Received: 06/21/2023] [Revised: 01/15/2024] [Accepted: 01/21/2024] [Indexed: 01/29/2024]
Abstract
BACKGROUND AND AIMS The duodenum has been shown to play a key role in glucose homeostasis. Duodenal mucosal resurfacing (DMR) is an endoscopic procedure for patients with type 2 diabetes (T2D) in which the duodenal mucosa is hydrothermally ablated. DMR improves glycemic control, but the underlying mechanisms remain unclear. Here, we report changes in glucoregulatory hormones and indices of insulin sensitivity and beta cell function after DMR. METHODS We included 28 patients on noninsulin glucose-lowering medications who underwent open-label DMR and a mixed meal test (MMT) in Revita-1 or Revita-2 studies. Inclusion criteria were a hemoglobin A1c from 7.6% to 10.4% and a body mass index of 24 to 40 kg/m2. Baseline and 3-month MMT data included plasma glucose, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), and gastric inhibitory polypeptide (GIP) concentrations. Glucoregulatory hormones, insulin sensitivity indices (Homeostatic Model Assessment for Insulin Resistance [HOMA-IR], Matsuda index [MI], and hepatic insulin resistance) and beta cell function (insulinogenic index, disposition index [DI], and insulin secretion rate [ISR]) were assessed. RESULTS Fasting insulin, glucagon, and C-peptide decreased significantly. Insulin sensitivity (HOMA-IR, MI, and hepatic insulin resistance) and beta cell function (DI and ISR) all improved significantly. Declines in postprandial glucose, mainly driven by a decrease in fasting levels, and in postprandial glucagon were observed, whereas GLP-1 and GIP did not change. CONCLUSIONS Insulin sensitivity and insulin secretion improved 3 months after DMR. It is unlikely that incretin changes are responsible for improved glucose control after DMR. These data add to the growing evidence validating the duodenum as a therapeutic target for patients with T2D. (Clinical trial registration numbers: NCT02413567 and NCT03653091.).
Collapse
Affiliation(s)
- Celine B E Busch
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Suzanne Meiring
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Annieke C G van Baar
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Amalia Gastaldelli
- Cardiometabolic Risk Laboratory, CNR Institute of Clinical Physiology, Pisa, Italy
| | - Ralph DeFronzo
- Diabetes Division, University of Texas Health Science Center, Texas Diabetes Institute, San Antonio, Texas, USA
| | - Geltrude Mingrone
- Division of Obesity and Metabolic Diseases, Fondazione Policlinico Universitario A. Gemelli IRCCS, Università Cattolica del Sacro Cuore, Rome, Italy; Department of Diabetes, School of Life Course Sciences, King's College London, London, UK
| | - Moira Hagen
- Fractyl Health Inc., Lexington, Massachusetts, USA
| | - Kelly White
- Fractyl Health Inc., Lexington, Massachusetts, USA
| | | | - Max Nieuwdorp
- Department of Internal and Vascular Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| | - Jacques J G H M Bergman
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, the Netherlands
| |
Collapse
|
|
6
|
Hoyt JA, Cozzi E, D'Alessio DA, Thompson CC, Aroda VR. A look at duodenal mucosal resurfacing: Rationale for targeting the duodenum in type 2 diabetes. Diabetes Obes Metab 2024; 26:2017-2028. [PMID: 38433708 DOI: 10.1111/dom.15533] [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: 12/05/2023] [Revised: 02/08/2024] [Accepted: 02/16/2024] [Indexed: 03/05/2024]
Abstract
Affecting 5%-10% of the world population, type 2 diabetes (T2DM) is firmly established as one of the major health burdens of modern society. People with T2DM require long-term therapies to reduce blood glucose, an approach that can mitigate the vascular complications. However, fewer than half of those living with T2DM reach their glycaemic targets despite the availability of multiple oral and injectable medications. Adherence and access to medications are major barriers contributing to suboptimal diabetes treatment. The gastrointestinal tract has recently emerged as a target for treating T2DM and altering the underlying disease course. Preclinical and clinical analyses have elucidated changes in the mucosal layer of the duodenum potentially caused by dietary excess and obesity, which seem to be prevalent among individuals with metabolic disease. Supporting these findings, gastric bypass, a surgical procedure which removes the duodenum from the intestinal nutrient flow, has remarkable effects that improve, and often cause remission of, diabetes. From this perspective, we explore the rationale for targeting the duodenum with duodenal mucosal resurfacing (DMR). We examine the underlying physiology of the duodenum and its emerging role in T2DM pathogenesis, the rationale for targeting the duodenum by DMR as a potential treatment for T2DM, and current data surrounding DMR. Importantly, DMR has been demonstrated to change mucosal abnormalities common in those with obesity and diabetes. Given the multifactorial aetiology of T2DM, understanding proximate contributors to disease pathogenesis opens the door to rethinking therapeutic approaches to T2DM, from symptom management toward disease modification.
Collapse
Affiliation(s)
- Jonah A Hoyt
- Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Emily Cozzi
- Research and Development, Fractyl Health, Inc, Lexington, Massachusetts, USA
| | - David A D'Alessio
- Division of Endocrinology and Metabolism, Dept. of Medicine, Duke University Medical Center, Durham, North Carolina, USA
| | - Chris C Thompson
- Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| | - Vanita R Aroda
- Brigham and Women's Hospital, Boston, Massachusetts, USA
- Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
7
|
Pessorrusso F, Mehta SV, Sullivan S. Update on Endoscopic Treatments for Obesity. Curr Obes Rep 2024; 13:364-376. [PMID: 38388770 DOI: 10.1007/s13679-024-00551-6] [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] [Indexed: 02/24/2024]
Abstract
PURPOSE OF REVIEW Increased morbidity seen with rising obesity rates continues to place an unheralded burden on our health system. Lack of higher bariatric surgery utilization and limitations with lifestyle modification and pharmacotherapy highlights the need for additional therapies for obesity. Endoscopic bariatric and metabolic therapies (EBMT) are effective, safe treatments for obesity. Current FDA-approved EBMT are confined to gastric modalities while small bowel directed therapies are still considered investigational. This review highlights current modalities of EBMT. RECENT FINDINGS Many randomized controlled trials have been performed, including both open label and sham-controlled, which have demonstrated safety and efficacy of EBMT over lifestyle therapy alone. In addition, emerging evidence from clinical experience further supports EBMT for treatment of obesity. Current evidence supports the safety and efficacy of EBMT for obesity treatment in conjunction with lifestyle therapy. They can also be used concurrently with weight loss medications to increase total weight loss.
Collapse
Affiliation(s)
- Fernanda Pessorrusso
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Academic Office 1, 12631 E. 17th Ave, Mail Stop B158, Aurora, CO, 80045, USA
| | - Sagar V Mehta
- Division of Gastroenterology, Geisinger Health System, Danville, PA, USA
| | - Shelby Sullivan
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Academic Office 1, 12631 E. 17th Ave, Mail Stop B158, Aurora, CO, 80045, USA.
| |
Collapse
|
|
8
|
Mukherjee K, Xiao C. GLP-2 regulation of intestinal lipid handling. Front Physiol 2024; 15:1358625. [PMID: 38426205 PMCID: PMC10902918 DOI: 10.3389/fphys.2024.1358625] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 01/31/2024] [Indexed: 03/02/2024] Open
Abstract
Lipid handling in the intestine is important for maintaining energy homeostasis and overall health. Mishandling of lipids in the intestine contributes to dyslipidemia and atherosclerotic cardiovascular diseases. Despite advances in this field over the past few decades, significant gaps remain. The gut hormone glucagon-like peptide-2 (GLP-2) has been shown to play pleotropic roles in the regulation of lipid handling in the intestine. Of note, GLP-2 exhibits unique actions on post-prandial lipid absorption and post-absorptive release of intestinally stored lipids. This review aims to summarize current knowledge in how GLP-2 regulates lipid processing in the intestine. Elucidating the mechanisms of GLP-2 regulation of intestinal lipid handling not only improves our understanding of GLP-2 biology, but also provides insights into how lipids are processed in the intestine, which offers opportunities for developing novel strategies towards prevention and treatment of dyslipidemia and atherosclerotic cardiovascular diseases.
Collapse
Affiliation(s)
| | - Changting Xiao
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
9
|
Mukherjee K, Wang R, Xiao C. Release of Lipids Stored in the Intestine by Glucagon-Like Peptide-2 Involves a Gut-Brain Neural Pathway. Arterioscler Thromb Vasc Biol 2024; 44:192-201. [PMID: 37970717 DOI: 10.1161/atvbaha.123.320032] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 11/07/2023] [Indexed: 11/17/2023]
Abstract
BACKGROUND The gut hormone GLP-2 (glucagon-like peptide-2) plays important roles in lipid handling in the intestine. During postabsorptive stage, it releases preformed chylomicrons stored in the intestine, the underlying mechanisms of which are not well understood. Previous studies implicate the involvement of neural pathways in GLP-2's actions on lipid absorption in the intestine, but the role of such mechanisms in releasing postabsorptive lipid storage has not been established. METHODS Here, in mesenteric lymph duct cannulated rats, we directly tested whether gut-brain neural communication mediates GLP-2's effects on postabsorptive lipid mobilization in the intestine. We performed total subdiaphragmatic vagotomy to disrupt the gut-brain neural communication and analyzed lipid output 5 hours after a lipid load in response to intraperitoneal GLP-2 or saline. RESULTS Peripheral GLP-2 administration led to increased lymph lipid output and activation of proopiomelanocortin neurons in the arcuate nucleus of hypothalamus. Disruption of gut-brain neural communication via vagotomy blunted GLP-2's effects on promoting lipid release in the intestine. CONCLUSIONS These results, for the first time, demonstrate a novel mechanism in which postabsorptive mobilization of intestinal lipid storage by GLP-2 enlists a gut-brain neural pathway.
Collapse
Affiliation(s)
- Kundanika Mukherjee
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Rita Wang
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| | - Changting Xiao
- Department of Anatomy, Physiology and Pharmacology, College of Medicine, University of Saskatchewan, Saskatoon, SK, Canada
| |
Collapse
|
|
10
|
Mahmood A, Faisal MN, Khan JA, Muzaffar H, Muhammad F, Hussain J, Aslam J, Anwar H. Association of a high-fat diet with I-FABP as a biomarker of intestinal barrier dysfunction driven by metabolic changes in Wistar rats. Lipids Health Dis 2023; 22:68. [PMID: 37237272 DOI: 10.1186/s12944-023-01837-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 05/23/2023] [Indexed: 05/28/2023] Open
Abstract
BACKGROUND The epithelial lining of the gut expresses intestinal fatty-acid binding proteins (I-FABPs), which increase in circulation and in plasma concentration during intestinal damage. From the perspective of obesity, the consumption of a diet rich in fat causes a disruption in the integrity of the gut barrier and an increase in its permeability. HYPOTHESIS There is an association between the expression of I-FABP in the gut and various metabolic changes induced by a high-fat (HF) diet. METHODS Wistar albino rats (n = 90) were divided into three groups (n = 30 per group), viz. One control and two HF diet groups (15 and 30%, respectively) were maintained for 6 weeks. Blood samples were thus collected to evaluate the lipid profile, blood glucose level and other biochemical tests. Tissue sampling was conducted to perform fat staining and immunohistochemistry. RESULTS HF diet-fed rats developed adiposity, insulin resistance, leptin resistance, dyslipidemia, and increased expression of I-FABP in the small intestine compared to the control group. Increased I-FABP expression in the ileal region of the intestine is correlated significantly with higher fat contents in the diet, indicating that higher I-FABP expression occurs due to increased demand of enterocytes to transport lipids, leading to metabolic alterations. CONCLUSION In summary, there is an association between the expression of I-FABP and HF diet-induced metabolic alterations, indicating that I-FABP can be used as a biomarker for intestinal barrier dysfunction.
Collapse
Affiliation(s)
- Aisha Mahmood
- Department of Physiology, The Islamia University of Bahawalpur, Bahawalpur, 63100, Pakistan
| | - Muhammad Naeem Faisal
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Junaid Ali Khan
- Faculty of Veterinary and Animal Sciences, Muhammad Nawaz Shareef University of Agriculture, Multan, Pakistan
| | - Humaira Muzaffar
- Department of Physiology, Government College University, Faisalabad, 38040, Pakistan
| | - Faqir Muhammad
- Faculty of Veterinary Science, Bahaudin Zakariya University, Multan, Pakistan
| | - Jazib Hussain
- Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Jawad Aslam
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad, 38040, Pakistan
| | - Haseeb Anwar
- Department of Physiology, Government College University, Faisalabad, 38040, Pakistan.
| |
Collapse
|
|
11
|
Bagheripour F, Jeddi S, Kashfi K, Ghasemi A. Metabolic effects of L-citrulline in type 2 diabetes. Acta Physiol (Oxf) 2023; 237:e13937. [PMID: 36645144 DOI: 10.1111/apha.13937] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 01/01/2023] [Accepted: 01/10/2023] [Indexed: 01/17/2023]
Abstract
The prevalence of type 2 diabetes (T2D) is increasing worldwide. Decreased nitric oxide (NO) bioavailability is involved in the pathophysiology of T2D and its complications. L-citrulline (Cit), a precursor of NO production, has been suggested as a novel therapeutic agent for T2D. Available data from human and animal studies indicate that Cit supplementation in T2D increases circulating levels of Cit and L-arginine while decreasing circulating glucose and free fatty acids and improving dyslipidemia. The underlying mechanisms for these beneficial effects of Cit include increased insulin secretion from the pancreatic β cells, increased glucose uptake by the skeletal muscle, as well as increased lipolysis and β-oxidation, and decreased glyceroneogenesis in the adipose tissue. Thus, Cit has antihyperglycemic, antidyslipidemic, and antioxidant effects and has the potential to be used as a new therapeutic agent in the management of T2D. This review summarizes available literature from human and animal studies to explore the effects of Cit on metabolic parameters in T2D. It also discusses the possible mechanisms underlying Cit-induced improved metabolic parameters in T2D.
Collapse
Affiliation(s)
- Fatemeh Bagheripour
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sajad Jeddi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Khosrow Kashfi
- Department of Molecular, Cellular and Biomedical Sciences, Sophie Davis School of Biomedical Education, City University of New York School of Medicine, New York, New York, USA
| | - Asghar Ghasemi
- Endocrine Physiology Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| |
Collapse
|
|
12
|
Arango-González A, Lara-Guzmán OJ, Rivera DA, Álvarez R, Salazar-Serrano D, Muñoz-Durango K, Escobar JS, Sierra JA. Putative intestinal permeability markers do not correlate with cardiometabolic health and gut microbiota in humans, except for peptides recognized by a widely used zonulin ELISA kit. Nutr Metab Cardiovasc Dis 2023; 33:112-123. [PMID: 36462977 DOI: 10.1016/j.numecd.2022.09.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND AIMS Cardiometabolic diseases refer to a group of interrelated conditions, sharing metabolic dysfunctions like insulin resistance, obesity, dyslipidemia, and hypertension. The gut microbiota has been associated with CMD and related conditions. Alterations in the intestinal epithelium permeability triggered by chronic stress and diet could bridge gut microbiota with inflammation and CMD development. Here, we assessed the relationship between intestinal permeability and circulating SCFAs with cardiometabolic health status (CMHS) and gut microbiota in a sample of 116 Colombian adults. METHODS AND RESULTS Plasma levels of lipopolysaccharide-binding protein (LBP), intestinal fatty acid-binding protein (I-FABP), claudin-3, and purported zonulin peptides (PZP) were measured by ELISA, whereas plasmatic levels of acetate, propionate, butyrate, isobutyrate, and valerate were measured by gas chromatography/mass spectrometry. In addition, for further statistical analysis, we took data previously published by us on this cohort, including gut microbiota and multiple CMD risk factors that served to categorize subjects as cardiometabolically healthy or cardiometabolically abnormal. From univariate and multivariate statistical analyses, we found the levels of I-FABP, LBP, and PZP increased in the plasma of cardiometabolically abnormal individuals, although only PZP reached statistical significance. CONCLUSIONS Our results did not confirm the applicability of I-FABP, LBP, claudin-3, or SCFAs as biomarkers for associating intestinal permeability with the cardiometabolic health status in these subjects. On the other hand, the poorly characterized peptides detected with the ELISA kit branded as "zonulin" were inversely associated with cardiometabolic dysfunctions and gut microbiota. Further studies to confirm the true identity of these peptides are warranted.
Collapse
Affiliation(s)
- Angela Arango-González
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia; Universidad CES, Facultad de Ciencias y Biotecnología, calle 10A #22-04, Medellin 050021, Colombia
| | - Oscar J Lara-Guzmán
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia
| | - Diego A Rivera
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia
| | - Rafael Álvarez
- Grupo de Investigación en Ciencias Farmacéuticas ICIF, Facultad de Ciencias y Biotecnología, Universidad CES, Calle 10A #22-04, Medellin 050021, Colombia
| | - Daniela Salazar-Serrano
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia; Universidad CES, Facultad de Ciencias y Biotecnología, calle 10A #22-04, Medellin 050021, Colombia
| | - Katalina Muñoz-Durango
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia
| | - Juan S Escobar
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia
| | - Jelver A Sierra
- Vidarium-Nutrition, Health and Wellness Research Center, Grupo Empresarial Nutresa, calle 8 sur #50-67, Medellin 050023, Colombia.
| |
Collapse
|
|
13
|
Zhang W, Zheng J, Zhang J, Li N, Yang X, Fang ZZ, Zhang Q. Associations of serum amino acids related to urea cycle with risk of chronic kidney disease in Chinese with type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1117308. [PMID: 36936143 PMCID: PMC10018121 DOI: 10.3389/fendo.2023.1117308] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 02/21/2023] [Indexed: 03/06/2023] Open
Abstract
OBJECTIVE Serum levels of amino acids related to urea cycle are associated with risk of type 2 diabetes mellitus (T2DM). Our study aimed to explore whether serum levels of amino acids related to urea cycle, i.e., arginine, citrulline, and ornithine, are also associated with increased risk of chronic kidney disease (CKD) in T2DM. METHODS We extracted medical records of 1032 consecutive patients with T2DM from the Electronic Administrative System of Liaoning Medical University First Affiliated Hospital (LMUFAH) system from May 2015 to August 2016. Of them, 855 patients with completed data available were used in the analysis. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. Serum amino acids were measured by mass spectrometry (MS) technology. Binary logistic regression was performed to obtain odds ratios (ORs) and their 95% confidence intervals (CIs). RESULTS 52.3% of the 855 T2DM patients were male, and 143 had CKD. In univariable analysis, high serum citrulline, high ratio of arginine to ornithine, and low ratio of ornithine to citrulline were associated with markedly increased risk of CKD (OR of top vs. bottom tertile: 2.87, 95%CI, 1.79-4.62 & 1.98, 95%CI,1.25-3.14 & 2.56, 95%CI, 1.61-4.07, respectively). In multivariable analysis, the ORs of citrulline and ornithine/citrulline ratio for CKD remained significant (OR of top vs. bottom tertile: 2.22, 95%CI, 1.29-3.82 & 2.24, 1.29-3.87, respectively). CONCLUSIONS In Chinese patients with T2DM, high citrulline and low ornithine/citrulline ratio were associated with increased risk of CKD.
Collapse
Affiliation(s)
- Wei Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Jun Zheng
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
| | - Jikun Zhang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Ninghua Li
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Xilin Yang
- Department of Epidemiology and Biostatistics, School of Public Health, Tianjin Medical University, Tianjin, China
| | - Zhong-Ze Fang
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Tianjin Medical University, Tianjin, China
- *Correspondence: Qiang Zhang, ; Zhong-Ze Fang,
| | - Qiang Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin Geriatrics Institute, Tianjin, China
- *Correspondence: Qiang Zhang, ; Zhong-Ze Fang,
| |
Collapse
|
|
14
|
Tahapary DL, Fatya AI, Kurniawan F, Marcella C, Rinaldi I, Tarigan TJE, Harbuwono DS, Yunir E, Soewondo P, Purnamasari D. Increased intestinal-fatty acid binding protein in obesity-associated type 2 diabetes mellitus. PLoS One 2023; 18:e0279915. [PMID: 36701395 PMCID: PMC9879407 DOI: 10.1371/journal.pone.0279915] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Accepted: 12/18/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Obesity is a traditional risk factor for type 2 diabetes mellitus (T2DM). However, recent studies reported that metabolically unhealthy obesity (MUO) exerts a higher risk of developing T2DM than metabolically healthy obesity (MHO) because of its higher state of insulin resistance. This may happen due to metabolic endotoxemia through gut dysbiosis and increased intestinal permeability. Our study aimed to know the association of intestinal permeability using intestinal fatty acid-binding protein (I-FABP) with obesity-related T2DM patients in Indonesia. METHODS This was a cross-sectional study that recruited 63 participants with obesity defined using body mass index (BMI) classification for the Asia-Pacific population (BMI ≥25 kg/m2). All participants were then grouped into T2DM and non-T2DM based on American Diabetes Association (ADA) diagnostic criteria. The I-FABP levels were measured using the enzyme-linked immunosorbent assay method. RESULTS The I-FABP level of T2DM group was higher compared to non-T2DM group, namely 2.82 (1.23) ng/mL vs. 1.78 (0.81) ng/mL (p<0.001; mean difference 1.033 with 95% CI 0.51-1.55). This difference was not attenuated even after adjustment for age. The fitted regression model using linear regression was: i-FABP = 1.787+1.034*(DM) (R2 = 18.20%, standardized ß = 0.442, p<0.001). CONCLUSIONS This study underscores the association of intestinal permeability with T2DM in people with obesity and supports the evidence of the potential role of intestinal permeability in the pathogenesis of obesity-related T2DM.
Collapse
Affiliation(s)
- Dicky L. Tahapary
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- * E-mail: (DLT); (PS)
| | - Atikah I. Fatya
- Department of Internal Medicine, Fa culty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Division of Hematology and Medical Oncology, Depa rtment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
| | - Farid Kurniawan
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Cicilia Marcella
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Ikhwan Rinaldi
- Department of Internal Medicine, Fa culty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Division of Hematology and Medical Oncology, Depa rtment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia
- Clinical Epidemiology and Evidence-based Medicine Unit, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Tri J. E. Tarigan
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Dante S. Harbuwono
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Em Yunir
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Pradana Soewondo
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
- * E-mail: (DLT); (PS)
| | - Dyah Purnamasari
- Division of Endocrinology, Metabolism, and Diabetes, Dep artment of Internal Medicine, Faculty of Medicine Universitas Indonesia, Depok City, Indonesia
- Metabolic, Cardiovascular, and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| |
Collapse
|
|
15
|
Abstract
Modern changes in diet and lifestyle have led to an explosion of insulin resistance and metabolic diseases around the globe which, if left unchecked, will become a principal driver of morbidity and mortality in the 21st century. The nature of the metabolic homeostatic shift within the body has therefore become a topic of considerable interest. While the gut has long been recognized as an acute nutrient sensor with signaling mechanisms to the other metabolic organs of the body, its role in regulating the body's metabolic status over longer periods of time has been underappreciated. Recent insights from bariatric surgery and intestinal nutrient stimulation experiments provide a window into the adaptive role of the intestinal mucosa in a foregut/hindgut metabolic balance model that helps to define metabolic parameters within the body-informing the metabolic regulation of insulin resistance versus sensitivity, hunger versus satiety, energy utilization versus energy storage, and protection from hypoglycemia versus protection from hyperglycemia. This intestinal metabolic balance model provides an intellectual framework with which to understand the distinct roles of proximal and distal intestinal segments in metabolic regulation. The model may also aid in the development of novel disease-modifying therapies that can correct the dysregulated metabolic signals from the intestine and stem the tide of metabolic diseases in society.
Collapse
Affiliation(s)
- Harith Rajagopalan
- Fractyl Health, Inc., Lexington,
MA, USA
- Harith Rajagopalan, M.D. PhD.,
Fractyl Health, Inc., 17 Hartwell Avenue, Lexington, MA 02421, USA.
| | | | - David C. Klonoff
- Diabetes Research Institute,
Mills-Peninsula Medical Center, San Mateo, California
| | - Alan D. Cherrington
- Department of Molecular
Physiology and Biophysics, Vanderbilt University School of Medicine,
Nashville, TN, USA
| |
Collapse
|
|
16
|
Shahi SK, Ghimire S, Lehman P, Mangalam AK. Obesity induced gut dysbiosis contributes to disease severity in an animal model of multiple sclerosis. Front Immunol 2022; 13:966417. [PMID: 36164343 PMCID: PMC9509138 DOI: 10.3389/fimmu.2022.966417] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 08/08/2022] [Indexed: 01/28/2023] Open
Abstract
Background Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the CNS. The etiology of MS is complex, and results from the interaction of multiple environmental and genetic factors. Although human leukocyte antigen-HLA alleles such as HLA-DR2 and -DR3 are considered the strongest genetic factors, the environmental factors responsible for disease predisposition are not well understood. Recently, diet and gut microbiota have emerged as an important environmental factors linked to the increased incidence of MS. Especially, western diets rich in protein and fat have been linked to the increased incidence of obesity. Numerous clinical data indicate a role of obesity and gut microbiota in MS; however, the mechanistic link between gut microbiota and obesity in the pathobiology of MS remains unclear. The present study determines the mechanisms driving MS severity in the context of obesity utilizing a high-fat diet (HFD) induced obese HLA-DR3 class-II transgenic mouse model of MS. Methods HLA-DR3 transgenic mice were kept on a standard HFD diet or Normal Chow (NC) for eight weeks. Gut microbiota composition and functional analysis were performed from the fecal DNA of mice. Experimental autoimmune encephalomyelitis-EAE (an animal model of MS) was induced by immunization with the proteolipid protein-PLP91-110 peptide in complete Freud's Adjuvant (CFA) and pertussis toxin. Results We observed that HFD-induced obesity caused gut dysbiosis and severe disease compared to mice on NC. Amelioration of disease severity in mice depleted of gut microbiota suggested an important role of gut bacteria in severe EAE in obese mice. Fecal microbiota analysis in HFD mice shows gut microbiota alterations with an increase in the abundance of Proteobacteria and Desulfovibrionaceae bacteria and modulation of various bacterial metabolic pathways including bacterial hydrogen sulfide biosynthetic pathways. Finally, mice on HFD showed increased gut permeability and systemic inflammation suggesting a role gut barrier modulation in obesity induced disease severity. Conclusions This study provides evidence for the involvement of the gut microbiome and associated metabolic pathways plus gut permeability in obesity-induced modulation of EAE disease severity. A better understanding of the same will be helpful to identify novel therapeutic targets to reduce disease severity in obese MS patients.
Collapse
Affiliation(s)
- Shailesh K. Shahi
- Department of Pathology, University of Iowa, Iowa City, IA, United States,*Correspondence: Ashutosh K. Mangalam, ; Shailesh K. Shahi,
| | - Sudeep Ghimire
- Department of Pathology, University of Iowa, Iowa City, IA, United States
| | - Peter Lehman
- Department of Pathology, University of Iowa, Iowa City, IA, United States
| | - Ashutosh K. Mangalam
- Department of Pathology, University of Iowa, Iowa City, IA, United States,Graduate Program in Immunology, University of Iowa, Iowa City, IA, United States,Graduate Program in Molecular Medicine, University of Iowa, Iowa City, IA, United States,*Correspondence: Ashutosh K. Mangalam, ; Shailesh K. Shahi,
| |
Collapse
|
|
17
|
Hoffmanová I, Sánchez D, Szczepanková A, Hábová V, Tlaskalová-Hogenová H. Serological markers of intestinal barrier impairment do not correlate with duration of diabetes and glycated hemoglobin in adult patients with type 1 and type 2 diabetes mellitus. Physiol Res 2022; 71:357-368. [PMID: 35616045 DOI: 10.33549/physiolres.934874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Growing evidence suggests that diabetes mellitus is associated with impairment of the intestinal barrier. However, it is not clear so far if the impairment of the intestinal barrier is a consequence of prolonged hyperglycemia or the consequence of external factors influencing the gut microbiota and intestinal mucosa integrity. Aim of the study was to perform an estimation of relationship between serological markers of impairment of the intestinal barrier: intestinal fatty acid-binding protein (I-FABP), cytokeratin 18 caspase-cleaved fragment (cCK-18), and soluble CD14 (sCD14) and markers of prolonged hyperglycemia, such as the duration of diabetes mellitus and glycated hemoglobin (HbA1c) via a correlation analysis in patients with diabetes mellitus. In 40 adult patients with type 1 diabetes mellitus and 30 adult patients with type 2 diabetes mellitus the estimation has been performed. Statistically significant positive correlation was found between cCK-18 and HbA1c (r=0.5047, p=0.0275) in patients with type 1 diabetes mellitus with fading insulitis (T1D). In patients with type 1 diabetes mellitus with ongoing insulitis (T1D/INS) and in patients with type 2 diabetes mellitus (T2D), no statistically significant positive correlations were found between serological markers of intestinal barrier impairment (I-FABP, cCK-18, sCD14) and duration of diabetes or levels of HbA1c. Similarly, in cumulative cohort of patients with T1D/INS and patients with T1D we revealed statistically positive correlation only between HbA1c and cCK-18 (r=0.3414, p=0.0311). Surprisingly, we found statistically significant negative correlation between the duration of diabetes mellitus and cCK-18 (r=-0.3050, p=0.0313) only in cumulative group of diabetic patients (T1D, T1D/INS, and T2D). Based on our results, we hypothesize that the actual condition of the intestinal barrier in diabetic patients is much more dependent on variable interactions between host genetic factors, gut microbiota, and environmental factors rather than effects of long-standing hyperglycemia (assessed by duration of diabetes mellitus or HbA1c).
Collapse
Affiliation(s)
- I Hoffmanová
- Department of Internal Medicine, Second Faculty of Medicine, Charles University Prague, and Motol University Hospital, Prague, Czech Republic; Laboratory of Cellular and Molecular Immunology, Institute of Microbiology of the Czech Academy of Sciences., Prague, Czech Republic.
| | | | | | | | | |
Collapse
|
|
18
|
Grande EM, Raka F, Hoffman S, Adeli K. GLP-2 Regulation of Dietary Fat Absorption and Intestinal Chylomicron Production via Neuronal Nitric Oxide Synthase (nNOS) Signaling. Diabetes 2022; 71:1388-1399. [PMID: 35476805 DOI: 10.2337/db21-1053] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 04/17/2022] [Indexed: 11/13/2022]
Abstract
Postprandial dyslipidemia is a metabolic condition commonly associated with insulin-resistant states, such as obesity and type 2 diabetes. It is characterized by the overproduction of intestinal chylomicron particles and excess atherogenic chylomicron remnants in circulation. We have previously shown that glucagon-like peptide 2 (GLP-2) augments dietary fat uptake and chylomicron production in insulin-resistant states; however, the underlying mechanisms remain unclear. Previous studies have implicated nitric oxide (NO) in the absorptive actions of GLP-2. In this study, we report a novel role for neuronal NO synthase (nNOS)-mediated NO generation in lipid uptake and chylomicron formation based on studies in C57BL/6J mice, nNOS-/- mice, and Syrian golden hamsters after intraduodenal and oral fat administration. GLP-2 treatment in wild-type (WT) mice significantly increased postprandial lipid accumulation and circulating apolipoprotein B48 protein levels, while these effects were abolished in nNOS-/- mice. nNOS inhibition in Syrian golden hamsters and protein kinase G (PKG) inhibition in WT mice also abrogated the effect of GLP-2 on postprandial lipid accumulation. These studies demonstrate a novel mechanism in which nNOS-generated NO is crucial for GLP-2-mediated lipid absorption and chylomicron production in both mouse and hamster models. Overall, our data implicate an nNOS-PKG-mediated pathway in GLP-2-mediated stimulation of dietary fat absorption and intestinal chylomicron production.
Collapse
Affiliation(s)
- Elisabeth M Grande
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Fitore Raka
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Simon Hoffman
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| | - Khosrow Adeli
- Molecular Medicine, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
19
|
Sianipar IR, Sestramita S, Pradnjaparamita T, Yunir E, Harbuwono DS, Soewondo P, Tahapary DL. The role of Intestinal-Fatty Acid Binding Proteins and Chitinase-3-Like Protein 1 across the spectrum of dysglycemia. Diabetes Metab Syndr 2022; 16:102366. [PMID: 34942410 DOI: 10.1016/j.dsx.2021.102366] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Revised: 12/07/2021] [Accepted: 12/09/2021] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS Recent studies underlie the importance of intestinal permeability and chronic inflammation in the pathogenesis of T2DM. Our study compared the concentrations of FABP2 and YKL40 as markers of intestinal permeability and inflammation among normoglycemia, prediabetes and T2DM. METHODS We recruited 122 participants (45 normoglycemic, 26 prediabetes, and 51 T2DM) of whom we measured the fasting serum levels of FABP2 and YKL-40 using ELISA method. RESULTS The levels of FABP2 were significantly higher in the T2DM group [2.890 (1.880-4.070)] in comparison to both prediabetes [2.025 (1.145-2.343), p = 0.0085] and normoglycemia group [1.72 (1.250-2.645), p = 0.011]. The levels of YKL-40 were also significantly higher in the T2DM group [68.70 (44.61-166.6)] in comparison to both prediabetes [28.85 (20.64-41.53), p < 0.0001] and normoglycemia group [28.64 (19.25-43.87), p < 0.001]. CONCLUSIONS Our study observed that the levels of FABP2 and YKL-40 were highest in the T2DM group supporting the available evidences on the role of intestinal permeability disruption and chronic low-grade inflammation in the pathogenesis of T2DM.
Collapse
Affiliation(s)
- Imelda R Sianipar
- Department of Medical Physiology, Faculty of Medicine, Universitas Indonesia, Indonesia.
| | - Sestramita Sestramita
- Graduate Student of Master Program in Biomedical Science, Faculty of Medicine, Universitas Indonesia, Indonesia
| | - Tika Pradnjaparamita
- Metabolic, Cardiovascular and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
| | - Em Yunir
- Metabolic, Cardiovascular and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, dr. Cipto Mangunkusumo National General Hospital/Faculty of Medicine Universitas Indonesia, Indonesia
| | - Dante S Harbuwono
- Metabolic, Cardiovascular and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, dr. Cipto Mangunkusumo National General Hospital/Faculty of Medicine Universitas Indonesia, Indonesia
| | - Pradana Soewondo
- Metabolic, Cardiovascular and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, dr. Cipto Mangunkusumo National General Hospital/Faculty of Medicine Universitas Indonesia, Indonesia.
| | - Dicky L Tahapary
- Metabolic, Cardiovascular and Aging Research Cluster, The Indonesian Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; Division of Endocrinology, Metabolism and Diabetes, Department of Internal Medicine, dr. Cipto Mangunkusumo National General Hospital/Faculty of Medicine Universitas Indonesia, Indonesia.
| |
Collapse
|
|
20
|
Klimontov VV, Koroleva EA, Khapaev RS, Korbut AI, Lykov AP. Carotid Artery Disease in Subjects with Type 2 Diabetes: Risk Factors and Biomarkers. J Clin Med 2021; 11:72. [PMID: 35011813 PMCID: PMC8745306 DOI: 10.3390/jcm11010072] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 12/17/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
Carotid atherosclerosis (CA) and, especially, carotid artery stenosis (CAS), are associated with a high risk of cardiovascular events in subjects with type 2 diabetes (T2D). In this study, we aimed to identify risk factors and biomarkers of subclinical CA and CAS in T2D individuals. High-resolution ultrasonography of carotid arteries was performed in 389 patients. Ninety-five clinical parameters were evaluated, including diabetic complications and comorbidities; antihyperglycemic, hypolipidemic, and antihypertensive therapy; indices of glycemic control and glucose variability (GV); lipid panels; estimated glomerular filtration rate (eGFR); albuminuria; blood cell count; and coagulation. Additionally, serum levels of calponin-1, relaxin, L-citrulline, and matrix metalloproteinase-2 and -3 (MMP-2, -3) were measured by ELISA. In univariate analysis, older age, male sex, diabetes duration, GV, diabetic retinopathy, chronic kidney disease, coronary artery disease, peripheral artery disease, and MMP-3 were associated with subclinical CA. In addition to these factors, long-term arterial hypertension, high daily insulin doses, eGFR, and L-citrulline were associated with CAS. In multivariate logistic regression, age, male sex, BMI, GV, and eGFR predicted CA independently; male sex, BMI, diabetes duration, eGFR, and L-citrulline were predictors of CAS. These results can be used to develop screening and prevention programs for CA and CAS in T2D subjects.
Collapse
Affiliation(s)
- Vadim V. Klimontov
- Research Institute of Clinical and Experimental Lymphology—Branch of the Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences (RICEL—Branch of IC&G SB RAS), 630060 Novosibirsk, Russia; (E.A.K.); (R.S.K.); (A.I.K.); (A.P.L.)
| | | | | | | | | |
Collapse
|
|
21
|
Bariatric Surgery Improves the Atherogenic Profile of Circulating Methylarginines in Obese Patients: Results from a Pilot Study. Metabolites 2021; 11:metabo11110759. [PMID: 34822417 PMCID: PMC8624057 DOI: 10.3390/metabo11110759] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 10/27/2021] [Accepted: 10/31/2021] [Indexed: 12/04/2022] Open
Abstract
Bariatric surgery improves obesity-related comorbidities. Methylarginines are biomarkers of cardiometabolic risk, liver steatosis, and insulin resistance. Here, we aimed to investigate methylarginines in obese patients undergoing bariatric surgery and compared them to age- and sex-matched healthy subjects. Thirty-one obese patients who underwent bariatric surgery and 31 healthy individuals were used for this retrospective study. The basal serum methylarginine levels were determined in the healthy individuals and the obese patients, before surgery and 6 and 12 months after surgery, by mass spectrometry. Compared with the healthy individuals, the obese patients displayed elevated monomethylarginine (mean change: +95%, p < 0.001), asymmetric-dimethylarginine (+105%, p < 0.001), symmetric-dimethylarginine (+25%, p = 0.003), and dimethylguanidino valerate (+32%, p = 0.008) concentrations. Bariatric surgery durably reduced the body mass index by 28% (12 months, 95%CI: 24–33, p = 0.002) and improved plasma lipids, insulin resistance, and liver function. Bariatric surgery reduced the serum levels of monomethylarginine and asymmetric-dimethylarginine by 12% (95%CI: 6–17) and 36% (95%CI: 27–45) (12 months, p = 0.003), respectively, but not symmetric-dimethylarginine or dimethylguanidino valerate. The monomethylarginine and asymmetric-dimethylarginine concentrations were strongly correlated with markers of dyslipidemia, insulin resistance, and a fatty liver. Serum dimethylguanidino valerate was primarily correlated with glycemia and renal function, whereas serum symmetric-dimethylarginine was almost exclusively associated with renal function. In conclusion, the monomethylarginine and asymmetric-dimethylarginine levels are efficiently decreased by bariatric surgery, leading to a reduced atherogenic profile in obese patients. Methylarginines follow different metabolic patterns, which could help for the stratification of cardiometabolic disorders in obese patients.
Collapse
|
|
22
|
Abstract
With the recent urbanization and globalization, the adult obesity rate has been increasing, which was paralleled with a dramatic surge in the incidence and prevalence of nonalcoholic fatty liver disease (NAFLD). NAFLD poses a growing threat to human health as it represents the most common cause of chronic liver disease in developed countries. It encompasses a wide spectrum of conditions starting from a build-up of fat in hepatocytes (steatosis), to developing inflammation (steatohepatitis), and reaching up to cirrhosis. It is also associated with higher rates of cardiovascular mortalities. Therefore, proper timely treatment is essential and weight loss remains the cornerstone in the treatment of obesity-related liver diseases. When diet, exercise, and lifestyle changes are not successful, the current recommendation for weight loss includes antiobesity medications and bariatric endoscopic and surgical interventions. These interventions have shown to result in significant weight loss and improve liver steatosis and fibrosis. In the current literature review, we highlight the expected outcomes and side effects of the currently existing options to have a weight-centric NAFLD approach.
Collapse
Affiliation(s)
- Anas Hashem
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
| | - Amani Khalouf
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
| | - Andres Acosta
- Division of Gastroenterology and Hepatology, Department of Medicine, Precision Medicine for Obesity Program, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
23
|
Development of Radiofrequency Ablation Generator and Balloon-Based Catheter for Microendoluminal Thin-Layer Ablation Therapy Using the Rat Duodenum as a Model of Low-Impedance Tissue. JOURNAL OF HEALTHCARE ENGINEERING 2021; 2021:9986874. [PMID: 34603652 PMCID: PMC8486529 DOI: 10.1155/2021/9986874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 09/07/2021] [Accepted: 09/14/2021] [Indexed: 12/03/2022]
Abstract
Radiofrequency ablation (RFA) is a routinely used, safe, and effective method for the tissue destruction. Often, in case of its application in malignant conditions, the extent of tissue destruction is insufficient due to the size of the target lesion, as well as due to the risk of heat-induced damage to the surrounding organs. Nevertheless, there are conditions requiring superficial precise-depth ablation with preservation of deeper layers. These are represented, for example, by mucosal resurfacing in case of Barrett's esophagus or treatment of recurrent mucosal bleeding in case of chronic radiation proctitis. Recently, new indications for intraluminal RFA use emerged, especially in the pancreatobiliary tract. In the case of intraductal use of RFA (e.g., biliary and pancreatic tract), there are currently available rigid and needle tip catheters. An expandable balloon-based RFA catheter suitable for use in such small-diameter tubular organs could be of benefit due to possible increase of contact between the probe and the target tissue; however, to prevent excessive tissue damage, a compatible generator suitable for low-impedance catheter/tissue is essential. This project aimed to develop a radiofrequency ablation generator and bipolar balloon-based catheter optimized for the application in the conditions of low-impedance tissue and (micro)endoluminal environment. Subsequent evaluation of biological effect in vivo was performed using duodenal mucosa in Wistar rat representing conditions of endoluminal radiofrequency ablation of low-impedance tissue. Experiments confirming the safety and feasibility of RFA with our prototype devices were conducted.
Collapse
|
|
24
|
Aliluev A, Tritschler S, Sterr M, Oppenländer L, Hinterdobler J, Greisle T, Irmler M, Beckers J, Sun N, Walch A, Stemmer K, Kindt A, Krumsiek J, Tschöp MH, Luecken MD, Theis FJ, Lickert H, Böttcher A. Diet-induced alteration of intestinal stem cell function underlies obesity and prediabetes in mice. Nat Metab 2021; 3:1202-1216. [PMID: 34552271 PMCID: PMC8458097 DOI: 10.1038/s42255-021-00458-9] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Accepted: 08/13/2021] [Indexed: 12/11/2022]
Abstract
Excess nutrient uptake and altered hormone secretion in the gut contribute to a systemic energy imbalance, which causes obesity and an increased risk of type 2 diabetes and colorectal cancer. This functional maladaptation is thought to emerge at the level of the intestinal stem cells (ISCs). However, it is not clear how an obesogenic diet affects ISC identity and fate. Here we show that an obesogenic diet induces ISC and progenitor hyperproliferation, enhances ISC differentiation and cell turnover and changes the regional identities of ISCs and enterocytes in mice. Single-cell resolution of the enteroendocrine lineage reveals an increase in progenitors and peptidergic enteroendocrine cell types and a decrease in serotonergic enteroendocrine cell types. Mechanistically, we link increased fatty acid synthesis, Ppar signaling and the Insr-Igf1r-Akt pathway to mucosal changes. This study describes molecular mechanisms of diet-induced intestinal maladaptation that promote obesity and therefore underlie the pathogenesis of the metabolic syndrome and associated complications.
Collapse
Affiliation(s)
- Alexandra Aliluev
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Sophie Tritschler
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
- School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Michael Sterr
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Lena Oppenländer
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Julia Hinterdobler
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
| | - Tobias Greisle
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Martin Irmler
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
| | - Johannes Beckers
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Experimental Genetics, Helmholtz Center Munich, Neuherberg, Germany
- Technical University of Munich, Freising, Germany
| | - Na Sun
- Research Unit of Analytical Pathology, Helmholtz Center Munich, Neuherberg, Germany
| | - Axel Walch
- Research Unit of Analytical Pathology, Helmholtz Center Munich, Neuherberg, Germany
| | - Kerstin Stemmer
- Institute of Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- Rudolf-Buchheim-Institute of Pharmacology, Justus Liebig University, Giessen, Germany
| | - Alida Kindt
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
| | - Jan Krumsiek
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
| | - Matthias H Tschöp
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Institute of Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technical University of Munich, Munich, Germany
| | - Malte D Luecken
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany
| | - Fabian J Theis
- Institute of Computational Biology, Helmholtz Center Munich, Neuherberg, Germany.
- Technical University of Munich, Munich, Germany.
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
- Technical University of Munich, Munich, Germany.
| | - Anika Böttcher
- Institute of Diabetes and Regeneration Research, Helmholtz Diabetes Center, Helmholtz Center Munich, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
| |
Collapse
|
|
25
|
Lingaiah S, Arffman RK, Morin-Papunen L, Tapanainen JS, Piltonen T. Markers of gastrointestinal permeability and dysbiosis in premenopausal women with PCOS: a case-control study. BMJ Open 2021; 11:e045324. [PMID: 34226215 PMCID: PMC8258572 DOI: 10.1136/bmjopen-2020-045324] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
OBJECTIVES Altered intestinal permeability and gut barrier dysfunction have been suggested to play a role in the pathogenetic mechanism of polycystic ovary syndrome (PCOS), the most common endocrine and metabolic condition in reproductive-aged women. However, data on intestinal permeability and dysbiosis of the gut microbiota in PCOS is still limited, with conflicting results. To this end, the concentrations of gastrointestinal permeability and gut dysbiosis markers were analysed in women with PCOS. DESIGN Case-control study. SETTING General community. PARTICIPANTS 104 women with PCOS and 203 body mass index (BMI) matched control women at age 46. PRIMARY AND SECONDARY OUTCOME MEASURES Serum levels of zonulin, fatty acid-binding protein 2 (FABP2), urinary levels of indican, and hormonal and metabolic parameters. RESULTS Serum levels of zonulin (128.0±17.0 vs 130.9±14.0 ng/mL, p=0.13) and FABP2 (1.5±0.9 vs 1.5±0.7 ng/mL, p=0.63) and urinary levels of indican (9.5±5.5 vs 8.4±4.2 mg/dL, p=0.07) were comparable in women with PCOS and controls in the whole study population. Likewise, when the study population was divided into different BMI groups as normal weight, overweight and obese, the levels of the above markers were comparable between the study groups. After BMI adjustment, zonulin levels correlated with the levels of high-sensitivity C reactive protein and homoeostasis model assessment of insulin resistance (p<0.05) both in women with PCOS and controls. CONCLUSIONS Intestinal permeability markers zonulin and FABP2, and the dysbiosis marker indican do not seem to be altered in women with PCOS at age 46 compared with BMI-matched controls. Serum zonulin levels correlated with BMI, insulin resistance and inflammatory marker levels, but did not segregate women with PCOS and controls. This suggests that metabolic factors, but not PCOS per se, is the driving force of dysbiosis in premenopausal women with PCOS.
Collapse
Affiliation(s)
- Shilpa Lingaiah
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Riikka K Arffman
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Laure Morin-Papunen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
| | - Juha S Tapanainen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
- Department of Obstetrics and Gynaecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland
| | - Terhi Piltonen
- Department of Obstetrics and Gynaecology, PEDEGO Research Unit, Medical Research Centre, Oulu University Hospital, University of Oulu, Oulu, Finland
| |
Collapse
|
|
26
|
Krysa JA, Ball GDC, Vine DF, Jetha M, Proctor SD. ApoB-lipoprotein remnant dyslipidemia and high-fat meal intolerance is associated with markers of cardiometabolic risk in youth with obesity. Pediatr Obes 2021; 16:e12745. [PMID: 33150705 DOI: 10.1111/ijpo.12745] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2020] [Revised: 09/30/2020] [Accepted: 10/05/2020] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Cardiovascular disease (CVD) originates in childhood and risk is exacerbated in obesity. Mechanisms of the etiologic link between early adiposity and CVD-risk remain unclear. Postprandial or non-fasting dyslipidemia is characterized by elevated plasma triglycerides (TG) and intestinal-apolipoprotein(apo)B48-remnants following a high-fat meal and is a known CVD-risk factor in adults. The aim of this study was to determine (a) whether the fasting concentration of apoB48-remnants can predict impaired non-fasting apoB48-lipoprotein metabolism (fat intolerance) and (b) the relationship of these biomarkers with cardiometabolic risk factors in youth with or without obesity. METHODS We assessed fasting and non-fasting lipids in youth without obesity (n = 22, 10 males, 12 females) and youth with obesity (n = 13, 5 males, 8 females) with a mean BMI Z-score of 0.19 ± 0.70 and 2.25 ± 0.31 (P = .04), respectively. RESULTS Fasting and non-fasting apoB48-remnants were elevated in youth with obesity compared to youth without obesity (apoB48: 18.04 ± 1.96 vs 8.09 ± 0.59, P < .0001, and apoB48AUC : 173.0 ± 20.86 vs 61.99 ± 3.44, P < .001). Furthermore, fasting plasma apoB48-remnants were positively correlated with the non-fasting response in apoB48AUC (r = 0.84, P < .0001) as well as other cardiometabolic risk factors including HOMA-IR (r = 0.61, P < .001) and leptin (r = 0.56, P < .0001). CONCLUSION Fasting apoB48-remnants are elevated in youth with obesity and predict apoB48 postprandial dyslipidemia. ApoB48-remnants are associated with the extent of fat intolerance and appear to be potential biomarker of CVD-risk in youth.
Collapse
Affiliation(s)
- Jacqueline A Krysa
- Division of Nutrition, Metabolic and Cardiovascular Diseases Laboratory, University of Alberta, Edmonton, Alberta, Canada
| | - Geoff D C Ball
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Donna F Vine
- Division of Nutrition, Metabolic and Cardiovascular Diseases Laboratory, University of Alberta, Edmonton, Alberta, Canada.,Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Mary Jetha
- Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
| | - Spencer D Proctor
- Division of Nutrition, Metabolic and Cardiovascular Diseases Laboratory, University of Alberta, Edmonton, Alberta, Canada.,Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada
| |
Collapse
|
|
27
|
de Oliveira GHP, de Moura DTH, Funari MP, McCarty TR, Ribeiro IB, Bernardo WM, Sagae VMT, Freitas JR, Souza GMDV, de Moura EGH. Metabolic Effects of Endoscopic Duodenal Mucosal Resurfacing: a Systematic Review and Meta-analysis. Obes Surg 2021; 31:1304-1312. [PMID: 33417100 DOI: 10.1007/s11695-020-05170-3] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 12/07/2020] [Accepted: 12/09/2020] [Indexed: 12/16/2022]
Abstract
Duodenal mucosal resurfacing (DMR) is an innovative endoscopic bariatric and metabolic therapy (EBMT) emerging in recent years. It uses the duodenum to achieve better glycemic and weight control. This study aimed to evaluate in a critical and systematic way the metabolic effects of this procedure. Electronic searches were performed evaluating the DMR procedure based on predefined inclusion and exclusion criteria. Changes in measured outcomes were evaluated using random-effects models by computing weighted mean differences (MD) and corresponding 95% CIs between pre-and post-procedure metabolic characteristics. Four studies were selected for qualitative and quantitative analysis. DMR demonstrated beneficial glycemic and hepatic metabolic effects among patients with non-insulin dependent type 2 diabetes (T2D) at 3 and 6 months post-procedure.
Collapse
Affiliation(s)
- Guilherme Henrique Peixoto de Oliveira
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Diogo Turiani Hourneaux de Moura
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Mateus Pereira Funari
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Thomas R McCarty
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital - Harvard Medical School, Boston, MA, USA
| | - Igor Braga Ribeiro
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil.
| | - Wanderley Marques Bernardo
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Vitor Massaro Takamatsu Sagae
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - João Remi Freitas
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Gabriel Mayo de Vieira Souza
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| | - Eduardo Guimarães Hourneaux de Moura
- Gastrointestinal Endoscopy Unit, Hospital das Clínicas, University of São Paulo School of Medicine, Av. Dr Enéas de Carvalho Aguiar, 225, 6o andar, bloco 3, Cerqueira Cesar, São Paulo, SP, 05403-010, Brazil
| |
Collapse
|
|
28
|
Macedo MH, Martínez E, Barrias CC, Sarmento B. Development of an Improved 3D in vitro Intestinal Model to Perform Permeability Studies of Paracellular Compounds. Front Bioeng Biotechnol 2020; 8:524018. [PMID: 33042961 PMCID: PMC7527803 DOI: 10.3389/fbioe.2020.524018] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022] Open
Abstract
The small intestine is the primary site of drug absorption following oral administration, making paramount the proper monitoring of the absorption process. In vitro tools to predict intestinal absorption are particularly important in preclinical drug development since they are less laborious and cost-intensive and raise less ethical considerations compared to in vivo studies. The Caco-2 model is considered the gold standard of in vitro intestinal models regarding the prediction of absorption of orally delivered compounds. However, this model presents several drawbacks, such as the expression of tighter tight junctions, not being suitable to perform permeability of paracellular compounds. Besides, cells are representative of only one intestinal cell type, without considering the role of non-absorptive cells on the absorption pathway of drugs. In the present study, we developed a new three-dimensional (3D) intestinal model that aims to bridge the gap between in vitro tools and animal studies. Our 3D model comprises a collagen layer with human intestinal fibroblasts (HIFs) embedded, mimicking the intestinal lamina propria and providing 3D support for the epithelium, composed of Caco-2 cells and mucus-producing HT29-MTX cells, creating a model that can better resemble, both in terms of composition and regarding the outcomes of drug permeability when testing paracellular compounds, the human small intestine. The optimization of the collagen layer with HIFs was performed, testing different collagen concentrations and HIF seeding densities in order to avoid collagen contraction before day 14, maintaining HIF metabolically active inside the collagen disks during time in culture. HIF morphology and extracellular matrix (ECM) deposition were assessed, confirming that fibroblasts presented a normal and healthy elongated shape and secreted fibronectin and laminin, remodeling the collagen matrix. Regarding the epithelial layer, transepithelial electrical resistance (TEER) values decreased when cells were in the 3D configuration, comparing with the 2D analogs (Caco-2 and coculture of Caco-2+HT29-MTX models), becoming more similar with in vivo values. The permeability assay with fluorescein isothiocyanate (FITC)–Dextran 4 kDa showed that absorption in the 3D models is significantly higher than that in the 2D models, confirming the importance of using a more biorelevant model when testing the paracellular permeability of compounds.
Collapse
Affiliation(s)
- Maria Helena Macedo
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Elena Martínez
- Institute for Bioengineering of Catalonia, Barcelona, Spain.,Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, Madrid, Spain.,Department of Electronics and Biomedical Engineering, Universitat de Barcelona, Barcelona, Spain
| | - Cristina C Barrias
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
| | - Bruno Sarmento
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.,CESPU-Instituto de Investigação e Formação Avançada em Ciências e Tecnologias da Saúde, Gandra, Portugal
| |
Collapse
|
|
29
|
Behaviour of plasma citrulline after bariatric surgery in the BARIASPERM cohort. Clin Nutr 2020; 40:505-510. [PMID: 32891457 DOI: 10.1016/j.clnu.2020.05.045] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 05/28/2020] [Accepted: 05/30/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Plasma citrulline is currently used in clinical practice as a marker of small bowel functional mass. Behaviour of plasma citrulline after bariatric surgery and its link with post-operative outcome are still poorly understood. OBJECTIVE Primary objective was to compare plasma citrulline 12 months after two types of bariatric surgery with pre-operative concentrations. Secondary objectives were to search for correlation between plasma citrulline variation and body weight and fat mass loss. DESIGN This is an ancillary study of the BARIASPERM study. Forty-six adult men (mean age 38.9 ± 7.9 years) who underwent gastric bypass (GB, n = 20) or sleeve gastrectomy (SG, n = 26) were included in this prospective study. Plasma citrulline was measured at baseline, 6 months and 12 months after surgery, as well as total body weight and fat mass measured by dual x-ray absorptiometry (DEXA). RESULTS Plasma citrulline increased significantly 12 months after surgery, both after gastric bypass and sleeve gastrectomy (respectively 30.2% [18.3-42.2] and 17.8% [5.8-29.7]). The increase was significantly higher after GB than after SG (p = 0.02) while total body weight and fat mass loss were not significantly different between GB and SG. The increase in plasma citrulline levels tended to be positively correlated with both weight and fat mass loss however the association did not reach statistical significance (p = 0.07 and p = 0.06 respectively). CONCLUSION These results confirm the increase in plasma citrulline after GB published in two previous small studies. Citrulline also significantly increased after SG, and in spite of similar weight loss obtained with both surgery types, citrulline increase was higher after GB than SG. This suggests different modifications of intestinal functional mass after these two different techniques.
Collapse
|
|
30
|
Boškoski I, Orlandini B, Gallo C, Bove V, Pontecorvi V, Perri V, Costamagna G. Metabolic endoscopy by duodenal mucosal resurfacing: expert review with critical appraisal of the current technique and results. Expert Rev Gastroenterol Hepatol 2020; 14:375-381. [PMID: 32299266 DOI: 10.1080/17474124.2020.1757429] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Duodenal mucosal resurfacing (DMR) is an endoscopic procedure for type 2 diabetes (T2D) consisting of circumferential hydrothermal ablation of the duodenal mucosa. AREAS COVERED A review was conducted on the reports available up to March-2020. On a total of 79 patients, DMR induced a significant mean HbA1c, FPG and HOMA-IR reduction at 6 months (0.9 ± 0.2%, 1.7 ± 0.5 mmol/L and 2.9 ± 1.1 mUI/L respectively - P < 0.001). DMR metabolic efficacy directly correlates with the length of the ablated mucosa (mean 3 months HbA1c reduction 1.2% vs 2.5% after short and long ablation respectively - P < 0.05), while it is independent of weight-loss. Severe AEs were registered in 3.7% of the cases. EXPERT OPINION DMR plays a promising role in metabolic impairment improvement inducing a morpho-functional duodenal alteration not necessarily depending on weight-loss. Technical-functional improvements of the device and appropriate training aimed at its correct use are needed to lower the rate of severe AEs and technical failure. The current role of DMR needs to be clarified, but it might be proposed for poorly controlled T2D in accurately selected patients. Evidence on DMR is still scanty and further research is mandatory to standardize the endoscopic technique and its indications.
Collapse
Affiliation(s)
- Ivo Boškoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Beatrice Orlandini
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Camilla Gallo
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Vincenzo Bove
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Valerio Pontecorvi
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Vincenzo Perri
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| | - Guido Costamagna
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS , Rome, Italy.,Centre for Endoscopic Research Therapeutics and Training (CERTT), Università Cattolica del Sacro Cuore di Roma Largo A. Gemelli , Rome, Italy
| |
Collapse
|
|
31
|
Wang H, Tang W, Zhang P, Zhang Z, He J, Zhu D, Bi Y. Modulation of gut microbiota contributes to effects of intensive insulin therapy on intestinal morphological alteration in high-fat-diet-treated mice. Acta Diabetol 2020; 57:455-467. [PMID: 31749050 DOI: 10.1007/s00592-019-01436-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/03/2019] [Indexed: 02/07/2023]
Abstract
AIMS Disturbance of intestinal homeostasis promotes the development of type 2 diabetes. Although intensive insulin therapy has been shown to promote extended glycemic remission in newly diagnosed type 2 diabetic patients through multiple mechanisms, its effect on intestinal homeostasis remains unknown. METHODS This study evaluated the effects of intensive insulin therapy on intestinal morphometric parameters in a hyperglycemic mice model induced by high-fat diet (HFD). 16S rRNA V4 region sequencing and multivariate analysis were utilized to evaluate the structural changes of gut microbiota. RESULTS HFD-induced increases in the lengths of villus, microvillus and crypt depth were significantly reversed after intensive insulin therapy. Moreover, intestinal proliferation was notably decreased after intensive insulin therapy, whereas intestinal apoptosis was further increased. Importantly, intensive insulin therapy significantly shifted the overall structure of the HFD-disrupted gut microbiota toward that of mice fed a normal diet and changed the gut microbial composition. The abundances of 54 operational taxonomic units (OTUs) were changed by intensive insulin therapy. Thirty altered OTUs correlated with two or more intestinal morphometric parameters and were designated 'functionally relevant phylotypes.' CONCLUSIONS For the first time, our data indicate that intensive insulin therapy recovers diabetes-associated gut structural abnormalities and restores the microbiome landscape. Moreover, specific altered 'functionally relevant phylotypes' correlates with improvement in diabetes-associated gut structural alterations.
Collapse
Affiliation(s)
- Hongdong Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Wenjuan Tang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Pengzi Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Zhou Zhang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Jielei He
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Dalong Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, 321 Zhongshan Road, Nanjing, 210008, China.
| |
Collapse
|
|
32
|
Le Gall M, Thenet S, Aguanno D, Jarry AC, Genser L, Ribeiro-Parenti L, Joly F, Ledoux S, Bado A, Le Beyec J. Intestinal plasticity in response to nutrition and gastrointestinal surgery. Nutr Rev 2020; 77:129-143. [PMID: 30517714 DOI: 10.1093/nutrit/nuy064] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The plasticity of a material corresponds to its capacity to change its feature under the effect of an external action. Intestinal plasticity could be defined as the ability of the intestine to modify its size or thickness and intestinal cells to modulate their absorption and secretion functions in response to external or internal cues/signals. This review will focus on intestinal adaptation mechanisms in response to diet and nutritional status. These physiological mechanisms allow a fine and rapid adaptation of the gut to promote absorption of ingested food, but they can also lead to obesity in response to overnutrition. This plasticity could thus become a therapeutic target to treat not only undernutrition but also obesity. How the intestine adapts in response to 2 types of surgical remodeling of the digestive tract-extensive bowel resection leading to intestinal failure and surgical treatment of pathological obesity (ie, bariatric surgeries)-will also be reviewed.
Collapse
Affiliation(s)
- Maude Le Gall
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France
| | - Sophie Thenet
- Centre de Recherche des Cordeliers, Sorbonne Université, EPHE, PSL University, Sorbonne Cités, UPD Univ Paris 05, INSERM, CNRS, Paris, France
| | - Doriane Aguanno
- Centre de Recherche des Cordeliers, Sorbonne Université, EPHE, PSL University, Sorbonne Cités, UPD Univ Paris 05, INSERM, CNRS, Paris, France
| | - Anne-Charlotte Jarry
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France
| | - Laurent Genser
- Sorbonne Université, INSERM, Nutriomics Team, Paris, France, and the Assistance Publique-Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Hepato-Biliary and Pancreatic Surgery, Liver Transplantation, Paris, France
| | - Lara Ribeiro-Parenti
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France.,Department of General and Digestive Surgery, University Hospital Bichat-Claude-Bernard, Paris, France
| | - Francisca Joly
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France.,Department of Gastroenterology, Inflammatory Bowel Diseases, Nutritional Support and Intestinal Transplantation, Paris, France
| | - Séverine Ledoux
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France.,Service des Explorations Fonctionnelles, Centre de référence de prise en charge de l'obésité, GHUPNVS, Hôpital Louis Mourier, Colombes, France
| | - André Bado
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France
| | - Johanne Le Beyec
- Centre de Recherche sur l'Inflammation, Inserm UMRS _1149, Université Paris Diderot, AP-HP, Paris, France.,Sorbonne Université, AP-HP, Hôpital Pitié-Salpêtrière-Charles Foix, Biochimie Endocrinienne et Oncologique, Paris, France
| |
Collapse
|
|
33
|
Abstract
Obesity poses a significant health care concern in the United States, with 39.8% of adults being classified as obese. Several different methods have been introduced to combat obesity, from medical therapy to surgical options. Bariatric surgery has been demonstrated to be superior to medical therapy alone for weight loss in obese patients. Despite this information, only about 1% of eligible patients undergo bariatric surgery per year. The reason for this treatment gap is multifactorial, but patient apprehension to undergo surgery is a major driving force. Many patients perceive bariatric surgery as dangerous, and believe that living with their current weight is safer than undergoing surgery. To combat this treatment gap, endoscopic therapies have been developed to reach more patients in a less invasive way. This article will review endoscopic treatment options currently available and approved by the Food and Drug Administration, as well as other treatment modalities that are currently in development.
Collapse
Affiliation(s)
- Leena Khaitan
- University Hospitals Cleveland Medical Center, Department of Surgery, Cleveland, OH
| | - Brian Shea
- University Hospitals Cleveland Medical Center, Department of Surgery, Cleveland, OH.
| |
Collapse
|
|
34
|
Lalande C, Drouin-Chartier JP, Tremblay AJ, Couture P, Veilleux A. Plasma biomarkers of small intestine adaptations in obesity-related metabolic alterations. Diabetol Metab Syndr 2020; 12:31. [PMID: 32292494 PMCID: PMC7144049 DOI: 10.1186/s13098-020-00530-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/13/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Evidence suggests that pathophysiological conditions such as obesity and type 2 diabetes (T2D) are associated with morphologic and metabolic alterations in the small intestinal mucosa. Exploring these alterations generally requires invasive methods, limiting data acquisition to subjects with enteropathies or undergoing bariatric surgery. We aimed to evaluate small intestine epithelial cell homeostasis in a cohort of men covering a wide range of adiposity and glucose homoeostasis statuses. METHODS Plasma levels of citrulline, a biomarker of enterocyte mass, and I-FABP, a biomarker of enterocyte death, were measured by UHPLC‑MS and ELISA in 154 nondiabetic men and 67 men with a T2D diagnosis. RESULTS Plasma citrulline was significantly reduced in men with insulin resistance and T2D compared to insulin sensitive men. Decreased citrulline levels were, however, not observed in men with uncontrolled metabolic parameters during T2D. Plasma I-FABP was significantly higher in men with T2D, especially in presence of uncontrolled glycemic and lipid profile parameters. Integration of both parameters, which estimate enterocyte turnover, was associated with glucose homeostasis as well as with T2D diagnosis. Differences in biomarkers levels were independent of age and BMI and glucose filtration rates. CONCLUSIONS Our study supports a decreased functional enterocyte mass and an increased enterocyte death rate in presence of metabolic alterations but emphasizes that epithelial cell homeostasis is especially altered in presence of severe insulin resistance and T2D. The marked changes in small intestine cellularity observed in obesity and diabetes are thus suggested to be part of gut dysfunctions, mainly at an advanced stage of the disease.
Collapse
Affiliation(s)
- Catherine Lalande
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - Jean-Philippe Drouin-Chartier
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - André J. Tremblay
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
| | - Patrick Couture
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
- Centre des maladies lipidiques, Centre Hospitalier Universitaire (CHU) de Québec, Québec, QC Canada
| | - Alain Veilleux
- École de nutrition, Faculté des sciences de l’agriculture et de l’alimentation, Université Laval, 2440, boulevard Hochelaga, Québec, QC G1V 0A6 Canada
- Centre Nutrition, santé et société (NUTRISS), Institut sur la nutrition et les aliments fonctionnels (INAF), Université Laval, Québec, QC Canada
- Centre de Recherche de l’Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, QC Canada
- Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health, Québec, QC Canada
| |
Collapse
|
|
35
|
Brunaldi VO, Ferreira Filho JA, Martone D. Endoscopic Techniques for Obesity and Diabetes. OBESITY AND DIABETES 2020:607-618. [DOI: 10.1007/978-3-030-53370-0_44] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
|
|
36
|
Wilbrink J, Bernards N, Mujagic Z, van Avesaat M, Pijls K, Klaassen T, van Eijk H, Nienhuijs S, Stronkhorst A, Wilms E, Troost F, Masclee A. Intestinal barrier function in morbid obesity: results of a prospective study on the effect of sleeve gastrectomy. Int J Obes (Lond) 2019; 44:368-376. [PMID: 31819200 DOI: 10.1038/s41366-019-0492-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2018] [Revised: 10/31/2019] [Accepted: 11/17/2019] [Indexed: 11/09/2022]
Abstract
BACKGROUND Obesity has been associated with impaired intestinal barrier function. It is not known whether bariatric surgery leads to changes in intestinal barrier function. We hypothesized that obesity is associated with disturbances in gastrointestinal barrier function, and that after bariatric surgery barrier function will improve. METHODS Prospective single center study in which we assessed segmental gut permeability by urinary recovery of a multisugar drink in 27 morbidly obese (BMI 43.3 ± 1.1 kg/m2) and 27 age and gender matched lean subjects (BMI 22.9 ± 0.43 kg/m2). Fecal calprotectin, SCFAs, plasma cytokines, and hsCRP were assessed as inflammatory and metabolic markers. Comparisons: (a) morbidly obese subjects vs. controls and (b) 2 and 6 months postsleeve vs. presleeve gastrectomy (n = 14). In another group of 10 morbidly obese and 11 matched lean subjects colonic and ileal biopsies were obtained in order to measure gene transcription of tight junction proteins. RESULTS Gastroduodenal permeability (urinary sucrose recovery) was significantly increased in obese vs. lean controls (p < 0.05). Small intestinal and colonic permeability (urinary recovery of lactulose/L-rhamnose and sucralose/erythritol, respectively) in obese subjects were not significantly different from controls. Morbidly obese subjects had a proinflammatory systemic and intestinal profile compared with lean subjects. After sleeve gastrectomy BMI decreased significantly (p < 0.001). Postsleeve gastroduodenal permeability normalized to values that do not differ from lean controls. CONCLUSIONS Gastroduodenal permeability, but not small intestinal or colonic permeability, is significantly increased in morbidly obese patients. After sleeve gastrectomy, gastroduodenal permeability normalized to values in the range of lean controls. Thus, the proximal gastrointestinal barrier is compromised in morbid obesity and is associated with a proinflammatory intestinal and systemic profile.
Collapse
Affiliation(s)
- Jennifer Wilbrink
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands. .,Department of Gastroenterology-Hepatology, Catharina Hospital, Eindhoven, The Netherlands. .,Department of Gastroenterology-Hepatology, Zuyderland Medical Centre Sittard-Geleen, Sittard-Geleen, The Netherlands. .,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands.
| | - Nienke Bernards
- Department of Gastroenterology-Hepatology, Catharina Hospital, Eindhoven, The Netherlands
| | - Zlatan Mujagic
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Mark van Avesaat
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Kirsten Pijls
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Tim Klaassen
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Hans van Eijk
- Department of Surgery, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Simon Nienhuijs
- Department of Surgery, Catharina Hospital, Eindhoven, The Netherlands
| | - Arnold Stronkhorst
- Department of Gastroenterology-Hepatology, Catharina Hospital, Eindhoven, The Netherlands
| | - Ellen Wilms
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Freddy Troost
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| | - Ad Masclee
- Division of Gastroenterology-Hepatology, Maastricht University Medical Center, Maastricht, The Netherlands.,NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht, The Netherlands
| |
Collapse
|
|
37
|
van Baar AC, Beuers U, Wong K, Haidry R, Costamagna G, Hafedi A, Deviere J, Ghosh SS, Lopez-Talavera JC, Rodriguez L, Galvao Neto MP, Sanyal A, Bergman JJ. Endoscopic duodenal mucosal resurfacing improves glycaemic and hepatic indices in type 2 diabetes: 6-month multicentre results. JHEP Rep 2019; 1:429-437. [PMID: 32039394 PMCID: PMC7005649 DOI: 10.1016/j.jhepr.2019.10.006] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 09/27/2019] [Accepted: 10/29/2019] [Indexed: 02/06/2023] Open
Abstract
Insulin resistance is a core pathophysiological defect underscoring type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). Both conditions improve with duodenal exclusion surgery. Duodenal mucosal resurfacing (DMR) is an endoscopic intervention developed to treat metabolic disease which has been shown to improve glycaemia in patients with poorly controlled T2DM. Herein, we aimed to further analyse the effects of DMR on hepatic and metabolic parameters in this patient cohort. METHODS Eighty-five patients with T2DM who received endoscopic DMR treatment were enrolled from 5 centres and followed up for 6 months. We assessed safety in all patients. Efficacy was evaluated in patients who received at least 9 cm of duodenal ablation (n = 67). Endpoints included HbA1c, fasting plasma glucose, weight and aminotransferase levels. Metabolomic analysis was conducted in a subgroup (n = 14). Data were analysed using paired t test or ANOVA for repeated measures with Bonferroni correction and correction for initial weight loss if applicable. RESULTS The DMR procedure was completed with no intraprocedural complications in the entire cohort. HbA1c was lower 6 months after DMR than at baseline (7.9 ± 0.2% vs. 9.0 ± 0.2% [mean ± SE], p ≪0.001). Fasting plasma glucose was also significantly lower 6 months after DMR compared to baseline (161 ± 7 mg/dl vs. 189 ± 6 mg/dl, p = 0.005). Body weight decreased slightly. At 6 months, alanine aminotransferase had decreased from 41 ± 3 IU/L to 29 ± 2 IU/L (p ≪0.001) and aspartate aminotransferase had decreased from 30 ± 2 IU/L to 23 ± 1 IU/L (p ≪0.001). Metabolomic analysis demonstrated that DMR had key lipid-lowering, insulin-sensitizing and anti-inflammatory effects, as well as increasing antioxidant capacity. Mean FIB-4 was also markedly decreased. CONCLUSION Hydrothermal ablation of the duodenum by DMR elicits a beneficial metabolic response in patients with T2DM. DMR also improves hepatic indices, potentially through an insulin-sensitizing mechanism. These encouraging data deserve further evaluation in randomized controlled trials. LAY SUMMARY Hydrothermal duodenal mucosal resurfacing (DMR) is an endoscopic technique designed to treat metabolic disease through ablation of the duodenal mucosa. DMR is a safe procedure which improves glycaemia and hepatic indices in patients with type 2 diabetes mellitus. DMR is an insulin-sensitizing intervention which can be complementary to lifestyle intervention approaches and pharmacological treatments aimed at preserving the pancreas and liver from failure. DMR is a potential therapeutic solution for patients with type 2 diabetes and fatty liver disease.
Collapse
Affiliation(s)
- Annieke C.G. van Baar
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Ulrich Beuers
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| | - Kari Wong
- Metabolon, Inc., Morrisville, NC, United States
| | - Rehan Haidry
- Department of Gastroenterology, University College Hospital NHS Foundation Trust, London, United Kingdom
| | - Guido Costamagna
- Digestive Endoscopy Unit. Fondazione Policlinico Universitario A. Gemelli - IRCCS, Rome, Italy
- Università Cattolica del S. Cuore, Rome, Italy
| | - Alia Hafedi
- Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
| | - Jacques Deviere
- Department of Gastroenterology, Erasme University Hospital, Brussels, Belgium
| | | | | | | | | | - Arun Sanyal
- Department of Gastroenterology & Hepatology, Virginia Commonwealth University, Richmond, VA, United States
| | - Jacques J.G.H.M. Bergman
- Department of Gastroenterology & Hepatology, Amsterdam University Medical Centers, location Academic Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
|
38
|
Loos CMM, Dorsch SC, Elzinga SE, Brewster-Barnes T, Vanzant ES, Adams AA, Urschel KL. A high protein meal affects plasma insulin concentrations and amino acid metabolism in horses with equine metabolic syndrome. Vet J 2019; 251:105341. [PMID: 31492392 DOI: 10.1016/j.tvjl.2019.105341] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 07/13/2019] [Accepted: 07/16/2019] [Indexed: 12/12/2022]
Abstract
Equine metabolic syndrome (EMS) is characterized by an abnormal insulin response to a glycemic challenge but despite the known insulinotropic effects of certain amino acids, there is a paucity of data evaluating the impact of dietary protein on insulin dynamics in these horses. The objective was therefore to assess insulin and amino acid responses following intake of a high protein meal in healthy horses and those with EMS. Six mature horses diagnosed with EMS and six age-matched control horses without EMS were used. Horses were fed 2g/kg body mass (BM) of a high protein pellet (31% crude protein) at time 0 and 30min, for a total of 4g/kg BM, following an overnight fast. Blood samples collected during a 4h period were analysed for plasma glucose, insulin, amino acids and urea concentrations. Glucose concentrations were not different between groups (P=0.2). Horses with EMS had a 9-fold greater insulinemic response to the consumption of a high protein meal compared with controls (P=0.046). Post-prandial levels of histidine, citrulline, tyrosine, valine, methionine, isoleucine, leucine and ornithine were higher in horses with EMS (P<0.05). Baseline urea nitrogen concentrations were not significantly different between groups (P=0.1). Knowing that certain amino acids are insulin secretagogues, these results illustrate that consumption of a high protein meal caused a hyperinsulinemic response and affected amino acid dynamics in horses with EMS. These findings suggest that dietary protein content should be taken into consideration in the management of horses with insulin dysregulation.
Collapse
Affiliation(s)
- C M M Loos
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40506, USA
| | - S C Dorsch
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40506, USA
| | - S E Elzinga
- Department of Neurology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - T Brewster-Barnes
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40506, USA
| | - E S Vanzant
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40506, USA
| | - A A Adams
- Department of Veterinary Sciences, University of Kentucky, Lexington, KY, 40506, USA
| | - K L Urschel
- Department of Animal and Food Sciences, University of Kentucky, Lexington, KY, 40506, USA.
| |
Collapse
|
|
39
|
Sikora M, Stec A, Chrabaszcz M, Waskiel-Burnat A, Zaremba M, Olszewska M, Rudnicka L. Intestinal Fatty Acid Binding Protein, a Biomarker of Intestinal Barrier, is Associated with Severity of Psoriasis. J Clin Med 2019; 8:jcm8071021. [PMID: 31336842 PMCID: PMC6678629 DOI: 10.3390/jcm8071021] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 07/04/2019] [Accepted: 07/11/2019] [Indexed: 12/18/2022] Open
Abstract
Alterations of intestinal microbiota play a significant role in the pathogenesis of psoriasis. Dysbiosis may cause disruption of the intestinal barrier, which contributes to immune activation by translocation of microbial antigens and metabolites. Intestinal fatty acid binding protein (I-FABP) serves as a biomarker of enterocyte damage. The aim of this study was to investigate clinical and metabolic factors affecting plasma concentration of I-FABP in patients with psoriasis. Eighty patients with psoriasis and 40 control subjects were enrolled in the study. Serum I-FABP (243.00 (108.88–787.10) vs. 114.38 (51.60–241.60) pg/ml, p < 0.001) and neutrophil to lymphocyte ratio (NLR; 2.59 (1.96–3.09) vs. 1.72 (1.36–47 2.11), p < 0.01) were significantly increased in patients with psoriasis compared to controls. A significant positive correlation was found between I-FABP and body mass index (BMI) (r = 0.82, p < 0.001), Psoriasis Area Severity Index (PASI) (r = 0.78, p < 0.001) and neutrophil to lymphocyte ratio (NLR) (r = 0.24, p < 0.001). Rising quartiles of I-FABP were associated with increasing values of BMI, PASI and NLR. The results of the logistic regression model confirmed an increased risk of higher disease severity with I-FABP concentration – odds ratio 3.34 per 100 pg/mL I-FABP increase. In conclusion, intestinal integrity in patients with psoriasis is affected by obesity, severity of the disease and systemic inflammation. The modulation of gut barrier may represent a new therapeutic approach for psoriasis.
Collapse
Affiliation(s)
- Mariusz Sikora
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland.
| | - Albert Stec
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Magdalena Chrabaszcz
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Anna Waskiel-Burnat
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Michal Zaremba
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Malgorzata Olszewska
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| | - Lidia Rudnicka
- Department of Dermatology, Medical University of Warsaw, Koszykowa 82a, 02-008 Warsaw, Poland
| |
Collapse
|
|
40
|
Bottani M, Cornaghi L, Donetti E, Ferraretto A. Excess of nutrient-induced morphofunctional adaptation and inflammation degree in a Caco2/HT-29 in vitro intestinal co-culture. Nutrition 2018; 58:156-166. [PMID: 30419477 DOI: 10.1016/j.nut.2018.07.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Accepted: 07/30/2018] [Indexed: 12/26/2022]
Abstract
OBJECTIVES The intestinal cell function can be modulated by the type and quantity of nutrients. The aim of this study was to evaluate the effects of an excess of nutrients on intestinal morphofunctional features and a possible association of inflammation in a 70/30 Caco2/HT-29 intestinal in vitro co-culture. METHODS An excess of nutrients (EX) was obtained by progressively increasing the medium change frequency with respect to standard cell growth conditions (ST) from confluence (T0) to 15 d after confluence (T15). RESULTS In comparison with the ST group, the EX group revealed a maintenance in the number of microvilli, an increase in follicle like-structures and mucus production, and a decrease in the number of tight junction. The specific activity of markers of intestinal differentiation, alkaline phosphatase and aminopeptidase N, and of the enterocyte differentiation specific marker, dipeptidyl peptidase-IV, were progressively raised. The transepithelial electrical resistance, indicative of the co-culture barrier properties, decreased, whereas Lucifer yellow Papp evaluation, an index of the paracellular permeability to large molecules, showed an increase. Reactive oxygen species and nitric oxide production, indicative of an oxidative status, together with interleukin-6, interleukin-8, indicative of a low-grade inflammation, and peptide YY secretion were higher in the EX group than in the ST group. The differences between ST and EX were particularly evident at T15. CONCLUSION These data support the suitability of our in vitro gut model for obesity studies at the molecular level and the necessity to standardize the medium frequency change in intestinal culture.
Collapse
Affiliation(s)
- Michela Bottani
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
| | - Laura Cornaghi
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
| | - Elena Donetti
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy
| | - Anita Ferraretto
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Milano, Italy; Centro Ricerca Metabolismi, San Donato Milanese, Italy.
| |
Collapse
|
|
41
|
Zhou W, Davis EA, Li K, Nowak RA, Dailey MJ. Sex differences influence intestinal epithelial stem cell proliferation independent of obesity. Physiol Rep 2018; 6:e13746. [PMID: 29952094 PMCID: PMC6021372 DOI: 10.14814/phy2.13746] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 05/23/2018] [Accepted: 05/27/2018] [Indexed: 12/25/2022] Open
Abstract
The intestinal epithelium is continuously regenerated by cell renewal of intestinal epithelial stem cells (IESCs) located in the intestinal crypts. Obesity affects this process and results in changes in the size and cellular make-up of the tissue, but it remains unknown if there are sex differences in obesity-induced alterations in IESC proliferation and differentiation. We fed male and female mice a 60% high-fat diet (HFD) or a 10% low-fat diet (LFD) for 3 months and investigated the differences in (1) the expression of markers of different intestinal epithelial cell types in vivo, and (2) lasting effects on IESC growth in vitro. We found that the growth of IESCs in vitro were enhanced in females compared with males. HFD induced similar in vivo changes and in vitro early growth of IESCs in males and females. The IESCs isolated and grown in vitro from females, though, showed an enhanced growth that was independent of obesity. To determine whether this effect was driven by sex steroid hormones, we used primary intestinal crypts isolated from male and female mice and investigated the differences in (1) the expression of steroid hormone receptors, and (2) cell proliferation in response to steroid hormones. We found that estrogen receptor α was expressed in crypts from both sexes, but estrogen had no effect on proliferation in either sex. These results suggest that obesity similarly effects IESCs in males and females, but IESCs in females have greater proliferation ability than males, but this is not driven by a direct effect of sex steroid hormones on IESCs or other crypt cells that provide essential niche support for IESCs.
Collapse
Affiliation(s)
- Weinan Zhou
- Department of Animal SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
| | - Elizabeth A. Davis
- Neuroscience ProgramUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
| | - Kailiang Li
- Department of Animal SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
| | - Romana A. Nowak
- Department of Animal SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
| | - Megan J. Dailey
- Department of Animal SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
- Neuroscience ProgramUniversity of Illinois at Urbana‐ChampaignUrbanaIllinois
| |
Collapse
|
|
42
|
Zhou W, Rowitz BM, Dailey MJ. Insulin/IGF-1 enhances intestinal epithelial crypt proliferation through PI3K/Akt, and not ERK signaling in obese humans. Exp Biol Med (Maywood) 2018; 243:911-916. [PMID: 29950119 DOI: 10.1177/1535370218785152] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
The intestinal epithelium is continuously regenerated through proliferation and differentiation of stem cells located in the intestinal crypts. Obesity affects this process and results in greater stem cell proliferation and altered tissue growth and function. Obesity-induced high levels of insulin and insulin-like growth factor-1 in the stem cell niche are found to impact proliferation in rodents indicating that insulin and insulin-like growth factor-1 receptors may play a role in modulating intestinal epithelial stem cell proliferation. To determine whether insulin or insulin-like growth factor-1 can induce proliferation in human intestinal epithelial stem cells, and if two downstream insulin and insulin-like growth factor-1 receptor signaling pathways, PI3K/Akt and ERK, are involved, we used primary small intestinal epithelial crypts isolated from obese humans and investigated (1) the effect of insulin or insulin-like growth factor-1 on crypt proliferation, and (2) the effect of insulin and insulin-like growth factor-1 signaling inhibitors on insulin or insulin-like growth factor-1-induced proliferation. We found that insulin and insulin-like growth factor-1 enhanced the proliferation of crypt cells, including intestinal epithelial stem cells. Inhibition of the PI3K/Akt pathway attenuated insulin and insulin-like growth factor-1-induced proliferation, but inhibition of the ERK pathway had no effect. These results suggest that the classical metabolic PI3K pathway and not the canonical proliferation ERK pathway is involved in the insulin/insulin-like growth factor-1-induced increase in crypt proliferation in obese humans, which may contribute to abnormal tissue renewal and function. Impact statement This study investigates if insulin or insulin-like growth factor-1 (IGF-1) induces intestinal epithelial proliferation in humans, and if insulin and IGF-1 receptor signaling is involved in this process in obesity. Although obesity-induced high levels of insulin and IGF-1 in the stem cell niche are found to impact the proliferation of intestinal epithelial stem cells in rodents, we are the first to investigate this effect in humans. We found that insulin and IGF-1 enhanced the proliferation of intestinal crypts (including stem cells and other crypt cells) isolated from obese humans, and PI3K/Akt, and not ERK signaling was involved in insulin or IGF-1-induced proliferation. The imbalance in signaling between PI3K/Akt and ERK pathways may point to a pathway-specific impairment in insulin/IGF-1 receptor signaling. We propose that this may contribute to reciprocal relationships between insulin/IGF-1 receptor resistance and intestinal epithelial proliferation that leads to abnormal tissue renewal and function.
Collapse
Affiliation(s)
- Weinan Zhou
- 1 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Blair M Rowitz
- 2 Carle Illinois College of Medicine, Carle Foundation Hospital, Urbana, IL 61801, USA
| | - Megan J Dailey
- 1 Department of Animal Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| |
Collapse
|
|
43
|
Shi L, Brunius C, Lehtonen M, Auriola S, Bergdahl IA, Rolandsson O, Hanhineva K, Landberg R. Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort. Diabetologia 2018; 61:849-861. [PMID: 29349498 PMCID: PMC6448991 DOI: 10.1007/s00125-017-4521-y] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2017] [Accepted: 11/13/2017] [Indexed: 01/09/2023]
Abstract
AIMS/HYPOTHESIS The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction. METHODS We established a nested case-control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case-control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case-control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index. RESULTS We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors. CONCLUSIONS/INTERPRETATION Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.
Collapse
Affiliation(s)
- Lin Shi
- Department of Molecular Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden.
- Department of Biology and Biological Engeneering, Food and Nutrition Science, Chalmers University of Technology, SE-412 96, Gothenburg, Sweden.
| | - Carl Brunius
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Marko Lehtonen
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
- LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
| | - Seppo Auriola
- School of Pharmacy, University of Eastern Finland, Kuopio, Finland
- LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
| | | | - Olov Rolandsson
- Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden
| | - Kati Hanhineva
- LC-MS Metabolomics Center, Biocenter Kuopio, Kuopio, Finland
- Institute of Public Health and Clinical Nutrition, Department of Clinical Nutrition, University of Eastern Finland, Kuopio, Finland
| | - Rikard Landberg
- Department of Molecular Sciences, Swedish University of Agricultural Sciences, Uppsala, Sweden
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
- Unit of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| |
Collapse
|
|
44
|
Julian V, Blondel R, Pereira B, Thivel D, Boirie Y, Duclos M. Body Composition Is Altered in Pre-Diabetic Patients With Impaired Fasting Glucose Tolerance: Results From the NHANES Survey. J Clin Med Res 2017; 9:917-925. [PMID: 29038669 PMCID: PMC5633092 DOI: 10.14740/jocmr3142w] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Accepted: 08/21/2017] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Previous studies suggest that type 2 diabetes mellitus (T2DM) is associated with a loss of muscle mass but the impact of fasting blood glucose (FBG) on body composition remains underappreciated in pre-diabetic subjects. The aim of this study was to determine the influence of FBG on lean mass (LM), fat mass (FM) and their distribution (trunk vs. appendicular), separately in middle-aged men and women. METHODS One thousand nine hundred and eleven (1,911) men (63.9 ± 11.7 years) and 1,977 women (63.7 ± 12.1 years) from the National Health and Nutrition Examination Survey (1999 - 2004) were divided into four groups: normal glucose tolerance (NGT), low impaired fasting glucose (IFG), high IFG and T2DM. Body composition was obtained from dual X-ray absorptiometry (DXA). RESULTS Of the patients, 68.7% had NGT, 16.1% low IFG, 9.4% high IFG and 5.8% T2DM. After adjustment for age, body mass index, ethnicity, smoking, alcohol and physical activity (PA), no change in appendicular LM was observed between groups, but significant increases in trunk FM (in both gender) and trunk LM (in women) were found with increased glucose intolerance (T2DM > IFG > NGT), as well as significant decreases in trunk and total LM/FM ratios (T2DM < IFG < NGT) and a significant increase in trunk/appendicular FM ratio (T2DM > IFG > NGT). CONCLUSIONS Elevated FBG within the normal range is not associated with a significant loss of appendicular LM, but modifications in LM and FM trunk and total distribution with IFG suggest that nutritional and physical lifestyle strategies should be implemented in the pre-diabetic state.
Collapse
Affiliation(s)
- Valerie Julian
- Service Medecine du Sport et Explorations Fonctionnelles, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France.,Unite de Nutrition Humaine, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France
| | - Romain Blondel
- Service Medecine du Sport et Explorations Fonctionnelles, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France
| | - Bruno Pereira
- Service de Biostatistique, CHU Clermont-Ferrand, Universite Clermont Auvergne, Clermont-Ferrand, France
| | - David Thivel
- Laboratoire AME2P, Universite Clermont Auvergne, Aubiere, France
| | - Yves Boirie
- Unite de Nutrition Humaine, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France.,Service de Nutrition Clinique CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France
| | - Martine Duclos
- Service Medecine du Sport et Explorations Fonctionnelles, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France.,Unite de Nutrition Humaine, CHU Clermont-Ferrand, INRA, Universite Clermont Auvergne, Clermont-Ferrand, France
| |
Collapse
|
|
45
|
Abstract
Purpose of review Endoscopic bariatric therapy (EBT) is a rapidly developing area that has now seen FDA approval of six endoscopic bariatric devices and procedures and there are a number of other novel EBTs progressing through various stages of development with newly published findings. This paper aims to assist readers in either selecting an appropriate therapy for their patient or deciding to incorporate these therapies into their practice. This paper provides an updated review of the available data on EBTs, both FDA approved and not, with a particular focus on effectiveness and safety, as well as guidance for discussing with your patient the decision to use endoscopic therapies. Findings The authors of a large meta-analysis of Orbera concluded its ideal balloon volume to be 600-650 mL. AspireAssist has had favorable effectiveness and safety data published in a large RCT. A large study of endoscopic sleeve gastroplasty has published findings at up to 24 months showing promising durability. Elipse, a swallowed intragastric balloon not requiring endoscopy for either insertion or removal, has had early favorable results published. A magnet-based system for creation of a gastrojejunostomy has published favorable findings from its pilot study. Summary EBTs are safe and effective therapies for weight loss when used in conjunction with lifestyle changes and fill an important gap in the management of obesity. There are now six FDA-approved EBTs available and several more in ongoing trials with favorable early findings. More study is needed to understand the role of EBTs used in combination or in sequence with medications and bariatric surgery.
Collapse
Affiliation(s)
- Gregory Pajot
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, USA
| | - Gerardo Calderon
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, USA
| | - Andrés Acosta
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, USA.
- Mayo Clinic, 200 First St. S.W., Charlton Bldg., Rm. 8-142, Rochester, MN, 55905, USA.
| |
Collapse
|
|
46
|
LIPINSKI LEANDROC, KMETIUK LOUISEB, MATHIAS PAULOC, MALTA ANANDA, FAVERO GIOVANIM, RIBEIRO TATIANEA, TOLEDO ALCEU, NETTO MARIORMONTEMOR, RODRIGUES MARCOSR. Oral insulin improves metabolic parameters in high fat diet fed rats. ACTA ACUST UNITED AC 2017; 89:1699-1705. [DOI: 10.1590/0001-3765201720170040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2017] [Accepted: 04/29/2017] [Indexed: 01/15/2023]
|
|
47
|
Stefanaki C, Peppa M, Mastorakos G, Chrousos GP. Examining the gut bacteriome, virome, and mycobiome in glucose metabolism disorders: Are we on the right track? Metabolism 2017; 73:52-66. [PMID: 28732571 DOI: 10.1016/j.metabol.2017.04.014] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2016] [Revised: 04/21/2017] [Accepted: 04/28/2017] [Indexed: 12/19/2022]
Abstract
Human gut microbiome is defined as the gene complement of the gut microbial community, measured via laboratory metagenomic techniques. It includes bacteriome, virome and mycobiome, which represent, respectively, the assemblages of bacteria, viruses and fungi, living in the human gut. Gut microbiota function as a living "organ" that interacts with the gastro-intestinal environment, provides nutrients and vitamins to the organism and transduces hormonal messages, essentially influencing the main metabolic pathways, including drug metabolism. A clear association between gut, and glucose metabolism disorders has recently emerged. Medications acting on glucose absorption in the gut, or enhancing gut hormone activity are already extensively employed in the therapy of diabetes. Moreover, the gut is characterized by immune, and autonomous neuronal features, which play a critical role in maintaining glucose metabolism homeostasis. Gut microbes respond to neuroendocrine, and immune biochemical messages, affecting the health, and behavior of the host. There is vast heterogeneity in the studies included in this review, hence a meta-analysis, or a systematic review were not applicable. In this article, we attempt to reveal the interplay between human gut microbiota physiology, and hyperglycemic states, synthesizing, and interpreting findings from human studies.
Collapse
Affiliation(s)
- Charikleia Stefanaki
- 1st Department of Pediatrics, Choremeio Research Laboratory, Athens University Medical School, National and Kapodistrian University of Athens, Medical School, Athens, Greece.
| | - Melpomeni Peppa
- Endocrine Unit, 2nd Department of Internal Medicine Propaedeutic, Research Institute and Diabetes Center, National and Kapodistrian University of Athens, Attikon University Hospital, Athens, Greece
| | - George Mastorakos
- Department of Endocrinology, Metabolism and Diabetes, Aretaieion University Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - George P Chrousos
- 1st Department of Pediatrics, Choremeio Research Laboratory, Athens University Medical School, National and Kapodistrian University of Athens, Medical School, Athens, Greece
| |
Collapse
|
|
48
|
Cherrington AD, Rajagopalan H, Maggs D, Devière J. Hydrothermal Duodenal Mucosal Resurfacing: Role in the Treatment of Metabolic Disease. Gastrointest Endosc Clin N Am 2017; 27:299-311. [PMID: 28292408 DOI: 10.1016/j.giec.2016.12.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The duodenum has become recognized as a metabolic signaling center that is involved in regulating insulin action and, therefore, insulin resistance states such as type 2 diabetes. Bariatric surgery and other manipulations of the upper intestine, in particular the duodenum, have shown that limiting nutrient exposure or contact in this key region exerts powerful metabolic effects. Early human clinical trial data suggest that endoscopic hydrothermal duodenal mucosal resurfacing is well tolerated in human subjects and has an acceptable safety profile. This article describes the rationale for this endoscopic approach and its early human use, including safety, tolerability, and early efficacy.
Collapse
Affiliation(s)
- Alan D Cherrington
- Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, 704A/710 Robinson Research Building, 2200 Pierce Avenue, Nashville, TN 37232-0615, USA.
| | | | - David Maggs
- Fractyl Laboratories, Inc, 17 Hartwell Avenue, Lexington, MA 02421, USA
| | - Jacques Devière
- Medical-Surgical Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Route de Lennik 808, Brussels 1070, Belgium
| |
Collapse
|
|
49
|
Zhao S, Liu W, Wang J, Shi J, Sun Y, Wang W, Ning G, Liu R, Hong J. Akkermansia muciniphila improves metabolic profiles by reducing inflammation in chow diet-fed mice. J Mol Endocrinol 2017; 58:1-14. [PMID: 27821438 DOI: 10.1530/jme-16-0054] [Citation(s) in RCA: 195] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Accepted: 11/06/2016] [Indexed: 12/13/2022]
Abstract
Abnormal shifts in the composition of gut microbiota contribute to the pathogenesis of metabolic diseases, including obesity and type 2 diabetes (T2DM). The crosstalk between gut microbes and the host affects the inflammatory status and glucose tolerance of the individuals, but the underlying mechanisms have not been elucidated completely. In this study, we treated the lean chow diet-fed mice with Akkermansia muciniphila, which is thought to be inversely correlated with inflammation status and body weight in rodents and humans, and we found that A. muciniphila supplementation by daily gavage for five weeks significantly alleviated body weight gain and reduced fat mass. Glucose tolerance and insulin sensitivity were also improved by A. muciniphila supplementation compared with the vehicle. Furthermore, A. muciniphila supplementation reduced gene expression related to fatty acid synthesis and transport in liver and muscle; meanwhile, endoplasmic reticulum (ER) stress in liver and muscle was also alleviated by A. muciniphila. More importantly, A. muciniphila supplementation reduced chronic low-grade inflammation, as reflected by decreased plasma levels of lipopolysaccharide (LPS)-binding protein (LBP) and leptin, as well as inactivated LPS/LBP downstream signaling (e.g. decreased phospho-JNK and increased IKBA expression) in liver and muscle. Moreover, metabolomics profiling in plasma also revealed an increase in anti-inflammatory factors such as α-tocopherol, β-sitosterol and a decrease of representative amino acids. In summary, our study demonstrated that A. muciniphila supplementation relieved metabolic inflammation, providing underlying mechanisms for the interaction of A. muciniphila and host health, pointing to possibilities for metabolic benefits using specific probiotics supplementation in metabolic healthy individuals.
Collapse
Affiliation(s)
- Shaoqian Zhao
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wen Liu
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Juan Shi
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yingkai Sun
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Laboratory of Endocrinology and MetabolismInstitute of Health Sciences, Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) & Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China
| | - Ruixin Liu
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jie Hong
- Department of Endocrinology and MetabolismShanghai Clinical Center for Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, China National Research Center for Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| |
Collapse
|
|
50
|
Lau E, Marques C, Pestana D, Santoalha M, Carvalho D, Freitas P, Calhau C. The role of I-FABP as a biomarker of intestinal barrier dysfunction driven by gut microbiota changes in obesity. Nutr Metab (Lond) 2016; 13:31. [PMID: 27134637 PMCID: PMC4851788 DOI: 10.1186/s12986-016-0089-7] [Citation(s) in RCA: 97] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 04/19/2016] [Indexed: 12/17/2022] Open
Abstract
Background Intestinal fatty-acid binding protein (I-FABP) is expressed in epithelial cells of the mucosal layer of the small intestine tissue. When intestinal mucosal damage occurs, I-FABP is released into the circulation and its plasma concentration increases. In the context of obesity, the gut barrier integrity can be disrupted by dietary fat while intestinal permeability increases. Objective To investigate whether intestinal fatty acid binding protein (I-FABP) is a suitable plasma marker of intestinal injury and inflammation in obesity. Methods Twelve male Wistar rats were randomly divided into two groups of six animals each: standard (St) and high-fat (HF) diet fed groups for 12 weeks. Results HF fed animals developed obesity, insulin resistance and seemed to present increased plasma levels of proinflammatory cytokines (MCP-1 and IL1β). The gut microbiota composition of these animals was also altered, with lower number of copies of Bacteroidetes, Prevotella spp. and Lactobacillus spp., in comparison with those from St diet group. Fecal lipopolysaccharide (LPS) concentrations tended to be increased in HF fed animals. Intestinal expression of TLR4 seemed to be also increased in HF fed animals suggesting that HF diet-induced dysbiosis may be behind the systemic inflammation observed. However, in contrast to other intestinal inflammatory diseases, plasma I-FABP levels were decreased in HF fed rats whereas I-FABP expression in jejunum tended to be increased. Conclusions HF diet-induced obesity is characterized by dysbiosis, insulin resistance and systemic inflammation. In this context, plasmatic I-FABP should not be used as a marker of the intestinal barrier dysfunction and the low-grade chronic inflammatory status.
Collapse
Affiliation(s)
- Eva Lau
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar São João, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Cláudia Marques
- Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.,CINTESIS, Centro de Investigação em Tecnologias e Serviços de Saúde, Porto, Portugal
| | - Diogo Pestana
- Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.,CINTESIS, Centro de Investigação em Tecnologias e Serviços de Saúde, Porto, Portugal
| | - Mariana Santoalha
- Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Davide Carvalho
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar São João, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,Departamento de Medicina, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Paula Freitas
- Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar São João, Porto, Portugal.,Instituto de Investigação e Inovação em Saúde, Porto, Portugal.,Departamento de Medicina, Faculdade de Medicina, Universidade do Porto, Porto, Portugal
| | - Conceição Calhau
- Departamento de Bioquímica, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.,CINTESIS, Centro de Investigação em Tecnologias e Serviços de Saúde, Porto, Portugal.,Nutrição e Metabolismo, NOVA Medical School
- Faculdade de Ciências Médicas, Universidade NOVA de Lisboa, Lisboa, Portugal
| |
Collapse
|