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Volčanšek Š, Koceva A, Jensterle M, Janež A, Muzurović E. Amylin: From Mode of Action to Future Clinical Potential in Diabetes and Obesity. Diabetes Ther 2025; 16:1207-1227. [PMID: 40332747 PMCID: PMC12085449 DOI: 10.1007/s13300-025-01733-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2025] [Accepted: 03/19/2025] [Indexed: 05/08/2025] Open
Abstract
Precision diabetology is increasingly becoming diabetes phenotype-driven, whereby the specific hormonal imbalances involved are taken into consideration. Concomitantly, body weight-favorable therapeutic approaches are being dictated by the obesity pandemic, which extends to all diabetes subpopulations. Amylin, an anorexic neuroendocrine hormone co-secreted with insulin, is deficient in individuals with diabetes and plays an important role in postprandial glucose homeostasis, with additional potential cardiovascular and neuroprotective functions. Its actions include suppressing glucagon secretion, delaying gastric emptying, increasing energy expenditure and promoting satiety. While amylin holds promise as a therapeutic agent, its translation into clinical practice is hampered by complex receptor biology, the limitations of animal models, its amyloidogenic properties and pharmacokinetic challenges. In individuals with advanced β-cell dysfunction, supplementing insulin therapy with pramlintide, the first and currently only approved injectable short-acting selective analog of amylin, has demonstrated efficacy in enhancing both postprandial and overall glycemic control in both type 2 diabetes (T2D) and type 1 diabetes (T1D) without increasing the risk of hypoglycemia or weight gain. Current research focuses on several key strategies, from enhancing amylin stability by attaching polyethylene glycol or carbohydrate molecules to amylin, to developing oral amylin formulations to improve patients' convenience, as well as developing various combination therapies to enhance weight loss and glucose regulation by targeting multiple receptors in metabolic pathways. The novel synergistically acting glucagon-like peptide-1 (GLP-1) receptor agonist combined with the amylin agonist, CagriSema, shows promising results in both glucose regulation and weight management. As such, amylin agonists (combined with other members of the incretin class) could represent the elusive drug candidate to address the multi-hormonal dysregulations of diabetes subtypes and qualify as a precision medicine approach that surpasses the long overdue division into T1DM and T2DM. Further development of amylin-based therapies or delivery systems is crucial to fully unlock the therapeutic potential of this intriguing hormone.Graphical abstract available for this article.
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Affiliation(s)
- Špela Volčanšek
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Andrijana Koceva
- Department of Endocrinology and Diabetology, University Medical Centre Maribor, Maribor, Slovenia
- Faculty of Medicine, University of Maribor, Maribor, Slovenia
| | - Mojca Jensterle
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Andrej Janež
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Center Ljubljana, Ljubljana, Slovenia
- Medical Faculty, University of Ljubljana, Ljubljana, Slovenia
| | - Emir Muzurović
- Endocrinology Section, Department of Internal Medicine, Clinical Centre of Montenegro, Podgorica, Montenegro.
- Faculty of Medicine, University of Montenegro, Podgorica, Montenegro.
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Suryaningtyas IT, Jasmadi, Dayarathne LA, Marasinghe CK, Je JY. Mussels as sustainable marine resources for bioactive peptides for health and the food industry. Food Funct 2025; 16:3255-3272. [PMID: 40261071 DOI: 10.1039/d4fo05397d] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/24/2025]
Abstract
The growing need for sustainable protein sources has led to increased interest in marine-based alternatives, particularly those with bioactive properties. Mussels, known for their abundance and environmental sustainability, have gained attention as potential sources for bioactive peptides (BAPs). This review focuses on the current research surrounding BAPs derived from marine mussels, exploring their applications in human health and the food industry. Through a comprehensive analysis of the existing literature, the review discusses the ecological significance of mussels, their nutritional value, and the health benefits of mussel-derived peptides, which include antioxidant, anti-inflammatory, anti-osteoporosis, and cardiovascular effects. Additionally, the review examines methods for extracting these peptides, their commercial availability, and the challenges faced in the field, along with future research directions. While mussels have traditionally been consumed for their nutritional benefits, the scientific investigation into their potential for producing BAPs is relatively recent. These peptides, obtained through processes like fermentation and hydrolysis, offer promising applications in functional foods and nutraceuticals. However, further research is necessary to optimize extraction techniques, overcome commercialization hurdles, and fully realize the potential of mussels as sustainable sources of BAPs for enhancing human health.
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Affiliation(s)
- Indyaswan Tegar Suryaningtyas
- Research Center for Marine-Integrated Bionics Technology, Pukyong National University, Busan 48513, Republic of Korea
- Research Center for Food Technology and Processing, National Research and Innovation Agency, Yogyakarta, 55861, Indonesia
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Jasmadi
- Research Center for Food Technology and Processing, National Research and Innovation Agency, Yogyakarta, 55861, Indonesia
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | - Lakshi Ayoda Dayarathne
- Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea
| | | | - Jae-Young Je
- Major of Human Bioconvergence, Division of Smart Healthcare, Pukyong National University, Busan 48513, Republic of Korea.
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Facciorusso A, Ramai D, Dhar J, Samanta J, Chandan S, Gkolfakis P, Crinò SF, Maida M, Anderloni A, Boskoski I, Triantafyllou K, Dinis-Ribeiro M, Hassan C, Fuccio L, Arvanitakis M. Effects of Glucagon-Like Peptide-1 Receptor Agonists on Upper Gastrointestinal Endoscopy: A Meta-Analysis. Clin Gastroenterol Hepatol 2025; 23:715-725.e3. [PMID: 39142543 DOI: 10.1016/j.cgh.2024.07.021] [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: 05/24/2024] [Revised: 06/27/2024] [Accepted: 07/02/2024] [Indexed: 08/16/2024]
Abstract
BACKGROUND AND AIMS Limited evidence exists regarding the impact of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on upper endoscopy. Therefore, a meta-analysis was conducted to comprehensively review the available evidence on this subject. METHODS A systematic bibliographic search was carried out until May 2024. Pooled estimates were analyzed using a random-effects model, with results presented as odds ratio (OR) and 95% confidence interval (CI). The primary outcome assessed was the rate of retained gastric content (RGC), while secondary outcomes included rates of aborted and repeated procedures, adverse event rate, and rates of aspiration. RESULTS This analysis included 13 studies involving a total of 84,065 patients. Patients receiving GLP-1RA therapy exhibited significantly higher rates of RGC (OR, 5.56; 95% CI, 3.35 to 9.23), a trend that was consistent among patients with diabetes (OR, 2.60; 95% CI, 2.23 to 3.02). Adjusted analysis, accounting for variables such as sex, age, body mass index, diabetes, and other therapies, confirmed the elevated rates of RGC in the GLP-1RA user group (adjusted OR, 4.20; 95% CI, 3.42 to 5.15). Furthermore, rates of aborted and repeated procedures were higher in the GLP-1RA user group (OR, 5.13; 95% CI, 3.01 to 8.75; and OR, 2.19; 95% CI, 1.43 to 3.35; respectively). However, no significant differences were found in AE and aspiration rates between the 2 groups (OR, 4.04; 95% CI, 0.63 to 26.03; and OR, 1.75; 95% CI, 0.64 to 4.77; respectively). CONCLUSION Use of GLP-1RAs is associated with increased retention of gastric contents and more frequent aborted procedures during upper endoscopy. However, the adverse event and aspiration rates do not seem different; therefore, adjusting fasting time instead of routinely withholding GLP-1RAs could be reasonable in these patients.
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Affiliation(s)
- Antonio Facciorusso
- Section of Gastroenterology, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy; Clinical Effectiveness Research Group, Institute of Health and Society, Faculty of Medicine, University of Oslo, Oslo, Norway.
| | - Daryl Ramai
- Division of Gastroenterology, Hepatology and Endoscopy, Brigham and Women's Hospital, Boston, Massachusetts
| | - Jahnvi Dhar
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Jayanta Samanta
- Department of Gastroenterology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Saurabh Chandan
- Center for Interventional Endoscopy, Advent Health, Orlando, Florida
| | - Paraskevas Gkolfakis
- Department of Gastroenterology, Konstantopoulio-Patision General Hospital of Nea Ionia, Athens, Greece
| | - Stefano Francesco Crinò
- Gastroenterology and Digestive Endoscopy Unit, Pancreas Institute, Department of Medicine, University Hospital of Verona, Verona, Italy
| | - Marcello Maida
- Department of Medicine and Surgery, School of Medicine and Surgery, University of Enna Kore, Enna, Italy
| | - Andrea Anderloni
- Endoscopy, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Ivo Boskoski
- Digestive Endoscopy Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Konstantinos Triantafyllou
- Hepatogastroenterology Unit, Second Department of Propaedeutic Internal Medicine, Medical School, Attikon University General Hospital, National and Kapodastrian University of Athens, Athens, Greece
| | - Mario Dinis-Ribeiro
- Porto Comprehensive Cancer Center and RISE@CI-IPO, University of Porto, Porto, Portugal; Gastroenterology Department, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Cesare Hassan
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Rozzano, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Italy
| | - Lorenzo Fuccio
- Department of Medical Sciences and Surgery, University of Bologna, Bologna, Italy
| | - Marianna Arvanitakis
- Department of Gastroenterology, Digestive Oncology and Hepatopancreatology, HUB Hôpital Erasme, Brussels, Belgium
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Do A, Zahrawi F, Mehal WZ. Therapeutic landscape of metabolic dysfunction-associated steatohepatitis (MASH). Nat Rev Drug Discov 2025; 24:171-189. [PMID: 39609545 DOI: 10.1038/s41573-024-01084-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/28/2024] [Indexed: 11/30/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) and its severe subgroup metabolic dysfunction-associated steatohepatitis (MASH) have become a global epidemic and are driven by chronic overnutrition and multiple genetic susceptibility factors. The physiological outcomes include hepatocyte death, liver inflammation and cirrhosis. The first therapeutic for MASLD and MASH, resmetirom, has recently been approved for clinical use and has energized this therapeutic space. However, there is still much to learn in clinical studies of MASH, such as the scale of placebo responses, optimal trial end points, the time required for fibrosis reversal and side effect profiles. This Review introduces aspects of disease pathogenesis related to drug development and discusses two main therapeutic approaches. Thyroid hormone receptor-β agonists, such as resmetirom, as well as fatty acid synthase inhibitors, target the liver and enable it to function within a toxic metabolic environment. In parallel, incretin analogues such as semaglutide improve metabolism, allowing the liver to self-regulate and reversing many aspects of MASH. We also discuss how combinations of therapeutics could potentially be used to treat patients.
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Affiliation(s)
- Albert Do
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
- Division of Gastroenterology, University of California, Davis, Davis, USA
| | - Frhaan Zahrawi
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA.
- West Haven Veterans Hospital, West Haven, CT, USA.
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Fraga CG, Cremonini E, Galleano M, Oteiza PI. Natural Products and Diabetes: (-)-Epicatechin and Mechanisms Involved in the Regulation of Insulin Sensitivity. Handb Exp Pharmacol 2025; 287:159-173. [PMID: 38421444 DOI: 10.1007/164_2024_707] [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: 03/02/2024]
Abstract
Type 2 diabetes (T2D) is a disease that occurs when cells do not respond normally to insulin, a condition called insulin resistance, which leads to high blood glucose levels. Although it can be treated pharmacologically, dietary habits beyond carbohydrate restriction can be highly relevant in the management of T2D. Emerging evidence supports the possibility that natural products (NPs) could contribute to managing blood glucose or counteract the undesirable effects of hyperglycemia and insulin resistance. This chapter summarizes the relevant preclinical evidence involving the flavonoid (-)-epicatechin (EC) in the optimization of glucose homeostasis, reducing insulin resistance and/or diabetes-associated disorders. Major effects of EC are observed on (i) intestinal functions, including digestive enzymes, glucose transporters, microbiota, and intestinal permeability, and (ii) redox homeostasis, including oxidative stress and inflammation. There is still a need for further clinical studies to confirm the in vitro and rodent data, allowing recommendations for EC, particularly in prediabetic and T2D patients. The collection of similar data and the lack of clinical evidence for EC is also applicable to other NPs.
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Affiliation(s)
- Cesar G Fraga
- Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina.
- Instituto de Bioquímica y Medicina Molecular (IBIMOL), UBA-CONICET, Buenos Aires, Argentina.
- Department of Nutrition, University of California, Davis, CA, USA.
| | | | - Monica Galleano
- Fisicoquímica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
- Instituto de Bioquímica y Medicina Molecular (IBIMOL), UBA-CONICET, Buenos Aires, Argentina
| | - Patricia I Oteiza
- Department of Nutrition, University of California, Davis, CA, USA
- Department of Environmental Toxicology, University of California, Davis, CA, USA
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Dulai AS, Min M, Sivamani RK. The Gut Microbiome's Influence on Incretins and Impact on Blood Glucose Control. Biomedicines 2024; 12:2719. [PMID: 39767626 PMCID: PMC11727616 DOI: 10.3390/biomedicines12122719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/25/2024] [Accepted: 11/25/2024] [Indexed: 01/16/2025] Open
Abstract
Obesity and type 2 diabetes mellitus (T2DM) have been increasing in prevalence, causing complications and strain on our healthcare systems. Notably, gut dysbiosis is implicated as a contributing factor in obesity, T2DM, and chronic inflammatory diseases. A pharmacology exists which modulates the incretin pathway to improve glucose control; this has proven to be beneficial in patients with obesity and T2DM. However, it is unclear how the gut microbiome may regulate insulin resistance, glucose control, and metabolic health. In this narrative review, we aim to discuss how the gut microbiome can modulate incretin pathways and related mechanisms to control glucose. To investigate this, Google Scholar and PubMed databases were searched using key terms and phrases related to the microbiome and its effects on insulin and glucose control. Emerging research has shown that several bacteria, such as Akkermansia and MN-Gup, have GLP-1-agonistic properties capable of reducing hyperglycemia. While more human research is needed to prove clinical benefit and identify long-term implications on health, the usage of pre-, pro-, and postbiotics has the potential to improve glucose control.
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Affiliation(s)
- Ajay S. Dulai
- Integrative Research Institute, Sacramento, CA 95819, USA
- Integrative Skin Science and Research, Sacramento, CA 95815, USA
| | - Mildred Min
- Integrative Research Institute, Sacramento, CA 95819, USA
- Integrative Skin Science and Research, Sacramento, CA 95815, USA
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA
| | - Raja K. Sivamani
- Integrative Research Institute, Sacramento, CA 95819, USA
- Integrative Skin Science and Research, Sacramento, CA 95815, USA
- College of Medicine, California Northstate University, Elk Grove, CA 95757, USA
- Pacific Skin Institute, Sacramento, CA 95815, USA
- Department of Dermatology, University of California-Davis, Sacramento, CA 95616, USA
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Zuñiga-Martínez BS, Domínguez-Avila JA, Montiel-Herrera M, Villegas-Ochoa MA, Robles-Sánchez RM, Ayala-Zavala JF, Viuda-Martos M, González-Aguilar GA. Consumption of Plant-Derived Phenolic Acids Modulates Hunger and Satiety Responses Due to Chemical Interactions with Enteroendocrine Mediators. Foods 2024; 13:3640. [PMID: 39594055 PMCID: PMC11593637 DOI: 10.3390/foods13223640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/08/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
Energy-dense foods are commonly rich in fat and simple sugars and poor in dietary fiber and micronutrients; regularly consuming them decreases the concentration and/or effect of anorexigenic hormones and may increase that of orexigenic ones, thereby decreasing satiety. In contrast, plant-derived phenolic-rich foods exert positive effects on satiety. In silico, in vitro, and in vivo investigations on some of most representative phenolic acids like chlorogenic acid (CGA), gallic acid (GA), ferulic acid (FA), and protocatechuic acid (PCA) have shown that they are able to modulate various hunger and satiety processes; however, there are few studies that show how their chemical structure contributes to achieve such effects. The objective of this review is to summarize how these phenolic acids can favorably modulate hormones and other satiety mediators, with emphasis on the chemical interactions exerted between the core of these compounds and their biological targets. The evidence suggests that they form interactions with certain hormones, their receptors, and/or enzymes involved in regulating hunger and satiety, which are attributed to their chemical structure (such as the position of hydroxyl groups). Further research is needed to continue understanding these molecular mechanisms of action and to utilize the knowledge in the development of health-promoting foods.
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Affiliation(s)
- B. Shain Zuñiga-Martínez
- Centro de Investigación en Alimentación y Desarrollo A. C., Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo 83304, SO, Mexico; (B.S.Z.-M.); (M.A.V.-O.); (J.F.A.-Z.); (G.A.G.-A.)
| | - J. Abraham Domínguez-Avila
- CONAHCYT-Centro de Investigación en Alimentación y Desarrollo A. C., Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo 83304, SO, Mexico
| | - Marcelino Montiel-Herrera
- Departmento de Medicina y Ciencias de la Salud, Universidad de Sonora, Blvd. Luis Encinas y Rosales s/n, Col Centro, Hermosillo 83000, SO, Mexico;
| | - Mónica A. Villegas-Ochoa
- Centro de Investigación en Alimentación y Desarrollo A. C., Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo 83304, SO, Mexico; (B.S.Z.-M.); (M.A.V.-O.); (J.F.A.-Z.); (G.A.G.-A.)
| | - Rosario Maribel Robles-Sánchez
- Departmento de Investigación y Posgrado en Alimentos, Universidad de Sonora, Blvd. Luis Encinas y Rosales s/n, Col Centro, Hermosillo 83000, SO, Mexico;
| | - J. Fernando Ayala-Zavala
- Centro de Investigación en Alimentación y Desarrollo A. C., Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo 83304, SO, Mexico; (B.S.Z.-M.); (M.A.V.-O.); (J.F.A.-Z.); (G.A.G.-A.)
| | - Manuel Viuda-Martos
- IPOA Research Group, Instituto de Investigación e Innovación Agroalimentaria y Agroambiental (CIAGRO-UMH), Universidad Miguel Hernández, 03312 Alicante, Spain;
| | - Gustavo A. González-Aguilar
- Centro de Investigación en Alimentación y Desarrollo A. C., Carretera Gustavo Enrique Astiazarán Rosas No. 46, Col. La Victoria, Hermosillo 83304, SO, Mexico; (B.S.Z.-M.); (M.A.V.-O.); (J.F.A.-Z.); (G.A.G.-A.)
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Mohan BP. Weight loss medications: A new Pandora's box? Gastrointest Endosc 2024; 100:928-929. [PMID: 39515920 DOI: 10.1016/j.gie.2024.05.018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2024] [Accepted: 05/21/2024] [Indexed: 11/16/2024]
Affiliation(s)
- Babu P Mohan
- Department of Medicine, University of Central Florida School of Medicine, Orlando Gastroenterology PA, Orlando, Florida, USA
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Chapman MB, Norwood DA, Price C, Abdulhadi B, Kyanam Kabir Baig K, Ahmed AM, Peter S, Routman JS, Sánchez-Luna SA, Duggan EW, Mulki R. Effects of glucagon-like peptide-1 receptor agonists on gastric mucosal visibility and retained gastric contents during EGD. Gastrointest Endosc 2024; 100:923-927. [PMID: 38759761 DOI: 10.1016/j.gie.2024.05.012] [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: 01/29/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/19/2024]
Abstract
BACKGROUND AND AIMS Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are increasingly used in diabetes and obesity management. Although GLP-1RAs delay gastric emptying, their impact on visibility during EGD remains uncertain. METHODS A 1:1 matched case-control study was conducted. Individuals undergoing EGD who were taking GLP-1RAs were matched to nonusers based on demographic characteristics and diabetes status. A validated scale (POLPREP) was used to determine gastric mucosal visibility scores. RESULTS A total of 84 pairs (N = 168) were included. GLP-1RA users had significantly lower visibility scores, with a 2.42 times higher likelihood of lower scores compared with nonusers. In addition, GLP-1RA users had a higher incidence of retained gastric contents (13.1% vs 4.8%; adjusted odds ratio, 4.62; P = .025) and aborted procedures due to this issue. No anesthesia-related adverse events were observed. CONCLUSIONS GLP-1RA use at the time of endoscopy exhibited higher odds of lower gastric mucosal visibility scores, retained contents, and aborted procedures. Further research is warranted.
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Affiliation(s)
- Malcolm B Chapman
- Division of General Internal Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Dalton A Norwood
- Division of Preventive Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Christopher Price
- Division of General Internal Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Basma Abdulhadi
- Division of Endocrinology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Kondal Kyanam Kabir Baig
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Ali M Ahmed
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Shajan Peter
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Justin S Routman
- Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Sergio A Sánchez-Luna
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Elizabeth W Duggan
- Department of Anesthesiology and Perioperative Medicine, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA
| | - Ramzi Mulki
- Division of Gastroenterology and Hepatology, Heersink School of Medicine, The University of Alabama at Birmingham, Alabama, USA.
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Forst T, De Block C, Del Prato S, Armani S, Frias J, Lautenbach A, Ludvik B, Marinez M, Mathieu C, Müller TD, Schnell O. The role of incretin receptor agonists in the treatment of obesity. Diabetes Obes Metab 2024; 26:4178-4196. [PMID: 39072877 DOI: 10.1111/dom.15796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/28/2024] [Accepted: 06/29/2024] [Indexed: 07/30/2024]
Abstract
INTRODRODUCTION Obesity and its associated metabolic conditions have become a significant global health problem in recent years, with many people living with obesity fulfilling criteria for pharmacological treatment. The development of the glucagon-like peptide-1 receptor agonists for chronic weight management has triggered new interest in the incretins and other hormones as targets for obesity, and investigations into dual and triple co-agonists. METHODS The objective of this narrative review was to summarize the available data on approved and emerging incretin-based agents for the treatment of obesity. RESULTS In clinical trials of currently available agents in people with overweight or obesity, weight loss of between 6% and 21% of baseline body weight has been observed, with between 23% and 94% of participants achieving 10% or higher weight loss, depending on the study and the agent used. Favourable outcomes have also been seen with regard to cardiovascular risk and outcomes, diabetes prevention, metabolic dysfunction-associated steatotic liver disease/steatohepatitis and prevention of weight regain after metabolic surgery. Limitations associated with these agents include high costs, the potential for weight regain once treatment is stopped, the potential loss of lean body mass and gastrointestinal adverse events; potential issues with respect to gallbladder and biliary diseases require further investigation. CONCLUSIONS Many dual and triple co-agonists are still in development, and more data are needed to assess the efficacy, safety and tolerability of these emerging therapies versus the established incretin-based therapies; however, data are promising, and further results are eagerly awaited.
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Affiliation(s)
- Thomas Forst
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science," Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Sara Armani
- CRS Clinical Research Services GmbH, Mannheim, Germany
| | - Juan Frias
- Biomea Fusion, Redwood City, California, USA
| | - Anne Lautenbach
- University Medical-Center Hamburg-Eppendorf, Hamburg, Germany
| | - Bernhard Ludvik
- Landstrasse Clinic and Karl Landsteiner Institute for Obesity and Metabolic Disorders, Vienna, Austria
| | | | | | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- Walther-Straub Institute of Pharmacology and Toxicology, Ludwig-Maximilians-Universität München (LMU), Munich, Germany
| | - Oliver Schnell
- Forschergruppe Diabetes e.V. at the Helmholtz Center Munich, Munich, Germany
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11
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Alade AA, Ahmed SA, Mujwar S, Kikiowo B, Akinnusi PA, Olubode SO, Olufemi OM, Ohilebo AA. Identification of levomenthol derivatives as potential dipeptidyl peptidase-4 inhibitors: a comparative study with gliptins. J Biomol Struct Dyn 2024; 42:4029-4047. [PMID: 37261796 DOI: 10.1080/07391102.2023.2217927] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Accepted: 05/20/2023] [Indexed: 06/02/2023]
Abstract
Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Adebowale A Alade
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | - Samad A Ahmed
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | - Somdutt Mujwar
- Chitkara College of Pharmacy, Chitkara University, Punjab, Rajpura, India
| | | | | | - Samuel O Olubode
- Department of Biochemistry, Adekunle Ajasin University, Ondo, Nigeria
| | | | - Abass A Ohilebo
- Department of Biochemistry, Faculty of Life Sciences, Ambrose Ali University Ekpoma, Edo, Nigeria
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12
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Pan Y, Bu T, Deng X, Jia J, Yuan G. Gut microbiota and type 2 diabetes mellitus: a focus on the gut-brain axis. Endocrine 2024; 84:1-15. [PMID: 38227168 DOI: 10.1007/s12020-023-03640-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 11/30/2023] [Indexed: 01/17/2024]
Abstract
Type 2 diabetes mellitus (T2DM) has become one of the most serious public healthcare challenges, contributing to increased mortality and disability. In the past decades, significant progress has been made in understanding the pathogenesis of T2DM. Mounting evidence suggested that gut microbiota (GM) plays a significant role in the development of T2DM. Communication between the GM and the brain is a complex bidirectional connection, known as the "gut-brain axis," via the nervous, neuroendocrine, and immune systems. Gut-brain axis has an essential impact on various physiological processes, including glucose metabolism, food intake, gut motility, etc. In this review, we provide an outline of the gut-brain axis. We also highlight how the dysbiosis of the gut-brain axis affects glucose homeostasis and even results in T2DM.
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Affiliation(s)
- Yi Pan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Institute of Endocrine and Metabolic Diseases, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Tong Bu
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Institute of Endocrine and Metabolic Diseases, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Xia Deng
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Institute of Endocrine and Metabolic Diseases, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Jue Jia
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Institute of Endocrine and Metabolic Diseases, Jiangsu University, Zhenjiang, Jiangsu, China
| | - Guoyue Yuan
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Jiangsu University, Institute of Endocrine and Metabolic Diseases, Jiangsu University, Zhenjiang, Jiangsu, China.
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13
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Sangsuriyothai P, Watari I, Serirukchutarungsee S, Satrawaha S, Podyma-Inoue KA, Ono T. Expression of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in the rat submandibular gland is influenced by pre- and post-natal high-fat diet exposure. Front Physiol 2024; 15:1357730. [PMID: 38595641 PMCID: PMC11002158 DOI: 10.3389/fphys.2024.1357730] [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: 12/18/2023] [Accepted: 02/20/2024] [Indexed: 04/11/2024] Open
Abstract
Background: Incretins, i.e., glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) promote insulin secretion to reduce postprandial blood sugar. Previous studies found incretins in the salivary glands. However, the role of GLP-1 and GIP in the submandibular gland (SMG) is unclear. This study investigates the effects of a high-fat diet (HFD) on the expression of GLP-1 and GIP throughout the development of rat SMG. Methods: Pregnant 11-week-old Wistar rats were divided into two groups: those fed on a standard diet (n = 5) and those fed on a HFD (n = 5). From day 7 of pregnancy and throughout the lactation period, all the rats were fed on either a chow diet or HFD. The newborns were divided into four subgroups (n = 6): standard diet males (SM), HFD males (HM), standard diet females (SF), and HFD females (HF). The SMGs of 3- and 10-week-old rats from each subgroup were collected under general anesthesia. Moreover, body weight, food intake, and fasting blood sugar were measured. The mRNA expression of GLP-1 and GIP was quantified, and the localization was observed using immunohistochemistry (p < 0.05). Results: GLP-1 mRNA expression was statistically significantly more upregulated in HM than in HF at 3 weeks. Moreover, GLP-1 mRNA expression was significantly higher in HM than in both SM and HF at 10 weeks. Although a decreasing trend was observed in GIP mRNA expression in both 3- and 10-week-old rats fed on a HFD, a significant difference between HM and SM only occurred at 3 weeks. Furthermore, the GIP mRNA expression of HM was lower than that of HF at 10 weeks. Immunohistochemical staining revealed GLP-1 and GIP expression mainly in the SMG duct system. Moreover, vacuolated cytoplasm in the duct was observed in rats fed on a HFD. Conclusion: Exposure to HFD during pre- and post-natal periods increased GLP-1 mRNA expression in the SMGs of male rats. However, GIP expression decreased following the HFD in male newborns. Furthermore, a decreasing trend of GIP mRNA expression was observed in male newborns after HFD feeding. Sex influenced incretin hormones secretion and obesity-related conditions. HFD during pre- and post-natal periods reprograms the epigenome, contributing to subsequent disease development.
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Affiliation(s)
- Pornchanok Sangsuriyothai
- Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Orthodontics, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Ippei Watari
- Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Saranya Serirukchutarungsee
- Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
- Department of Pedodontics and Preventive Dentistry, Faculty of Dentistry, Srinakharinwirot University, Bangkok, Thailand
| | - Sirichom Satrawaha
- Department of Orthodontics, Faculty of Dentistry, Chulalongkorn University, Bangkok, Thailand
| | - Katarzyna Anna Podyma-Inoue
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Takashi Ono
- Department of Orthodontic Science, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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14
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Fernandes MF, Aristizabal-Henao JJ, Marvyn PM, M'Hiri I, Wiens MA, Hoang M, Sebastian M, Nachbar R, St-Pierre P, Diaguarachchige De Silva K, Wood GA, Joseph JW, Doucette CA, Marette A, Stark KD, Duncan RE. Renal tubule-specific Atgl deletion links kidney lipid metabolism to glucagon-like peptide 1 and insulin secretion independent of renal inflammation or lipotoxicity. Mol Metab 2024; 81:101887. [PMID: 38280449 PMCID: PMC10850971 DOI: 10.1016/j.molmet.2024.101887] [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: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 01/29/2024] Open
Abstract
OBJECTIVE Lipotoxic injury from renal lipid accumulation in obesity and type 2 diabetes (T2D) is implicated in associated kidney damage. However, models examining effects of renal ectopic lipid accumulation independent of obesity or T2D are lacking. We generated renal tubule-specific adipose triglyceride lipase knockout (RT-SAKO) mice to determine if this targeted triacylglycerol (TAG) over-storage affects glycemic control and kidney health. METHODS Male and female RT-SAKO mice and their control littermates were tested for changes in glycemic control at 10-12 and 16-18 weeks of age. Markers of kidney health and blood lipid and hormone concentrations were analyzed. Kidney and blood lysophosphatidic acid (LPA) levels were measured, and a role for LPA in mediating impaired glycemic control was evaluated using the LPA receptor 1/3 inhibitor Ki-16425. RESULTS All groups remained insulin sensitive, but 16- to 18-week-old male RT-SAKO mice became glucose intolerant, without developing kidney inflammation or fibrosis. Rather, these mice displayed lower circulating insulin and glucagon-like peptide 1 (GLP-1) levels. Impaired first-phase glucose-stimulated insulin secretion was detected and restored by Exendin-4. Kidney and blood LPA levels were elevated in older male but not female RT-SAKO mice, associated with increased kidney diacylglycerol kinase epsilon. Inhibition of LPA-mediated signaling restored serum GLP-1 levels, first-phase insulin secretion, and glucose tolerance. CONCLUSIONS TAG over-storage alone is insufficient to cause renal tubule lipotoxicity. This work is the first to show that endogenously derived LPA modulates GLP-1 levels in vivo, demonstrating a new mechanism of kidney-gut-pancreas crosstalk to regulate insulin secretion and glucose homeostasis.
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Affiliation(s)
- Maria F Fernandes
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | | | - Phillip M Marvyn
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Iman M'Hiri
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Meghan A Wiens
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Monica Hoang
- School of Pharmacy, University of Waterloo, Ontario, Canada
| | - Manuel Sebastian
- Max Rady College of Medicine, University of Manitoba, Manitoba, Canada
| | - Renato Nachbar
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | - Philippe St-Pierre
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | | | - Geoffrey A Wood
- Ontario Veterinary College, University of Guelph, Ontario, Canada
| | - Jamie W Joseph
- School of Pharmacy, University of Waterloo, Ontario, Canada
| | | | - André Marette
- Québec Heart and Lung Institute, Department of Medicine, Laval University, Québec, Canada
| | - Ken D Stark
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada
| | - Robin E Duncan
- Department of Kinesiology and Health Sciences, University of Waterloo, Ontario, Canada.
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15
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Aravindhan V, Yuvaraj S. Immune-endocrine network in diabetes-tuberculosis nexus: does latent tuberculosis infection confer protection against meta-inflammation and insulin resistance? Front Endocrinol (Lausanne) 2024; 15:1303338. [PMID: 38327565 PMCID: PMC10848915 DOI: 10.3389/fendo.2024.1303338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/02/2024] [Indexed: 02/09/2024] Open
Abstract
Tuberculosis patients with diabetes, have higher sputum bacillary load, delayed sputum conversion, higher rates of drug resistance, higher lung cavitary involvement and extra-pulmonary TB infection, which is called as "Diabetes-Tuberculosis Nexus". However, recently we have shown a reciprocal relationship between latent tuberculosis infection and insulin resistance, which has not been reported before. In this review, we would first discuss about the immune-endocrine network, which operates during pre-diabetes and incipient diabetes and how it confers protection against LTBI. The ability of IR to augment anti-TB immunity and the immunomodulatory effect of LTBI to quench IR were discussed, under IR-LTB antagonism. The ability of diabetes to impair anti-TB immunity and ability of active TB to worsen glycemic control, were discussed under "Diabetes-Tuberculosis Synergy". The concept of "Fighter Genes" and how they confer protection against TB but susceptibility to IR was elaborated. Finally, we conclude with an evolutionary perspective about how IR and LTBI co-evolved in endemic zones, and have explained the molecular basis of "IR-LTB" Antagonism" and "DM-TB Synergy", from an evolutionary perspective.
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Affiliation(s)
- Vivekanandhan Aravindhan
- Department of Genetics, Dr Arcot Lakshmanasamy Mudaliyar Post Graduate Institute of Basic Medical Sciences (Dr ALM PG IBMS), University of Madras, Chennai, India
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16
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López-Ojeda W, Hurley RA. Glucagon-Like Peptide 1: An Introduction and Possible Implications for Neuropsychiatry. J Neuropsychiatry Clin Neurosci 2024; 36:A4-86. [PMID: 38616646 DOI: 10.1176/appi.neuropsych.20230226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/16/2024]
Affiliation(s)
- Wilfredo López-Ojeda
- Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center (MIRECC) and Research and Academic Affairs Service Line, W.G. Hefner Veterans Affairs Medical Center, Salisbury, N.C. (López-Ojeda, Hurley); Department of Psychiatry and Behavioral Medicine (López-Ojeda, Hurley) and Department of Radiology (Hurley), Wake Forest University School of Medicine, Winston-Salem, N.C.; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Hurley)
| | - Robin A Hurley
- Veterans Affairs Mid-Atlantic Mental Illness Research, Education and Clinical Center (MIRECC) and Research and Academic Affairs Service Line, W.G. Hefner Veterans Affairs Medical Center, Salisbury, N.C. (López-Ojeda, Hurley); Department of Psychiatry and Behavioral Medicine (López-Ojeda, Hurley) and Department of Radiology (Hurley), Wake Forest University School of Medicine, Winston-Salem, N.C.; Menninger Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston (Hurley)
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17
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Pocai A. G protein-coupled receptors and obesity. Front Endocrinol (Lausanne) 2023; 14:1301017. [PMID: 38161982 PMCID: PMC10757641 DOI: 10.3389/fendo.2023.1301017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024] Open
Abstract
G protein-coupled receptors (GPCRs) have emerged as important drug targets for various chronic diseases, including obesity and diabetes. Obesity is a complex chronic disease that requires long term management predisposing to type 2 diabetes, heart disease, and some cancers. The therapeutic landscape for GPCR as targets of anti-obesity medications has undergone significant changes with the approval of semaglutide, the first peptide glucagon like peptide 1 receptor agonist (GLP-1RA) achieving double digit weight loss (≥10%) and cardiovascular benefits. The enhanced weight loss, with the expected beneficial effect on obesity-related complications and reduction of major adverse cardiovascular events (MACE), has propelled the commercial opportunity for the obesity market leading to new players entering the space. Significant progress has been made on approaches targeting GPCRs such as single peptides that simultaneously activate GIP and/or GCGR in addition to GLP1, oral tablet formulation of GLP-1, small molecules nonpeptidic oral GLP1R and fixed-dose combination as well as add-on therapy for patients already treated with a GLP-1 agonist.
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Affiliation(s)
- Alessandro Pocai
- Cardiovascular and Metabolic Disease, Johnson & Johnson Innovative Medicine Research & Development, Spring House, PA, United States
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18
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Wang Q, Lin H, Shen C, Zhang M, Wang X, Yuan M, Yuan M, Jia S, Cao Z, Wu C, Chen B, Gao A, Bi Y, Ning G, Wang W, Wang J, Liu R. Gut microbiota regulates postprandial GLP-1 response via ileal bile acid-TGR5 signaling. Gut Microbes 2023; 15:2274124. [PMID: 37942583 PMCID: PMC10730136 DOI: 10.1080/19490976.2023.2274124] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 10/18/2023] [Indexed: 11/10/2023] Open
Abstract
The gut microbiota interacts with intestinal epithelial cells through microbial metabolites to regulate the release of gut hormones. We investigated whether the gut microbiota affects the postprandial glucagon-like peptide-1 (GLP-1) response using antibiotic-treated mice and germ-free mice. Gut microbiome depletion completely abolished postprandial GLP-1 response in the circulation and ileum in a lipid tolerance test. Microbiome depletion did not influence the GLP-1 secretory function of primary ileal cells in response to stimulators in vitro, but dramatically changed the postprandial dynamics of endogenous bile acids, particularly ω-muricholic acid (ωMCA) and hyocholic acid (HCA). The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) but not farnesoid X receptor (FXR), participated in the regulation of postprandial GLP-1 response in the circulation and ileum, and ωMCA or HCA stimulated GLP-1 secretion via TGR5. Finally, fecal microbiota transplantation or ωMCA and HCA supplementation restored postprandial GLP-1 response. In conclusion, gut microbiota is indispensable for maintaining the postprandial GLP-1 response specifically in the ileum, and bile acid (ωMCA and HCA)-TGR5 signaling is involved in this process. This study helps to understand the essential interplay between the gut microbiota and host in regulating postprandial GLP-1 response and opens the foundation for new therapeutic targets.
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Affiliation(s)
- Qiaoling Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Huibin Lin
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chongrong Shen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Minchun Zhang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xingyu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Miaomiao Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mingyang Yuan
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sheng Jia
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhiwen Cao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chao Wu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Banru Chen
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Aibo Gao
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yufang Bi
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Guang Ning
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Weiqing Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiqiu Wang
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ruixin Liu
- Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai Key Laboratory for Endocrine Tumor, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
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19
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Musazadeh V, Tandorost A, Zarezadeh M, Jafarzadeh J, Ghavami Z, Jamilian P, Ostadrahimi A. Can omega-3 fatty acids and vitamin E co-supplementation affect obesity indices? INT J VITAM NUTR RES 2023; 93:471-480. [PMID: 35796416 DOI: 10.1024/0300-9831/a000757] [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: 11/19/2022]
Abstract
Background: Studies have shown that vitamin E as an antioxidant protects omega-3 fatty acids (FAs) from oxidation. Several studies have evaluated the effect of omega-3 FAs and vitamin E co-supplementation on obesity indices; however, the results are inconsistent. The present systematic review and meta-analysis was conducted to address the role of omega-3 FAs plus vitamin E on obesity indices. Methods: Cochrane Library, PubMed, Scopus, Embase, and Web of Science databases were searched up to February 2022. Among all of the qualified studies, 10 articles were selected. The effect size was presented as weighted mean difference (WMD) and 95% confidence interval (CI). Fixed-effects model was employed to perform meta-analysis. Subgroup analysis and publication bias assessment were carried out. Results: Ten eligible randomized controlled trials comprising 558 participants were included. The average dose of omega-3 FAs and vitamin E co-supplementation in studies was 1000-4000 mg/day and 400 IU, respectively. Intervention duration varied from 6 to 16 weeks. There was no significant effect of omega-3 and vitamin E co-supplementation on body weight (BW) (WMD=0.14 kg; 95% CI: -0.13 to 0.42; p=0.297), and body mass index (BMI) (WMD=0.08, 95% CI: -0.01 to 0.16, p=0.073). However, subgroup analysis showed that it might increase BMI in women over 50 years and if the intervention lasted more than 8 weeks. Conclusion: There was no significant impact of combined omega-3 FAs and vitamin E supplementation on BW and BMI; however, it should be noted that the intervention has an increasing impact when supplementation duration was >8 weeks and in individuals with type 2 diabetes mellitus, >50 years old, and BMI>25 kg/m2.
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Affiliation(s)
- Vali Musazadeh
- Student Research Committee, Tabriz University of Medical Sciences, Iran
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Iran
| | | | - Meysam Zarezadeh
- Student Research Committee, Tabriz University of Medical Sciences, Iran
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Iran
| | - Jaber Jafarzadeh
- School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Iran
| | - Zoha Ghavami
- Student Research Committee, Tabriz University of Medical Sciences, Iran
| | | | - Alireza Ostadrahimi
- Nutrition Research Center, School of Nutrition and Food Sciences, Tabriz University of Medical Sciences, Iran
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Abstract
Obesity, which has currently reached pandemic dimensions, is usually accompanied by diabetes mellitus type 2 (T2DM). These two conditions share common pathophysiological mechanisms. Adipose tissue secretes cytokines which are involved in inflammation and various endocrine functions. As for T2DM, it is characterized also by inflammation, mitochondrial dysfunction, and hyperinsulinemia. These conditions occur also in other diseases related to obesity and T2DM, like cardiovascular disease (CVD) and nonalcoholic fatty liver disease (NAFLD). Thus, management of obesity-related complications with lifestyle modification, anti-obesity drugs, and bariatric surgery, all contribute to improvement in any of these conditions. This review provides an overview of the literature addressing the association between obesity and T2DM, briefly discussing the pathophysiological mechanisms linking these conditions and outlining the management approach at the overlap of obesity and T2DM.
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Affiliation(s)
- Chrysoula Boutari
- Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippokration General Hospital, Thessaloniki, Greece; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Antea DeMarsilis
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Christos S Mantzoros
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Boston VA Healthcare System, Boston, MA, USA.
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21
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Ko J, Fonseca VA, Wu H. Pax4 in Health and Diabetes. Int J Mol Sci 2023; 24:8283. [PMID: 37175989 PMCID: PMC10179455 DOI: 10.3390/ijms24098283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/01/2023] [Accepted: 05/04/2023] [Indexed: 05/15/2023] Open
Abstract
Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of β cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote β cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional β-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of β cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic β cells and its potential as a therapeutic target for diabetes.
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Affiliation(s)
| | | | - Hongju Wu
- Section of Endocrinology, Department of Medicine, Tulane University Health Science Center, New Orleans, LA 70112, USA; (J.K.); (V.A.F.)
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22
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Hassanzadeh-Rostami Z, Ghobadi S, Faghih S. Effects of whole grain intake on glucagon-like peptide 1 and glucose-dependent insulinotropic peptide: a systematic review and meta-analysis. Nutr Rev 2023; 81:384-396. [PMID: 35960172 DOI: 10.1093/nutrit/nuac056] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
CONTEXT Whole grain intake may control help glycemia and reduce food intake by affecting the secretion of glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). OBJECTIVE This systematic review and meta-analysis aimed to assess the postprandial and long-term effects of whole grains on GLP-1 and GIP levels. DATA SOURCES PubMed, Web of Science, and Scopus online databases were searched systematically to identify relevant randomized clinical trials (RCTs) published up to April 2021. STUDY SELECTION RCTs that evaluated the effects of whole grains, compared with refined grains, on the postprandial area under the curve (AUC) value, the postprandial serum concentration of incretins from 0 to 180 minutes, or the fasting level of incretins after at least 14 days of intervention were included. RESULTS Nineteen studies were included in the meta-analysis. The results showed that acute intake of whole grains could not significantly change the AUC value of GLP-1 or GIP. However, the AUC value of GIP was reduced more significantly in (1) unhealthy participants (standard mean difference [SMD] -1.08; 95%CI, -2.07 to -0.10; I2 = 75.9%) compared with healthy participants, and (2) those with a baseline fasting blood glucose of ≥99 mg/dL (SMD -0.71; 95%CI, -1.30 to -0.11; I2 = 74.4%) compared with those with a baseline value of < 99 mg/dL. On the other hand, the results of time-response evaluation during 0 to 180 minutes after the intake of test meals showed that serum concentrations of GIP decreased significantly from 0 to 30 minutes (coefficient = -44.72; P = 0.005), but increased from 60 to 180 minutes (coefficient = 27.03; P = 0.005). However, long-term studies found no significant effects of whole grains on fasting concentrations of GLP-1 or GIP. CONCLUSION Whole grain intake did not affect postprandial levels of GLP-1 but enhanced postprandial levels of GIP from 60 to 180 minutes. Further high-quality trials are required to assess the long-term effects of whole grain intake on serum levels of incretins. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration no. CRD42021256695.
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Affiliation(s)
- Zahra Hassanzadeh-Rostami
- are with the Department of Community Nutrition, Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Saeed Ghobadi
- is with the Non-Communicable Disease Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | - Shiva Faghih
- are with the Department of Community Nutrition, Nutrition Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Iran
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23
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De la Cruz-Concepción B, Flores-Cortez YA, Barragán-Bonilla MI, Mendoza-Bello JM, Espinoza-Rojo M. Insulin: A connection between pancreatic β cells and the hypothalamus. World J Diabetes 2023; 14:76-91. [PMID: 36926659 PMCID: PMC10011898 DOI: 10.4239/wjd.v14.i2.76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/13/2022] [Accepted: 01/17/2023] [Indexed: 02/14/2023] Open
Abstract
Insulin is a hormone secreted by pancreatic β cells. The concentration of glucose in circulation is proportional to the secretion of insulin by these cells. In target cells, insulin binds to its receptors and activates phosphatidylinositol-3-kinase/protein kinase B, inducing different mechanisms depending on the cell type. In the liver it activates the synthesis of glycogen, in adipose tissue and muscle it allows the capture of glucose, and in the hypothalamus, it regulates thermogenesis and appetite. Defects in insulin function [insulin resistance (IR)] are related to the development of neurodegenerative diseases in obese people. Furthermore, in obesity and diabetes, its role as an anorexigenic hormone in the hypothalamus is diminished during IR. Therefore, hyperphagia prevails, which aggravates hyper-glycemia and IR further, becoming a vicious circle in which the patient cannot regulate their need to eat. Uncontrolled calorie intake induces an increase in reactive oxygen species, overcoming cellular antioxidant defenses (oxidative stress). Reactive oxygen species activate stress-sensitive kinases, such as c-Jun N-terminal kinase and p38 mitogen-activated protein kinase, that induce phos-phorylation in serine residues in the insulin receptor, which blocks the insulin signaling pathway, continuing the mechanism of IR. The brain and pancreas are organs mainly affected by oxidative stress. The use of drugs that regulate food intake and improve glucose metabolism is the conventional therapy to improve the quality of life of these patients. Currently, the use of antioxidants that regulate oxidative stress has given good results because they reduce oxidative stress and inflammatory processes, and they also have fewer side effects than synthetic drugs.
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Affiliation(s)
- Brenda De la Cruz-Concepción
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Yaccil Adilene Flores-Cortez
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Martha Isela Barragán-Bonilla
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Juan Miguel Mendoza-Bello
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
| | - Monica Espinoza-Rojo
- Molecular and Genomic Biology Laboratory, Faculty of Chemical-Biological Sciences, Autonomous University of Guerrero, Chilpancingo 39070, Guerrero, Mexico
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24
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Concentration of Selected Adipokines and Factors Regulating Carbohydrate Metabolism in Patients with Head and Neck Cancer in Respect to Their Body Mass Index. Int J Mol Sci 2023; 24:ijms24043283. [PMID: 36834693 PMCID: PMC9959515 DOI: 10.3390/ijms24043283] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 01/29/2023] [Accepted: 02/04/2023] [Indexed: 02/10/2023] Open
Abstract
Head and neck cancers (HNCs) are a group of tumors not common in European populations. So far, not much is known about the role of obesity, adipokines, glucose metabolism, and inflammation in the pathogenesis of HNC. The aim of the study was to determine the concentrations of ghrelin, omentin-1, adipsin, adiponectin, leptin, resistin, visfatin, glucagon, insulin, C-peptide, glucagon-like peptide-1 (GLP-1), plasminogen activator inhibitor-1 (PAI-1), and gastric inhibitory peptide (GIP) in the blood serum of HNC patients depending on their body mass index (BMI). The study included 46 patients divided into two groups according to their BMI values: the normal BMI group (nBMI) included 23 patients with BMI < 25 kg/m2 and the increased BMI group (iBMI) included patients with BMI ≥ 25 kg/m2. A control group (CG) included 23 healthy people (BMI < 25 kg/m2). Statistically significant differences in the levels of adipsin, ghrelin, glucagon, PAI-1, and visfatin were shown between nBMI and CG. In the case of nBMI and iBMI, statistically significant differences were observed in the concentrations of adiponectin, C-peptide, ghrelin, GLP-1, insulin, leptin, omentin-1, PAI-1, resistin, and visfatin. The obtained results indicate a disruption of endocrine function of adipose tissue and impaired glucose metabolism in HNC. Obesity, which is not a typical risk factor for HNC, may aggravate the negative metabolic changes associated with this type of neoplasm. Ghrelin, visfatin, PAI-1, adipsin, and glucagon might be related to head and neck carcinogenesis. They seem to be promising directions for further research.
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25
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Odongo K, Hironao KY, Yamashita Y, Ashida H. Development of sandwich ELISAs for detecting glucagon-like peptide-1 secretion from intestinal L-cells and their application in STC-1 cells and mice. J Clin Biochem Nutr 2023; 72:28-38. [PMID: 36777078 PMCID: PMC9899920 DOI: 10.3164/jcbn.22-78] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 09/03/2022] [Indexed: 11/05/2022] Open
Abstract
Certain nutrients stimulate glucagon-like peptide-1 (GLP-1) secretion from the intestinal enteroendocrine L-cells, but due to rapid degradation by the DPP-4 enzyme, >90% is converted to inactive metabolite before reaching the target organs via circulation. Plants are a source of potent bioactive compounds that promote endogenous secretion of GLP-1 from L-cells. To search for the effective bioactive compound from a vast library of natural compounds, a reliable and low-cost assay is required considering the high cost of commercial assays. We developed a low-cost sandwich enzyme-linked immunosorbent assays (s-ELISAs) for detecting 'total', 'sensitive active', and 'wide-range active' GLP-1. The s-ELISAs exhibited high sensitivity with measurement ranges between 0.94~240, 0.98~62.5, and 4.8~4,480 pmol/L, respectively. High precision was observed; i.e., CVs within 5% and 20% for intra- and inter-assay variations, respectively, and excellent recovery of exogenous GLP-1 from assay buffer. The developed s-ELISAs had the same performance as the commercial kits and approximately 80% cheaper cost. For their application, cinnamtannin A2-induced GLP-1 secretion was confirmed in STC-1 cells consistent with our previous findings. The s-ELISAs were further validated by measuring plasma GLP-1 level in mice after oral administration of black soy bean seed coat extract containing cinnamtannin A2.
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Affiliation(s)
- Kevin Odongo
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Ken-yu Hironao
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Yoko Yamashita
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan
| | - Hitoshi Ashida
- Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, 1-1 Rokkodai-cho, Nada-ku, Kobe 657-8501, Japan,To whom correspondence should be addressed. E-mail:
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26
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Xie Y, Zhou Q, He Q, Wang X, Wang J. Opportunities and challenges of incretin-based hypoglycemic agents treating type 2 diabetes mellitus from the perspective of physiological disposition. Acta Pharm Sin B 2022. [DOI: 10.1016/j.apsb.2022.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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Pilszyk A, Niebrzydowska M, Pilszyk Z, Wierzchowska-Opoka M, Kimber-Trojnar Ż. Incretins as a Potential Treatment Option for Gestational Diabetes Mellitus. Int J Mol Sci 2022; 23:ijms231710101. [PMID: 36077491 PMCID: PMC9456218 DOI: 10.3390/ijms231710101] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2022] [Revised: 08/30/2022] [Accepted: 09/02/2022] [Indexed: 11/16/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is a metabolic disease affecting an increasing number of pregnant women around the world. It is not only associated with numerous perinatal complications but also has long-term consequences impacting maternal health and fetal development. To prevent them, it is important to keep glucose levels under control. As much as 15-30% of GDM patients will require treatment with insulin, metformin, or glyburide. With that in mind, it is crucial to keep searching for novel and improved pharmacotherapies. Nowadays, there are ongoing studies investigating the use of other groups of drugs that have proven successful in the treatment of T2DM. Glucagon-like peptide-1 (GLP-1) receptor agonist and dipeptidyl peptidase-4 (DPP-4) inhibitor are among the drugs targeting the incretin system and are currently receiving significant attention. The aim of our review is to demonstrate the potential of these medications in treating GDM and preventing its later complications. It seems that both groups may be successful in the GDM management used alone or as an addition to better-known drugs, including metformin and glyburide. However, more clinical trials are needed to confirm their importance in GDM treatment and to demonstrate effective therapeutic strategies.
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28
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Model JFA, Rocha DS, Fagundes ADC, Vinagre AS. Physiological and pharmacological actions of glucagon like peptide-1 (GLP-1) in domestic animals. Vet Anim Sci 2022; 16:100245. [PMID: 35372707 PMCID: PMC8966211 DOI: 10.1016/j.vas.2022.100245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/25/2022] [Accepted: 03/14/2022] [Indexed: 11/25/2022] Open
Abstract
GLP-1 improves peripheral glucose uptake in healthy dogs and cats. GLP-1 analogues administration in diabetic cats reduces exogenous insulin requirement. Dogs cardiomyocytes apoptosis is reduced by GLP-1-derived molecules action. Analogues of glucagon like peptide-1 (GLP-1) and other drugs that increase this peptide half-life are used worldwide in human medicine to treat type 2 diabetes mellitus (DM) and obesity. These molecules can increase insulin release and satiety, interesting effects that could also be useful in the treatment of domestic animals pathologies, however their use in veterinary medicine are still limited. Considering the increasing incidence of DM and obesity in cats and dogs, the aim of this review is to summarize the available information about the physiological and pharmacological actions of GLP-1 in domestic animals and discuss about its potential applications in veterinary medicine. In diabetic dogs, the use of drugs based on GLP-1 actions reduced blood glucose and increased glucose uptake, while in diabetic cats they reduced glycemic variability and exogenous insulin administration. Thus, available evidence indicates that GLP-1 based drugs could become alternatives to DM treatment in domestic animals. Nevertheless, current data do not provide enough elements to recommend these drugs widespread clinical use.
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29
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Eugenol alleviated nonalcoholic fatty liver disease in rat via a gut-brain-liver axis involving glucagon-like Peptide-1. Arch Biochem Biophys 2022; 725:109269. [PMID: 35508252 DOI: 10.1016/j.abb.2022.109269] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/27/2022] [Accepted: 04/28/2022] [Indexed: 12/16/2022]
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30
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L’intestin un organe endocrine : de la physiologie aux implications thérapeutiques en nutrition. NUTR CLIN METAB 2022. [DOI: 10.1016/j.nupar.2021.12.179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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31
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Fernandes MF, Tomczewski MV, Duncan RE. Glucagon-like Peptide-1 Secretion Is Inhibited by Lysophosphatidic Acid. Int J Mol Sci 2022; 23:ijms23084163. [PMID: 35456981 PMCID: PMC9025735 DOI: 10.3390/ijms23084163] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 04/07/2022] [Accepted: 04/08/2022] [Indexed: 12/27/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) potentiates glucose-stimulated insulin secretion (GSIS). While dozens of compounds stimulate GLP-1 secretion, few inhibit. Reduced GLP-1 secretion and impaired GSIS occur in chronic inflammation. Lysophosphatidic acids (LPAs) are bioactive phospholipids elevated in inflammation. The aim of this study was to test whether LPA inhibits GLP-1 secretion in vitro and in vivo. GLUTag L-cells were treated with various LPA species, with or without LPA receptor (LPAR) antagonists, and media GLP-1 levels, cellular cyclic AMP and calcium ion concentrations, and DPP4 activity levels were analyzed. Mice were injected with LPA, with or without LPAR antagonists, and serum GLP-1 and DPP4 activity were measured. GLUTag GLP-1 secretion was decreased ~70–90% by various LPAs. GLUTag expression of Lpar1, 2, and 3 was orders of magnitude higher than Lpar4, 5, and 6, implicating the former group in this effect. In agreement, inhibition of GLP-1 secretion was reversed by the LPAR1/3 antagonist Ki16425, the LPAR1 antagonists AM095 and AM966, or the LPAR2 antagonist LPA2-antagonist 1. We hypothesized involvement of Gαi-mediated LPAR activity, and found that intracellular cyclic AMP and calcium ion concentrations were decreased by LPA, but restored by Ki16425. Mouse LPA injection caused an ~50% fall in circulating GLP-1, although only LPAR1 or LPAR1/3 antagonists, but not LPAR2 antagonism, prevented this. GLUTag L-cell and mouse serum DPP4 activity was unchanged by LPA or LPAR antagonists. LPA therefore impairs GLP-1 secretion in vitro and in vivo through Gαi-coupled LPAR1/3 signaling, providing a new mechanism linking inflammation with impaired GSIS.
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Winquist RJ, Gribkoff VK. Cardiovascular effects of GLP-1 receptor agonism. ADVANCES IN PHARMACOLOGY (SAN DIEGO, CALIF.) 2022; 94:213-254. [PMID: 35659373 DOI: 10.1016/bs.apha.2022.02.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists are extensively used in type 2 diabetic patients for the effective control of hyperglycemia. It is now clear from outcomes trials that this class of drugs offers important additional benefits to these patients due to reducing the risk of developing major adverse cardiac events (MACE). This risk reduction is, in part, due to effective glycemic control in patients; however, the various outcomes trials, further validated by subsequent meta-analysis of the outcomes trials, suggest that the risk reduction in MACE is also dependent on glycemic-independent mechanisms operant in cardiovascular tissues. These glycemic-independent mechanisms are likely mediated by GLP-1 receptors found throughout the cardiovascular system and by the complex signaling cascades triggered by the binding of agonists to the G-protein coupled receptors. This heterogeneity of signaling pathways underlying different downstream effects of GLP-1 agonists, and the discovery of biased agonists favoring specific signaling pathways, may have import in the future treatment of MACE in these patients. We review the evidence supporting the glycemic-independent evidence for risk reduction of MACE by the GLP-1 receptor agonists and highlight the putative mechanisms underlying these benefits. We also comment on the different signaling pathways which appear important for mediating these effects.
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Affiliation(s)
| | - Valentin K Gribkoff
- Section on Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, United States; TheraStat LLC, Weston, MA, United States
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33
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Tacad DKM, Tovar AP, Richardson CE, Horn WF, Krishnan GP, Keim NL, Krishnan S. Satiety Associated with Calorie Restriction and Time-Restricted Feeding: Peripheral Hormones. Adv Nutr 2022; 13:792-820. [PMID: 35191467 PMCID: PMC9156388 DOI: 10.1093/advances/nmac014] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 12/08/2021] [Accepted: 02/11/2022] [Indexed: 12/14/2022] Open
Abstract
Calorie restriction (CR) is a common approach to inducing negative energy balance. Recently, time-restricted feeding (TRF), which involves consuming food within specific time windows during a 24-h day, has become popular owing to its relative ease of practice and potential to aid in achieving and maintaining a negative energy balance. TRF can be implemented intentionally with CR, or TRF might induce CR simply because of the time restriction. This review focuses on summarizing our current knowledge on how TRF and continuous CR affect gut peptides that influence satiety. Based on peer-reviewed studies, in response to CR there is an increase in the orexigenic hormone ghrelin and a reduction in fasting leptin and insulin. There is likely a reduction in glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK), albeit the evidence for this is weak. After TRF, unlike CR, fasting ghrelin decreased in some TRF studies, whereas it showed no change in several others. Further, a reduction in fasting leptin, insulin, and GLP-1 has been observed. In conclusion, when other determinants of food intake are held equal, the peripheral satiety systems appear to be somewhat similarly affected by CR and TRF with regard to leptin, insulin, and GLP-1. But unlike CR, TRF did not appear to robustly increase ghrelin, suggesting different influences on appetite with a potential decrease of hunger after TRF when compared with CR. However, there are several established and novel gut peptides that have not been measured within the context of CR and TRF, and studies that have evaluated effects of TRF are often short-term, with nonuniform study designs and highly varying temporal eating patterns. More evidence and studies addressing these aspects are needed to draw definitive conclusions.
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Affiliation(s)
- Debra K M Tacad
- Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA,Department of Nutrition, University of California Davis, Davis, CA, USA
| | - Ashley P Tovar
- Department of Nutrition, University of California Davis, Davis, CA, USA
| | | | - William F Horn
- Obesity and Metabolism Research Unit, USDA-Agricultural Research Service Western Human Nutrition Research Center, Davis, CA, USA
| | - Giri P Krishnan
- Department of Medicine, School of Medicine, University of California San Diego, San Diego, CA, USA
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Rufini A, Malisan F, Condò I, Testi R. Drug Repositioning in Friedreich Ataxia. Front Neurosci 2022; 16:814445. [PMID: 35221903 PMCID: PMC8863941 DOI: 10.3389/fnins.2022.814445] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Accepted: 01/07/2022] [Indexed: 12/14/2022] Open
Abstract
Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.
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Affiliation(s)
- Alessandra Rufini
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
- Saint Camillus International University of Health and Medical Sciences, Rome, Italy
- *Correspondence: Alessandra Rufini,
| | - Florence Malisan
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Ivano Condò
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
| | - Roberto Testi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Rome, Italy
- Fratagene Therapeutics, Rome, Italy
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Liu QR, Aseer KR, Yao Q, Zhong X, Ghosh P, O’Connell JF, Egan JM. Anti-Inflammatory and Pro-Autophagy Effects of the Cannabinoid Receptor CB2R: Possibility of Modulation in Type 1 Diabetes. Front Pharmacol 2022; 12:809965. [PMID: 35115945 PMCID: PMC8804091 DOI: 10.3389/fphar.2021.809965] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 12/21/2021] [Indexed: 11/13/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from loss of insulin-secreting β-cells in islets of Langerhans. The loss of β-cells is initiated when self-tolerance to β-cell-derived contents breaks down, which leads to T cell-mediated β-cell damage and, ultimately, β-cell apoptosis. Many investigations have demonstrated the positive effects of antagonizing cannabinoid receptor 1 (CB1R) in metabolic diseases such as fatty liver disease, obesity, and diabetes mellitus, but the role of cannabinoid receptor 2 (CB2R) in such diseases is relatively unknown. Activation of CB2R is known for its immunosuppressive roles in multiple sclerosis, rheumatoid arthritis, Crohn’s, celiac, and lupus diseases, and since autoimmune diseases can share common environmental and genetic factors, we propose CB2R specific agonists may also serve as disease modifiers in diabetes mellitus. The CNR2 gene, which encodes CB2R protein, is the result of a gene duplication of CNR1, which encodes CB1R protein. This ortholog evolved rapidly after transitioning from invertebrates to vertebrate hundreds of million years ago. Human specific CNR2 isoforms are induced by inflammation in pancreatic islets, and a CNR2 nonsynonymous SNP (Q63R) is associated with autoimmune diseases. We collected evidence from the literature and from our own studies demonstrating that CB2R is involved in regulating the inflammasome and especially release of the cytokine interleukin 1B (IL-1β). Furthermore, CB2R activation controls intracellular autophagy and may regulate secretion of extracellular vesicles from adipocytes that participate in recycling of lipid droplets, dysregulation of which induces chronic inflammation and obesity. CB2R activation may play a similar role in islets of Langerhans. Here, we will discuss future strategies to unravel what roles, if any, CB2R modifiers potentially play in T1DM.
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Affiliation(s)
- Qing-Rong Liu
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
- *Correspondence: Qing-Rong Liu, ; Josephine M. Egan,
| | - Kanikkai Raja Aseer
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Qin Yao
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Xiaoming Zhong
- Ben May Department for Cancer Research, The University of Chicago, Chicago, IL, United States
| | - Paritosh Ghosh
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Jennifer F. O’Connell
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
| | - Josephine M. Egan
- Laboratory of Clinical Investigation, National Institute on Aging, NIH, Baltimore, MD, United States
- *Correspondence: Qing-Rong Liu, ; Josephine M. Egan,
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Laurindo LF, Barbalho SM, Guiguer EL, da Silva Soares de Souza M, de Souza GA, Fidalgo TM, Araújo AC, de Souza Gonzaga HF, de Bortoli Teixeira D, de Oliveira Silva Ullmann T, Sloan KP, Sloan LA. GLP-1a: Going beyond Traditional Use. Int J Mol Sci 2022; 23:739. [PMID: 35054924 PMCID: PMC8775408 DOI: 10.3390/ijms23020739] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 12/28/2021] [Accepted: 12/30/2021] [Indexed: 02/07/2023] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a human incretin hormone derived from the proglucagon molecule. GLP-1 receptor agonists are frequently used to treat type 2 diabetes mellitus and obesity. However, the hormone affects the liver, pancreas, brain, fat cells, heart, and gastrointestinal tract. The objective of this study was to perform a systematic review on the use of GLP-1 other than in treating diabetes. PubMed, Cochrane, and Embase were searched, and the PRISMA guidelines were followed. Nineteen clinical studies were selected. The results showed that GLP-1 agonists can benefit defined off-medication motor scores in Parkinson's Disease and improve emotional well-being. In Alzheimer's disease, GLP-1 analogs can improve the brain's glucose metabolism by improving glucose transport across the blood-brain barrier. In depression, the analogs can improve quality of life and depression scales. GLP-1 analogs can also have a role in treating chemical dependency, inhibiting dopaminergic release in the brain's reward centers, decreasing withdrawal effects and relapses. These medications can also improve lipotoxicity by reducing visceral adiposity and decreasing liver fat deposition, reducing insulin resistance and the development of non-alcoholic fatty liver diseases. The adverse effects are primarily gastrointestinal. Therefore, GLP-1 analogs can benefit other conditions besides traditional diabetes and obesity uses.
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Affiliation(s)
- Lucas Fornari Laurindo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Sandra Maria Barbalho
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Elen Landgraf Guiguer
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
- Department of Biochemistry and Nutrition, School of Food and Technology of Marilia (FATEC), Marília 17500-000, SP, Brazil
| | - Maricelma da Silva Soares de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Gabriela Achete de Souza
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Thiago Marques Fidalgo
- Department of Psychiatry, Federal University of São Paulo, R. Sena Madureira 04021-001, SP, Brazil;
| | - Adriano Cressoni Araújo
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Heron F. de Souza Gonzaga
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
- Postgraduate Program in Structural and Functional Interactions in Rehabilitation, University of Marília, Marília 17525-902, SP, Brazil
| | - Daniel de Bortoli Teixeira
- Postgraduate Program in Animal Health, Production and Environment, University of Marilia, Marília 17525-902, SP, Brazil;
| | - Thais de Oliveira Silva Ullmann
- Department of Biochemistry and Pharmacology, School of Medicine, University of Marília, Avenida Higino Muzzi Filho, Marília 17525-902, SP, Brazil; (L.F.L.); (E.L.G.); (M.d.S.S.d.S.); (G.A.d.S.); (A.C.A.); (H.F.d.S.G.); (T.d.O.S.U.)
| | - Katia Portero Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
| | - Lance Alan Sloan
- Texas Institute for Kidney and Endocrine Disorders, Lufkin, TX 75904, USA; (K.P.S.); (L.A.S.)
- Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555, USA
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Colca JR, Scherer PE. The metabolic syndrome, thiazolidinediones, and implications for intersection of chronic and inflammatory disease. Mol Metab 2022; 55:101409. [PMID: 34863942 PMCID: PMC8688722 DOI: 10.1016/j.molmet.2021.101409] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 11/24/2021] [Accepted: 11/27/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Chronic disease appears connected to obesity. However, evidence suggests that chronic metabolic diseases are more specifically related to adipose dysfunction rather than to body weight itself. SCOPE OF REVIEW Further study of the first generation "insulin sensitizer" pioglitazone and molecules based on its structure suggests that is possible to decouple body weight from the metabolic dysfunction that drives adverse outcomes. The growing understanding of the mechanism of action of these agents together with advances in the pathophysiology of chronic metabolic disease offers a new approach to treat chronic conditions, such as type 2 diabetes, fatty liver disease, and their common organ and vascular sequelae. MAJOR CONCLUSIONS We hypothesize that treating adipocyte dysfunction with new insulin sensitizers might significantly impact the interface of infectious disease and chronic metabolic disease.
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Affiliation(s)
- Jerry R Colca
- Department of Biomedical Sciences, Western Michigan University School of Medicine, Kalamazoo, MI 49008, USA; Cirius Therapeutics, Kalamazoo, MI 49007, USA
| | - Philipp E Scherer
- Touchstone Diabetes Center, Department of Internal Medicine, USA; Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
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Rosenberg J, Jacob J, Desai P, Park J, Donovan L, Kim JY. Incretin Hormones: Pathophysiological Risk Factors and Potential Targets for Type 2 Diabetes. J Obes Metab Syndr 2021; 30:233-247. [PMID: 34521773 PMCID: PMC8526293 DOI: 10.7570/jomes21053] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/11/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023] Open
Abstract
Type 2 diabetes (T2D) is a multifaceted metabolic disorder associated with distinctive pathophysiological disturbances. One of the pathophysiological risk factors observed in T2D is dysregulation of the incretin hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Both hormones stimulate insulin secretion by acting postprandially on pancreatic β-cell receptors. Oral glucose administration stimulates increased insulin secretion in comparison with isoglycemic intravenous glucose administration, a phenomenon known as the incretin effect. While the evidence for incretin defects in individuals with T2D is growing, the etiology behind this attenuated incretin effect in T2D is not clearly understood. Given their central role in T2D pathophysiology, incretins are promising targets for T2D therapeutics. The present review synthesizes the recent attempts to explain the biological importance of incretin hormones and explore potential pharmacological approaches that target the incretins.
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Affiliation(s)
- Jared Rosenberg
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jordan Jacob
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Priya Desai
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Jeremy Park
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Lorin Donovan
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
| | - Joon Young Kim
- Department of Exercise Science, David B. Falk College of Sport and Human Dynamics, Syracuse University, Syracuse, NY, USA
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Zhang D, Wen Z, Jiang T, Sun Y. The incessant increase curve during oral glucose tolerance tests in Chinese adults with type 2 diabetes and its association with gut hormone levels. Peptides 2021; 143:170595. [PMID: 34116121 DOI: 10.1016/j.peptides.2021.170595] [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: 03/14/2021] [Revised: 05/28/2021] [Accepted: 06/03/2021] [Indexed: 11/20/2022]
Abstract
Glucose curve shapes during oral glucose tolerance tests (OGTTs) are mainly classified as incessant increase, monophasic and biphasic. Youth with an incessant increase curve have worse β-cell function. The aim of this paper was to investigate the incessant increase curve in Chinese adults with type 2 diabetes (T2DM), and its association with β-cell function and gut hormone levels. Eighty-nine Chinese patients (59 males and 30 females) were included in this study with a mean age of 50.56 ± 16.00 years. They were all recently diagnosed with T2DM and underwent 180-min OGTTs. Data on demographics, β-cell function, and insulin sensitivity were also collected. Gut hormones, including glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and ghrelin, were also detected during the OGTT. A total of 39.3 % of subjects had an incessant increase in the glucose response curve, while 59.6 % had a monophasic curve. Because only one curve was classified as biphasic, patients with a biphasic curve were omitted from further research. Lower plasma C-peptide, HOMA2-β, area under the curve (AUC) of C-peptide, and ratio of AUC of insulin to AUC of glucose were found in patients with incessant increase curves compared to those with monophasic curves (P < 0.05). Higher glycated hemoglobin (HbA1c) was found in subjects with an incessant increase curve (P < 0.05). Importantly, fasting plasma ghrelin was lower and incremental ghrelin at 120 min was higher in the incessant increase group (P < 0.05), irrespective of age, sex, body mass index (BMI), fasting glucose, and fasting insulin. Time to peak is also a parameter of the OGTT curve shape. In the late-peak group, GLP-1 at 120 min and the AUC of GLP-1 were elevated compared with those in the early-peak group (P < 0.05). In Chinese adults with T2DM, the incessant increase in OGTT shape indicated impaired insulin secretion. Lower fasting ghrelin and absence of ghrelin drops after glucose load may be associated with the incessant increase OGTT shape. In addition, compensatory elevated GLP-1 dose not prevent peak delay in the OGTT curve. Gut hormones may have an effect on OGTT shapes in T2DM adults.
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Affiliation(s)
- Dongxue Zhang
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Zhen Wen
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
| | - Tao Jiang
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.
| | - Yuyan Sun
- Department of Endocrinology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China
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Yoshinari Y, Kosakamoto H, Kamiyama T, Hoshino R, Matsuoka R, Kondo S, Tanimoto H, Nakamura A, Obata F, Niwa R. The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster. Nat Commun 2021; 12:4818. [PMID: 34376687 PMCID: PMC8355161 DOI: 10.1038/s41467-021-25146-w] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 07/24/2021] [Indexed: 02/08/2023] Open
Abstract
The enteroendocrine cell (EEC)-derived incretins play a pivotal role in regulating the secretion of glucagon and insulins in mammals. Although glucagon-like and insulin-like hormones have been found across animal phyla, incretin-like EEC-derived hormones have not yet been characterised in invertebrates. Here, we show that the midgut-derived hormone, neuropeptide F (NPF), acts as the sugar-responsive, incretin-like hormone in the fruit fly, Drosophila melanogaster. Secreted NPF is received by NPF receptor in the corpora cardiaca and in insulin-producing cells. NPF-NPFR signalling resulted in the suppression of the glucagon-like hormone production and the enhancement of the insulin-like peptide secretion, eventually promoting lipid anabolism. Similar to the loss of incretin function in mammals, loss of midgut NPF led to significant metabolic dysfunction, accompanied by lipodystrophy, hyperphagia, and hypoglycaemia. These results suggest that enteroendocrine hormones regulate sugar-dependent metabolism through glucagon-like and insulin-like hormones not only in mammals but also in insects.
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Affiliation(s)
- Yuto Yoshinari
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Hina Kosakamoto
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
| | - Takumi Kamiyama
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Ryo Hoshino
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Rena Matsuoka
- Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Shu Kondo
- Genetic Strains Research Center, National Institute of Genetics, Mishima, Shizuoka, Japan
| | - Hiromu Tanimoto
- Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi, Japan
| | - Akira Nakamura
- Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan
- Laboratory of Germline Development, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
| | - Fumiaki Obata
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo, Japan
- Laboratory for Nutritional Biology, RIKEN Center for Biosystems Dynamics Research, Kobe, Hyogo, Japan
- Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Kyoto, Japan
- AMED-PRIME, Japan Agency for Medical Research and Development Chiyoda-ku, Tokyo, Japan
| | - Ryusuke Niwa
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan.
- AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo, Japan.
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Lee SE, Lee NY, Kim SH, Kim KA, Kim YS. Effect of liraglutide 3.0mg treatment on weight reduction in obese antipsychotic-treated patients. Psychiatry Res 2021; 299:113830. [PMID: 33677189 DOI: 10.1016/j.psychres.2021.113830] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/21/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND Patients treated with antipsychotics experience significant weight gain and accompanying metabolic disorders. We investigated the efficacy of liraglutide 3.0 mg in reducing the weight of antipsychotic-treated obese patients. METHOD We retrospectively reviewed 16 obese patients with schizophrenia or bipolar disorder who were treated with 3.0 mg of liraglutide each. During the 16 weeks of treatment, changes in body weight and Clinical Global Impression-Severity scale (CGI-S) were analyzed. The participants were divided into responders (lost at least 5% of body weight) and non-responders for analysis. RESULTS Treatment with liraglutide 3.0 mg significantly decreased body weight (estimated marginal mean, 93.2 kg at baseline and 88.9 kg at 16 weeks; p < 0.001) as well as waist circumference, BMI and plasma glucose levels. Six of 16 patients (37.5%) complained of a modest degree of nausea. Six of the 12 subjects (50%) completing 16 weeks of treatment were responders. There were no significant differences in baseline characteristics between responders and non-responders. There was no worsening of CGI-S scores. CONCLUSION Liraglutide 3.0 mg significantly decreased body weight in obese patients treated with antipsychotics without altering the status of psychiatric diseases. A randomized controlled study is required to corroborate the results of this study.
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Affiliation(s)
- Seung Eun Lee
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi-do, South Korea
| | - Nam Young Lee
- Department of Neuropsychiatry, Dongguk University Ilsan Hospital, Goyang, Gyeonggi-do, South Korea
| | - Se Hyun Kim
- Department of Psychiatry, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea
| | - Kyoung-Ah Kim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Gyeonggi-do, South Korea
| | - Yong Sik Kim
- Department of Psychiatry, Nowon Eulji Hospital, Eulji University College of Medicine, Seoul, South Korea; Institute of Clinical Psychopharmacology, Dongguk University College of Medicine, Goyang, Gyeonggi-do, South Korea.
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Frohlich J, Chaldakov GN, Vinciguerra M. Cardio- and Neurometabolic Adipobiology: Consequences and Implications for Therapy. Int J Mol Sci 2021; 22:ijms22084137. [PMID: 33923652 PMCID: PMC8072708 DOI: 10.3390/ijms22084137] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 04/08/2021] [Accepted: 04/13/2021] [Indexed: 12/12/2022] Open
Abstract
Studies over the past 30 years have revealed that adipose tissue is the major endocrine and paracrine organ of the human body. Arguably, adiopobiology has taken its reasonable place in studying obesity and related cardiometabolic diseases (CMDs), including Alzheimer's disease (AD), which is viewed herein as a neurometabolic disorder. The pathogenesis and therapy of these diseases are multiplex at basic, clinical and translational levels. Our present goal is to describe new developments in cardiometabolic and neurometabolic adipobiology. Accordingly, we focus on adipose- and/or skeletal muscle-derived signaling proteins (adipsin, adiponectin, nerve growth factor, brain-derived neuroptrophic factor, neurotrophin-3, irisin, sirtuins, Klotho, neprilysin, follistatin-like protein-1, meteorin-like (metrnl), as well as growth differentiation factor 11) as examples of metabotrophic factors (MTFs) implicated in the pathogenesis and therapy of obesity and related CMDs. We argue that these pathologies are MTF-deficient diseases. In 1993 the "vascular hypothesis of AD" was published and in the present review we propose the "vasculometabolic hypothesis of AD." We discuss how MTFs could bridge CMDs and neurodegenerative diseases, such as AD. Greater insights on how to manage the MTF network would provide benefits to the quality of human life.
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Affiliation(s)
- Jan Frohlich
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic;
| | - George N. Chaldakov
- Department of Anatomy and Cell Biology and Research Institute of the Medical University, 9002 Varna, Bulgaria;
- Department of Translational Stem Cell Biology, Research Institute of the Medical University, 9002 Varna, Bulgaria
| | - Manlio Vinciguerra
- International Clinical Research Center, St. Anne’s University Hospital, 656 91 Brno, Czech Republic;
- Department of Translational Stem Cell Biology, Research Institute of the Medical University, 9002 Varna, Bulgaria
- Correspondence: or
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Model JFA, Lima MV, Ohlweiler R, Lopes Vogt É, Rocha DS, Souza SKD, Türck P, Araújo ASDR, Vinagre AS. Liraglutide improves lipid and carbohydrate metabolism of ovariectomized rats. Mol Cell Endocrinol 2021; 524:111158. [PMID: 33444670 DOI: 10.1016/j.mce.2021.111158] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 12/30/2020] [Accepted: 12/31/2020] [Indexed: 12/16/2022]
Abstract
Considering that post-menopausal women and ovariectomized rodents develop obesity associated with increased visceral fat, this study was developed to investigate if liraglutide, a glucagon-like peptide 1 (GLP1) analogue, could improve the metabolism of estrogen (E2) deficient females. Wistar rats were ovariectomized (OVX), and subdivided in four groups: sham saline, sham liraglutide, OVX saline, and OVX liraglutide. After sixty days, metabolic parameters of blood, heart, liver, brown (BAT) and white adipose tissue (WAT) visceral depots, and, heart oxidative homeostasis, were evaluated. Castration increased the animals' body weight, the relative weight of the WAT depots, hepatic triglycerides and cardiac glycogen content. Liraglutide treatment reversed these effects, decreased WAT depots weight and increased glucose oxidation and lipogenesis in BAT and WAT. In addition, liraglutide enhanced adrenalin (A) lipolytic effect. These results indicate that liraglutide may be a promising treatment to restore lipid homeostasis and prevent weight gain associated with E2 deficiency.
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Affiliation(s)
| | - Matheus Vieira Lima
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Renata Ohlweiler
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Éverton Lopes Vogt
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Débora Santos Rocha
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Samir Khal de Souza
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | - Patrick Türck
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil
| | | | - Anapaula Sommer Vinagre
- Department of Physiology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, RS, Brazil.
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Cremonini E, Daveri E, Mastaloudis A, Oteiza PI. (-)-Epicatechin and Anthocyanins Modulate GLP-1 Metabolism: Evidence from C57BL/6J Mice and GLUTag Cells. J Nutr 2021; 151:1497-1506. [PMID: 33693759 PMCID: PMC8659349 DOI: 10.1093/jn/nxab029] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/18/2020] [Accepted: 01/26/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Generated in intestinal L cells through cleavage of proglucagon (Gcg), glucagon-like peptide 1 (GLP-1) is secreted and rapidly inactivated by dipeptidyl peptidase IV (DPP-IV). GLP-1 regulates insulin secretion and overall glucose homeostasis. The capacity of dietary bioactives to increase GLP-1 circulating levels, and therefore increase insulin secretion and glucose metabolism, has gained significant interest of late. OBJECTIVES We evaluated the effects of (-)-epicatechin (EC) and different anthocyanins (ACs) and AC metabolites on GLP-1 metabolism in mice and on GLUTag cells. METHODS We fed 6-week-old C57BL/6J male mice a control diet or a control diet supplemented with either 40 mg AC or 20 mg EC/kg body weight for 14 weeks (AC) or 15 weeks (EC). Intestinal mRNA levels of Gcg and Dpp-iv were measured. In vitro, GLUTag cells were incubated in the presence or absence of different ACs, the AC metabolite protocatechuic acid (PCA), and EC. GLP-1 secretion and the main pathways involved in its release were assessed. RESULTS Long-term supplementation with EC or AC increased mouse GLP-1 plasma concentrations (55% and 98%, respectively; P < 0.05). In mice, 1) EC and AC increased Gcg mRNA levels in the ileum (91%) and colon (41%), respectively (P < 0.05); and 2) AC lowered ileum Dpp-iv mRNA levels (35%), while EC decreased plasma DPP-IV activity (15%; P < 0.05). In GLUTag cells, 1) cyanidin, delphinidin, PCA, and EC increased GLP-1 secretion (53%, 33%, 53%, and 68%, respectively; P < 0.05); and 2) cyanidin, delphinidin, EC, and PCA increased cyclin adenosine monophosphate levels (25-50%; P < 0.05) and activated protein kinase A (PKA; 100%, 50%, 80%, and 86%, respectively; P < 0.05). CONCLUSIONS In mice, EC and ACs regulated different steps in GLP-1 regulation, leading to increased plasma GLP-1. Cyanidin, delphinidin, PCA, and EC promoted GLP-1 secretion from GLUTag cells by activating the PKA-dependent pathway. These findings support the beneficial actions of these flavonoids in sustaining intestinal and glucose homeostasis through the modulation of the GLP-1 metabolism.
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Affiliation(s)
- Eleonora Cremonini
- Department of Nutrition and of Environmental Toxicology, University of California, Davis, CA, USA
| | - Elena Daveri
- Department of Nutrition and of Environmental Toxicology, University of California, Davis, CA, USA
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Meister J, Wang L, Pydi SP, Wess J. Chemogenetic approaches to identify metabolically important GPCR signaling pathways: Therapeutic implications. J Neurochem 2021; 158:603-620. [PMID: 33540469 DOI: 10.1111/jnc.15314] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 01/21/2021] [Accepted: 01/29/2021] [Indexed: 12/16/2022]
Abstract
DREADDs (Designer Receptors Exclusively Activated by a Designer Drug) are designer G protein-coupled receptors (GPCRs) that are widely used in the neuroscience field to modulate neuronal activity. In this review, we will focus on DREADD studies carried out with genetically engineered mice aimed at elucidating signaling pathways important for maintaining proper glucose and energy homeostasis. The availability of muscarinic receptor-based DREADDs endowed with selectivity for one of the four major classes of heterotrimeric G proteins (Gs , Gi , Gq , and G12 ) has been instrumental in dissecting the physiological and pathophysiological roles of distinct G protein signaling pathways in metabolically important cell types. The novel insights gained from this work should inform the development of novel classes of drugs useful for the treatment of several metabolic disorders including type 2 diabetes and obesity.
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Affiliation(s)
- Jaroslawna Meister
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Lei Wang
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Sai P Pydi
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | - Jürgen Wess
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
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Resveratrol Affects Insulin Signaling in Type 2 Diabetic Goto-Kakizaki Rats. Int J Mol Sci 2021; 22:ijms22052469. [PMID: 33671110 PMCID: PMC7957525 DOI: 10.3390/ijms22052469] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/24/2021] [Accepted: 02/25/2021] [Indexed: 12/19/2022] Open
Abstract
Resveratrol is a biologically active diphenolic compound exerting multiple beneficial effects in the organism, including anti-diabetic properties. This action is, however, not fully elucidated. In the present study, we examined effects of resveratrol on some parameters related to insulin signaling, and also on diabetes-associated dysregulation in Goto-Kakizaki (GK) rats with congenital type 2 diabetes. Resveratrol was given at the dose of 20 mg/kg b.w. for 10 weeks. It was shown that the expression and phosphorylation levels of insulin receptor in the skeletal muscle of GK rats were significantly decreased, compared with control animals. However, these changes were totally prevented by resveratrol. Liver expression of the insulin receptor was also reduced, but in this case, resveratrol was ineffective. Resveratrol was also demonstrated to significantly influence parameters of insulin binding (dissociation constant and binding capacity) in the skeletal muscle and liver. Moreover, it was shown that the expression levels of proteins related to intracellular glucose transport (GLUT4 and TUG) in adipose tissue of GK rats were significantly decreased. However, treatment with resveratrol completely abolished these changes. Resveratrol was found to induce normalization of TUG expression in the skeletal muscle. Blood levels of insulin and GIP were elevated, whereas proinsulin and GLP-1 diminished in GK rats. However, concentrations of these hormones were not affected by resveratrol. These results indicate that resveratrol partially ameliorates diabetes-associated dysregulation in GK rats. The most relevant finding covers the normalization of the insulin receptor expression in the skeletal muscle and also GLUT4 and TUG in adipose tissue.
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Marrano N, Biondi G, Borrelli A, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. Irisin and Incretin Hormones: Similarities, Differences, and Implications in Type 2 Diabetes and Obesity. Biomolecules 2021; 11:286. [PMID: 33671882 PMCID: PMC7918991 DOI: 10.3390/biom11020286] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 02/09/2021] [Accepted: 02/12/2021] [Indexed: 12/11/2022] Open
Abstract
Incretins are gut hormones that potentiate glucose-stimulated insulin secretion (GSIS) after meals. Glucagon-like peptide-1 (GLP-1) is the most investigated incretin hormone, synthesized mainly by L cells in the lower gut tract. GLP-1 promotes β-cell function and survival and exerts beneficial effects in different organs and tissues. Irisin, a myokine released in response to a high-fat diet and exercise, enhances GSIS. Similar to GLP-1, irisin augments insulin biosynthesis and promotes accrual of β-cell functional mass. In addition, irisin and GLP-1 share comparable pleiotropic effects and activate similar intracellular pathways. The insulinotropic and extra-pancreatic effects of GLP-1 are reduced in type 2 diabetes (T2D) patients but preserved at pharmacological doses. GLP-1 receptor agonists (GLP-1RAs) are therefore among the most widely used antidiabetes drugs, also considered for their cardiovascular benefits and ability to promote weight loss. Irisin levels are lower in T2D patients, and in diabetic and/or obese animal models irisin administration improves glycemic control and promotes weight loss. Interestingly, recent evidence suggests that both GLP-1 and irisin are also synthesized within the pancreatic islets, in α- and β-cells, respectively. This review aims to describe the similarities between GLP-1 and irisin and to propose a new potential axis-involving the gut, muscle, and endocrine pancreas that controls energy homeostasis.
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Affiliation(s)
| | | | | | | | | | | | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, I-70124 Bari, Italy; (N.M.); (G.B.); (A.B.); (A.C.); (S.P.); (L.L.); (A.N.)
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Incretin Hormones in Obesity and Related Cardiometabolic Disorders: The Clinical Perspective. Nutrients 2021; 13:nu13020351. [PMID: 33503878 PMCID: PMC7910956 DOI: 10.3390/nu13020351] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
The prevalence of obesity continues to grow rapidly worldwide, posing many public health challenges of the 21st century. Obese subjects are at major risk for serious diet-related noncommunicable diseases, including type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Understanding the mechanisms underlying obesity pathogenesis is needed for the development of effective treatment strategies. Dysregulation of incretin secretion and actions has been observed in obesity and related metabolic disorders; therefore, incretin-based therapies have been developed to provide new therapeutic options. Incretin mimetics present glucose-lowering properties, together with a reduction of appetite and food intake, resulting in weight loss. In this review, we describe the physiology of two known incretins—glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), and their role in obesity and related cardiometabolic disorders. We also focus on the available and incoming incretin-based medications that can be used in the treatment of the above-mentioned conditions.
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Abstract
Obesity is an important public health issue that has been on the rise over the last decades. It calls for effective prevention and treatment. Bariatric surgery is the most effective medical therapy for weight loss in morbid obesity, but we are in need for less aggressive treatments. Glucagon-like-peptide-1 receptor agonists are a group of incretin-based drugs that have proven to be productive for obesity treatment. Through activation of the GLP-1 receptor they not only have an important role stimulating insulin secretion after meals, but with their extrapancreatic actions, both peripheral and central, they also help reduce body weight by promoting satiety and delaying gastric emptying. Liraglutide in a dose of 3 mg is currently the only drug of this group that is approved by the FDA to treat obesity, with weight losses up to 8.5 kg in relatively short periods of time. Here we review the data so far collected of GLP-1 use for obesity with and without diabetes, including the recent data of oral semaglutide.
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Affiliation(s)
- Alejandra Perez-Montes DE Oca
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital and Research Institute, Autonomous University of Barcelona, Badalona, Spain
| | - Silvia Pellitero
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital and Research Institute, Autonomous University of Barcelona, Badalona, Spain -
| | - Manel Puig-Domingo
- Department of Endocrinology and Nutrition, Germans Trias i Pujol University Hospital and Research Institute, Autonomous University of Barcelona, Badalona, Spain
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Song LL, Wang X, Yang ZJ, Kong XM, Chen XP, Zhang B, Yang WY. Factors associated with improvement in waist-to-height ratio among newly diagnosed type 2 diabetes patients treated with acarbose or metformin: A randomized clinical trial study. World J Diabetes 2020; 11:514-526. [PMID: 33269063 PMCID: PMC7672790 DOI: 10.4239/wjd.v11.i11.514] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 08/13/2020] [Accepted: 09/14/2020] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND The waist-to-height ratio (WHtR) is a promising anthropometric measure used to evaluate cardiovascular risk in diabetes and metabolic syndrome patients. The metformin and acarbose in Chinese as the initial hypoglycaemic treatment trial demonstrated that acarbose and metformin reduced the WHtR after 24 wk of treatment.
AIM To investigate the factors associated with a decrease in the WHtR in newly diagnosed Chinese type 2 diabetes patients receiving acarbose or metformin monotherapy.
METHODS At 24 wk, 343 patients in the acarbose treatment and 333 patients in the metformin treatment were included in this analysis. On the basis of the reduction in the WHtR, these participants were divided into the following two groups: Low ΔWHtR group and high ΔWHtR group. Metabolic and related parameters associated with a high ΔWHtR were investigated using univariate and multivariate logistic regression analyses.
RESULTS A significant decrease in the WHtR was observed in both treatment groups (acarbose: -0.015, 95% confidence interval [CI]: -0.018 to -0.012, P < 0.001; metformin: -0.013, 95%CI: -0.016 to -0.010, P < 0.001). In both the acarbose and metformin groups, the WHtR of the women was more likely to be reduced than that of the men. In the acarbose group, a lower baseline area under the curve of glucagon-like peptide 1 (AUCGLP-1) was associated with a high ΔWHtR (odds ratio [OR] = 0.796, P < 0.001), while a higher baseline AUCGLP-1 was associated with a high ΔWHtR in the patients treated with metformin (OR = 1.133, P = 0.025). Regarding the changes from baseline, an increase in AUCGLP-1 was associated with a high ΔWHtR in the acarbose (OR = 1.121, P = 0.016) but not metformin group. A higher reduction in high-density lipoprotein cholesterol/non-high-density lipoprotein cholesterol was also associated with a high ΔWHtR in the acarbose arm (OR = 20.735, P = 0.001). In the metformin arm, a higher reduction in fasting plasma glucose (OR = 0.843, P = 0.039) and total cholesterol was associated with a high ΔWHtR (OR = 0.743, P = 0.013).
CONCLUSION A lower glucagon-like peptide 1 level and higher increase in glucagon-like peptide 1 are associated with a high reduction in the WHtR in newly diagnosed Chinese diabetes patients receiving treatment with acarbose.
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Affiliation(s)
- Lu-Lu Song
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xin Wang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Zhao-Jun Yang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Mu Kong
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Xiao-Ping Chen
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Bo Zhang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
| | - Wen-Ying Yang
- Department of Endocrinology, China-Japan Friendship Hospital, Beijing 100029, China
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