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Papatheodorou K, Shubrook JH. Beta-cell preservation in T2DM using a pathophysiologic approach. Postgrad Med 2025; 137:235-242. [PMID: 40247637 DOI: 10.1080/00325481.2025.2494502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2024] [Revised: 04/11/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
Type 2 diabetes and obesity rates continue to rise. Type 2 diabetes affects 1-2 million new individuals annually. Despite a wide range of treatment options for type 2 diabetes, many people still fail to achieve therapeutic goals. Treating type 2 diabetes more proactively with a pathophysiologic approach can ensure higher rates of success and reduce complications. This article summarizes the progressive understanding of the pathophysiology of diabetes, draws a connection between illness and beta-cell health, and introduces the pathophysiologic approach to type 2 diabetes and its focus on beta-cell preservation. This article compiled clinical data, evidence-based medicine, and experimental results to create a comprehensive narrative review.
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Affiliation(s)
| | - Jay H Shubrook
- Department of Clinical Sciences and Community Health, Touro University, California, College of Osteopathic Medicine, Vallejo, CA, USA
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2
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Ling W, Wang YC, Huang Y, Ou YF, Jiang YC. Islet β-cell function preservation by different anti-diabetic treatments in Chinese elderly patients with type 2 diabetes mellitus. World J Diabetes 2025; 16:94976. [PMID: 39959281 PMCID: PMC11718476 DOI: 10.4239/wjd.v16.i2.94976] [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: 03/29/2024] [Revised: 09/07/2024] [Accepted: 12/03/2024] [Indexed: 12/30/2024] Open
Abstract
BACKGROUND The preservation of islet β-cell function in elderly patients with type 2 diabetes mellitus (T2DM) is a top priority for diabetic control. AIM To assess the preservation of islet β-cell function among elderly Chinese patients with T2DM after different anti-diabetic treatments. METHODS In this longitudinal observational study, elderly patients with T2DM treated with insulin, oral antidiabetic drugs or a combination of both were enrolled to disclose their islet β-cell function between baseline and follow-up. Islet β-cell function was determined by the plasma Homeostasis Model for β-cell function (HOMA-β), C-peptide and area under the curve (AUC) based on oral glucose tolerance test. Changes in β-cell function (decrement or increment from baseline) between different therapy groups were the outcomes. RESULTS In total, 745 elderly patients (≥ 60 years) with T2DM [insulin monotherapy, n = 105; oral anti-diabetic drugs (OAD) monotherapy, n = 321; insulin plus OAD, n = 319] had their baseline and follow-up β-cell function assessed during a median observation period of 4.5 years (range, 3.0-7.2 years). Overall, islet β-cell function (HOMA-β, fasting C-peptide, fasting insulin, AUCc-pep, AUCins, AUCc-pep/AUCglu, AUCins/AUCglu) consistently deteriorated over time regardless of the three different antidiabetic treatments. No statistical differences in decrement were observed among the three groups regarding the islet β-cell function indices. All three groups showed an increased ratio of delayed insulin secretion response after 4.5 years of observation. CONCLUSION In Chinese elderly patients with T2DM, islet β-cell function progressively declines regardless of insulin supplement or insulin plus OAD treatments.
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Affiliation(s)
- Wei Ling
- Department of Science Laboratory, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541002, Guangxi Zhuang Autonomous Region, China
| | - Yan-Chao Wang
- Center for Diabetic Systems Medicine, Guangxi Key Laboratory of Excellence, Guilin 541100, Guangxi Zhuang Autonomous Region, China
| | - Yi Huang
- Faculty of Basic Medicine, Guilin Medical University, Guilin 541100, Guangxi Zhuang Autonomous Region, China
| | - Yang-Fu Ou
- Department of Geriatrics, The Affiliated Hospital of Guilin Medical University, Guilin 541001, Guangxi Zhuang Autonomous Region, China
| | - Yan-Chun Jiang
- Department of Neurology, Nanxishan Hospital of Guangxi Zhuang Autonomous Region, Guilin 541002, Guangxi Zhuang Autonomous Region, China
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Ning X, Munir KM, Davis SN. Drugs stimulating insulin secretion in early clinical development for the treatment of type 1 diabetes: what's new? Expert Opin Investig Drugs 2024; 33:1199-1208. [PMID: 39645243 DOI: 10.1080/13543784.2024.2439501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 11/24/2024] [Accepted: 12/03/2024] [Indexed: 12/09/2024]
Abstract
INTRODUCTION Type 1 diabetes is a chronic autoimmune condition characterized by the selective destruction of insulin-producing beta cells in the pancreas. The etiology of T1D is multifactorial, with a combination of genetic susceptibility and environmental triggers believed to underlie beta-cell destruction. Preserving and prolonging beta-cell function in T1D is a pivotal therapeutic objective that can mitigate disease progression and improve glycemic control. AREAS COVERED Insulin secretagogues have long been used in the management of type 2 diabetes, but do not have a significant beneficial effect in individuals with long-standing type 1 diabetes. Enhancement of beta-cell function early in the course of type 1 diabetes may offer important benefits in glycemic control and reduced hypoglycemia risk. Glucagon-like peptide-1 receptor agonists, glucokinase activators, free fatty acid receptor agonists, and glimins are drug classes which may offer benefit in enhancing insulin secretion in individuals with type 1 diabetes. EXPERT OPINION Drugs which enhance insulin secretion in individuals may offer clinical benefits to individuals with type 1 diabetes. However, the lack of beta-cell capacity introduces a challenge without regeneration of insulin-producing cells. Stem cell therapies combined with regulation of islet autoimmunity may offer the best prospect of increased insulin secretion in individuals with T1D.
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Affiliation(s)
- Xinyuan Ning
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Center for Diabetes and Endocrinology, Baltimore, MD, USA
| | - Kashif M Munir
- Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Center for Diabetes and Endocrinology, Baltimore, MD, USA
| | - Stephen N Davis
- Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
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Nabi-Afjadi M, Ostadhadi S, Liaghat M, Pasupulla AP, Masoumi S, Aziziyan F, Zalpoor H, Abkhooie L, Tarhriz V. Revolutionizing type 1 diabetes management: Exploring oral insulin and adjunctive treatments. Biomed Pharmacother 2024; 176:116808. [PMID: 38805967 DOI: 10.1016/j.biopha.2024.116808] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 05/20/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024] Open
Abstract
Type 1 diabetes (T1D) is a chronic autoimmune condition that affects millions of people worldwide. Insulin pumps or injections are the standard treatment options for this condition. This article provides a comprehensive overview of the several type 1 diabetes treatment options, focusing on oral insulin. The article is divided into parts that include immune-focused treatments, antigen vaccination, cell-directed interventions, cytokine-directed interventions, and non-immunomodulatory adjuvant therapy. Under the section on non-immunomodulatory adjunctive treatment, the benefits and drawbacks of medications such as metformin, amylin, sodium-glucose cotransporter inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 Ras), and verapamil are discussed. The article also discusses the advantages of oral insulin, including increased patient compliance and more dependable and regular blood sugar control. However, several variables, including the enzymatic and physical barriers of the digestive system, impair the administration of insulin via the mouth. Researchers have looked at a few ways to get over these challenges, such as changing the structure of the insulin molecule, improving absorption with the use of absorption enhancers or nanoparticles, and taking oral insulin together with other medications. Even with great advancements in the use of these treatment strategies, T1D still needs improvement in the therapeutic difficulties. Future studies in these areas should focus on creating tailored immunological treatments, looking into combination medications, and refining oral insulin formulations in an attempt to better control Type 1 Diabetes. The ultimate objective is to create accurate, customized strategies that will enhance glycemic management and the quality of life for individuals with the condition.
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Affiliation(s)
- Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
| | - Samane Ostadhadi
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Isfahan, Iran
| | - Mahsa Liaghat
- Department of Medical Laboratory Sciences, Faculty of Medical Sciences, Islamic Azad University, Kazerun Branch, Kazerun, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Ajay Prakash Pasupulla
- Oral and Maxillofacial Pathology, School of Medicine, Colllege of health Sciences, Wachemo University, Hosanna, Ethiopia
| | - Sajjad Masoumi
- Department of Medical Biotechnology, National institute of Genetic Engineering and Biotechnology, Tehran, Iran
| | - Fatemeh Aziziyan
- Department of Biochemistry, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran; Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran
| | - Hamidreza Zalpoor
- Network of Immunity in Infection, Malignancy & Autoimmunity (NIIMA), Universal Scientific Education & Research Network (USERN), Tehran, Iran; Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Leila Abkhooie
- Razi Herbal Medicines Research Center, Lorestan University of Medical Sciences, Khorramabad, Iran; Department of Medical Biotechnology, School of Medicine, Lorestan University of Medical Sciences, Khorramabad, Iran
| | - Vahideh Tarhriz
- Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA.
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Kondo Y, Satoh S, Terauchi Y. Effects of dulaglutide and trelagliptin on beta-cell function in patients with type 2 diabetes: a randomized controlled study: DUET-beta study. Diabetol Int 2024; 15:474-482. [PMID: 39101164 PMCID: PMC11291836 DOI: 10.1007/s13340-024-00717-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 03/18/2024] [Indexed: 08/06/2024]
Abstract
Aims This randomized, open-label, parallel-group, controlled trial compared the effects of dulaglutide and trelagliptin on beta-cell function in patients with type 2 diabetes. Materials and methods For 24 weeks, participants received dulaglutide (0.75 mg/week) or trelagliptin (100 mg/week), after which beta-cell function was evaluated using a glucagon stimulation test-based disposition index. The primary endpoint was the change in disposition index over the 24-week treatment period. Results Fifty patients with type 2 diabetes who received metformin with or without basal insulin were randomized to receive dulaglutide or trelagliptin. Forty-eight patients completed the 24-week dulaglutide (n = 23) or trelagliptin (n = 25) treatment. The dulaglutide group reduced HbA1c levels more than the trelagliptin group (dulaglutide: - 0.77% ± 0.07% vs. trelagliptin: - 0.57% ± 0.07%; p = 0.04). Change in disposition index during the 24 weeks did not differ between the groups (dulaglutide: - 0.07 ± 1.08 vs. trelagliptin: + 0.59 ± 1.04; p = 0.66), but the dulaglutide group increased HOMA2-%β levels more than the trelagliptin group (dulaglutide: + 26.2 ± 4.3% vs. trelagliptin: + 5.4 ± 4.1%; p = 0.001). The dulaglutide group showed greater body fat mass reduction than the trelagliptin group (dulaglutide: - 1.2 ± 0.3 kg vs. trelagliptin: - 0.3 ± 0.2 kg; p = 0.02) without skeletal muscle mass loss. Conclusion Dulaglutide and trelagliptin had similar effects on beta-cell function according to the glucagon stimulation test-based disposition index. However, dulaglutide promoted improved HOMA2-%β levels compared to trelagliptin and body fat mass was reduced without loss of skeletal muscle mass (UMIN-CTR 000024164). Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00717-6.
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Affiliation(s)
- Yoshinobu Kondo
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
- Department of Endocrinology and Metabolism, Chigasaki Municipal Hospital, 5-15-1 Honson, Chigasaki, Kanagawa 253-0042 Japan
- Tsunashima-East Internal Medicine and Diabetes Clinic, 2-2-14 Tsunashima-Higashi, Kouhoku-ku, Yokohama, Kanagawa 223-0052 Japan
| | - Shinobu Satoh
- Department of Endocrinology and Metabolism, Chigasaki Municipal Hospital, 5-15-1 Honson, Chigasaki, Kanagawa 253-0042 Japan
- Department of Diabetes and Metabolism, Fujisawa Shonandai Hospital, 2345 Takakura, Fujisawa, Kanagawa 252-0802 Japan
| | - Yasuo Terauchi
- Department of Endocrinology and Metabolism, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004 Japan
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Moon JH, Choe HJ, Lim S. Pancreatic beta-cell mass and function and therapeutic implications of using antidiabetic medications in type 2 diabetes. J Diabetes Investig 2024; 15:669-683. [PMID: 38676410 PMCID: PMC11143426 DOI: 10.1111/jdi.14221] [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: 01/21/2024] [Revised: 03/23/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Nowadays, the focus of diabetes treatment has switched from lowering the glucose level to preserving glycemic homeostasis and slowing the disease progression. The main pathophysiology of both type 1 diabetes and long-standing type 2 diabetes is pancreatic β-cell mass loss and dysfunction. According to recent research, human pancreatic β-cells possess the ability to proliferate in response to elevated insulin demands. It has been demonstrated that in insulin-resistant conditions in humans, such as obesity or pregnancy, the β-cell mass increases. This ability could be helpful in developing novel treatment approaches to restore a functional β-cell mass. Treatment strategies aimed at boosting β-cell function and mass may be a useful tool for managing diabetes mellitus and stopping its progression. This review outlines the processes of β-cell failure and detail the many β-cell abnormalities that manifest in people with diabetes mellitus. We also go over standard techniques for determining the mass and function of β-cells. Lastly, we provide the therapeutic implications of utilizing antidiabetic drugs in controlling the mass and function of pancreatic β-cells.
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Affiliation(s)
- Joon Ho Moon
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
| | - Hun Jee Choe
- Department of Internal MedicineHallym University Dongtan Sacred Heart HospitalHwaseongSouth Korea
| | - Soo Lim
- Department of Internal MedicineSeoul National University College of MedicineSeongnamSouth Korea
- Department of Internal MedicineSeoul National University Bundang HospitalSeongnamSouth Korea
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Purnell JQ. Metabolic-Bariatric Surgery for Type 2 Diabetes: Time(ing) for a Change. Diabetes 2024; 73:542-544. [PMID: 38507589 PMCID: PMC10958576 DOI: 10.2337/dbi23-0022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 01/08/2024] [Indexed: 03/22/2024]
Affiliation(s)
- Jonathan Q. Purnell
- Knight Cardiovascular Institute and Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health & Science University, Portland, OR
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Rolandsson O, Tornevi A, Steneberg P, Edlund H, Olsson T, Andreasson U, Zetterberg H, Blennow K. Acute Hyperglycemia Induced by Hyperglycemic Clamp Affects Plasma Amyloid-β in Type 2 Diabetes. J Alzheimers Dis 2024; 99:1033-1046. [PMID: 38728183 DOI: 10.3233/jad-230628] [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: 05/12/2024]
Abstract
Background Individuals with type 2 diabetes (T2D) have an increased risk of cognitive symptoms and Alzheimer's disease (AD). Mis-metabolism with aggregation of amyloid-β peptides (Aβ) play a key role in AD pathophysiology. Therefore, human studies on Aβ metabolism and T2D are warranted. Objective The objective of this study was to examine whether acute hyperglycemia affects plasma Aβ1-40 and Aβ1-42 concentrations in individuals with T2D and matched controls. Methods Ten participants with T2D and 11 controls (median age, 69 years; range, 66-72 years) underwent hyperglycemic clamp and placebo clamp (saline infusion) in a randomized order, each lasting 4 hours. Aβ1-40, Aβ1-42, and insulin-degrading enzyme (IDE) plasma concentrations were measured in blood samples taken at 0 and 4 hours of each clamp. Linear mixed-effect regression models were used to evaluate the 4-hour changes in Aβ1-40 and Aβ1-42 concentrations, adjusting for body mass index, estimated glomerular filtration rate, and 4-hour change in insulin concentration. Results At baseline, Aβ1-40 and Aβ1-42 concentrations did not differ between the two groups. During the hyperglycemic clamp, Aβ decreased in the control group, compared to the placebo clamp (Aβ1-40: p = 0.034, Aβ1-42: p = 0.020), IDE increased (p = 0.016) during the hyperglycemic clamp, whereas no significant changes in either Aβ or IDE was noted in the T2D group. Conclusions Clamp-induced hyperglycemia was associated with increased IDE levels and enhanced Aβ40 and Aβ42 clearance in controls, but not in individuals with T2D. We hypothesize that insulin-degrading enzyme was inhibited during hyperglycemic conditions in people with T2D.
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Affiliation(s)
- Olov Rolandsson
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
| | - Andreas Tornevi
- Department of Public Health and Clinical Medicine, Sustainable Health, Umeå University, Umeå, Sweden
| | - Pär Steneberg
- Department of Medical and Translational Biology, Umeå University, Umeå, Sweden
| | - Helena Edlund
- Department of Medical and Translational Biology, Umeå University, Umeå, Sweden
| | - Tommy Olsson
- Public Health and Clinical Medicine, Internal Medicine, Umeå University, Umeå, Sweden
| | - Ulf Andreasson
- Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Henrik Zetterberg
- Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
- Dementia Research Institute at UCL, London, UK
- Hong Kong Center for Neurodegenerative Diseases, Hong Kong, China
- Wisconsin Alzheimer's Disease Research Center, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
| | - Kaj Blennow
- Institute of Neuroscience and Physiology, the Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Paris Brain Institute, ICM, Pitié-Salpetriere Hospital, Sorbonne University, Paris, France
- Department of Neurology, Neurodegenerative Disorder Research Center, Division of Life Sciences and Medicine, and Institute on Aging and Brain Disorders, University of Science and Technology of China and First Affiliated Hospital of USTC, Hefei, China
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Hong KF, Liu PY, Zhang W, Gui DK, Xu YH. The Efficacy and Safety of Astragalus as an Adjuvant Treatment for Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis. JOURNAL OF INTEGRATIVE AND COMPLEMENTARY MEDICINE 2024; 30:11-24. [PMID: 37433206 DOI: 10.1089/jicm.2022.0767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/13/2023]
Abstract
Objective: This meta-analysis evaluated the beneficial and potential adverse effects of Astragalus in the treatment of patients with type 2 diabetes mellitus (T2DM). Methods: The authors searched for randomized controlled trials of Astragalus treatment for patients with T2DM in the following databases: PubMed, Embase, Cochrane Library, China Knowledge Resource Integrated Database (CNKI), Wanfang Data, China Science and Technology Journal Database (CQVIP), and SinoMed. Two reviewers conducted independent selection of studies, data extraction, and coding, as well as the assessment of risk of bias in the studies included. Standard meta-analysis and, if appropriate, meta-regression were performed using the STATA, v.15.1, software. Results: This meta-analysis encompasses 20 studies and a total of 953 participants. Compared to the control group (CG), the observation group (OG) decreased fasting plasma glucose (FPG) (WMD = -0.67, 95% CI: -1.13∼-0.20, P = 0.005), 2 hours postprandial plasma glucose (2hPG) (WMD = -0.67 (95% CI: -1.13∼-0.20, P=0.005), glycated hemoglobin A1C (HbA1c) (WMD = -0.93, 95% CI: -1.22∼-0.64, P = 0.000), homeostatic model assessment for insulin resistance (HOMA-IR) (WMD = -0.45, 95% CI: -0.99∼0.99, P = 0.104), insulin sensitive index (WMD = 0.42, 95% CI: 0.13-0.72, P = 0.004). The total effective ratio of the OG is more effective than CG (RR = 1.33, 95% CI: 1.26-1.40, P = 0.000), the significant effective ratio (RR = 1.69, 95% CI: 1.48-1.93, P = 0.000). Conclusions: Astragalus may provide specific benefits for T2DM patients as an adjuvant treatment. Nonetheless, the certainty of the evidence and risk of bias fell short of optimal performance, indicating the need for additional clinical research to ascertain potential effects. PROSPERO REGISTRATION NUMBER CRD42022338491.
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Affiliation(s)
- Kin-Fong Hong
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China
| | - Pei-Yu Liu
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China
| | - Wei Zhang
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - Ding-Kun Gui
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
| | - You-Hua Xu
- Faculty of Medicine, Macau University of Science and Technology, Taipa, China
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Nreu B, Dicembrini I, Tinti F, Mannucci E, Monami M. Pancreatitis and pancreatic cancer in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonists: an updated meta-analysis of randomized controlled trials. Minerva Endocrinol (Torino) 2023; 48:206-213. [PMID: 32720500 DOI: 10.23736/s2724-6507.20.03219-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/16/2023]
Abstract
INTRODUCTION An association between glucagon-like peptide-1 receptor agonists (GLP1-RA) and risk of pancreatitis and pancreatic cancer has been suggested. Since its first description, several new trials (including three cardiovascular outcome trials) have been published, substantially increasing the available data set. This suggests the need for an update of the previous meta-analysis. EVIDENCE ACQUISITION A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials, with duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. The endpoints were pancreatitis, pancreatic cancer reported as serious adverse events. Mantel-Haenszel Odds Ratio (MH-OR) with 95% confidence interval (95% CI) was calculated for all outcomes defined above, on an intention-to-treat basis. EVIDENCE SYNTHESIS A total of 43 trials fulfilling inclusion criteria (all reporting data on pancreatitis and pancreatic cancer) was identified. GLP-1 RA showed no association with pancreatitis (MH-OR 1.24 [0.94, 1.64]; P=0.13) and pancreatic cancer (MH-OR 1.28 [0.87, 1.89]; P=0.20). CONCLUSIONS No clear evidence of risk for pancreatitis was observed, whereas data on pancreatic cancer are too scarce to draw any conclusion.
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Affiliation(s)
- Besmir Nreu
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Ilaria Dicembrini
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Federico Tinti
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Edoardo Mannucci
- Department of Diabetology, Careggi University Hospital, Florence, Italy
| | - Matteo Monami
- Department of Diabetology, Careggi University Hospital, Florence, Italy -
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Hao S, Umpierrez GE, Vellanki P. Intervention with Therapeutic Agents, Understanding the Path to Remission to Type 2 Diabetes: Part 2. Endocrinol Metab Clin North Am 2023; 52:39-47. [PMID: 36754496 PMCID: PMC10158502 DOI: 10.1016/j.ecl.2022.07.004] [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
Type 2 diabetes is characterized by progressive decline in pancreatic β-cell function. Newer agents, such as glucagon-like peptide-1 receptor agonist (GLP-1RA) and dual incretin agonists, can augment β-cell function and delay the need for additional antihyperglycemics. However, the effect on β-cell function ceases after stopping the medications. When combined with intensive lifestyle modifications, higher doses of GLP-1RA than those used for diabetes treatment can be used to induce weight loss. More research is needed on whether the weight loss achieved with GLP1-RA can be sustained after stopping medication and in turn can sustain diabetes remission.
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Affiliation(s)
- Shuai Hao
- Division of Pediatric Endocrinology, Children's Healthcare of Atlanta, Emory University School of Medicine, 1400 Tullie Road Northeast, Atlanta, GA 30329, USA
| | - Guillermo E Umpierrez
- Division of Endocrinology, Metabolism & Lipids, Emory University School of Medicine, 69 Jesse Hill Jr Drive Southeast, Glenn Building, Atlanta, GA 30303, USA
| | - Priyathama Vellanki
- Division of Endocrinology, Metabolism & Lipids, Emory University School of Medicine, 69 Jesse Hill Jr Drive Southeast, Glenn Building, Atlanta, GA 30303, USA.
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Bai S, Lin C, Jiao R, Cai X, Hu S, Lv F, Yang W, Zhu X, Ji L. Is the steady-state concentration, duration of action, or molecular weight of GLP-1RA associated with cardiovascular and renal outcomes in type 2 diabetes? Eur J Intern Med 2023; 109:79-88. [PMID: 36628824 DOI: 10.1016/j.ejim.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 01/02/2023] [Accepted: 01/05/2023] [Indexed: 01/09/2023]
Abstract
IMPORTANCE Disparities were found in the cardiovascular and renal outcomes among different glucagon-like peptide 1 receptor agonist (GLP-1RA) subtypes. However, whether the characteristics of GLP-1RA itself are associated with these disparities remains unclear. OBJECTIVE To assess the association between the steady-state concentration, duration of action, or molecular weight of GLP-1RA and the risks of cardiovascular and renal outcomes in patients with type 2 diabetes (T2D). DATA SOURCES PubMed, MEDLINE, EMBASE, Cochrane and Clinicaltrial.gov from inception to April 2022. STUDY SELECTION Randomized controlled trials (RCTs) investigating GLP-1RAs in patients with T2D were included. DATA EXTRACTION AND SYNTHESIS Literature screening and data extraction were performed independently by 2 researchers. The outcomes were computed as odds ratio (OR) and its 95% confidence interval (CI). Subgroup analyses were conducted according to steady-state concentration, duration of action and molecular weight of GLP-1RAs. MAIN OUTCOMES AND MEASURES Primary outcomes were major adverse cardiovascular events (MACE), composite renal outcome and all-cause mortality. RESULTS In all, 61 RCTs were included. When compared with non-GLP-1RA agents, GLP-1RAs with high steady-state concentration were associated with greater risk reduction in MACE (p for subgroup difference = 0.01) and the composite renal outcome (p for subgroup difference = 0.008) in patients with T2D. Greater risk reductions in MACE between GLP-1RA users versus non-GLP-RA users were observed in long acting stratum when compared with short acting stratum (p for subgroup difference = 0.04) in patients with T2D. The molecular weight of GLP-1RAs was not associated with the risk of cardiovascular and renal outcomes. CONCLUSIONS AND RELEVANCE GLP-1RAs with high steady-state concentrations might be associated with greater risk reductions in cardiovascular and renal outcomes in patients with T2D. Long acting GLP-1RAs might outperform short acting ones in reducing the risk of cardiovascular outcomes. These findings provided new insights for guiding the clinical applications of GLP-1RAs in patients with T2D.
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Affiliation(s)
- Shuzhen Bai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Ruoyang Jiao
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Xingyun Zhu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, Beijing, China.
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Retnakaran R, Ye C, Emery A, Kramer CK, Zinman B. The metabolic effects of adding exenatide to basal insulin therapy when targeting remission in early type 2 diabetes in a randomized clinical trial. Nat Commun 2022; 13:6109. [PMID: 36244997 PMCID: PMC9573864 DOI: 10.1038/s41467-022-33867-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/06/2022] [Indexed: 12/24/2022] Open
Abstract
Combining a glucagon-like peptide-1 receptor agonist (GLP1-RA) with basal insulin is an emerging option when initiating injectable therapy in longstanding type 2 diabetes (T2DM). Recognizing that short-term insulin therapy can improve beta-cell function and induce glycemic remission in early T2DM, we hypothesized that adding the short-acting GLP1-RA exenatide to basal insulin in early T2DM may enhance the achievability of these outcomes. In this completed, 20-week, open-label, parallel-arm trial at an academic hospital, 103 individuals aged 30-80 years with <7 years duration of T2DM were randomized (by computer-generated sequence) to 8-weeks treatment with (i) insulin glargine (Glar; n = 33), (ii) glargine + thrice-daily lispro (Glar/Lispro; n = 35), or (iii) glargine + twice-daily exenatide (Glar/Exenatide; n = 35), followed by 12-weeks washout. The analyzed population of 102 participants (median 3.5 years of T2DM, A1c 6.6% ±0.7%) consisted of 33 on Glar, 35 on Glar/Lispro and 34 on Glar/Exenatide. Oral glucose tolerance tests at baseline, 4-weeks, 8-weeks and 20-weeks enabled assessment of beta-cell function (Insulin Secretion-Sensitivity Index-2 (ISSI-2)) and glycemic control. Mean ISSI-2 over the 8-week intervention (primary outcome) did not differ across the groups (Glar/Exenatide 237 ± 11; Glar/Lispro 208 ± 11; Glar 223 ± 11; p = 0.19). Baseline-adjusted A1c at 8-weeks (secondary outcome) was lowest in Glar/Exenatide followed by Glar/Lispro and Glar (mean 5.9% vs 6.0% vs 6.2%; p = 0.0007). After 12-weeks washout, however, neither baseline-adjusted A1c nor baseline-adjusted ISSI-2 (secondary outcomes) differed between the groups, nor did (additional outcome) rates of remission (Glar/Exenatide 26.7%, Glar/Lispro 43.8%, Glar 32.1%; p = 0.35). There were no severe hypoglycemia episodes. In conclusion, adding exenatide to basal insulin in early T2DM does not further enhance underlying beta-cell function or the capacity to achieve diabetes remission, despite yielding on-treatment glycemic benefit.
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Affiliation(s)
- Ravi Retnakaran
- grid.416166.20000 0004 0473 9881Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada ,grid.17063.330000 0001 2157 2938Division of Endocrinology, University of Toronto, Toronto, Canada ,grid.416166.20000 0004 0473 9881Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Chang Ye
- grid.416166.20000 0004 0473 9881Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
| | - Alexandra Emery
- grid.416166.20000 0004 0473 9881Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada
| | - Caroline K. Kramer
- grid.416166.20000 0004 0473 9881Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada ,grid.17063.330000 0001 2157 2938Division of Endocrinology, University of Toronto, Toronto, Canada ,grid.416166.20000 0004 0473 9881Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
| | - Bernard Zinman
- grid.416166.20000 0004 0473 9881Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Canada ,grid.17063.330000 0001 2157 2938Division of Endocrinology, University of Toronto, Toronto, Canada ,grid.416166.20000 0004 0473 9881Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Canada
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Utzschneider KM, Ehrmann DA, Arslanian SA, Barengolts E, Buchanan TA, Caprio S, Edelstein SL, Hannon TS, Kahn SE, Kozedub A, Mather KJ, Nadeau KJ, Sam S, Tripputi M, Xiang AH, El ghormli L, The RISE Consortium. Weight loss and β-cell responses following gastric banding or pharmacotherapy in adults with impaired glucose tolerance or type 2 diabetes: a randomized trial. Obesity (Silver Spring) 2022; 30:1579-1588. [PMID: 35894078 PMCID: PMC10849844 DOI: 10.1002/oby.23475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/22/2022] [Accepted: 04/19/2022] [Indexed: 12/30/2022]
Abstract
OBJECTIVE The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes. METHODS The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time. RESULTS BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function. CONCLUSIONS Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function.
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Affiliation(s)
- Kristina M. Utzschneider
- VA Puget Sound Health Care System, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | - David A. Ehrmann
- Department of Medicine, The University of Chicago, Chicago, Illinois, USA
| | - Silva A. Arslanian
- UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | | | - Thomas A. Buchanan
- Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Sonia Caprio
- Department of Pediatrics, Yale University, New Haven, Connecticut, USA
| | | | - Tamara S. Hannon
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Steven E. Kahn
- VA Puget Sound Health Care System, Seattle, Washington, USA
- Department of Medicine, University of Washington, Seattle, Washington, USA
| | | | - Kieren J. Mather
- Department of Internal Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Kristen J. Nadeau
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Susan Sam
- Department of Medicine, The University of Chicago, Chicago, Illinois, USA
| | - Mark Tripputi
- George Washington University Biostatistics Center, Rockville, Maryland, USA
| | - Anny H. Xiang
- Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, California, USA
| | - Laure El ghormli
- George Washington University Biostatistics Center, Rockville, Maryland, USA
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Heise T, Mari A, DeVries JH, Urva S, Li J, Pratt EJ, Coskun T, Thomas MK, Mather KJ, Haupt A, Milicevic Z. Effects of subcutaneous tirzepatide versus placebo or semaglutide on pancreatic islet function and insulin sensitivity in adults with type 2 diabetes: a multicentre, randomised, double-blind, parallel-arm, phase 1 clinical trial. Lancet Diabetes Endocrinol 2022; 10:418-429. [PMID: 35468322 DOI: 10.1016/s2213-8587(22)00085-7] [Citation(s) in RCA: 128] [Impact Index Per Article: 42.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 03/04/2022] [Accepted: 03/04/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, shows a remarkable ability to lower blood glucose, enabling many patients with long-standing type 2 diabetes to achieve normoglycaemia. We aimed to understand the physiological mechanisms underlying the action of tirzepatide in type 2 diabetes. METHODS This multicentre, randomised, double-blind, parallel-arm, phase 1 study was done at two centres in Germany. Eligible patients were aged 20-74 years, had type 2 diabetes for at least 6 months, and were being treated with lifestyle advice and stable doses of metformin, with or without one additional stable dose of another oral antihyperglycaemic medicine, 3 months before study entry. Via a randomisation table, patients were randomly assigned (3:3:2) to subcutaneously receive either tirzepatide 15 mg, semaglutide 1 mg, or placebo once per week. Endpoint measurements were done at baseline and the last week of therapy (week 28). The primary endpoint was the effect of tirzepatide versus placebo on the change in clamp disposition index (combining measures of insulin secretion and sensitivity) from baseline to week 28 of treatment and was analysed in the pharmacodynamic analysis set, which comprised all randomly assigned participants who received at least one dose of a study drug and had evaluable pharmacodynamic data. Safety was analysed in the safety population, which comprised all randomly assigned participants who received at least one dose of a study drug. Secondary endpoints included the effect of tirzepatide versus semaglutide on the change in clamp disposition index from baseline to week 28 of treatment, glucose control, total insulin secretion rate, M value (insulin sensitivity), and fasting and postprandial glucagon concentrations. Exploratory endpoints included the change in fasting and postprandial insulin concentrations. This study is registered with ClinicalTrials.gov, NCT03951753, and is complete. FINDINGS Between June 28, 2019, and April 8, 2021, we screened 184 individuals and enrolled 117 participants, all of whom were included in the safety population (45 in the tirzepatide 15 mg group, 44 in the semaglutide 1 mg group, and 28 in the placebo group). Because of discontinuations and exclusions due to missing or unevaluable data, 39 patients in each treatment group and 24 patients in the placebo group comprised the pharmacodynamic analysis set. With tirzepatide, the clamp disposition index increased from a least squares mean of 0·3 pmol m-2 L min-2 kg-1 (SE 0·03) at baseline by 1·9 pmol m-2 L min-2 kg-1 (0·16) to total 2·3 pmol m-2 L min-2 kg-1 (SE 0·16) at week 28 and, with placebo, the clamp disposition index did not change much from baseline (least squares mean at baseline 0·4 pmol m-2 L min-2 kg-1 [SE 0·04]; change from baseline 0·0 pmol m-2 L min-2 kg-1 [0·03]; least squares mean at week 28 0·3 [SE 0·03]; estimated treatment difference [ETD] tirzepatide vs placebo 1·92 [95% CI 1·59-2·24]; p<0·0001). The improvement with tirzepatide in clamp disposition index was significantly greater than with semaglutide (ETD 0·84 pmol m-2 L min-2 kg-1 [95% CI 0·46-1·21]). This result reflected significant improvements in total insulin secretion rate (ETD 102·09 pmol min-1 m-2 [51·84-152·33]) and insulin sensitivity (ETD 1·52 mg min-1 kg-1 [0·53-2·52]) for tirzepatide versus semaglutide. On meal tolerance testing, tirzepatide significantly reduced glucose excursions (lower insulin and glucagon concentrations) compared with placebo, with effects on these variables being greater than with semaglutide. The safety profiles of tirzepatide and semaglutide were similar, with gastrointestinal adverse events being the most common (11 [24%], 13 [30%], and seven [25%] with nausea; nine [20%], 13 [30%], and six [21%] with diarrhoea; and three [7%], five [11%], and one [4%] with vomiting, for tirzepatide, semaglutide, and placebo, respectively). There were no deaths. INTERPRETATION The glycaemic efficacy of GIP/GLP-1 receptor agonist tirzepatide in type 2 diabetes results from concurrent improvements in key components of diabetes pathophysiology, namely β-cell function, insulin sensitivity, and glucagon secretion. These effects were large and help to explain the remarkable glucose-lowering ability of tirzepatide seen in phase 3 studies. FUNDING Eli Lilly.
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Affiliation(s)
| | - Andrea Mari
- Institute of Neuroscience, National Research Council, Padova, Italy
| | | | | | - Jing Li
- Eli Lilly, Indianapolis, IN, USA
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Xie D, Gao Z, Liu M, Wang D. Effect of Metformin Intervention on Pancreatic β-Cell Apoptosis. J BIOMATER TISS ENG 2022. [DOI: 10.1166/jbt.2022.3013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Metformin is shown to have hypoglycemic effects. However, the relationship between metformin’s intervention in FFA-induced endoplasmic reticulum stress-mediated insulin resistance (IR) and insulin β-cell apoptosis under high-glucose condition remains unclear. Our study
intends to assess their relationship. Human pancreatic β-cells were treated with metformin and cell proliferation and IR were detected by MTT assay along with detection of Wnt/β-catenin signaling by RT-PCR, cell cycle and apoptosis by flow cytometry. Metformin inhibited
β cell proliferation which was mediated by FFA-induced endoplasmic reticulum stress in a time-dependent and dose-dependent manner as well as induced cell cycle arrest at G2/M phase. In addition, metformin inhibited β-catenin signaling activation and decreased the expression
of c-myc, Dvl-2, survivin, Dvl-3, GSK-3β (p-ser9) and promoted GSK-3 (p-tyr216) and Axin-2 expression. In conclusion, metformin inhibits Wnt/β-catenin signaling and promotes FFA to induce endoplasmic reticulum stress, thereby mediating pancreatic β-cells
behaviors.
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Affiliation(s)
- Dongqian Xie
- Department of Pharmaceutical, The Number Two Hospital of Baoding, Baoding, Hebei, 071000, China
| | - Zhicheng Gao
- Department of Pharmaceutical, The Number Two Hospital of Baoding, Baoding, Hebei, 071000, China
| | - Mei Liu
- Department of Rehabilitation Medicine, The Number Two Hospital of Baoding, Baoding, Hebei, 071000, China
| | - Defeng Wang
- Department of Pharmacy, Baoding Qingyuan Maternal and Child Health Hospital, The Number Two Hospital of Baoding, Baoding, Hebei, 071000, China
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Chen X, Xu Y, Zhang J, Shao S, Duan Y, Liu P, Shen L, Zhang J, Zeng J, Lin M, Zhao S, Ma J, Zhao T, Hu J, Liao Y, Chen X, Hu S, Xue Y, Zeng Z, He W, Liu Z, Li W, Liu L, Yin P, Yu X. Exenatide Twice Daily Plus Glargine Versus Aspart 70/30 Twice Daily in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Premixed Human Insulin and Metformin. Endocr Pract 2021; 27:790-797. [PMID: 33831552 DOI: 10.1016/j.eprac.2021.03.015] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Many patients with type 2 diabetes treated with premixed insulin gradually have inadequate glycemic control and switch to a basal-bolus regimen, which raises some concerns for weight gain and increased hypoglycemic risk. Switching to combination use of glp-1 agonist and basal insulin may be an alternative option. METHODS After a 12-week premixed human insulin 70/30 dosage optimization period, 200 patients with HbA1c of 7.0% to 10.0% were randomized into 24-week treatment groups with exenatide twice a day plus glargine or with aspart 70/30 twice a day. RESULTS After 24 weeks, the patients receiving exenatide plus glargine (n = 90) had improved HbA1c control compared with those receiving aspart 70/30 (n = 90) (least squares mean change: ‒0.59 vs ‒0.13%; difference [95% CI]: ‒0.45 [‒0.74 to ‒0.17]) in the full analysis set population. Weight decreased 3.5 kg with exenatide and decreased 0.4 kg with aspart 70/30 (P < .001). The insulin dose was reduced 10.7 units/day (95% CI, ‒12.2 to ‒9.2 units; P < .001) with exenatide, and increased 9.7 units/day (95% CI, 8.2 to 11.2 units; P < .001) with aspart 70/30. The most common adverse events were gastrointestinal adverse effects in the exenatide group (nausea [21%], vomiting [16%], diarrhea [13%]). The incidence of hypoglycemia was similar in 2 groups (27% for exenatide and 38% for aspart 70/30; P = .1). CONCLUSION In premixed human insulin‒treated patients with type 2 diabetes with inadequate glycemic control, switching to exenatide twice a day plus glargine was superior to aspart 70/30 twice a day for glycemic and weight control.
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Affiliation(s)
- Xi Chen
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongping Xu
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jianhua Zhang
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shiyin Shao
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanran Duan
- Department of Epidemiology and Health Statistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Peiwen Liu
- Clinic of Peiwen Liu, Xinhua Hospital, Wuhan, China
| | - Liya Shen
- Division of Endocrinology, Department of Internal Medicine, Wuhan Sixth Hospital, Wuhan, China
| | - Jing Zhang
- Division of Endocrinology, Department of Internal Medicine, Combine Traditional Chinese and Western Medicine Hospital, Wuhan, China
| | - Jiaoe Zeng
- Division of Endocrinology, Department of Internal Medicine, Jingzhou Central Hospital, Jingzhou, China
| | - Mei Lin
- Division of Endocrinology, Department of Internal Medicine, Wuhan PuAi Hospital, Wuhan, China
| | - Shi Zhao
- Division of Endocrinology, Department of Internal Medicine, Wuhan Central Hospital, Wuhan, China
| | - Jianhua Ma
- Division of Endocrinology, Department of Internal Medicine, Nanjing First Hospital, Nanjing, China
| | - Tao Zhao
- Division of Endocrinology, Department of Internal Medicine, Xiaogan Central Hospital, Xiaogan, China
| | - Juping Hu
- Division of Endocrinology, Department of Internal Medicine, The Third People's Hospital of Hubei Province, Wuhan, China
| | - Yong Liao
- Division of Endocrinology, Department of Internal Medicine, The Armed Police General Hospital, Chongqing, China
| | - Xiaowen Chen
- Division of Endocrinology, Department of Internal Medicine, Huangshi Central Hospital, Huangshi, China
| | - Shufang Hu
- Division of Endocrinology, Department of Internal Medicine, Hankou Railway Hospital. Wuhan, China
| | - Yaoming Xue
- Division of Endocrinology, Department of Internal Medicine, Nanfang Hospital, Southern Medical University. Guangzhou, China
| | - Zhaoyang Zeng
- Division of Endocrinology, Department of Internal Medicine, Yichang Central Hospital, Yichang, China
| | - Wentao He
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhelong Liu
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Wenjun Li
- Computer Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Liegang Liu
- Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ping Yin
- Department of Epidemiology and Health Statistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuefeng Yu
- Division of Endocrinology, Branch of National Clinical Research Center for Metabolic Disease, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function. Handb Exp Pharmacol 2021; 274:439-465. [PMID: 34114119 DOI: 10.1007/164_2021_474] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Beta-cell dysfunction and beta-cell death are critical events in the development of type 2 diabetes mellitus (T2DM). Therefore, the goals of modern T2DM management have shifted from merely restoring normoglycemia to maintaining or regenerating beta-cell mass and function. In this review we summarize current and novel approaches to achieve these goals, ranging from lifestyle interventions to N-methyl-D-aspartate receptor (NMDAR) antagonism, and discuss the mechanisms underlying their effects on beta-cell physiology and glycemic control. Notably, timely intervention seems critical, but not always strictly required, to maximize the effect of any approach on beta-cell recovery and disease progression. Conventional antidiabetic medications are not disease-modifying in the sense that the disease does not progress or reoccur while on treatment or thereafter. More invasive approaches, such as bariatric surgery, are highly effective in restoring normoglycemia, but are reserved for a rather small proportion of obese individuals and sometimes associated with serious adverse events. Finally, we recapitulate the broad range of effects mediated by peripheral NMDARs and discuss recent evidence on the potential of NMDAR antagonists to be developed as a novel class of antidiabetic drugs. In the future, a more refined assessment of disease risk or disease subtype might enable more targeted therapies to prevent or treat diabetes.
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Simental-Mendía LE, Sánchez-García A, Linden-Torres E, Simental-Mendía M. Impact of glucagon-like peptide-1 receptor agonists on adiponectin concentrations: A meta-analysis of randomized controlled trials. Br J Clin Pharmacol 2021; 87:4140-4149. [PMID: 33835520 DOI: 10.1111/bcp.14855] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 03/06/2021] [Accepted: 04/04/2021] [Indexed: 12/29/2022] Open
Abstract
AIMS Previous studies have reported an elevation in adiponectin concentrations using glucagon-like peptide-1 receptor agonists (GLP-1 RA) therapy; however, this possible pleiotropic effect is still uncertain. Thus, the objective of this meta-analysis of randomized controlled trials was to assess the impact of GLP-1 RA on adiponectin levels. METHODS This systematic review and meta-analysis included randomized controlled trials investigating the effect of GLP-1 RA on circulating adiponectin concentrations. Studies from PubMed, Web of Science, Scopus, and Google Scholar databases were included. A random-effects model and a sensitivity analysis using the leave 1-out method were conducted. RESULTS A meta-analysis of 20 randomized controlled trials involving 1497 individuals demonstrated a significant increase in adiponectin levels after GLP-1 RA administration (weighted mean difference [WMD]: 0.59 μg/mL, 95% confidence interval [CI]: 0.10, 1.08, P = .02). Particularly, liraglutide had a significant effect on adiponectin (WMD: 0.55 μg/mL, 95% CI: 0.04, 1.06, P = .04), while exenatide did not affect these concentrations (WMD: 0.60 μg/mL, 95% CI: -0.23, 1.42, P = .16). CONCLUSION GLP-1 RA treatment is associated with an increase in adiponectin levels.
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Affiliation(s)
- Luis E Simental-Mendía
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico
| | - Adriana Sánchez-García
- Universidad Autonoma de Nuevo Leon, Endocrinology Division, University Hospital "Dr. José E. González", School of Medicine, Monterrey, NL, Mexico
| | - Enrique Linden-Torres
- Unidad de Investigación Biomédica, Delegación Durango, Instituto Mexicano del Seguro Social, Mexico
| | - Mario Simental-Mendía
- Universidad Autonoma de Nuevo Leon, Department of Orthopedics and Traumatology, University Hospital "Dr. José E. González", School of Medicine, Monterrey, NL, Mexico
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Backeström A, Papadopoulos K, Eriksson S, Olsson T, Andersson M, Blennow K, Zetterberg H, Nyberg L, Rolandsson O. Acute hyperglycaemia leads to altered frontal lobe brain activity and reduced working memory in type 2 diabetes. PLoS One 2021; 16:e0247753. [PMID: 33739980 PMCID: PMC7978337 DOI: 10.1371/journal.pone.0247753] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 02/15/2021] [Indexed: 01/23/2023] Open
Abstract
How acute hyperglycaemia affects memory functions and functional brain responses in individuals with and without type 2 diabetes is unclear. Our aim was to study the association between acute hyperglycaemia and working, semantic, and episodic memory in participants with type 2 diabetes compared to a sex- and age-matched control group. We also assessed the effect of hyperglycaemia on working memory–related brain activity. A total of 36 participants with type 2 diabetes and 34 controls (mean age, 66 years) underwent hyperglycaemic clamp or placebo clamp in a blinded and randomised order. Working, episodic, and semantic memory were tested. Overall, the control group had higher working memory (mean z-score 33.15 ± 0.45) than the group with type 2 diabetes (mean z-score 31.8 ± 0.44, p = 0.042) considering both the placebo and hyperglycaemic clamps. Acute hyperglycaemia did not influence episodic, semantic, or working memory performance in either group. Twenty-two of the participants (10 cases, 12 controls, mean age 69 years) were randomly invited to undergo the same clamp procedures to challenge working memory, using 1-, 2-, and 3-back, while monitoring brain activity by blood oxygen level–dependent functional magnetic resonance imaging (fMRI). The participants with type 2 diabetes had reduced working memory during the 1- and 2-back tests. fMRI during placebo clamp revealed increased BOLD signal in the left lateral frontal cortex and the anterior cingulate cortex as a function of working memory load in both groups (3>2>1). During hyperglycaemia, controls showed a similar load-dependent fMRI response, whereas the type 2 diabetes group showed decreased BOLD response from 2- to 3-back. These results suggest that impaired glucose metabolism in the brain affects working memory, possibly by reducing activity in important frontal brain areas in persons with type 2 diabetes.
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Affiliation(s)
- Anna Backeström
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
- * E-mail:
| | - Konstantin Papadopoulos
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
| | - Sture Eriksson
- Department of Public Health and Clinical Medicine, Nutritional Research, Umeå University, Umeå, Sweden
| | - Tommy Olsson
- Department of Public Health and Clinical Medicine, Medicine, Umeå University, Umeå, Sweden
| | - Micael Andersson
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden
| | - Kaj Blennow
- Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
| | - Henrik Zetterberg
- Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at the University of Gothenburg, Mölndal, Sweden
- Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
- Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, United Kingdom
- UK Dementia Research Institute at UCL, London, United Kingdom
| | - Lars Nyberg
- Department of Integrative Medical Biology, Umeå University, Umeå, Sweden
- Umeå Center for Functional Brain Imaging, Umeå University, Umeå, Sweden
- Department of Radiation Sciences, Umeå University, Umeå, Sweden
| | - Olov Rolandsson
- Department of Public Health and Clinical Medicine, Family Medicine, Umeå University, Umeå, Sweden
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21
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Maselli DB, Camilleri M. Effects of GLP-1 and Its Analogs on Gastric Physiology in Diabetes Mellitus and Obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1307:171-192. [PMID: 32077010 DOI: 10.1007/5584_2020_496] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The processing of proglucagon in intestinal L cells results in the formation of glucagon, GLP-1, and GLP-2. The GLP-1 molecule becomes active through the effect of proconvertase 1, and it is inactivated by dipeptidyl peptidase IV (DPP-IV), so that the half-life of endogenous GLP-1 is 2-3 min. GLP-1 stimulates insulin secretion from β cells in the islets of Langerhans. Human studies show that infusion of GLP-1 results in slowing of gastric emptying and increased fasting and postprandial gastric volumes. Retardation of gastric emptying reduces postprandial glycemia. Exendin-4 is a peptide agonist of the GLP-1 receptor that promotes insulin secretion. Chemical modifications of exendin-4 and GLP-1 molecules have been accomplished to prolong the half-life of GLP-1 agonists or analogs. This chapter reviews the effects of GLP-1-related drugs used in treatment of diabetes or obesity on gastric motor functions, chiefly gastric emptying. The literature shows that diverse methods have been used to measure effects of the GLP-1-related drugs on gastric emptying, with most studies using the acetaminophen absorption test which essentially measures gastric emptying of liquids during the first hour and capacity to absorb the drug over 4-6 h, expressed as AUC. The most valid measurements by scintigraphy (solids or liquids) and acetaminophen absorption at 30 or 60 min show that GLP-1-related drugs used in diabetes or obesity retard gastric emptying, and this is associated with reduced glycemia and variable effects on food intake and appetite. GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity. The effects on gastric emptying are reduced with long-acting preparations or long-term use of short-acting preparations as a result of tachyphylaxis. The dual agonists targeting GLP-1 and another receptor (GIP) do not retard gastric emptying, based on reports to date. In summary, GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity, and their effects are mediated, at least in part, by retardation of gastric emptying.
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Affiliation(s)
- Daniel B Maselli
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Michael Camilleri
- Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
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22
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Pan H, Su Y, Xie Y, Wang W, Qiu W, Chen W, Lu W, Lu Z, Wang W, Shang A. Everestmab, a novel long-acting GLP-1/anti GLP-1R nanobody fusion protein, exerts potent anti-diabetic effects. ARTIFICIAL CELLS NANOMEDICINE AND BIOTECHNOLOGY 2021; 48:854-866. [PMID: 32468873 DOI: 10.1080/21691401.2020.1770268] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
In the present study, a novel single domain antibody (sdAb) fusion protein, named everestmab, composing of a mutated GLP-1(A8G) fused to the tandem bispecific humanized GLP-1R-targeting and albumin-binding nanobodies was designed and characterized for the therapies for type 2 diabetes mellitus (T2DM). Surface plasmon resonance (SPR) measurements demonstrated everestmab associates with serum albumins of rat and monkey species with high affinity, and tends to be cross-reactive with rat and monkey species. In vitro GLP-1R binding and activation assays revealed that everestmab can specifically activate the GLP-1R, and the antagonist exendin-4 (9-39) did not inhibit the activation yet. In vivo multiple oral glucose tolerance tests (OGTTs) and hypoglycaemic efficacy tests proved that a single injection of everestmab reduced the blood glucose for at least 144 h in Goto-Kakizaki (GK) rats. The plasma half-lives of 4.1 and 7.8 days were observed after a single s.c. administration of everestmab in SD rats and cynomolgus monkeys, respectively. Chronic treatment of everestmab to GK and diet induced obese (DIO) rats achieved beneficial effects on weight reducing, HbA1c lowering, glucose tolerance, liver and pancreas islet function impairment. In summary, everestmab is a unique G-protein-coupled receptor-targeted nanobody fusion protein and exerts potential as a therapeutic treatment for T2DM.
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Affiliation(s)
- Hongchao Pan
- Department of Laboratory Medicine, Shanghai SimpleGene Medical Laboratory, Shanghai, P. R. China.,Department of Laboratory Medicine, Tongji Hospital of Tongji University, Shanghai, P. R. China
| | - Yunnan Su
- Department of Neurology, Baoshan Branch, Shanghai General Hospital, Shanghai, P. R. China
| | - Yini Xie
- Department of Laboratory Medicine, The People's Hospital of Jiedong, Jieyang, P. R. China
| | - Weiyong Wang
- Department of Medical Center, Yandong Hospital of Yancheng City, Yancheng, P. R. China
| | - Wanli Qiu
- Department of Medical Center, Yandong Hospital of Yancheng City, Yancheng, P. R. China
| | - Wei Chen
- Department of Experimental Medicine Center, The Sixth People's Hospital of Yancheng City, Yancheng, P. R. China
| | - Wenying Lu
- Department of Experimental Medicine Center, The Sixth People's Hospital of Yancheng City, Yancheng, P. R. China
| | - Zhao Lu
- Department of Laboratory Medicine, Key Laboratory of Pharmaceutical Chemistry, China Pharmaceutical University, NanJing, P. R. China
| | - Weiwei Wang
- Department of Experimental Medicine Center, The Sixth People's Hospital of Yancheng City, Yancheng, P. R. China
| | - Anquan Shang
- Department of Laboratory Medicine, Tongji Hospital of Tongji University, Shanghai, P. R. China
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23
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Puddu A, Maggi D. Emerging Role of Caveolin-1 in GLP-1 Action. Front Endocrinol (Lausanne) 2021; 12:668012. [PMID: 33935978 PMCID: PMC8079975 DOI: 10.3389/fendo.2021.668012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 03/22/2021] [Indexed: 11/13/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) is a gut hormone mainly produced in the intestinal epithelial endocrine L cells, involved in maintaining glucose homeostasis. The use of GLP-1 analogous and dipeptidyl peptidase-IV (DPP-IV) inhibitors is well-established in Type 2 Diabetes. The efficacy of these therapies is related to the activation of GLP-1 receptor (GLP-1R), which is widely expressed in several tissues. Therefore, GLP-1 is of great clinical interest not only for its actions at the level of the beta cells, but also for the extra-pancreatic effects. Activation of GLP-1R results in intracellular signaling that is regulated by availability of downstream molecules and receptor internalization. It has been shown that GLP-1R co-localizes with caveolin-1, the main component of caveolae, small invagination of the plasma membrane, which are involved in controlling receptor activity by assembling signaling complexes and regulating receptor trafficking. The aim of this review is to outline the important role of caveolin-1 in mediating biological effects of GLP-1 and its analogous.
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24
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Li Y, Han MM, He Q, Liu ZA, Liang D, Hou JT, Zhang Y, Liu YF. Exenatide once weekly combined with metformin reduced glycemic variability in type 2 diabetes by using flash glucose monitoring system. World J Diabetes 2020; 11:654-665. [PMID: 33384771 PMCID: PMC7754172 DOI: 10.4239/wjd.v11.i12.654] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 10/09/2020] [Accepted: 10/26/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple studies demonstrate that fluctuating blood glucose level produces greater damage compared with sustained hyperglycemia. Flash glucose monitoring system is an effective method in documenting blood glucose variability, contributing to better glucose management and reduced hypoglycemic event occurrence.
AIM To investigate the improvement in glycemic variability (GV), blood glucose level, and metabolic indexes of patients with type 2 diabetes mellitus after combined treatment of exenatide once weekly (EXQW) and metformin.
METHODS Twenty-five patients with type 2 diabetes mellitus suffering from poor blood glucose control under metformin treatment were recruited. The recruited patients were prescribed with oral metformin only (maintaining a dosage of metformin at ≥ 1500 mg/day) for 2 wk (screening period), and then given EXQW (2 mg, subcutaneous injection) for 12 wk (experimental period). The flash glucose monitoring system was used to document blood glucose values during the screening period and the last 2 wk of the experimental period.
RESULTS Four patients were excluded for various reasons, yielding a total of 21 patients, including 17 males and 4 females, with an average age of 48.8 years, who completed this study. The estimated glycated hemoglobin, mean blood glucose, fasting and postprandial blood glucose levels, and percentage of blood glucose above 7.8 mmol/L decreased compared to those at baseline (P = 0.003, 0.003, 0.008, 0.010, 0.014, 0.017, and 0.005, respectively), while the percentage of blood glucose between 3.9 and 7.8 mmol/L significantly increased (P = 0.005). Parameters of GV including standard deviation of blood glucose, mean amplitude of glycemic excursions, mean of daily difference, area under the curve difference between percentiles 25 and 75, and area under the curve difference between percentiles 10 and 90 were significantly lower compared to that of baseline (P = 0.017, 0.006, 0.000, 0.024, 0.036, respectively). The durations of blood glucose below 3.9 mmol/L during the day and nocturnal periods significantly increased after treatment (P = 0.041 and 0.028, respectively), but there was no significant increase in severe hypoglycemia (< 3.0 mmol/L) compared with that at baseline (P = 0.207). In addition, some metabolic indicators improved after EXQW treatment.
CONCLUSION EXQW combined with metformin can effectively improve blood glucose levels, reduce GV, and improve metabolic indicators. However, there is still a risk of nocturnal hypoglycemia, and careful attention should be paid to patients with EXQW treatment.
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Affiliation(s)
- Yang Li
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Min-Min Han
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Qiong He
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Zi-Ang Liu
- Department of First Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Dong Liang
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Jing-Tian Hou
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yi Zhang
- Department of Pharmacology, Basic Medical College, Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
| | - Yun-Feng Liu
- Department of Endocrinology, First Hospital of Shanxi Medical University, Taiyuan 030001, Shanxi Province, China
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25
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Marrano N, Biondi G, Cignarelli A, Perrini S, Laviola L, Giorgino F, Natalicchio A. Functional loss of pancreatic islets in type 2 diabetes: How can we halt it? Metabolism 2020; 110:154304. [PMID: 32599081 DOI: 10.1016/j.metabol.2020.154304] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 06/14/2020] [Accepted: 06/25/2020] [Indexed: 02/08/2023]
Abstract
The loss of beta-cell functional mass is a necessary and early condition in the development of type 2 diabetes (T2D). In T2D patients, beta-cell function is already reduced by about 50% at diagnosis and further declines thereafter. Beta-cell mass is also reduced in subjects with T2D, and islets from diabetic donors are smaller compared to non-diabetic donors. Thus, beta-cell regeneration and/or preservation of the functional islet integrity should be highly considered for T2D treatment and possibly cure. To date, the available anti-diabetes drugs have been developed as "symptomatic" medications since they act to primarily reduce elevated blood glucose levels. However, a truly efficient anti-diabetes medication, capable to prevent the onset and progression of T2D, should stop beta-cell loss and/or promote the restoration of fully functional beta-cell mass, independently of reducing hyperglycemia and ameliorating glucotoxicity on the pancreatic islets. This review provides a view of the experimental and clinical evidence on the ability of available anti-diabetes drugs to exert protective effects on beta-cells, with a specific focus on human pancreatic islets and clinical trials. Potential explanations for the lack of concordance between evidence of beta-cell protection in vitro and of persistent amelioration of beta-cell function in vivo are also discussed.
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Affiliation(s)
- Nicola Marrano
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Giuseppina Biondi
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Angelo Cignarelli
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy
| | - Sebastio Perrini
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Luigi Laviola
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Francesco Giorgino
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
| | - Annalisa Natalicchio
- Department of Emergency and Organ Transplantation, Section of Internal Medicine, Endocrinology, Andrology and Metabolic Diseases, University of Bari Aldo Moro, Bari, Italy.
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26
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Nreu B, Dicembrini I, Tinti F, Sesti G, Mannucci E, Monami M. Major cardiovascular events, heart failure, and atrial fibrillation in patients treated with glucagon-like peptide-1 receptor agonists: An updated meta-analysis of randomized controlled trials. Nutr Metab Cardiovasc Dis 2020; 30:1106-1114. [PMID: 32448716 DOI: 10.1016/j.numecd.2020.03.013] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/13/2020] [Accepted: 03/14/2020] [Indexed: 01/27/2023]
Abstract
BACKGROUND AND AIMS Glucagon-like Peptide 1 Receptor Agonists (GLP1-RA) has been associated with a reduction of major cardiovascular events (MACE) and mortality on the basis of the results of cardiovascular outcome trials (CVOT). Several meta-analyses on this issue have been recently published; however, they were all restricted to CVOT, with the exclusion of all studies designed for other endpoints; moreover, other cardiovascular endpoints, such as atrial fibrillation and heart failure have not been fully explored. METHODS AND RESULTS A Medline search for GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, or semaglutide) was performed, collecting all randomized clinical trials with a duration ≥52 weeks, enrolling patients with type 2 diabetes, and comparing a GLP-1 receptor agonist with placebo or any other non-GLP-1 receptor agonist drug. We included 43 trials, enrolling 63,134 patients. A significant reduction of MACE (MH-OR 0.87 [0.83, 0.92]), all-cause mortality (MH-OR 0.89 [0.83, 0.96]), and a nonstatistical trend toward reduction of heart failure (MH-OR 0.93 [0.85, 1.01]) was observed - GLP1-RA did not increase the risk of atrial fibrillation (MH-OR 0.94 [0.84, 1.04]). CONCLUSION The present meta-analysis confirms the favorable effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events, cardiovascular and all-cause mortality, stroke, and possibly myocardial infarction. Conversely, the effects on heart failure remain uncertain. Available data on atrial fibrillation seems to exclude any major safety issues in this respect. REGISTRATION NUMBER (PROSPERO) CRD42018115577.
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Affiliation(s)
- Besmir Nreu
- Diabetology, Careggi Hospital and University of Florence, Italy
| | | | - Federico Tinti
- Diabetology, Careggi Hospital and University of Florence, Italy
| | - Giorgio Sesti
- Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology of the Sapienza University of Rome, Rome, Italy
| | | | - Matteo Monami
- Diabetology, Careggi Hospital and University of Florence, Italy.
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27
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Wysham C, Shubrook J. Beta-cell failure in type 2 diabetes: mechanisms, markers, and clinical implications. Postgrad Med 2020; 132:676-686. [PMID: 32543261 DOI: 10.1080/00325481.2020.1771047] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
It is well known that type 2 diabetes mellitus (T2D) is a globally increasing health burden. Despite recent therapeutic advances and the availability of many different classes of antihyperglycemic therapy, a large proportion of people do not achieve glycemic control. A decline in pancreatic beta-cell function has been defined as a key contributing factor to progression of T2D. In fact, a significant proportion of beta-cell secretory capacity is thought to be lost well before the diagnosis of T2D is made. Several models have been proposed to explain the reduction in beta-cell function, including reduced beta-cell number, beta-cell exhaustion, and dedifferentiation or transdifferentiation into other cell types. However, there have been reports that suggest remission of T2D is possible, and it is believed that beta-cell dysfunction may be, in part, reversible. As such, the question of whether beta cells are committed to failure in people with T2D is complex. It is now widely accepted that early restoration of normoglycemia may protect beta-cell function. Key to the successful implementation of this approach in clinical practice is the appropriate assessment of individuals at risk of beta-cell failure, and the early implementation of appropriate treatment options. In this review, we discuss the progression of T2D in the context of beta-cell failure and describe how C-peptide testing can be used to assess beta-cell function in primary care practice. In conclusion, significant beta-cell dysfunction is likely in individuals with certain clinical characteristics of T2D, such as long duration of disease, high glycated hemoglobin (≥9%), and/or long-term use of therapies that continuously stimulate the beta cell. In these people, measurement of beta-cell status could assist with choice of appropriate therapy to delay or potentially reverse beta-cell dysfunction and the progression of T2D.
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Affiliation(s)
- Carol Wysham
- Department of Diabetes and Endocrinology, Rockwood Diabetes & Endocrinology Clinic , Spokane, WA, USA
| | - Jay Shubrook
- College of Osteopathic Medicine, Touro University California , Vallejo, CA, USA
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28
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Abdul-Ghani MA, Jayyousi A, DeFronzo RA, Asaad N, Al-Suwaidi J. Insulin Resistance the Link between T2DM and CVD: Basic Mechanisms and Clinical Implications. Curr Vasc Pharmacol 2020; 17:153-163. [PMID: 29032755 DOI: 10.2174/1570161115666171010115119] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 09/05/2017] [Accepted: 09/27/2017] [Indexed: 01/04/2023]
Abstract
Insulin resistance (IR) is a cardinal feature of type 2 diabetes mellitus (T2DM). It also is associated with multiple metabolic abnormalities which are known cardiovascular disease (CVD) risk factors. Thus, IR not only contributes to the development of hyperglycemia in T2DM patients, but also to the elevated CVD risk. Improving insulin sensitivity is anticipated to both lower the plasma glucose concentration and decrease CVD risk in T2DM patients, independent of glucose control. We review the molecular mechanisms and metabolic consequences of IR in T2DM patients and discuss the importance of addressing IR in the management of T2DM.
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Affiliation(s)
- Muhammad A Abdul-Ghani
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States.,Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Amin Jayyousi
- Cardio-Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
| | - Ralph A DeFronzo
- Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, United States
| | - Nidal Asaad
- Cardio-Metabolic Institute, Hamad Medical Corporation, Doha, Qatar
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29
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Ehrhardt N, Fazeli S, Rao S, Amdur R. Use of Premixed Insulin, Metformin, and a Glucagon-Like Peptide 1 Receptor Agonist as a Therapeutic Approach for Uncontrolled Type 2 Diabetes. Diabetes Spectr 2020; 33:182-189. [PMID: 32425456 PMCID: PMC7228818 DOI: 10.2337/ds19-0025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVE | To explore the use of premixed insulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, and metformin as combination therapy for type 2 diabetes. DESIGN AND METHODS | All adult patients with type 2 diabetes who had been prescribed premixed insulin and a GLP-1 receptor agonist simultaneously at our outpatient clinic were selected for retrospective review. We reviewed A1C, weight, cumulative daily insulin dose, and adverse events over 12 months. RESULTS | A total of 72 patients received premixed insulin and a GLP-1 receptor agonist, of which 32 met inclusion criteria. The average duration of type 2 diabetes for these patients was 14.2 ± 7.1 years. Mean A1C at baseline was 10.5 ± 2.1%. At 12 months, mean A1C was 8.3 ± 1.9%. The change in mean A1C after 12 months was -2.2% (95% CI -3.433 to -1.014, P <0.0001). At 12 months, the mean cumulative insulin dose was 33.3 units less than before the therapy change (95% CI -57.13 to -9.46, P = 0.0030). Average weight change at 12 months was -2.2 kg (95% CI -27.6 to 37.6, P = NS). After 12 months, 61% of included patients (19 of 31) had an A1C ≤8%. Six additional patients were not included in analysis because they stopped the regimen after <3 months because of adverse events. CONCLUSION | Despite a decreased cumulative daily dose of insulin, patients with historically uncontrolled type 2 diabetes using metformin, premixed insulin, and a GLP-1 receptor agonist in combination experienced improved glycemic control over 12 months. Prospective randomized trials are needed to better assess the potential benefit of this combination therapy.
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Affiliation(s)
- Nicole Ehrhardt
- Division of Endocrinology, George Washington University, Washington, DC
| | - Sasan Fazeli
- Division of Endocrinology, George Washington University, Washington, DC
| | - Sanjana Rao
- George Washington University, School of Medicine and Health Sciences, Washington, DC
| | - Richard Amdur
- George Washington University, School of Medicine and Health Sciences, Washington, DC
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30
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Papaetis GS. Liraglutide Therapy in a Prediabetic State: Rethinking the Evidence. Curr Diabetes Rev 2020; 16:699-715. [PMID: 31886752 DOI: 10.2174/1573399816666191230113446] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 11/20/2019] [Accepted: 12/12/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Prediabetes is defined as a state of glucose metabolism between normal glucose tolerance and type 2 diabetes. Continuous β-cell failure and death are the reasons for the evolution from normal glucose tolerance to prediabetes and finally type 2 diabetes. INTRODUCTION The necessity of new therapeutic approaches in order to prevent or delay the development of type 2 diabetes is obligatory. Liraglutide, a long-acting GLP-1 receptor agonist, has 97% homology for native GLP-1. Identification of the trophic and antiapoptotic properties of liraglutide in preclinical studies, together with evidence of sustained β-cell function longevity during its administration in type 2 diabetes individuals, indicated its earliest possible administration during this disease, or even before its development, so as to postpone or delay its onset. METHODS Pubmed and Google databases have been thoroughly searched and relevant studies were selected. RESULTS This paper explores the current evidence of liraglutide administration both in humans and animal models with prediabetes. Also, it investigates the safety profile of liraglutide treatment and its future role to postpone or delay the evolution of type 2 diabetes. CONCLUSION Liralgutide remains a valuable tool in our therapeutic armamentarium for individuals who are overweight or obese and have prediabetes. Future well designed studies will give valuable information that will help clinicians to stratify individuals who will derive the most benefit from this agent, achieving targeted therapeutic strategies.
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Affiliation(s)
- Georgios S Papaetis
- Internal Medicine and Diabetes Clinic, Eleftherios Venizelos Avenue 62, Paphos, Cyprus
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Cao C, Yang S, Zhou Z. GLP-1 receptor agonists and risk of cancer in type 2 diabetes: an updated meta-analysis of randomized controlled trials. Endocrine 2019; 66:157-165. [PMID: 31420784 DOI: 10.1007/s12020-019-02055-z] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 08/06/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE Some preliminary studies reported a link between GLP-1 receptor agonists (GLP-1RAs) and thyroid/pancreatic neoplasms, while its human relevance remained undetermined. The present meta-analysis was performed to collect information on cancers associated with GLP-1RAs in patients with type 2 diabetes mellitus (T2DM). METHODS Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science and ClinicalTrials.gov were extensively searched to identify randomized controlled trials that reported cancer events in T2DM patients treated with GLP-1RAs for at least 52 weeks, up to March 18, 2019. Odds ratio (OR) with 95% Confidence Interval (CI) was calculated for overall cancer (primary outcome), thyroid and pancreatic cancer. RESULTS A total of 37 eligible trials were identified. The OR for overall cancer associated with GLP-1RAs was 1.03 (95% CI 0.95-1.12; p = 0.41) compared with comparators. Subgroup analyses showed that treatment with albiglutide was associated with a lower risk of overall cancer (OR 0.76 [95% CI 0.60-0.97]; p = 0.03), and no elevated risk of overall cancer was identified for other GLP-1RAs. No significant differences in the risks of thyroid nor pancreatic cancer were disclosed between GLP-1RAs and comparators. CONCLUSIONS This meta-analysis did not suggest any increased risk of cancers associated with GLP-1RAs use in T2DM. The reduction in the risk of overall cancer associated with albiglutide needs to be examined further.
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Affiliation(s)
- Chuqing Cao
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Shuting Yang
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China
| | - Zhiguang Zhou
- Department of Metabolism & Endocrinology, The Second Xiangya Hospital, Central South University, No. 139 Renmin Road, Changsha, 410011, Hunan, China.
- Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, China.
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Fiorentino TV, Casiraghi F, Davalli AM, Finzi G, La Rosa S, Higgins PB, Abrahamian GA, Marando A, Sessa F, Perego C, Guardado-Mendoza R, Kamath S, Ricotti A, Fiorina P, Daniele G, Paez AM, Andreozzi F, Bastarrachea RA, Comuzzie AG, Gastaldelli A, Chavez AO, Di Cairano ES, Frost P, Luzi L, Dick EJ, Halff GA, DeFronzo RA, Folli F. Exenatide regulates pancreatic islet integrity and insulin sensitivity in the nonhuman primate baboon Papio hamadryas. JCI Insight 2019; 4:93091. [PMID: 31536476 DOI: 10.1172/jci.insight.93091] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022] Open
Abstract
The glucagon-like peptide-1 receptor agonist exenatide improves glycemic control by several and not completely understood mechanisms. Herein, we examined the effects of chronic intravenous exenatide infusion on insulin sensitivity, β cell and α cell function and relative volumes, and islet cell apoptosis and replication in nondiabetic nonhuman primates (baboons). At baseline, baboons received a 2-step hyperglycemic clamp followed by an l-arginine bolus (HC/A). After HC/A, baboons underwent a partial pancreatectomy (tail removal) and received a continuous exenatide (n = 12) or saline (n = 12) infusion for 13 weeks. At the end of treatment, HC/A was repeated, and the remnant pancreas (head-body) was harvested. Insulin sensitivity increased dramatically after exenatide treatment and was accompanied by a decrease in insulin and C-peptide secretion, while the insulin secretion/insulin resistance (disposition) index increased by about 2-fold. β, α, and δ cell relative volumes in exenatide-treated baboons were significantly increased compared with saline-treated controls, primarily as the result of increased islet cell replication. Features of cellular stress and secretory dysfunction were present in islets of saline-treated baboons and absent in islets of exenatide-treated baboons. In conclusion, chronic administration of exenatide exerts proliferative and cytoprotective effects on β, α, and δ cells and produces a robust increase in insulin sensitivity in nonhuman primates.
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Affiliation(s)
- Teresa Vanessa Fiorentino
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.,Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Francesca Casiraghi
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Alberto M Davalli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Department of Medicine, Endocrinology Unit, Ospedale San Raffaele, Milan, Italy
| | - Giovanna Finzi
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Stefano La Rosa
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Paul B Higgins
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Gregory A Abrahamian
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Alessandro Marando
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Fausto Sessa
- Unit of Pathology, Ospedale di Circolo and Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Carla Perego
- Department of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy
| | - Rodolfo Guardado-Mendoza
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Subhash Kamath
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Andrea Ricotti
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Paolo Fiorina
- Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, Division of Health Science, Harvard University, Boston, Massachusetts, USA
| | - Giuseppe Daniele
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Ana M Paez
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Francesco Andreozzi
- Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro, Italy.,Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Raul A Bastarrachea
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Anthony G Comuzzie
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Amalia Gastaldelli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Institute of Clinical Physiology, National Research Council, Pisa, Italy
| | - Alberto O Chavez
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Eliana S Di Cairano
- Department of Pharmacology and Biomolecular Science, University of Milan, Milan, Italy
| | - Patrice Frost
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Livio Luzi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.,Metabolism Research Centre, IRCCS Policlinico San Donato, Milan, Italy
| | - Edward J Dick
- Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA
| | - Glenn A Halff
- Department of Surgery, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Ralph A DeFronzo
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA
| | - Franco Folli
- Division of Diabetes, Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.,Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.,Department of Health Science, University of Milan, Milan, Italy
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Guyton J, Jeon M, Brooks A. Glucagon-like peptide 1 receptor agonists in type 1 diabetes mellitus. Am J Health Syst Pharm 2019; 76:1739-1748. [PMID: 31612934 DOI: 10.1093/ajhp/zxz179] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
PURPOSE The role of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in the treatment of type 1 diabetes mellitus (T1DM), including efficacy and safety evidence, is reviewed. SUMMARY Currently approved treatment options for glycemic control in T1DM include insulin, which combats insulin deficiency but does not effectively target disease progression or alpha cell dysfunction; and pramlintide, whose use requires multiple daily doses and involves a high likelihood of gastrointestinal side effects. GLP-1 RAs have a unique mechanism of action in T1DM, addressing alpha cell dysfunction and thereby suppressing inappropriate glucagon secretion. GLP-1 RA dosing varies from once weekly to twice daily, and the class is well tolerated in patients with type 2 diabetes. Among the GLP-1 RAs, exenatide and liraglutide have been studied in patients with T1DM, with published evidence consistently demonstrating weight loss, decreases in total daily insulin requirements, and modest improvements in glycemic control. GLP-1 RA therapy appears to be well tolerated in patients with T1DM and is associated with nonsignificant increases in hypoglycemia risk. CONCLUSION GLP-1 RA therapy represents an important add-on therapy option for achieving decreased insulin doses, weight loss, and modest improvements in HbA1c levels without significantly increasing hypoglycemia risk in patients with T1DM. Patients who have detectable C-peptide and/or are overweight or cannot achieve glycemic goals without hypoglycemia have been found to benefit the most from GLP-1 RA therapy. Further studies are warranted to evaluate these agents' potential impact on clinical outcomes such as microvascular and macrovascular complications.
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Affiliation(s)
- Justinne Guyton
- St. Louis College of Pharmacy, St. Louis, MO, and St. Louis County Department of Public Health, St. Louis, MO
| | - Michelle Jeon
- St. Louis College of Pharmacy, St. Louis, MO, and Walgreens Pharmacy, St. Louis, MO
| | - Amie Brooks
- St. Louis College of Pharmacy, St. Louis, MO
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Morillas C, Escalada J, Palomares R, Bellido D, Gómez-Peralta F, Pérez A. Treatment of Type 2 Diabetes by Patient Profile in the Clinical Practice of Endocrinology in Spain: Delphi Study Results from the Think Twice Program. Diabetes Ther 2019; 10:1893-1907. [PMID: 31359366 PMCID: PMC6778580 DOI: 10.1007/s13300-019-0671-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION The aim of this Delphi study is to unveil the management of patients with type 2 diabetes (T2D) and different levels of complexity in the clinical practice in Spain. METHODS Based on the common management practices of T2D profiles reported by Spanish endocrinologists, a Delphi questionnaire of 55 statements was developed and responded to by a national panel (n = 101). RESULTS A consensus was reached for 30 of the 55 statements. Regarding overweight patients inadequately controlled with metformin, treatment with a sodium-glucose transport protein 2 inhibitor (SGLT2-I) is preferred over treatment with a dipeptidyl peptidase-4 inhibitor (DPP4-I). If the patient is already being treated with a DPP4-I, an SGLT2-I is added on to the treatment regimen rather than replacing the DPP4-I. Conversely, if the treatment regimen includes a sulfonylurea, it is usually replaced by other antihyperglycemic agents. Current treatment trends in uncontrolled obese patients include the addition of an SGLT2-I or a glucagon-like peptide-1 receptor agonist (GLP1-RA) to background therapy. When the glycated hemoglobin target is not reached, triple therapy with metformin + GLP1-RA + SGLT2-I is initiated. Although SGLT2-Is are the treatment of choice in patients with T2D and heart failure or uncontrolled hypertension, no consensus was reached regarding the preferential use of SGLT2-Is or GLP1-RAs in patients with established cardiovascular disease. CONCLUSION Consensus has been reached for a variety of statements regarding the management of several T2D profiles. Achieving a more homogeneous management of complex patients with T2D may require further evidence and a better understanding of the key drivers for treatment choice. FUNDING Logistic support was provided by ESTEVE Pharmaceuticals S.A Spain.
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Affiliation(s)
| | | | | | - Diego Bellido
- Hospital Arquitecto Marcide, Complejo Hospitalario Universitario de Ferrol [CHUF], El Ferrol, Spain
| | | | - Antonio Pérez
- Hospital de la Santa Creu i Sant Pau, CIBERDEM, c/de Sant Quintí, Barcelona, Spain
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Jung SJ, Nguyen NTT, Lee SA, Seo SH, Choi ES, Lee HW, Seong GH, Bae ON, Lee E. In-vivo half-life and hypoglycemic bioactivity of a fusion protein of exenatide and elastin-based polypeptide from recombinant Saccharomyces cerevisiae. J Biotechnol 2019; 303:16-24. [DOI: 10.1016/j.jbiotec.2019.06.304] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2019] [Revised: 06/07/2019] [Accepted: 06/26/2019] [Indexed: 10/26/2022]
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The RISE Consortium. Lack of Durable Improvements in β-Cell Function Following Withdrawal of Pharmacological Interventions in Adults With Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes. Diabetes Care 2019; 42:1742-1751. [PMID: 31178434 PMCID: PMC6702605 DOI: 10.2337/dc19-0556] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Accepted: 05/02/2019] [Indexed: 02/03/2023]
Abstract
OBJECTIVE The Restoring Insulin Secretion (RISE) Adult Medication Study compared pharmacological approaches targeted to improve β-cell function in individuals with impaired glucose tolerance (IGT) or treatment-naive type 2 diabetes of <12 months duration. RESEARCH DESIGN AND METHODS A total of 267 adults with IGT (n = 197, 74%) or recently diagnosed type 2 diabetes (n = 70, 26%) were studied. Participants were randomized to receive 12 months of metformin alone, 3 months of insulin glargine with a target fasting glucose <5 mmol/L followed by 9 months of metformin, 12 months of liraglutide combined with metformin, or 12 months of placebo. β-Cell function was assessed using hyperglycemic clamps at baseline, 12 months (on treatment), and 15 months (3 months off treatment). The primary outcome was β-cell function at 15 months compared with baseline. RESULTS All three active treatments produced on-treatment reductions in weight and improvements in HbA1c compared with placebo; the greatest reductions were seen in the liraglutide plus metformin group. At 12 months, glucose-stimulated C-peptide responses improved in the three active treatment groups and were greatest in the liraglutide plus metformin group, but the arginine-stimulated incremental C-peptide response was reduced in the liraglutide plus metformin group. Despite on-treatment benefits, 3 months after treatment withdrawal there were no sustained improvements in β-cell function in any treatment group. CONCLUSIONS In adults with IGT or recently diagnosed type 2 diabetes, interventions that improved β-cell function during active treatment failed to produce persistent benefits after treatment withdrawal. These observations suggest that continued intervention may be required to alter the progressive β-cell dysfunction in IGT or early type 2 diabetes.
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Muskiet MHA, Bunck MC, Heine RJ, Cornér A, Yki-Järvinen H, Eliasson B, Joles JA, Diamant M, Tonneijck L, van Raalte DH. Exenatide twice-daily does not affect renal function or albuminuria compared to titrated insulin glargine in patients with type 2 diabetes mellitus: A post-hoc analysis of a 52-week randomised trial. Diabetes Res Clin Pract 2019; 153:14-22. [PMID: 31078666 DOI: 10.1016/j.diabres.2019.05.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 04/30/2019] [Accepted: 05/03/2019] [Indexed: 12/23/2022]
Abstract
AIMS To compare the effects of long-term treatment with the GLP-1RA exenatide twice-daily versus titrated insulin glargine (iGlar) on renal function and albuminuria in type 2 diabetes (T2DM) patients. METHODS We post-hoc evaluated renal outcome-data of 54 overweight T2DM patients (mean ± SD age 60 ± 8 years, HbA1c 7.5 ± 0.9%, eGFR 86 ± 16 mL/min/1.73 m2, median [IQR] urinary albumin-to-creatinine-ratio (UACR) 0.75 [0.44-1.29] mg/mmol) randomised to exenatide 10 µg twice-daily or titrated iGlar on-top-of metformin for 52-weeks. Renal efficacy endpoints were change in creatinine clearance (CrCl) and albuminuria (urinary albumin-excretion [UAE] and UACR) based on 24-h urines, collected at baseline and Week-52. eGFR and exploratory endpoints were collected throughout the intervention-period, and after a 4-week wash-out. RESULTS HbA1c-reductions were similar with exenatide (mean ± SEM -0.80 ± 0.10%) and iGlar (-0.79 ± 0.14%; treatment-difference 0.02%; 95% CI -0.31 to 0.42%). Change from baseline to Week-52 in CrCl, UAE or UACR did not statistically differ; only iGlar reduced albuminuria (P < 0.05; within-group). eGFR decreased from baseline to Week-4 with exenatide (-3.9 ± 2.1 mL/min/1.73 m2; P = 0.069) and iGlar (-2.7 ± 1.2 mL/min/1.73 m2; P = 0.034), without treatment-differences in ensuing trajectory. Exenatide versus iGlar reduced bodyweight (-5.4 kg; 2.9-7.9; P < 0.001), but did not affect blood pressure, lipids or plasma uric acid. CONCLUSIONS Among T2DM patients without overt nephropathy, one-year treatment with exenatide twice-daily does not affect renal function-decline or onset/progression of albuminuria compared to titrated iGlar. TRIAL REGISTRATION ClinicalTrials.gov ID: NCT00097500.
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Affiliation(s)
- M H A Muskiet
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands.
| | - M C Bunck
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands; Eli Lilly and Co., Indianapolis, IN, USA
| | - R J Heine
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands; Eli Lilly and Co., Indianapolis, IN, USA
| | - A Cornér
- Research Programs' Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - H Yki-Järvinen
- Research Programs' Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
| | - B Eliasson
- Lundberg Laboratory for Diabetes Research, Sahlgrenska University Hospital, Göteborg, Sweden
| | - J A Joles
- Department of Nephrology and Hypertension, University Medical Center, Utrecht, the Netherlands
| | - M Diamant
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
| | - L Tonneijck
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
| | - D H van Raalte
- Diabetes Centre, Amsterdam University Medical Centers, location VUMC, Amsterdam, the Netherlands
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Chen X, Zhang J, Zhou Z. Targeting Islets: Metabolic Surgery Is More than a Bariatric Surgery. Obes Surg 2019; 29:3001-3009. [DOI: 10.1007/s11695-019-03979-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Blonde L, Anderson JE, Chava P, Dendy JA. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin 2019; 35:793-804. [PMID: 30370783 DOI: 10.1080/03007995.2018.1541790] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
OBJECTIVE Achieving and maintaining recommended glycemic targets, including those for glycated hemoglobin A1c (A1C), is key to improving outcomes in patients with type 2 diabetes (T2D). As fasting plasma glucose and postprandial glucose contribute to overall A1C, targeting both is essential for sustaining glycemic control. METHODS This review examines the complementary mechanisms of action of glucagon-like peptide 1 (GLP-1) receptor agonists and basal insulin; they both enhance glucose-stimulated insulin release and suppress glucagon secretion. GLP-1 receptor agonists also slow gastric emptying and increase satiety. RESULTS Adding a GLP-1 receptor agonist to therapy with a basal insulin analog has been associated with improved overall glycemic control, with comparable risk of hypoglycemia and no weight gain. Titratable fixed-ratio co-formulations of basal insulin and a GLP-1 receptor agonist have been shown to improve glycemic control, with less complex dosing schedules, possibly increasing treatment adherence. The slow titration of fixed-ratio co-formulations has been shown to reduce the occurrence and severity of gastrointestinal adverse events associated with the use of a separate GLP-1 receptor agonist. Titratable fixed-ratio co-formulations also mitigate insulin-associated weight gain, and show a comparable risk of hypoglycemia to basal insulin use alone. CONCLUSIONS The efficacy and safety of titratable fixed-ratio co-formulations have been demonstrated for insulin degludec/liraglutide and insulin glargine/lixisenatide in the DUAL and LixiLan trials, respectively, in both insulin-naive and -experienced patients. Titratable fixed-ratio co-formulations represent an attractive treatment option for many patients with T2D.
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Affiliation(s)
- Lawrence Blonde
- a Ochsner Diabetes Clinical Research Unit, Frank Riddick Diabetes Institute, Department of Endocrinology , Ochsner Medical Center , New Orleans , LA , USA
| | | | - Pavan Chava
- c Ochsner Medical Center , Department of Endocrinology , New Orleans , LA , USA
| | - Jared A Dendy
- c Ochsner Medical Center , Department of Endocrinology , New Orleans , LA , USA
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Abstract
The clinical onset of type 1 diabetes is characterized by the destruction of the insulin-producing β cells of the pancreas and is caused by autoantigen-induced inflammation (insulitis) of the islets of Langerhans. The current standard of care for type 1 diabetes mellitus patients allows for management of the disease with exogenous insulin, but patients eventually succumb to many chronic complications such as limb amputation, blindness, and kidney failure. New therapeutic approaches now on the horizon are looking beyond glycemic management and are evaluating new strategies from protecting and regenerating endogenous islets to treating the underlying autoimmunity through selective modulation of key immune cell populations. Currently, there are no effective treatments for the autoimmunity that causes the disease, and strategies that aim to delay or prevent the onset of the disease will play an important role in the future of diabetes research. In this review, we summarize many of the key efforts underway that utilize molecular approaches to selectively modulate this disease and look at new therapeutic paradigms that can transform clinical treatment.
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Affiliation(s)
- Daniel Sheehy
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Sean Quinnell
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
| | - Arturo J. Vegas
- Department of Chemistry, Boston University, Boston, Massachusetts 02215, United States
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Watada H, Shiramoto M, Irie S, Terauchi Y, Yamada Y, Shiosakai K, Myobatake Y, Taguchi T. G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic β-cells in Japanese type 2 diabetes mellitus patients. J Diabetes Investig 2019; 10:84-93. [PMID: 29624887 PMCID: PMC6319480 DOI: 10.1111/jdi.12849] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Revised: 03/06/2018] [Accepted: 03/28/2018] [Indexed: 12/17/2022] Open
Abstract
AIMS/INTRODUCTION Pancreatic β-cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein-coupled receptor 119 agonist DS-8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS This single-center, 4-week, randomized, double-blind, cross-over study enrolled 21 Japanese drug-naïve type 2 diabetes mellitus patients aged ≥20 years with glycated hemoglobin ≥7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS-8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic-hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4-week treatment period. Primary end-points were first-phase insulin secretion (insulin area under the curve [AUC]180-190 min and C-peptide AUC180-190 min during the clamp test) and second-phase insulin secretion (insulin AUC190-300 min and C-peptide AUC190-300 min ). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. RESULTS DS-8500a significantly increased first- and second-phase insulin AUC (P = 0.0011, P = 0.0112) and C-peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C-peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high-density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment-emergent adverse events occurred. CONCLUSION DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity.
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Affiliation(s)
- Hirotaka Watada
- Department of Metabolism and EndocrinologyJuntendo University Graduate School of MedicineTokyoJapan
| | | | - Shin Irie
- SOUSEIKAI Hakata ClinicHakataFukuokaJapan
| | - Yasuo Terauchi
- Department of Endocrinology and MetabolismYokohama City University Graduate School of MedicineYokohamaKanagawaJapan
| | - Yuichiro Yamada
- Department of Endocrinology, Diabetes and Geriatric MedicineAkita University School of MedicineAkitaJapan
| | | | - Yusuke Myobatake
- Clinical Development Department, Daiichi Sankyo Co., LtdTokyoJapan
| | - Takashi Taguchi
- Clinical Development Department, Daiichi Sankyo Co., LtdTokyoJapan
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Yin TT, Bi Y, Li P, Shen SM, Wang WM, Jiang C, Gao CX, Wang Y, Gao LJ, Zhu DL, Feng WH. Effects of exenatide versus insulin glargine on body composition in overweight and obese T2DM patients: a randomized controlled trial. Nutr Metab (Lond) 2018; 15:67. [PMID: 30302121 PMCID: PMC6167818 DOI: 10.1186/s12986-018-0295-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 07/27/2018] [Indexed: 12/13/2022] Open
Abstract
Background Weight loss, especially fat mass reduction, helps to improve blood glucose control, insulin sensitivity, and β-cell function. This study aimed to compare the effect of exenatide and glargine on body composition in overweight and obese patients with type 2 diabetes (T2DM) who do not achieve adequate glycemic control with metformin. Methods We performed a prospective, randomized study of 37 overweight or obese patients with T2DM who had inadequate glycemic control with metformin. The patients were treated with either exenatide or glargine for 16 weeks. Dual-energy X-ray absorptiometry was used to assess body composition. Results Post-intervention weight, body mass index (BMI), waist circumference, body mass, and fat mass were lower in patients treated with exenatide, while weight and BMI significantly increased with glargine. Reductions in weight, BMI, body fat mass, and percent fat mass (except for gynoid) were greater with exenatide than with glargine, and percent lean tissue (other than the limbs) increased with exenatide. In all body regions except for the limbs, fat mass decreased with exenatide to a greater extent than lean tissue. Glucose control, insulin resistance, and β-cell function were not different between the treatment groups. Conclusions For overweight and obese patients whose T2DM was inadequately controlled with metformin, exenatide and glargine achieved similar improvements in glycemic control, insulin sensitivity, and β-cell function.However, exenatide produced better weight and fat mass reduction, which were beneficial for blood glucose control. Our findings may guide the selection of appropriate drugs for glycemic and weight control. Trial registration NCT02325960, registered 25 December 2014.
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Affiliation(s)
- Ting-Ting Yin
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China.,2Department of Endocrinology, Drum Tower Clinical Hospital, Medical School of Southeast University, Zhongshan Road 321, Nanjing, 210008 China
| | - Yan Bi
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Ping Li
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Shan-Mei Shen
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Wei-Min Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Can Jiang
- Department of Endocrinology, Jining No1. People's Hospital, Shandong, China
| | - Cai-Xia Gao
- Department of Traditional Chinese Medicine, Yan'an People's Hospital, Yan'an, China
| | - Yan Wang
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Li-Jun Gao
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China.,2Department of Endocrinology, Drum Tower Clinical Hospital, Medical School of Southeast University, Zhongshan Road 321, Nanjing, 210008 China
| | - Da-Long Zhu
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China
| | - Wen-Huan Feng
- Department of Endocrinology, Drum Tower Hospital Affiliated to Nanjing University Medical School, Nanjing, China.,2Department of Endocrinology, Drum Tower Clinical Hospital, Medical School of Southeast University, Zhongshan Road 321, Nanjing, 210008 China
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Miyagi M, Uchino H, Kumashiro N, Higa M, Shin K, Sasamoto M, Kitazato H, Tamaki M, Matsuhisa M, Hirose T. Up-Titration Strategy After DPP-4 Inhibitor-Based Oral Therapy for Type 2 Diabetes: A Randomized Controlled Trial Shifting to a Single-Dose GLP-1 Enhancer Versus Adding a Variable Basal Insulin Algorithm. Diabetes Ther 2018; 9:1959-1968. [PMID: 30121725 PMCID: PMC6167274 DOI: 10.1007/s13300-018-0486-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Indexed: 12/02/2022] Open
Abstract
INTRODUCTION It is unclear whether adding basal insulin or enhancing incretin signaling with a glucagon-like peptide-1 receptor agonist (GLP-1RA) is more effective as an up-titration strategy after dipeptidyl peptidase-4 inhibitor (DPP-4i)-based oral antidiabetic drug (OAD) therapy. GLP-1RAs can be injected without dose adjustment, unlike basal insulin. Our objective was to examine the efficacy of changing patients inadequately controlled with oral DPP-4i-based OAD therapy to injectable GLP-1RA and discontinuing the DPP4i versus adding basal insulin glargine (IGlar) with the continuation of the oral DPP4i. METHODS Sixty patients with type 2 diabetes (T2DM) and glycated hemoglobin (HbA1c) between 7.0% and 10.0% on DPP-4i-based OAD therapy were randomized to either adding IGlar and remaining on the DPP-4i or liraglutide and discontinuing the DPP-4i for 24 weeks. Patients in the IGlar group started with 0.1 unit/kg and were titrated according to the algorithm. In the liraglutide group, the DPP-4i was replaced with liraglutide 0.9 mg/day, the maximum dose in Japan. We evaluated HbA1c, glycated albumin (GA), and anthropometrics. RESULTS HbA1c was significantly lower at week 24 (- 1.0 ± 0.9% in the IGlar group and - 0.6 ± 0.8% in the liraglutide group), but the difference between groups was not significant. Changes in GA were similar (- 2.9 ± 3.2% vs. - 2.6 ± 3.2%) in both groups. Body weight (BW) was significantly lower only in the liraglutide group (+ 0.5 ± 2.6 kg vs. - 2.2 ± 2.0 kg). The rate of minor hypoglycemic episodes was similar for both groups. CONCLUSION For poorly controlled T2DM on DPP-4i-based OAD therapy, switching to single-dose liraglutide to enhance incretin signaling is as effective as dose-titrated basal IGlar, but significant BW reduction was only seen in the liraglutide group. These results suggest that enhancing incretin signaling with a single-dose injectable GLP-1 RA might be an alternative to dose-titrated basal insulin therapy in patients with T2DM poorly controlled with DPP-4i-based OAD therapy. These findings should be confirmed in a longer and larger trial. TRIAL REGISTRATION Trial Registry (UMIN-CTR) as UMIN000012224.
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Affiliation(s)
- Masahiko Miyagi
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan
| | - Hiroshi Uchino
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan.
| | - Naoki Kumashiro
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan
| | - Mariko Higa
- Division of Diabetes and Endocrinology, Saiseikai Yokohama-city Tobu Hospital, Kanagawa, Japan
| | | | | | - Hiroji Kitazato
- Division of Diabetes and Endocrinology, Omori Red-Cross Hospital, Tokyo, Japan
| | - Motoyuki Tamaki
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Munehide Matsuhisa
- Diabetes Therapeutics and Research Center, Institute of Advanced Medical Sciences, Tokushima University, Tokushima, Japan
| | - Takahisa Hirose
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University Graduate School of Medicine, Tokyo, Japan
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Menzel C, Holzeisen T, Laffleur F, Zaichik S, Abdulkarim M, Gumbleton M, Bernkop-Schnürch A. In vivo evaluation of an oral self-emulsifying drug delivery system (SEDDS) for exenatide. J Control Release 2018; 277:165-172. [DOI: 10.1016/j.jconrel.2018.03.018] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2018] [Revised: 03/10/2018] [Accepted: 03/18/2018] [Indexed: 12/15/2022]
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Zhong X, Yang S, Liu T, Ji S, Hu J, Li H. Engineering a novel protease-based Exendin-4 derivative for type 2 antidiabetic therapeutics. Eur J Med Chem 2018; 150:841-850. [PMID: 29597167 DOI: 10.1016/j.ejmech.2018.03.050] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2018] [Revised: 03/16/2018] [Accepted: 03/18/2018] [Indexed: 11/26/2022]
Abstract
To develop an effective long-acting antidiabetic agent, we designed a novel Exendin-4 derivative (termed LEx4) containing an albumin-binding domain (ABD), a protease-cleavable linker and a native Exendin-4. Here, we present the LEx4 with balanced glucoregulatory activity and prolonged in vivo activity. As a first step, the LEx4 with purity more than 99% was prepared. Microscale thermophoresis (MST) results demonstrated that LEx4 associates with rat and monkey serum albumin with high-affinity (Ka = 1.26 × 106 M-1 and 1.52 × 106 M-1, respectively). Then the stability test in vitro showed the enhanced antiproteolytic ability of LEx4 in rat and human plasma compared to native Exendin-4. Oral glucose tolerance test (OGTT) in type 2 diabetic mice showed the glucose-lowering efficacy of LEx4 was clearly dosage-dependent within 25-250 nmol/kg. In addition, the protracted antidiabetic effects of LEx4 were further confirmed by both multiple OGTTs and hypoglycemic efficacies test in type 2 diabetic mice. In Sprague Dawley (SD) rats, LEx4 also showed 3.3-fold longer elimination half-life (t1/2) than native Exendin-4. Furthermore, once daily injection of LEx4 to db/db mice achieved long-term beneficial effects on body weight, blood biochemical values, glucose tolerance and pancreatic tissue. We believe LEx4 has superior pharmaceutical potential as a therapeutic drug to against type-2 diabetes mellitus (T2DM) based on these results. This strategy of albumin binding is also applicable to other bioactive peptides for development of long-acting therapeutic drugs.
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Affiliation(s)
- Xia Zhong
- Department of Life Science and Technology College, Jinan University, Guangzhou, 510000, China.
| | - Shaomin Yang
- Department of Pain Medicine and Shenzhen Municipal Key Laboratory for Pain Medicine, The Affliated Nanshan People's Hospital of Shenzhen University, Shenzhen Municipal Sixth People's Hospital, Shenzhen, 518060, China
| | - Tianxiang Liu
- Department of Life Science and Technology College, Jinan University, Guangzhou, 510000, China; Guanhao Biotech Inc. Guangzhou, 510000, China
| | - Shundong Ji
- The First Affiliated Hospital of Soochow University, Suzhou, 215000, China
| | - Jinrui Hu
- Department of Life Science and Technology College, Jinan University, Guangzhou, 510000, China
| | - Hongjian Li
- Department of Life Science and Technology College, Jinan University, Guangzhou, 510000, China
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Tran S, Kramer CK, Zinman B, Choi H, Retnakaran R. Effect of chronic liraglutide therapy and its withdrawal on time to postchallenge peak glucose in type 2 diabetes. Am J Physiol Endocrinol Metab 2018; 314:E287-E295. [PMID: 29183873 DOI: 10.1152/ajpendo.00374.2017] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Delayed timing of peak serum glucose following an oral glucose challenge can predict declining β-cell function and worsening glucose tolerance over time. Accordingly, postchallenge peak glucose is typically delayed in patients with type 2 diabetes (T2DM). However, little is known about the capacity of antidiabetic medications to reverse this delay. Thus, we sought to evaluate the effect of the glucagon-like peptide-1 agonist liraglutide on time to peak glucose in early T2DM. In this secondary analysis of a double-blind placebo-controlled trial, 51 patients with T2DM of 2.6 ± 1.9 yr duration were randomized to daily subcutaneous liraglutide or placebo injection for 48 wk, with oral glucose tolerance test (OGTT) performed every 12 wk while on therapy and after a 2-wk washout. On each OGTT, time to peak glucose was determined from venous glucose measurements at 0, 10, 20, 30, 60, 90, and 120 min. At randomization, most patients in both arms exhibited peak glucose at 90 min postchallenge. By 12 wk, 65.4% of the liraglutide arm had shifted to an earlier peak (vs. 36% on placebo; P = 0.19), with little change thereafter at 24, 36, and 48 wk. After the 2-wk washout, however, 57.7% of those who had been on liraglutide reverted to a later peak (vs. 4.5% on placebo; P < 0.001). This shift was associated with declining β-cell function ( P = 0.001), resulting in higher 2-h blood glucose at washout in the liraglutide arm compared with placebo ( P = 0.001). Thus, although liraglutide possibly might improve the delay in peak glucose, its cessation yielded a worsening thereof and higher glycemia. The mechanisms underlying these observations and their clinical implications warrant further investigation.
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Affiliation(s)
- Susan Tran
- Department of Medicine, University of Toronto , Toronto, Ontario , Canada
| | - Caroline K Kramer
- Department of Medicine, University of Toronto , Toronto, Ontario , Canada
- Division of Endocrinology, University of Toronto , Toronto, Ontario , Canada
| | - Bernard Zinman
- Department of Medicine, University of Toronto , Toronto, Ontario , Canada
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital , Toronto, Ontario , Canada
- Division of Endocrinology, University of Toronto , Toronto, Ontario , Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, Ontario , Canada
| | - Haysook Choi
- Leadership Sinai Centre for Diabetes, Mount Sinai Hospital , Toronto, Ontario , Canada
| | - Ravi Retnakaran
- Department of Medicine, University of Toronto , Toronto, Ontario , Canada
- Division of Endocrinology, University of Toronto , Toronto, Ontario , Canada
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital , Toronto, Ontario , Canada
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Abstract
Much progress has been made in type 1 diabetes research. Biological replacement of islet function has been achieved with pancreas transplantation and with islet transplantation. In the future, human embryonic stem cells and/or induced pluripotent stem cells may offer a potentially unlimited source of cells for islet replacement. Another potential strategy is to induce robust beta cell replication so that regeneration of islets can be achieved. Immune interventions are being studied with the hope of arresting the type 1 diabetes disease process to either prevent the disease or help preserve beta cell function. Mechanical replacement of islet cell function involves the use of glucose sensor-controlled insulin infusion systems. As all of these avenues are pursued, headlines often overstate the case, thus hyping any given advance, which provides enormous hope for patients and families seeking a cure for type 1 diabetes. Often, however, it is an animal study or a pilot trial that is being described. The reality is that translation to successful trials in human beings may not be readily achievable. This article discusses both the hype and the hopes in type 1 diabetes research.
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Affiliation(s)
- Jay S Skyler
- Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Avenue - Suite 3054, Miami, FL, 33136, USA.
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Upadhyay J, Polyzos SA, Perakakis N, Thakkar B, Paschou SA, Katsiki N, Underwood P, Park KH, Seufert J, Kang ES, Sternthal E, Karagiannis A, Mantzoros CS. Pharmacotherapy of type 2 diabetes: An update. Metabolism 2018; 78:13-42. [PMID: 28920861 DOI: 10.1016/j.metabol.2017.08.010] [Citation(s) in RCA: 139] [Impact Index Per Article: 19.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Revised: 08/24/2017] [Accepted: 08/26/2017] [Indexed: 12/22/2022]
Abstract
Type 2 diabetes (T2DM) is a leading cause of morbidity and mortality worldwide and a major economic burden. The prevalence of T2DM is rising, suggesting more effective prevention and treatment strategies are necessary. The aim of this narrative review is to summarize the pharmacologic treatment options available for patients with T2DM. Each therapeutic class is presented in detail, outlining medication effects, side effects, glycemic control, effect on weight, indications and contraindications, and use in selected populations (heart failure, renal insufficiency, obesity and the elderly). We also present representative cost for each antidiabetic category. Then, we provide an individualized guide for initiation and intensification of treatment and discuss the considerations and rationale for an individualized glycemic goal.
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Affiliation(s)
- Jagriti Upadhyay
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
| | - Stergios A Polyzos
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Nikolaos Perakakis
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA; Divisions of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany
| | - Bindiya Thakkar
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Stavroula A Paschou
- Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Niki Katsiki
- Second Propedeutic Department of Internal Medicine, Medical School, Aristotle University of Thessaloniki, Hippocration Hospital, Thessaloniki, Greece
| | - Patricia Underwood
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Kyung-Hee Park
- Department of Family Medicine, Hallym University Sacred Heart Hospital, Gyeonggi-do, Republic of Korea
| | - Jochen Seufert
- Divisions of Endocrinology and Diabetology, Department of Internal Medicine II, University Hospital of Freiburg, Freiburg, Germany
| | - Eun Seok Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Elliot Sternthal
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA
| | - Asterios Karagiannis
- First Department of Pharmacology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Christos S Mantzoros
- Section of Endocrinology, Diabetes and Metabolism, Boston VA Healthcare System, Boston, MA, USA; Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
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Liu X, Zhang Y, Zheng SY, Lin R, Xie YJ, Chen H, Zheng YX, Liu E, Chen L, Yan JH, Xu W, Mai TT, Gong Y. Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome. Clin Endocrinol (Oxf) 2017; 87:767-774. [PMID: 28834553 DOI: 10.1111/cen.13454] [Citation(s) in RCA: 75] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 07/20/2017] [Accepted: 08/19/2017] [Indexed: 02/06/2023]
Abstract
CONTEXT Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment. OBJECTIVE To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS. DESIGN This is a 24-week open-label prospective, randomized, clinical study. PATIENTS AND MEASUREMENTS This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 μg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks. RESULTS After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05). CONCLUSIONS Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.
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Affiliation(s)
- Xin Liu
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Ying Zhang
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
- Key Laboratory for Major Obstetric Diseases of Guangdong Higher Education Institutes, Guangzhou, Guangdong, China
| | - Si-Yuan Zheng
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Rong Lin
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yi-Juan Xie
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Hui Chen
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yong-Xiong Zheng
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - En Liu
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Lin Chen
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jia-He Yan
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Wei Xu
- Department of Cardiology, Huadu District People's Hospital of Guangzhou, Guangzhou, Guangdong, China
| | - Ting-Ting Mai
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yi Gong
- Department of Endocrinology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
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Nguyen TTB, Jin YY, Chung HJ, Hong ST. Pharmabiotics as an Emerging Medication for Metabolic Syndrome and Its Related Diseases. Molecules 2017; 22:E1795. [PMID: 29064399 PMCID: PMC6151620 DOI: 10.3390/molecules22101795] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Revised: 10/17/2017] [Accepted: 10/20/2017] [Indexed: 12/15/2022] Open
Abstract
Metabolic syndrome (MetS) is a cluster of metabolic risk factors associated with central obesity, hyperglycemia, insulin resistance, dyslipidemia and high blood pressure. In recent decades, because of the remarkable increase in both prevalence and severity, MetS and its related diseases such as cardiovascular diseases (CVDs), obesity, hypertension and diabetes have become the main global burden and challenge in strategic management involving prevention and treatment. However, currently, the preventions and treatments based on pharmaceutical interventions do not provide a solution for MetS and its related diseases. Recently, gut microbiota showed clear evidence of preventing and/or treating MetS, shedding light on treating MetS and its related diseases through a completely different approach. In this review, we will interpret the effects of current pharmaceutical drugs used in preventing and treating MetS and its related diseases to understand remaining issues of those interventions. We will explore the possibility of developing gut microbiota as pharmabiotics in a completely new medication option for treating MetS and its related diseases.
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Affiliation(s)
- Thi Thanh Binh Nguyen
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk 54907, Korea.
| | - Yan Yan Jin
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk 54907, Korea.
| | - Hea-Jong Chung
- Department of Microbiology, Seonam University Medical School, Namwon, Chonbuk 55321, Korea.
| | - Seong-Tschool Hong
- Department of Biomedical Sciences and Institute for Medical Science, Chonbuk National University Medical School, Jeonju, Chonbuk 54907, Korea.
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