GLP ‐1 receptor activated insulin secretion from pancreatic β‐cells: mechanism and glucose dependence

Abstract

The major goal in the treatment of type 2 diabetes mellitus is to control the hyperglycaemia characteristic of the disease. However, treatment with common therapies such as insulin or insulinotrophic sulphonylureas ( SU ), while effective in reducing hyperglycaemia, may impose a greater risk of hypoglycaemia, as neither therapy is self‐regulated by ambient blood glucose concentrations. Hypoglycaemia has been associated with adverse physical and psychological outcomes and may contribute to negative cardiovascular events; hence minimization of hypoglycaemia risk is clinically advantageous. Stimulation of insulin secretion from pancreatic β‐cells by glucagon‐like peptide 1 receptor ( GLP‐1R ) agonists is known to be glucose‐dependent. GLP‐1R agonists potentiate glucose‐stimulated insulin secretion and have little or no activity on insulin secretion in the absence of elevated blood glucose concentrations. This ‘glucose‐regulated’ activity of GLP‐1R agonists makes them useful and potentially safer therapeutics for overall glucose control compared to non‐regulated therapies; hyperglycaemia can be reduced with minimal hypoglycaemia. While the inherent mechanism of action of GLP‐1R agonists mediates their glucose dependence, studies in rats suggest that SUs may uncouple this dependence. This hypothesis is supported by clinical studies showing that the majority of events of hypoglycaemia in patients treated with GLP‐1R agonists occur in patients treated with a concomitant SU . This review aims to discuss the current understanding of the mechanisms by which GLP ‐1R signalling promotes insulin secretion from pancreatic β‐cells via a glucose‐dependent process.

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    Not in our library10.1111/j.1469-7793.1997.105bl.x

93. 93.

    Eliasson L, Ma X, Renström E, et al. SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. J Gen Physiol. 2003;121:181-197.

    Not in our library10.1085/jgp.20028707

94. 94.

    Kemp DM, Habener JF. Synergistic effect of dimethyl sulfoxide on glucagon-like peptide 1 (GLP-1)-stimulated insulin secretion and gene transcription in INS-1 cells: characterization and implications. Biochem Pharmacol. 2002;64:689-697.

    Not in our library10.1016/s0006-2952(02)01212-1

95. 95.

    Buse JB, Rosenstock J, Sesti G, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47.

    Not in our library10.1016/s0140-6736(09)60659-0

96. 96.

    de Heer J, Holst JJ. Sulfonylurea compounds uncouple the glucose dependence of the insulinotropic effect of glucagon-like peptide 1. Diabetes. 2007;56:438-443.

    Not in our library10.2337/db06-0738

97. 97.

    Kadowaki T, Namba M, Yamamura A, Sowa H, Wolka AM, Brodows RG. Exenatide exhibits dose-dependent effects on glycemic control over 12 weeks in Japanese patients with suboptimally controlled type 2 diabetes. Endocr J. 2009;56:415-424.

    Not in our library10.1507/endocrj.k08e-296

Cited by papers we hold 11

• The efficacy and safety of oral semaglutide for glycaemic management in adults with type 2 diabetes compared to subcutaneous semaglutide, placebo, and other GLP-1 RA comparators: A systematic review and network meta-analysis · 2022
  Not checked
• L‐arginine as a potential GLP‐1‐mediated immunomodulator of Th17‐related cytokines in people with obesity and asthma · 2021
  Not checked
• The metabolic impact of small intestinal nutrient sensing · 2021
  No notice
• Glucagon-Like Peptide-1: A Focus on Neurodegenerative Diseases · 2019
  No notice
• The Short-Chain Fatty Acid Acetate in Body Weight Control and Insulin Sensitivity · 2019
  No notice
• Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial · 2018
  No notice
• Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function · 2018
  No notice
• GLP-1 receptor signalling promotes β-cell glucose metabolism via mTOR-dependent HIF-1α activation · 2017
  No notice
• Microneedle-array patches loaded with dual mineralized protein/peptide particles for type 2 diabetes therapy · 2017
  No notice
• An Update on the Effect of Incretin-Based Therapies on β-Cell Function and Mass · 2016
  Not checked
• Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects · 2015
  No notice

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