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Review
. 2014:121:23-65.
doi: 10.1016/B978-0-12-800101-1.00002-8.

Regulation of glucose homeostasis by GLP-1

Prashant Nadkarni  1 , Oleg G Chepurny  2 , George G Holz  3
Affiliations
Review

Regulation of glucose homeostasis by GLP-1

Prashant Nadkarni et al. Prog Mol Biol Transl Sci. 2014.

Abstract

Glucagon-like peptide-1(7-36)amide (GLP-1) is a secreted peptide that acts as a key determinant of blood glucose homeostasis by virtue of its abilities to slow gastric emptying, to enhance pancreatic insulin secretion, and to suppress pancreatic glucagon secretion. GLP-1 is secreted from L cells of the gastrointestinal mucosa in response to a meal, and the blood glucose-lowering action of GLP-1 is terminated due to its enzymatic degradation by dipeptidyl-peptidase-IV (DPP-IV). Released GLP-1 activates enteric and autonomic reflexes while also circulating as an incretin hormone to control endocrine pancreas function. The GLP-1 receptor (GLP-1R) is a G protein-coupled receptor that is activated directly or indirectly by blood glucose-lowering agents currently in use for the treatment of type 2 diabetes mellitus (T2DM). These therapeutic agents include GLP-1R agonists (exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, and langlenatide) and DPP-IV inhibitors (sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin). Investigational agents for use in the treatment of T2DM include GPR119 and GPR40 receptor agonists that stimulate the release of GLP-1 from L cells. Summarized here is the role of GLP-1 to control blood glucose homeostasis, with special emphasis on the advantages and limitations of GLP-1-based therapeutics.

Keywords: Diabetes; GLP-1; Glucagon; Glucose; Hyperglycemia; Incretin hormone; Insulin.

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Conflict of interest statement

All authors declare no conflict of interest concerning any of the concepts addressed in this review of the literature.

Figures

Figure 2.1
Figure 2.1
Role of GLP-1 in β-cell stimulus-secretion coupling. GLP-1 binds to its GPCR in order to stimulate cAMP production and to potentiate GSIS. One cAMP-dependent action of GLP-1 is mediated by PKA that phosphorylates secretory granule-associated proteins (e.g., Snapin) in order to facilitate Ca2+-dependent exocytosis of insulin. The PKA-independent action of GLP-1 is mediated by the cAMP-regulated guanine nucleotide exchange factor Epac2. Binding of cAMP to Epac2 results in sequential activation of Rap1 GTPase and PLCε, thereby promoting PIP2 hydrolysis and intracellular Ca2+ mobilization. GLP-1 also exerts PKA and Epac2-mediated actions to enhance glucose-dependent KATP channel closure, thereby promoting Ca2+ influx through VDCCs. The primary role of GLP-1 relevant to insulin secretion is to act as a β-cell glucose sensitizer in order to enhance insulin exocytosis mediated by the triggering and amplification pathways of GSIS. Abbreviations: GK, glucokinase; ΔVm, depolarization; Kv, voltage-dependent K+ channel, KCa, calcium-activated K+ channel.
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References

    1. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876–913. - PubMed
    1. Holst JJ. The physiology of glucagon-like peptide-1. Physiol Rev. 2007;87:1409–1439. - PubMed
    1. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153–165. - PubMed
    1. Burcelin R. The gut-brain axis: a major glucoregulatory player. Diabetes Metab. 2010;36(Suppl 3):S54–S58. - PubMed
    1. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705. - PubMed

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