The Role of cAMP in Beta Cell Stimulus-Secretion and Intercellular Coupling.

Andraž Stožer,Viljem Pohorec,Lidija Križančić Bombek,Maša Skelin Klemen,Jurij Dolenšek,Marko Gosak,Eva Paradiž Leitgeb

doi:10.3390/cells10071658

Abstract

Pancreatic beta cells secrete insulin in response to stimulation with glucose and other nutrients, and impaired insulin secretion plays a central role in development of diabetes mellitus. Pharmacological management of diabetes includes various antidiabetic drugs, including incretins. The incretin hormones, glucagon-like peptide-1 and gastric inhibitory polypeptide, potentiate glucose-stimulated insulin secretion by binding to G protein-coupled receptors, resulting in stimulation of adenylate cyclase and production of the secondary messenger cAMP, which exerts its intracellular effects through activation of protein kinase A or the guanine nucleotide exchange protein 2A. The molecular mechanisms behind these two downstream signaling arms are still not fully elucidated and involve many steps in the stimulus–secretion coupling cascade, ranging from the proximal regulation of ion channel activity to the central Ca2+ signal and the most distal exocytosis. In addition to modifying intracellular coupling, the effect of cAMP on insulin secretion could also be at least partly explained by the impact on intercellular coupling. In this review, we systematically describe the possible roles of cAMP at these intra- and inter-cellular signaling nodes, keeping in mind the relevance for the whole organism and translation to humans.

Highlights

Insulin secreted by pancreatic beta cells regulates storage and usage of nutrients, and its relative or absolute lack results in diabetes mellitus that affects more than 460 million people around the world, a number that is expected to increase to 700 million by 2045 [1]
Of the two L-VDCC subtypes expressed in beta cells, both can mediate the GLP-1induced potentiation of glucose-induced insulin secretion, Cav1.3 seems to be preferentially coupled to glucagon-like peptide-1 (GLP-1) receptor activation
Coadministration of liraglutide and glimepiride (SU) resulted in increased blood glucose during oral glucose tolerance test (OGTT) in Epac2A KO mice on high fat diet (HFD). These results indicate that the glucose-lowering effect of the combination of liraglutide and glimepiride is diminished in Epac2A KO mice

Summary

Introduction

Insulin secreted by pancreatic beta cells regulates storage and usage of nutrients, and its relative or absolute lack results in diabetes mellitus that affects more than 460 million people around the world, a number that is expected to increase to 700 million by 2045 [1]. Of the two L-VDCC subtypes expressed in beta cells, both can mediate the GLP-1induced potentiation of glucose-induced insulin secretion, Cav1.3 seems to be preferentially coupled to GLP-1 receptor activation This signaling pathway depends on intact intracellular stores, PKA and PKC activation [125]. PKA-dependent phosphorylation of Snapin appears to play a role in the merger of both cAMP stimulated pathways as well as in facilitation of exocytotic protein interactions and subsequent GSIS [49] Taken together, these studies show that PKA and Epac2A, while not responsible for the triggering of exocytosis, contribute meaningfully to trafficking of insulin granules and facilitate their fusion with the plasma membrane

The Role of cAMP in Intercellular Coupling

The Role of cAMP during the Development of Insulin Resistance

Findings

Conclusions