The roles of G-protein coupled receptors (GPCRs) in insulin secretion

Over the past decades, the number of anti-diabetic drugs has increased dramatically from the conventional sulphonylureas and biguanides to a plethora of drug classes with different molecular targets. These include the thiazolidinedione which are agonists for the nuclear receptor P-PARg; the gliptins which inhibit dipeptidylpeptidase-4; the meglitinides which block KATP channels and GLP-1 receptor agonists such as exenatide, lixisenatide and liraglutide. This development provides patients and physicians with more choices for the pharmacological management of type 2 diabetes.

Recent studies using transgenic mice have shown promising results that the M3-muscarinic acetylcholine receptor (M3R) may be another potential drug target for the treatment of type 2 diabetes, as selective activation of M3R in pancreatic islet b-cells can augment glucose-induced insulin secretion and enhance glucose tolerance in mice. Further delineation of the molecular pathways involved in M3R-mediated glucose-induced insulin secretion will enhance our understanding of the process and identify potential novel targets for the treatment of Type 2 Diabetes.

The aims of the project were:
> To characterise the mechanisms involved in M3R-mediated glucose-induced insulin secretion and beta-cell survival for the identification of potential drug targets for the management of type 2 diabetes.
> To investigate the roles of other GPCR agonists (FFAs, S1P, serotonin) in the regulation of insulin secretion.

A novel pathway by which M3R used to augment glucose-induced insulin secretion has been identified. The pathway involved the phosphorylation of the receptor, recruitment of b-arrestin to the receptor followed by activation of Protein Kinase D1 (PKD1). This pathway is important for the sustained enteric phase of digestion, which requires prolonged release of insulin.

This is distinct from the more conventional pathway where M3R mediates insulin secretion via Gq/11-coupling to calcium and PKC pathways. This conventional pathway is thought to mediate the early cephalic phase of transient insulin secretion. Further delineation of the novel pathway may identify novel target for the treatment of type 2 diabetes.

Publications

Kong KC, Butcher AJ, McWilliams P, Jones D, Wess J, Hamdan FF, Werry T, Rosethorne EM, Charlton SJ, Munson SE, Cragg HA, Smart AD, Tobin AB (2010): M3-muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1. Proc Natl Acad Sci U S A 107, 21181-21186

Kong KC, Tobin AB (2011): The role of M3-muscarinic receptor signalling in insulin secretion. Commun Integr Biol 4, 489-491.

Kong KC, Tobin AB (2011): M3-muscarinic receptor signalling pathways: therapeutic targets for diabetes? Future Medicine: Diabetes Management

Tobin AB, Butcher AJ, Kong KC (2008): Location, location, location...site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling. Trends Pharmacol Sci 8, 413-420.

Kong KC, Gandhi U, Martin TJ, Anz CB, Yan H, Misior AM, Pascual RM, Deshpande DA, Penn RB. (2008): Endogenous Gs-coupled receptors in smooth muscle exhibit differential susceptibility to GRK2/3-mediated desensitization. Biochemistry 47, 9279-9288

Kong KC, Billington CK, Gandhi U, Panettieri Jr. RA, Penn RB (2006): Cooperative mitogenic signalling by G protein-coupled receptors and growth factors is dependent on Gq/11. FASEB J 20, 1558-1560

Kong KC*, Billington CK*, Bhattacharyya R, Wedegaertner PB, Panettieri Jr. RA, Chan TO, Penn RB (2005): Cooperative regulation of p70S6 kinase by receptor tyrosine kinases and G protein-coupled receptors augments airway smooth muscle growth. Biochemistry 44, 14595-14605.