Prkar1a in the Regulation of Insulin Secretion

Abstract

The incidence of type 2 diabetes mellitus (T2DM) is rapidly increasing worldwide with significant consequences on individual quality of life as well as economic burden on states’ healthcare costs. While origins of the pathogenesis of T2DM are poorly understood, an early defect in glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is considered a hallmark of T2DM [1].

Upon a glucose stimulus, insulin is secreted in a biphasic manner with an early first-phase burst of insulin, which is followed by a second, more sustained phase of insulin output [2]. First phase insulin secretion is diminished early in T2DM as well is in subjects who are at risk of developing T2DM [3] [4] [5] [6].

An effective treatment of T2DM with incretin hormone glucagon-like peptide-1 (GLP-1) or its long acting peptide analogue exendin-4 (E4), restores first-phase and augments second-phase glucose stimulated insulin secretion. This effect of incretin action occurs within minutes of GLP-1/E4 infusion in T2DM humans. An additional important consideration is that incretin hormones augment GSIS only above a certain glucose threshold, which is slightly above the normal glucose range. This ensures that incretin hormones stimulate GSIS only when glucose levels are high, while they are ineffective when insulin levels are below a certain threshold [7] [8].

Activation of the GLP-1 receptor, which is highly expressed on pancreatic β-cells, stimulates 2 ­distinct intracellular signaling pathways: a) the cAMP-protein kinase A branch and b) the cAMP-EPAC2 (EPAC=exchange protein activated by cAMP) branch. While the EPAC2 branch is considered to mediate GLP-1 effects on first-phase GSIS, the PKA branch is necessary for the former branch to be active [9] [10]. However, how these 2 branches interplay and converge and how their effects on insulin secretion and insulin vesicle exocytosis are coordinated is poorly understood.

Thus, at the outset of our studies we have a poorly understood intracellular interplay of cAMP-dependent signaling pathways, which – when stimulated – restore glucose-dependent first phase and augment second phase insulin secretion in the ailing β-cells of T2DM.

Key words

type 2 diabetes - Prkar1a - insulin secretion

• References

• 1 Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: from pathophysiology to prevention and management. Lancet 2011; 378: 169-181
• 2 Del Prato S, Tiengo A. The importance of first-phase insulin secretion: implications for the therapy of type 2 diabetes mellitus. Diabetes Metab Res Rev 2001; 17: 164-174
• 3 Gerich JE. Is reduced first-phase insulin release the earliest detectable abnormality in individuals destined to develop type 2 diabetes?. Diabetes 2002; 51 (Suppl. 01) S117-S121
• 4 Lillioja S, Mott DM, Howard BV, Bennett PH, Yki-Jarvinen H, Frimond D, Nyomba BL, Zurlo F, Swinburn B, Bogardus C. Impaired glucose tolerance as a disorder of insulin action. Longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 1988; 318: 1217-1225
• 5 Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H. Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 1995; 95: 690-698
• 6 Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte Jr D. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest 1984; 74: 1318-1328
• 7 Egan JM, Clocquet AR, Elahi D. The insulinotropic effect of acute exendin-4 administered to humans: comparison of nondiabetic state to type 2 diabetes. J Clin Endocrinol Metab 2002; 87: 1282-1290
• 8 Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, Fineman MS, Kim DD, Nauck MA. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2005; 90: 5991-5997
• 9 Drucker DJ. The biology of incretin hormones. Cell Metab 2006; 3: 153-165
• 10 Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696-1705
• 11 Petyuk VA, Qian WJ, Hinault C, Gritsenko MA, Singhal M, Monroe ME, Camp 2nd DG, Kulkarni RN, Smith RD. Characterization of the mouse pancreatic islet proteome and comparative analysis with other mouse tissues. J Proteome Res 2008; 7: 3114-3126
• 12 Chheda MG, Ashery U, Thakur P, Rettig J, Sheng ZH. Phosphorylation of Snapin by PKA modulates its interaction with the SNARE complex. Nat Cell Biol 2001; 3: 331-338
• 13 Fukui K, Yang Q, Cao Y, Takahashi N, Hatakeyama H, Wang H, Wada J, Zhang Y, Marselli L, Nammo T, Yoneda K, Onishi M, Hagashiyama S, Matsuzawa Y, Gonzalez FJ, Weir GC, Kasai H, Shimomura I, Miyagawa J, Wollheim CB, Yamagata K. The HNF-1 target collectrin controls insulin exocytosis by SNARE complex formation. Cell Metab 2005; 2: 373-384
• 14 Copeland RJ, Bullen JW, Hart GW. Cross-talk between GlcNAcylation and phosphorylation: roles in insulin resistance and glucose toxicity. Am J Physiol Endocrinol Metab 2008; 295: E17-E28
• 15 Akimoto Y, Hart GW, Wells L, Vosseller K, Yamamoto K, Munetomo E, Ohara-Imaizumi M, Nishiwaki C, Nagamatsu S, Hirano H, Kawakami H. Elevation of the post-translational modification of proteins by O-linked N-acetylglucosamine leads to deterioration of the glucose-stimulated insulin secretion in the pancreas of diabetic Goto-Kakizaki rats. Glycobiology 2007; 17: 127-140
• 16 Wang Z, Udeshi ND, Slawson C, Compton PD, Sakabe K, Cheung WD, Shabanowitz J, Hunt DE, Hart GW. Extensive crosstalk between O-GlcNAcylation and phosphorylation regulates cytokinesis. Sci Signal 2010; 3 ra2
• 17 Zeidan Q, Hart GW. The intersections between O-GlcNAcylation and phosphorylation: implications for multiple signaling pathways. J Cell Sci 2010; 123: 13-22
• 18 Peyot ML, Pepin E, Lamontagne J, Latour MG, Zarrouki B, lussier R, Pineda M, Jetton TL, Madiraju SR, Joly E, Prentki M. Beta Cell Failure in Diet-Induced Obese mice stratified according to body weight gain: secretory dysfunction and altered islet lipid metabolism without steatosis or reduced beta cell mass. Diabetes 2010; 59: 2178-2187
• 19 Song WJ, Seshadri M, Ashraf U, Mdluli T, Mondal P, Keil M, Azevedo M, Kirschner LS, Stratakis CA, Hussain MA. Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metab 2011; 13: 308-319