Editors' ChoiceMetabolism

Promoting Insulin Secretion

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Sci. Signal.  25 Mar 2014:
Vol. 7, Issue 318, pp. ec82
DOI: 10.1126/scisignal.2005252

To cope with the mild hyperglycemia that occurs in prediabetic states, pancreatic β cells compensate by increasing insulin secretion, a process that requires calcium influx into β cells through L-type voltage-gated calcium channels (VGCCs). Sakamaki et al. (see also Belgardt and Stoffel) found that salt-inducible kinase 2 (SIK2) was required not only for this compensatory response but also for normal insulin secretion. Mice with a β cell–specific, inducible knockout of Sik2 (SABKO mice) had higher blood glucose concentrations, decreased glucose clearance, and lower plasma insulin concentrations after feeding. Islets from SABKO mice had the same insulin content as those from control mice but secreted less insulin after glucose stimulation, suggesting a defect in insulin secretion. SIK2 phosphorylated Ser91 in p35. p35 stimulates the activity of CDK5, a kinase that attenuates insulin secretion by phosphorylating (at Ser783) and inhibiting the L-type VGCC, thereby reducing calcium influx. In a heterologous expression system, overexpression of SIK2 led to the proteasomal degradation of p35 in a manner that required the phosphorylation of Ser91 by SIK2 and the ubiquitin E3 ligase PJA2. Coimmunoprecipitation experiments revealed complexes of SIK2 and p35 and of p35 and PJA2 in MIN6 cells (a pancreatic β cell line). Manipulations that increased the abundance of p35, such as knockdown of SIK2 or PJA2, increased phosphorylation of Ser783 in the L-type VGCC and decreased calcium influx in MIN6 cells. Silencing p35 in islets from wild-type mice increased calcium influx and restored calcium influx in islets from SABKO mice. Insulin secretion was increased after glucose stimulation to amounts similar to those released from wild-type islets in islets from SABKO mice by silencing p35 or inhibiting CDKs. SIK2 abundance was increased in islets from mice fed a high-fat diet or from ob/ob mice, which are a genetic model of obesity. Impaired glucose clearance in response to a high-fat diet was more pronounced in SABKO mice than in control mice. Islets from ob/ob mice secrete more insulin, a phenotype that was attenuated by SIK2 knockdown. SIK2 was subjected to proteasomal degradation in MIN6 cells cultured under low-glucose conditions and was stabilized under high-glucose conditions. Thus, SIK2 promotes insulin secretion by preventing the inhibition of calcium channels, and strategies that enhance SIK2 activity could be used to stimulate insulin secretion in prediabetic states.

J.-I. Sakamaki, A. Fu, C. Reeks, S. Baird, C. Depatie, M. Al Azzabi, N. Bardeesy, A.-C. Gingras, S.-P. Yee, R. A. Screaton, Role of the SIK2–p35–PJA2 complex in pancreatic β-cell functional compensation. Nat. Cell Biol. 16, 234–244 (2014). [PubMed]

B.-F. Belgardt, M. Stoffel, SIK2 regulates insulin secretion. Nat. Cell Biol. 16, 210-212 (2014). [PubMed]