SIK2 controls dynamics of insulin production in pancreatic β cells
Date Issued
2014
Date
2014
Author(s)
Tai, Pei-Han
Abstract
Salt-inducible Kinase 2 (SIK2), is a member of AMPK family, has been reported to play an important role in metabolism and it also regulatesβcell survival by driving IRS-2(insulin receptor substrate 2) gene expression upon glucose stimulation. The SIK2 expression was previously found in not only cytosol but also insulin vesicles; however, the specific function of SIK2 in pancreaticβcells remains unclear. Here we hypothesized that inhibition of SIK2 kinase activity may lead to the insulin vesicle translocation from reserve pool to readily releasable pool. Vesicle dynamic were imaged in single pancreatic RINm5F cells by total internal reflection fluorescence microscope. Inactivation of SIK2 kinase by treated relatively inhibitor, compound C, resulted in unconstrained reserved pool insulin vesicle mobilization and concomitant increase in insulin release. On the other hand, SIK2 kinase activity is physically inhibited while phosphorylation at Ser-587 by cAMP-PKA in pancreaticβcells. An hour treatment of 0.3 uM compound C or 16.7 mM glucose stimulation made isolated islets increase insulin secretion and higher SIK2-pS587 expression. Therefore, we concluded that SIK2 kinase activity is critical for forbidding insulin secretion through restricting their vesicle movement.
Furthermore, for examine the physiological relevance of SIK2 in pancreatic βcells, the β cell-specific sik2 transgenic mice were generated by using bacterial artificial chromosomes (BACs) system. Glucose-stimulated insulin secretion test from 11-week-old transgenic mice fed with regular diet showed higher fasting blood glucose and lower insulin secretion compared to control. Moreover, under metabolic stress, 20-week-old transgenic mice had been fed with high fat diet for 12 week showed significant decreased in glucose clearance rate. This phenotype might result from suppression of insulin vesicle transportation by over-expressed SIK2 protein. The slightly increasedα cells, which was the phenomenon in early stage of diabetes was also observed. The gene expression profile was examined by real-time PCR, and over-expression of sik2 inβcell resulted in down-regulated Ins1 mRNA level. We speculated that this may result from an inhibitory effect on the CREB activity by over-expression of sik2. Above phenotypes indicated that theβcell specific sik2 transgenic mice might have the tendency for development abnormal glucose homeostasis. Taken together, our results uncovered a novel function of SIK2 in the regulation of insulin secretion inβ-cells via insulin transcription and insulin vesicle transportation. These findings suggested that SIK2 is an attractive target for developing new strategies for diabetes.
Subjects
SIK2
磷酸酶活性
胰島素囊泡
運送
禁食血糖
SDGs
Type
other
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