Ghrelin inhibits insulin secretion through the AMPK–UCP2 pathway in β cells

AbstractGhrelin inhibits insulin secretion partly via induction of IA-2β. However, the orexigenic effect of ghrelin is mediated by the AMP-activated protein kinase (AMPK)–uncoupling protein 2 (UCP2) pathway. Here, we demonstrate that ghrelin’s inhibitory effect on insulin secretion also occurs through the AMPK-UCP2 pathway. Ghrelin increased AMPK phosphorylation and UCP2 mRNA expression in MIN6 insulinoma cells. Overexpression or downregulation of UCP2 attenuated or enhanced insulin secretion, respectively. Furthermore, AMPK activator had a similar effect to ghrelin on UCP2 and insulin secretion in MIN6 cells. In conclusion, ghrelin’s inhibitory effect on insulin secretion is partly mediated by the AMPK-UCP2 pathway, which is independent of the IA-2β pathway

Genetic Associations of Type 2 Diabetes with Islet Amyloid Polypeptide Processing and Degrading Pathways in Asian Populations

10.1371/journal.pone.0062378PLoS ONE86

IA-2β, but not IA-2, is induced by ghrelin and inhibits glucose-stimulated insulin secretion

Ghrelin is a newly discovered peptide and an endogenous ligand for growth hormone (GH) secretagogue (GHS) receptor. It has been shown to possess various central and peripheral effects, including GH secretion, food intake, and gastric and cardiac effects. Ghrelin and the GHS receptor are expressed also in pancreatic islets. We have identified several ghrelin-induced genes by PCR-select subtraction methods, among which is a β-cell autoantigen for type 1 diabetes, IA-2β. Administration of ghrelin increased IA-2β mRNA in mouse brain, pancreas, and insulinoma cell lines (MIN6 and βTC3). However, the expression of IA-2, another structurally related β-cell autoantigen, was not induced by ghrelin. Administration of ghrelin or overexpression of IA-2β, but not overexpression of IA-2, inhibited glucose-stimulated insulin secretion in MIN6 insulinoma cells and, moreover, inhibition of IA-2β expression by the RNA interference technique ameliorated ghrelin's inhibitory effects on glucose-stimulated insulin secretion. These findings strongly suggest that inhibitory effects of ghrelin on glucose-stimulated insulin secretion are at least partly due to increased expression of IA-2β induced by ghrelin. Our data demonstrate the link among ghrelin, IA-2β, and glucose-stimulated insulin secretion

Identification of KCNJ15 as a Susceptibility Gene in Asian Patients with Type 2 Diabetes Mellitus

Recent advances in genome research have enabled the identification of new genomic variations that are associated with type 2 diabetes mellitus (T2DM). Via fine mapping of SNPs in a candidate region of chromosome 21q, the current study identifies potassium inwardly-rectifying channel, subfamily J, member 15 (KCNJ15) as a new T2DM susceptibility gene. KCNJ15 is expressed in the β cell of the pancreas, and a synonymous SNP, rs3746876, in exon 4 (C566T) of this gene, with T allele frequency among control subjects of 3.1%, showed a significant association with T2DM affecting lean individuals in three independent Japanese sample sets (p = 2.5 × 10−7, odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.76–3.67) and with unstratified T2DM (p = 6.7 × 10−6, OR = 1.76, 95% CI = 1.37–2.25). The diabetes risk allele frequency was, however, very low among Europeans in whom no association between this variant and T2DM could be shown. Functional analysis in human embryonic kidney 293 cells demonstrated that the risk allele of the synonymous SNP in exon 4 increased KCNJ15 expression via increased mRNA stability, which resulted in the higher expression of protein as compared to that of the nonrisk allele. We also showed that KCNJ15 is expressed in human pancreatic β cells. In conclusion, we demonstrated a significant association between a synonymous variant in KCNJ15 and T2DM in lean Japanese patients with T2DM, suggesting that KCNJ15 is a previously unreported susceptibility gene for T2DM among Asians