Alterations in MicroRNA Expression Contribute to Fatty Acid–Induced Pancreatic β-Cell Dysfunction

Abstract

OBJECTIVE-Visceral obesity and elevated plasma free fatty acids are predisposing factors for type 2 diabetes. Chronic exposure to these lipids is detrimental for pancreatic ␤-cells, resulting in reduced insulin content, defective insulin secretion, and apoptosis. We investigated the involvement in this phenomenon of microRNAs (miRNAs), a class of noncoding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation. RESEARCH DESIGN AND METHODS-We analyzed miRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for 3 days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in miRNA expression and determined the impact of the miRNAs affected by palmitate on insulin secretion and apoptosis.RESULTS-Prolonged exposure of the ␤-cell line MIN6B1 and pancreatic islets to palmitate causes a time-and dose-dependent increase of miR34a and miR146. Elevated levels of these miRNAs are also observed in islets of diabetic db/db mice. miR34a rise is linked to activation of p53 and results in sensitization to apoptosis and impaired nutrient-induced secretion. The latter effect is associated with inhibition of the expression of vesicle-associated membrane protein 2, a key player in ␤-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increased apoptosis. Treatment with oligonucleotides that block miR34a or miR146 activity partially protects palmitate-treated cells from apoptosis but is insufficient to restore normal secretion. CONCLUSIONS-Our findings suggest that at least part of the detrimental effects of palmitate on ␤-cells is caused by alterations in the level of specific miRNAs. Diabetes 57:2728-2736, 2008

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway

“…In our study, we selected 19 miRNAs that are differentially expressed in islets of HSD mice relative to HPD and normal mice, based on gene-chip microarray analysis. Among these miRNAs, miR-34a-5p displayed the largest fold increase, which was in line with previous observations that a high level of miR-34a-5p was present in the islets of diabetic db/db mice and pancreatic islets exposed to palmitic acid [34]. To demonstrate the potential role of miR-34a-5p in HSDmediated lipotoxicity in beta cells, endogenous miR-34a-5p was abrogated by AMO-34a-5p in both mice and INS-1 cells.…”

“…The mechanistic pathways responsible for HSD-induced lipotoxicity in pancreatic beta cells are not fully understood. Recent evidence has provided new clues that miRNAs are involved in the regulation of beta cell failure and type 2 diabetes [32][33][34]. In our study, we selected 19 miRNAs that are differentially expressed in islets of HSD mice relative to HPD and normal mice, based on gene-chip microarray analysis.…”

Identification of microRNAs with a role in glucose stimulated insulin secretion by expression profiling of MIN6 cells

“…Overexpression of mir-34a in MIN6 B1 cells leads to reduced GSIS, possibly through its target protein VAMP2 which plays a role in -cell exocytosis [23]. Since each miRNA can target multiple mRNAs, regulation of insulin secretion may be controlled by a small network of miRNAs co-ordinately targeting the extensive range of proteins involved in regulation of exocytosis.…”

Clinical relevance of epigenetics in the onset and management of type 2 diabetes mellitus

“…50 On the other hand, the inhibition of miR34a or miR-146 by oligonucleotides, partially protects palmitate-treated b-cells from apoptosis, but cannot restore normal insulin secretion. 106 …”