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 β-cells resulting in reduced insulin content, defective insulin secretion and apoptosis. We investigated the involvement in this phenomenon of microRNAs, a class of non-coding RNAs regulating gene expression by sequence-specific inhibition of mRNA translation.

Research design and methods: We analyzed microRNA expression in insulin-secreting cell lines or pancreatic islets exposed to palmitate for thee days and in islets from diabetic db/db mice. We studied the signaling pathways triggering the changes in microRNA expression and determined the impact of the microRNAs affected by palmitate on insulin secretion and apoptosis.

Results: Prolonged exposure of the β-cell line MIN6B1 and pancreatic islets to palmitate causes a time- and dose-dependent increase of miR34a and miR146. Elevated levels of these microRNAs are observed also 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 VAMP2, a key player in β-cell exocytosis. Higher miR146 levels do not affect the capacity to release insulin but contribute to increase 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 β-cells is caused by alterations in the level of specific microRNAs.