MicroRNA-7a regulates pancreatic β cell function

Abstract

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic β cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of β cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in β cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates β cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in β cells developed diabetes due to impaired insulin secretion and β cell dedifferentiation. Interestingly, perturbation of miR-7a expression in β cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine β cell mass. Furthermore, we found that miR-7a levels are decreased in obese/ diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated β cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic β cells and support a role for miR-7 in the adaptation of pancreatic β cell function in obesity and type 2 diabetes.

MicroRNAs: An adaptive mechanism in the pancreatic β-cell…and beyond?

“…Similarly, miR-7 and miR-184 have been shown to be highly enriched in the central nervous system and eye, respectively [11]. Recent studies using mouse knockouts have shown that loss of these three abundant miRNAs will increase β-cell exocytosis however it still remains unclear whether all miRNAs present in the β-cell are committed to an identical functional role and whether they perform the same function in all cell types where they are present [12] [9] [8]. For example, while miR-375 regulates exocytosis and compensatory proliferation of the β-cell, it has not been determined whether it functions in these capacities in the other neuroendocrine cell types where it is expressed [8] [13].…”

Role of islet microRNAs in diabetes: which model for which question?

“…Indeed, the islets of type 2 diabetic donors were found to express higher levels of miR-187, miR-187*, miR-224 and miR-589 and decreased levels of miR-7, miR-369, miR-487a, miR-655 and miR-656 (see Table 3) [13]. Similar changes in the expression of miR-187 and miR-7a were confirmed by independent research groups [25,34]. These data will need to be reproduced in additional laboratories, but if confirmed, what value will the experiments carried out in rodents have?…”

“…Inhibition of miR-7 using antisense oligonucleotides in isolated adult mouse islet cells was found to activate the mechanistic target of rapamycin (mTOR) pathway and promote beta cell proliferation [24]. However, beta cell-specific MiR-7 knockout mice did not show significant differences in beta cell survival or proliferation, but displayed enhanced insulin release as a result of increased expression of key components of the exocytotic machinery, permitting an improved response to a glucose challenge [25].…”

“…Diet-induced obese mice are probably more representative of human obesity. However, this model is characterised by large inter-individual differences in the response to high-fat-diet feeding and the animals become glucose intolerant but usually do not develop overt type 2 [20,25] diabetes. For other popular rodent strains such as the GotoKakizaki rat the precise causes of the disease remain unclear [38], and the form of diabetes developed by these animals may be representative only of a very particular subgroup of type 2 diabetes cases in humans.…”

Insulin secretion in health and disease: nutrients dictate the pace

“…Indeed, down-regulation of miR-203, miR-210 and miR-383 resulted in an increase in apoptosis both in rat and human β-cells (109) . Altered expression in islets from diabetic donors of miR-7a, miR-187 and a cluster of miRNA in an imprinted locus on human chromosome 14q32 have also been reported and are associated with impaired insulin secretion and β-cell dysfunction (113)(114)(115) . Moreover, the expression of several miRNA was also modified in the islets of ob/ob and db/db obese mice that are deficient in leptin or leptin receptor, respectively (104,109,116,117) .…”