期刊
DIABETES
卷 65, 期 1, 页码 53-61出版社
AMER DIABETES ASSOC
DOI: 10.2337/db15-0770
关键词
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资金
- VIB
- Research Foundation Flanders (FWO)
- European Research Council (ERC)
- Queen Elizabeth Foundation
- KUL-University of Leuven/Flemish Government
- National Institutes of Health [DK-59637, DK-020593, DK-078188, DK-043748]
- JDRF Australia
The microRNA-29 (miR-29) family is among the most abundantly expressed microRNA in the pancreas and liver. Here, we investigated the function of miR-29 in glucose regulation using miR-29a/b-1 (miR-29a)-deficient mice and newly generated miR-29b-2/c (miR-29c)deficient mice. We observed multiple independent functions of the miR-29 family, which can be segregated into a hierarchical physiologic regulation of glucose handling. miR-29a, and not miR-29c, was observed to be a positive regulator of insulin secretion in vivo, with dysregulation of the exocytotic machinery sensitizing beta-cells to overt diabetes after unfolded protein stress. By contrast, in the liver both miR-29a and miR-29c were important negative regulators of insulin signaling via phosphatidylinositol 3-kinase regulation. Global or hepatic insufficiency of miR-29 potently inhibited obesity and prevented the onset of diet-induced insulin resistance. These results demonstrate strong regulatory functions for the miR-29 family in obesity and diabetes, culminating in a hierarchical and dose-dependent effect on premature lethality.
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