Expression of miRNA-29 in Pancreatic β-Cells Promotes Inflammation and Diabetes Via TRAF3

Abstract

Type 2 diabetes mellitus (T2DM) is recognized as a chronic low-grade inflammatory disease characterized by insulin resistance and pancreatic β-cell dysfunction; however, the underlying molecular mechanism remains unclear. Here, we report a new β-cell–macrophage crosstalk pathway mediated by the “miRNA-29-TNF receptor-associated factor 3 (TRAF3)” axis. β-cell specific transgenic miR-29a/b-1 mice are predisposed to develop glucose intolerance and insulin resistance when fed a high-fat diet (HFD). The metabolic effect of β-cell miR-29 is largely mediated through macrophages, as either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improved metabolic parameters in the transgenic mice. Mechanistically, our data showed that miR-29 promoted the recruitment and activation of circulating monocytes/macrophages, and hence inflammation, via miR-29 exosomes in a TRAF3-dependent manner. Our results demonstrate the ability of β cells to modulate the systemic inflammatory tone and glucose homeostasis via miR-29 in response to nutrient overload.