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

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 key β cell-macrophage crosstalk pathway mediated by the miRNA-29-TNF-receptor-associated factor 3 (TRAF3) axis. β cell-specific transgenic miR-29a/b/c 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 because either depletion of macrophages or reconstitution with miR-29-signaling defective bone marrow improves metabolic parameters in the transgenic mice. Mechanistically, our data show that miR-29 promotes the recruitment and activation of circulating monocytes and 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. [Display omitted] •miR-29 in β cells causes diabetes due to defective insulin secretion and action•Prediabetic β cell-derived exosomal miR-29 drives macrophage-induced inflammation•Systematic inflammation reset by miR-29/TRAF3 axis promotes diabetes predisposition•Blocking miR-29 effects attenuates inflammation and diabetes Systematic low-grade inflammation contributes to development of diabetes. Sun et al. report that prediabetic β cells release exosomal miR-29 to reset macrophage inflammatory tone, thus causing insulin resistance and diabetes, which can be rescued by blocking miR-29 effects.