Pancreatic β cells control glucose homeostasis via the secretion of exosomal miR-29 family

Secreted microRNAs (miRNAs) are novel endocrine factors that play essential pathological and physiological roles. Here, we report that pancreatic β cell‐released exosomal miR‐29 family members (miR‐29s) regulate hepatic insulin sensitivity and control glucose homeostasis. Cultured pancreatic islets were shown to secrete miR‐29s in response to high levels of free fatty acids (FFAs) in vitro. In vivo, high levels of FFAs, promoted by either high‐fat diet (HFD) feeding (physiopathological) or fasting (physiological), increased the secretion of miR‐29s into plasma. Intravenous administration of exosomal miR‐29s attenuated insulin sensitivity. The overexpression of miR‐29s in the β cells of transgenic (TG) mice promoted the secretion of miR‐29s and inhibited the insulin‐mediated suppression of glucose output in the liver. We used selective overexpression of traceable heterogenous mutant miR‐29s in β cells to confirm that islet‐derived exosomal miR‐29s target insulin signalling in the liver and blunt hepatic insulin sensitivity. Moreover, in vivo disruption of miR‐29s expression in β cells reversed HFD‐induced insulin resistance. In vitro experiments demonstrated that isolated exosomes enriched in miR‐29s inhibited insulin signalling in the liver and increased hepatic glucose production. These results unveil a novel β cell‐derived secretory signal—exosomal miR‐29s—and provide insight into the roles of miR‐29s in manipulating glucose homeostasis.