Differential roles of autophagy in insulin production and sensitivity

Malfunction of autophagy, a lysosomal degradation pathway, has been linked to increased incidences of type 2 diabetes. During autophagy, autophagosomal vesicles enwrap bulk cytosol, damaged organelles and misfolded proteins and deliver them to lysosomes for breakdown. Both sedentary lifestyle and overly rich nutrition, the two causative factors of the global prevalence of obesity and diabetes, impairs the autophagy activity; whereas fasting and physical exercise, two effective methods to prevent diabetes, can potently induce autophagy. Thus, autophagy may mediate the beneficial effects of fasting and exercise against diabetes, and it is intriguing to investigate whether and how stimulation of autophagy may protect against type 2 diabetes. Accordingly, we generated a mouse line that manifests constitutively active autophagy even without treatment of autophagy inducers, caused by a knock-in point mutation in the essential autophagy gene Becn1. Interestingly, these autophagy-hyperactive mice are more glucose intolerant, but are more insulin sensitive, than mice with normal levels of autophagy in response to high-fat diet challenge. Using our autophagy-hyperactive and -deficient mouse models and novel autophagy-inducing natural chemicals we identified from a library screen, we found that autophagy hyperactivation leads to reduced insulin secretion, due to sequestration of insulin granules by autophagosomes in the islets. These data suggest that insulin-producing β cells and insulin-responsive cells may require different levels of autophagy for optimal metabolic function. We propose a model that chronic autophagy activation degrades insulin granules and decreases insulin load in β cells, but improves insulin sensitivity in insulin-responsive metabolic tissues.