Systematic proteomic analysis identifies ß-site amyloid precursor protein cleaving enzyme 2 and 1 (BACE2 and BACE1) substrates in pancreatic ß-cells.

Expansion of functional islet ß-cell mass is a physiological process to compensate for increased insulin demand. Deficiency or pharmacological inhibition of the plasma membrane protease BACE2 enhances pancreatic ß-cell function and proliferation, and therefore BACE2 is a putative target for the therapeutic intervention under conditions of ß-cell loss and dysfunction. To gain a molecular understanding of BACE2 function, we performed a systematic and quantitative proteomic analysis to map the natural substrate repertoire of BACE2 and its homologue BACE1 in ß-cells. Loss- and gain-of-function studies of in vitro and in vivo models identified specific and functionally heterogeneous targets. Our analysis revealed non-redundant roles of BACE1/2 in ectodomain shedding with BACE1 regulating a broader and BACE2 a more distinct set of ß-cell-enriched substrates including two proteins of the seizure 6 protein family (SEZ6L and SEZ6L2). Lastly, our study provides insights into the global ß-cell sheddome and secretome, an important prerequisite to uncover novel mechanisms contributing to ß-cell homeostasis and a resource for therapeutic target and biomarker discoveries.

MicroRNA-7a regulates pancreatic ß cell function.

Dysfunctional microRNA (miRNA) networks contribute to inappropriate responses following pathological stress and are the underlying cause of several disease conditions. In pancreatic ß cells, miRNAs have been largely unstudied and little is known about how specific miRNAs regulate glucose-stimulated insulin secretion (GSIS) or impact the adaptation of ß cell function to metabolic stress. In this study, we determined that miR-7 is a negative regulator of GSIS in ß cells. Using Mir7a2 deficient mice, we revealed that miR-7a2 regulates ß cell function by directly regulating genes that control late stages of insulin granule fusion with the plasma membrane and ternary SNARE complex activity. Transgenic mice overexpressing miR-7a in ß cells developed diabetes due to impaired insulin secretion and ß cell dedifferentiation. Interestingly, perturbation of miR-7a expression in ß cells did not affect proliferation and apoptosis, indicating that miR-7 is dispensable for the maintenance of endocrine ß cell mass. Furthermore, we found that miR-7a levels are decreased in obese/diabetic mouse models and human islets from obese and moderately diabetic individuals with compensated ß cell function. Our results reveal an interconnecting miR-7 genomic circuit that regulates insulin granule exocytosis in pancreatic ß cells and support a role for miR-7 in the adaptation of pancreatic ß cell function in obesity and type 2 diabetes.

Bace2 is a ß cell-enriched protease that regulates pancreatic ß cell function and mass.

Decreased ß cell mass and function are hallmarks of type 2 diabetes. Here we identified, through a siRNA screen, beta site amyloid precursor protein cleaving enzyme 2 (Bace2) as the sheddase of the proproliferative plasma membrane protein Tmem27 in murine and human ß cells. Mice with functionally inactive Bace2 and insulin-resistant mice treated with a newly identified Bace2 inhibitor both display augmented ß cell mass and improved control of glucose homeostasis due to increased insulin levels. These results implicate Bace2 in the control of ß cell maintenance and provide a rational strategy to inhibit this protease for the expansion of functional pancreatic ß cell mass.