The peptide hormone, insulin, regulates metabolism to homeostatically maintain blood glucose levels within a narrow physiological range. In pancreatic ?-cells, insulin is made and stored at high concentration within secretory granules. Physiological stimulation of insulin secretion (multiple times per day) requires active synthesis o new insulin to replenish secretory granule reserves. Insulin synthesis begins with translation of preproinsulin for delivery into the lumen of the endoplasmic reticulum (ER). Therein, proinsulin must fold properly, which is easier than it sounds because proinsulin is a """"""""disulfide-challenged"""""""" protein. In particular, when ?-cells are forced to synthesize higher levels of proinsulin than they are genetically-programmed to handle, they risk proinsulin misfolding with disulfide mispairing, which leads to insulin deficiency, secretory pathway stress and even ?-cell death. Moreover, proinsulin misfolding caused by coding sequence mutations in the INS gene triggers autosomal dominant diabetes, i.e., diabetes that occurs in spite of a perfectly normal second INS allele that ordinarily is sufficient to provide more than enough insulin for the body's needs. The objective of this new grant cycle is to bring new tools to this problem in order to better understand proinsulin folding and export from the ER, and to determine whether it is possible to decrease proinsulin misfolding and enhance proinsulin export in pancreatic ?-cells in vivo. Finally, we push towards a goal of monitoring intrapancreatic insulin content in health, and during onset and progression of diabetes.
Insulin is secreted to the bloodstream from only one cell type in the body: beta cells of pancreatic islets. Making new insulin in beta cells begins with synthesi of proinsulin, and in our last grant cycle we showed that misfolded mutant proinsulin can entrap normal proinsulin in the early secretory pathway of beta cells, preventing adequate insulin production and secretion. In this cycle we examine rate-limiting steps in proinsulin folding and export, and offer a new potential therapy to overcome proinsulin folding failure to improve insulin production and secretion from pancreatic beta cells.
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