Peptide Hormone Sorting to the Secretory/Storage Granule

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

DESCRIPTION (provided by applicant): 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.