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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK048280-21
Application #
8760398
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Haft, Carol R
Project Start
1994-09-01
Project End
2019-06-30
Budget Start
2014-09-12
Budget End
2015-06-30
Support Year
21
Fiscal Year
2014
Total Cost
$507,745
Indirect Cost
$181,221
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Liu, Ming; Wright, Jordan; Guo, Huan et al. (2014) Proinsulin entry and transit through the endoplasmic reticulum in pancreatic beta cells. Vitam Horm 95:35-62
Prabhu, Yogikala; Blanco, Elias H; Liu, Ming et al. (2014) Defective transport of the obesity mutant PC1/3 N222D contributes to loss of function. Endocrinology 155:2391-401
Guo, Huan; Xiong, Yi; Witkowski, Piotr et al. (2014) Inefficient translocation of preproinsulin contributes to pancreatic ? cell failure and late-onset diabetes. J Biol Chem 289:16290-302
Haataja, Leena; Snapp, Erik; Wright, Jordan et al. (2013) Proinsulin intermolecular interactions during secretory trafficking in pancreatic ? cells. J Biol Chem 288:1896-906
Wright, Jordan; Birk, Julia; Haataja, Leena et al. (2013) Endoplasmic reticulum oxidoreductin-1? (Ero1?) improves folding and secretion of mutant proinsulin and limits mutant proinsulin-induced endoplasmic reticulum stress. J Biol Chem 288:31010-8
Liu, Ming; Lara-Lemus, Roberto; Shan, Shu-ou et al. (2012) Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes. Diabetes 61:828-37
Rajpal, Gautam; Schuiki, Irmgard; Liu, Ming et al. (2012) Action of protein disulfide isomerase on proinsulin exit from endoplasmic reticulum of pancreatic ?-cells. J Biol Chem 287:43-7
Hodish, Israel; Absood, Afaf; Liu, Leanza et al. (2011) In vivo misfolding of proinsulin below the threshold of frank diabetes. Diabetes 60:2092-101
Khoo, Cynthia; Yang, Juxiang; Rajpal, Gautam et al. (2011) Endoplasmic reticulum oxidoreductin-1-like * (ERO1l*) regulates susceptibility to endoplasmic reticulum stress and is induced by insulin flux in *-cells. Endocrinology 152:2599-608
Liu, Ming; Haataja, Leena; Wright, Jordan et al. (2010) Mutant INS-gene induced diabetes of youth: proinsulin cysteine residues impose dominant-negative inhibition on wild-type proinsulin transport. PLoS One 5:e13333

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