Defects in the earliest events of insulin biosynthesis link to pancreatic beta cell failure and late onset diabetes

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 834-867-Islet Biology
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-848
Huan Guo1, Yi Xiong1, Roberto lara-Lemus1, Kathryn Hutchison1, Shu-ou Shan2, Peter Arvan1 and Ming Liu*1
1University of Michigan Medical School, Ann Arbor, MI, 2California Institution of Technology
In pancreatic beta cells, insulin biosynthesis begins as a precursor, preproinsulin (pPI), within the cytosol. To enter the secretory pathway, newly synthesized pPI driven by its signal peptide undergoes co- and post-translational translocation targeting to and across the endoplasmic reticulum (ER) membrane, where pPI is cleaved by signal peptidase, forming proinsulin that folds in the ER. Among those early events of insulin biosynthesis, proinsulin misfolding and ER stress have drawn increasing attention as a cause of beta cell failure and diabetes. However, no studies have yet addressed potential defects at the entry point of pPI into the secretory pathway. Herein, we reveal that inefficient translocation of pPI does indeed lead to pancreatic beta cell failure and diabetes in humans. Specifically, after targeting to the ER, two recently reported mutant pPIs associated with late onset diabetes fail to be efficiently translocated across the ER membrane. The inefficient translocation is caused by a disorientation of signal peptide of pPI when it interacts with and inserts into the Sec61 translocon at the ER membrane. The disorientated signal peptide anchors untranslocated pPI into the ER membrane, through which the proinsulin domain of pPI is exposed to the cytosol. Therefore, unlike other mutant (pre)proinsulins causing proinsulin misfolding in the ER lumen, inducing ER stress and leading to early onset diabetes, the untranslocated pPI accumulates outside the ER, activates heat shock response, retards pancreatic beta cell growth, and promotes pancreatic beta cell death. Our findings unveil a novel pathway that leads to beta cell failure and late onset diabetes.

Nothing to Disclose: HG, YX, RL, KH, SOS, PA, ML

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This works was supported primarily by NIH RO1-DK088856 (to M.L.), and also by NIH RO1-DK48280 (to P.A.).