Inadequate insulin secretion triggers diabetes. Normally, pancreatic -cells synthesize more than 300,000 molecules per minute of the insulin precursor, proinsulin, and these molecules must rapidly fold before their export from the endoplasmic reticulum (ER) ? for eventual processing to insulin. Unfortunately, proinsulin folding in the ER always leaves a small subset of misfolded proinsulin molecules (in particular, those forming mispaired disulfide bonds) that can attack ?bystander proinsulin?, triggering ?-cell ER stress, as occurs for the ~30 different INS gene coding sequence mutations in patients suffering from the autosomal dominant Mutant INS-gene induced Diabetes of Youth (MIDY). Significantly, islet ?-cells of individuals with wild-type INS genes also have proinsulin misfolding. In this multi-P.I. R-01 proposal, the applicants' central hypothesis is that normally, the amount of misfolded proinsulin is kept at sub-threshold levels by active ER-associated degradation (ERAD) of proinsulin that prevents excessive accumulation of misfolded proinsulin forms. Failure of efficient ERAD allows the low-level misfolded proinsulin to accumulate and trigger many of the same phenotypes seen in MIDY. Thus ? ironically ? efficient ERAD of proinsulin (in one subset of molecules) is actually coupled to proper folding of proinsulin (in another subset of molecules). Thus, ?--cell secretory capacity depends on the efficiency of ERAD. If correct, then if proinsulin ERAD should become impaired, misfolded proinsulin may accumulate, triggering pancreatic ?-cell dysfunction. Remarkably, our preliminary data establish that ?-cell-specific knockout of the ERAD gene product, SEL1, triggers a dramatic reduction of islet insulin, accompanied by a striking intracellular accumulation of proinsulin in ?-cells. As a consequence of diminished insulin production, mice with ?-cell SEL1 deficiency are predisposed to diabetes. To our knowledge, no other groups have pursued ?-cell ERAD as the critical homeostatic regulator of proinsulin quality control. We wish to define and quantify the molecular pathways regulating this process, and study the process in physiologically relevant diabetes models, including human islets. The group is uniquely qualified to address this central premise: Dr. Tsai is an expert in molecular mechanisms of protein retrotranslocation for ERAD; Dr. Qi is a leader in the development of whole animal models that can directly test the pathophysiologic role of ERAD in tissues; Dr. Liu is a world's leader in preproinsulin translocation across the ER membrane and along with Dr. Arvan, they have elucidated our current molecular understanding of the pathogenic mechanism underlying MIDY. The focus on disposal of misfolded proinsulin is the critical nexus shared by all of us. A more complete understanding of the molecular steps leading to -cell failure is critical to the development of new therapies for diabetes. With this in mind, we believe that work proposed by this group will be paradigm- shifting for the field.

Public Health Relevance

To make bioactive insulin, pancreatic ?-cells must synthesize and rapidly fold the precursor protein, proinsulin. Folding failure for a fraction of proinsulin is addressed by ?-cells via a process known as Endoplasmic Reticulum Associated Degradation (ERAD). This project group has discovered, and will further elucidate, how inefficient ERAD of proinsulin contributes to endoplasmic reticulum stress, ?-cell failure, and diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK111174-01
Application #
9193956
Study Section
Special Emphasis Panel (ZRG1-EMNR-C (02)M)
Program Officer
Haft, Carol R
Project Start
2016-07-15
Project End
2020-06-30
Budget Start
2016-07-15
Budget End
2017-06-30
Support Year
1
Fiscal Year
2016
Total Cost
$613,025
Indirect Cost
$217,525
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
Cunningham, Corey N; He, Kaiyu; Arunagiri, Anoop et al. (2017) Chaperone-Driven Degradation of a Misfolded Proinsulin Mutant in Parallel With Restoration of Wild-Type Insulin Secretion. Diabetes 66:741-753
Shi, Guojun; Somlo, Diane RM; Kim, Geun Hyang et al. (2017) ER-associated degradation is required for vasopressin prohormone processing and systemic water homeostasis. J Clin Invest 127:3897-3912
Qi, Ling; Tsai, Billy; Arvan, Peter (2017) New Insights into the Physiological Role of Endoplasmic Reticulum-Associated Degradation. Trends Cell Biol 27:430-440