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Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes

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posted on 30.08.2021, 03:33 by Maroof Alam, Anoop Arunagiri, Leena Haataja, Mauricio Torres, Dennis Larkin, John Kappler, Niyun Jin, Peter Arvan

Throughout evolution, proinsulin has exhibited significant sequence variation in both C-peptide and insulin moieties. As the proinsulin coding sequence evolves, the gene product continues to be under selection pressure both for ultimate insulin bioactivity and for the ability of proinsulin to be folded for export through the secretory pathway of pancreatic b-cells. The substitution proinsulin-R(B22)E is known to yield a bioactive insulin, although R(B22)Q has been reported as a mutation that falls within the spectrum of Mutant INS-gene induced Diabetes of Youth (MIDY). Here we have studied mice expressing heterozygous (or homozygous) proinsulin-R(B22)E knocked into the Ins2 locus. Neither females nor males bearing the heterozygous mutation develop diabetes at any age examined, but subtle evidence of increased proinsulin misfolding in the endoplasmic reticulum is demonstrable in isolated islets from the heterozygotes. Moreover, males have indications of glucose intolerance and within a few week exposure to a high-fat diet, they develop frank diabetes. Diabetes is more severe in homozygotes, and the development of disease parallels a progressive heterogeneity of b-cells with increasing fractions of proinsulin-rich/insulin-poor cells, as well as glucagon-positive cells. Evidently, sub-threshold predisposition to proinsulin misfolding can go undetected, but provides genetic susceptibility to diet-induced b-cell failure.


This work was supported by NIH R01-DK48280 and NIH P01 AI-118688. We acknowledge support from Leroux Devon in the Michigan Biomedical Research Electron Microscopy Core Facility, the Michigan Tissue and Molecular Pathology (Histology) Core for help with sample preparation, the Michigan Diabetes Research Center Morphology Core (NIH P30 DK020572), the University of Michigan Protein Folding Diseases Initiative, as well as institutional funds from the Howard Hughes Medical Institute at University of Colorado Anschutz Medical School, and National Jewish Health.