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

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Proinsulin sequence variation is critical for insulin bioactivity and proper folding for export from pancreatic beta-cells.
• Mutations in the insulin gene (INS) can lead to diabetes, with R(B22)Q being associated with INS-gene-induced diabetes of youth.

Purpose of the Study:

• To investigate the impact of the proinsulin-R(B22)E substitution on insulin processing, beta-cell function, and diabetes development in vivo.
• To assess the role of proinsulin misfolding as a susceptibility factor for diet-induced diabetes.

Main Methods:

• Generation and analysis of mice with heterozygous and homozygous proinsulin-R(B22)E knock-in mutations at the Ins2 locus.
• Assessment of glucose tolerance, beta-cell morphology, proinsulin folding, and insulin content in islets under normal and high-fat diet conditions.

Main Results:

• Heterozygous mice showed subtle endoplasmic reticulum proinsulin misfolding but no overt diabetes. Male heterozygotes developed glucose intolerance and frank diabetes upon high-fat diet exposure.
• Homozygous mice exhibited more severe diabetes, characterized by beta-cell heterogeneity, including proinsulin-rich/insulin-poor and glucagon-positive cells.

Conclusions:

• Subthreshold proinsulin misfolding can create a genetic susceptibility to beta-cell failure.
• Dietary factors can unmask this predisposition, leading to the development of diabetes, particularly in males and individuals with homozygous mutations.