Predisposition to Proinsulin Misfolding as a Genetic Risk to Diet-Induced Diabetes.
Maroof AlamAnoop ArunagiriLeena HaatajaMauricio TorresDennis LarkinJohn KapplerNiyun JinPeter ArvanPublished in: Diabetes (2021)
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 β-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. 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 developed 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 weeks of exposure to a high-fat diet, they developed frank diabetes. Diabetes was more severe in homozygotes, and the development of disease paralleled a progressive heterogeneity of β-cells with increasing fractions of proinsulin-rich/insulin-poor cells as well as glucagon-positive cells. Evidently, subthreshold predisposition to proinsulin misfolding can go undetected but provides genetic susceptibility to diet-induced β-cell failure.
Keyphrases
- type diabetes
- glycemic control
- induced apoptosis
- high fat diet
- cardiovascular disease
- cell cycle arrest
- endoplasmic reticulum stress
- genome wide
- blood glucose
- adipose tissue
- copy number
- multiple sclerosis
- dna methylation
- cell proliferation
- blood pressure
- physical activity
- signaling pathway
- oxidative stress
- single cell
- gene expression
- metabolic syndrome
- diabetic rats
- drug induced
- endothelial cells
- high glucose
- solid state
- stress induced