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

Abstract

and anti-proinsulin immunoblotting is shown below, highlighting the presence of aberrant disulfidelinked proinsulin complexes. B) Quantitation of islet proinsulin and insulin protein levels (each point an independent male animal) by Western blotting as in panel A (mean ± s.d.; * p < 0.05; ** p < 0.01). Supplement Fig. S2. Circulating proinsulin, and proinsulin-to-insulin ratio, from 11.5 week old HFD-fed Ins2-proinsulin-R(B22)E heterozygous males (pink symbols), superimposed onto the data reproduced from Figs 2G and H. Horizontal asterisks represent statistical differences (mean ± s.d.) along the X-axis (blood glucose); vertical asterisks indicate statistical differences along the Y-axis (proinsulin level, or proinsulin-to-insulin ratio). Supplement Fig. S3. Transmission electron micrographs of islets cells from the genotypes (and diet) included in this study. Random blood glucose at the time of euthanasia is indicated on each figure. Scale bars are shown on all figures. A) Typical β-cell from male WT mouse and Ins2proinsulin-R(B22)E heterozygote on normal chow diet (age 4 weeks). B) Another typical β-cell from the animals analyzed in panel A, at higher magnification to highlight ER and secretory granule morphology. C) β-cell from WT mouse fed a HFD for 6 weeks with organelles labeled on the figure. ISG = immature secretory granule. VTCs are a pre-Golgi compartment. D) Upper left image: low-power of islet from HFD-fed male Ins2-proinsulin-R(B22)E heterozygote (age 6 weeks). "Cell A and B" are β-cells; "Cell C" is an α-cell. Note that Cell B is poorly granulated.

Proinsulin folding and trafficking defects trigger a common pathological disturbance of endoplasmic reticulum homeostasis

“…Proinsulin in the ER is susceptible to misfolding (Haataja et al, 2016), and primary defects in proinsulin folding from INS gene mutations account for the development of diabetes in the syndrome known as MIDY (Arunagiri et al, 2018). Recent reports are also consistent with the idea that a partial or subtle predisposition to proinsulin misfolding can be genetically encoded (Alam et al, 2021), and when combined with an environmental/dietary component, this results in defective proinsulin trafficking (Alarcon et al, 2016;Arunagiri et al, 2019). Molecular crowding as well as the high rate of proinsulin biosynthesis within the ER (Yong et al, 2021) may help to account for proinsulin misfolding in individuals expressing exclusively WT proinsulin (Liu et al, 2018;Liu et al, 2021).…”

“…Molecular crowding as well as the high rate of proinsulin biosynthesis within the ER (Yong et al, 2021 ) may help to account for proinsulin misfolding in individuals expressing exclusively WT proinsulin (Liu et al, 2018 ; Liu et al, 2021 ). Additionally, despite the presumptively protective isomerase activity of ER oxidoreductases (Jang et al, 2019 ; Rajpal et al, 2012 ; Rohli et al, 2022 ), unfavorable metabolic or genetic factors may result in misfolding of proinsulin that cannot progress from the ER into the distal secretory pathway (Alam et al, 2021 ; Arunagiri et al, 2019 ). Among the many genetic variants linked to diabetes are genes expressed in β‐cells that impact on ER homeostasis and ER‐to‐Golgi trafficking (see Introduction).…”

Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identity

“…Misfolding of proinsulin monomers can promote the formation of aberrant intermolecular proinsulin disulfide bonds (Alam et al, 2021; Arunagiri et al, 2019; Haataja et al, 2021; Sun et al, 2020). We examined this possibility using anti-proinsulin immunoblotting of protein extracts from stem cell derived beta cell clusters, and resolved by nonreducing SDS-PAGE.…”

Recent Advances of Integrative Bio-Omics Technologies to Improve Type 1 Diabetes (T1D) Care

“…Specifically, in individuals with the rare genetic syndrome called Mutant INS-gene-induced Diabetes of Youth (MIDY), a mutation in the proinsulin-R(B22)E and Q causes misfolding of the proinsulin protein in the endoplasmic reticulum. This triggers rapid insulin deficiencies and results in glucose intolerance upon exposure to a high-fat diet [33][34][35]. Interestingly, molecular studies in animal models propose that evolution is maintaining islet cell heterogeneity and that mutations affecting protein-folding might serve as important predictors for diabetes outcomes, especially hypoglycemia [33].…”

“…This triggers rapid insulin deficiencies and results in glucose intolerance upon exposure to a high-fat diet [33][34][35]. Interestingly, molecular studies in animal models propose that evolution is maintaining islet cell heterogeneity and that mutations affecting protein-folding might serve as important predictors for diabetes outcomes, especially hypoglycemia [33].…”