INS-gene mutations: From genetics and beta cell biology to clinical disease

Abstract

A growing list of insulin gene mutations causing a new form of monogenic diabetes has drawn increasing attention over the past seven years. The mutations have been identified in the untranslated regions of the insulin gene as well as the coding sequence of preproinsulin including within the signal peptide, insulin B-chain, C-peptide, insulin A-chain, and the proteolytic cleavage sites both for signal peptidase and the prohormone convertases. These mutations affect a variety of different steps of insulin biosynthesis in pancreatic beta cells. Importantly, although many of these mutations cause proinsulin misfolding with early onset autosomal dominant diabetes, some of the mutant alleles appear to engage different cellular and molecular mechanisms that underlie beta cell failure and diabetes. In this article, we review the most recent advances in the field and discuss challenges as well as potential strategies to prevent/delay the development and progression of autosomal dominant diabetes caused by INS-gene mutations. It is worth noting that although diabetes caused by INS gene mutations is rare, increasing evidence suggests that defects in the pathway of insulin biosynthesis may also be involved in the progression of more common types of diabetes. Collectively, the (pre)proinsulin mutants provide insightful molecular models to better understand the pathogenesis of all forms of diabetes in which preproinsulin processing defects, proinsulin misfolding, and ER stress are involved.

Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research

“…Over recent years, more than 50 different insulin mutations have been discovered (reviewed in [193]). Two thirds of them lead to Mutant INS-gene-induced Diabetes of Youth, defined as a diabetic condition with insulin deficiency but no beta-cell autoimmunity that is transmitted in an autosomal-dominant manner [193].…”

“…Over recent years, more than 50 different insulin mutations have been discovered (reviewed in [193]). Two thirds of them lead to Mutant INS-gene-induced Diabetes of Youth, defined as a diabetic condition with insulin deficiency but no beta-cell autoimmunity that is transmitted in an autosomal-dominant manner [193]. All mutations within this group affect proinsulin folding in the endoplasmic reticulum (ER), with the majority targeting one of six cysteine residues essential for the formation of three disulfide bonds.…”

“…To establish a large animal model of permanent neonatal diabetes mellitus, we generated transgenic pigs expressing the mutant insulin C94Y corresponding to the human C96Y mutation [193] as well as the C96Y mutant mouse, which is also known as "Akita" mouse [196]. The mutation targets the cysteine residue (A7) within the Achain of the insulin molecule, disrupting the C(B7)-C(A7) interchain disulfide bond [40,193,196].…”

“…The mutation targets the cysteine residue (A7) within the Achain of the insulin molecule, disrupting the C(B7)-C(A7) interchain disulfide bond [40,193,196]. As porcine Cpeptide lacks two amino acids compared to human insulin and mouse Ins2, the porcine mutation refers to C94Y.…”

Mice deficient for ERAD machinery component Sel1L develop central diabetes insipidus

“…Expression of mutant MIDY proinsulin prevents WT proinsulin from exiting the ER, which is essential for insulin production in pancreatic β cells. Retention of WT insulin decreases overall insulin production and is toxic, thereby decreasing β cell numbers, which suggests that blockade of WT proinsulin by mutant proinsulin in MIDY is a triggering event in the onset of insulin deficiency (12).…”