Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth. Trends Endocrinol Metab

Division of Metabolism, Endocrinology and Diabetes, University of Michigan Medical Center, Ann Arbor, MI, USA.
Trends in Endocrinology and Metabolism (Impact Factor: 9.39). 11/2010; 21(11):652-9. DOI: 10.1016/j.tem.2010.07.001
Source: PubMed


Type 1B diabetes (typically with early onset and without islet autoantibodies) has been described in patients bearing small coding sequence mutations in the INS gene. Not all mutations in the INS gene cause the autosomal dominant Mutant INS-gene Induced Diabetes of Youth (MIDY) syndrome, but most missense mutations affecting proinsulin folding produce MIDY. MIDY patients are heterozygotes, with the expressed mutant proinsulins exerting dominant-negative (toxic gain of function) behavior in pancreatic beta cells. Here we focus primarily on proinsulin folding in the endoplasmic reticulum, providing insight into perturbations of this folding pathway in MIDY. Accumulated evidence indicates that, in the molecular pathogenesis of the disease, misfolded proinsulin exerts dominant effects that initially inhibit insulin production, progressing to beta cell demise with diabetes.

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    • "Presumably the mechanism of disease is similar to those of previously described A24D mutation. It causes misfolding and defective trafficking of proinsulin, exerting dominant-negative effect on insulin production and b-cell apoptosis [4] [5] [10] [14]. Although INS gene differs between humans and rodents, INS2 missense mutations in Akita and Munich mice models result in proteotoxic disruption of interchain disulphide bond formation [6] [7] [15]. "
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    ABSTRACT: In this report we present a family with permanent neonatal diabetes, heterozygous for a novel INS gene missense mutation, p.A24V, manifested with marked hyperglycemia and ketoacidosis, unstable glycemic control, requiring insulin therapy, rapid progression of long-term complications and accompanying physical pathological signs and brain lesions. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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    • "However, abnormal proinsulin processing or trafficking is known to be one of the hallmarks of prediabetes. This is supported by studies of the Akita mouse and in some patients with neonatal diabetes mellitus (NDM) that arise from mutations in the Insulin gene, resulting in improper folding of the mutant protein [7], [18], [19]. Akita mice have a progressive deterioration of secretory organelle structure and function, which is thought to be the primary cause of diabetes in these mice. "
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    • "Diabetes of youth (MIDY) is a syndrome caused by a heterozygous mutation of the coding sequence of proinsulin leading to an autosomal-dominant and insulin-deficient diabetes [31]. This mutation has been shown to be the second most common cause of permanent neonatal diabetes related to ER stress [32, 33]. In line with these observations, inducible expression of the human analogue proinsulin C96Y mutation of Akita mice in rat insulinoma-1 (INS-1) caused ER stress and cell apoptosis. "
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