Proinsulin misfolding and diabetes: mutant INS gene-induced diabetes of youth

• Published in: Trends in endocrinology and metabolism Vol. 21; no. 11; pp. 652 - 659
• Main Authors: Liu, Ming, Hodish, Israel, Haataja, Leena, Lara-Lemus, Roberto, Rajpal, Gautam, Wright, Jordan, Arvan, Peter
• Format: Journal Article
• Language: English
• Published: Cambridge, MA Elsevier Ltd 01.11.2010; Cell Press
• Subjects: Amino Acid Sequence; Animals; Autoantibodies; Biological and medical sciences; Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology & Metabolism; Endocrinopathies; Endoplasmic Reticulum - metabolism; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Humans; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Medical sciences; Models, Biological; Molecular Sequence Data; Mutation - physiology; Proinsulin - chemistry; Proinsulin - genetics; Proinsulin - metabolism; Proinsulin - physiology; Protein Folding; Proteostasis Deficiencies - genetics; Proteostasis Deficiencies - metabolism; Vertebrates: endocrinology; Endocrinopathy; Mutation; Gene; Diabetes mellitus
• ISSN: 1043-2760; 1879-3061
• DOI: 10.1016/j.tem.2010.07.001

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 M utant I NS-gene Induced D iabetes of Y outh (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.