Reduced Insulin Exocytosis in Human Pancreatic β-cells With Gene Variants Linked to Type 2 Diabetes.

Summary, in English

The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for β-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in β-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.

• Author: Anders Rosengren; Matthias Braun; Taman Mahdi; Sofia A Andersson; Mary E Travers; Makoto Shigeto; Enming Zhang; Peter Almgren; Claes Ladenvall; Annika Axelsson; Anna Edlund; Morten Gram Pedersen; Anna Jonsson; Reshma Ramracheya; Yunzhao Tang; Jonathan N Walker; Amy Barrett; Paul R V Johnson; Valeriya Lyssenko; Mark I McCarthy; Leif Groop; S Albert Salehi; Anna L Gloyn; Erik Renström; Patrik Rorsman; Lena Eliasson
• Department/s: Diabetes - Islet Patophysiology; Diabetes - Islet Cell Exocytosis; Translational Muscle Research; Islet cell physiology; EXODIAB: Excellence of Diabetes Research in Sweden; EpiHealth: Epidemiology for Health
• Publishing year: 2012
• Language: English
• Pages: 1726-1733
• Publication/Series: Diabetes
• Volume: 61
• Issue: 7
• Links: http://www.ncbi.nlm.nih.gov/pubmed/22492527?dopt=Abstract; http://dx.doi.org/10.2337/db11-1516
• Document type: Journal article
• Publisher: American Diabetes Association Inc.
• Topic: Endocrinology and Diabetes
• Status: Published
• Research group: Diabetes - Islet Patophysiology; Diabetes - Islet Cell Exocytosis; Genomics, Diabetes and Endocrinology; Islet cell physiology
• ISBN/ISSN/Other: ISSN: 1939-327X