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

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
Publishing year: 2012
Language: English
Pages: 1726-1733
Publication/Series: Diabetes
Volume: 61
Issue: 7
Document type: Journal article
Publisher: American Diabetes Association Inc.

Abstract 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.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Islet patophysiology
  • Islet cell exocytosis
  • Diabetes and Endocrinology
  • Islet cell physiology
  • ISSN: 1939-327X
Erik Renström
E-mail: erik [dot] renstrom [at] med [dot] lu [dot] se

Deputy head of department

Department of Clinical Sciences, Malmö

+46 40 39 11 57

+46 40 39 11 57

Principal investigator

Islet patophysiology

+46 40 39 11 57

+46 40 39 11 57

20-3-308

33

Lund University Diabetes Centre, CRC, SUS Malmö, Entrance 72, House 91:12. SE-205 02 Malmö. Telephone: +46 40 39 10 00