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

Rosengren, Anders LU ; Braun, Matthias; Mahdi, Taman LU ; Andersson, Sofia A LU ; Travers, Mary E; Shigeto, Makoto; Zhang, Enming LU ; Almgren, Peter LU ; Ladenvall, Claes LU and Axelsson, Annika LU , et al. (2012) In Diabetes 61(7). p.1726-1733
Abstract
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... (More)
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. (Less)
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type
Contribution to journal
publication status
published
subject
in
Diabetes
volume
61
issue
7
pages
1726 - 1733
publisher
American Diabetes Association Inc.
external identifiers
  • wos:000305543900013
  • pmid:22492527
  • scopus:84863207933
ISSN
1939-327X
DOI
10.2337/db11-1516
language
English
LU publication?
yes
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c0434fdd-ac4a-4e7a-9b90-560137d8cf31 (old id 2519630)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22492527?dopt=Abstract
date added to LUP
2012-05-06 15:05:50
date last changed
2017-11-19 03:02:35
@article{c0434fdd-ac4a-4e7a-9b90-560137d8cf31,
  abstract     = {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       = {Rosengren, Anders and Braun, Matthias and Mahdi, Taman and Andersson, Sofia A and Travers, Mary E and Shigeto, Makoto and Zhang, Enming and Almgren, Peter and Ladenvall, Claes and Axelsson, Annika and Edlund, Anna and Pedersen, Morten Gram and Jonsson, Anna and Ramracheya, Reshma and Tang, Yunzhao and Walker, Jonathan N and Barrett, Amy and Johnson, Paul R V and Lyssenko, Valeriya and McCarthy, Mark I and Groop, Leif and Salehi, S Albert and Gloyn, Anna L and Renström, Erik and Rorsman, Patrik and Eliasson, Lena},
  issn         = {1939-327X},
  language     = {eng},
  number       = {7},
  pages        = {1726--1733},
  publisher    = {American Diabetes Association Inc.},
  series       = {Diabetes},
  title        = {Reduced Insulin Exocytosis in Human Pancreatic β-cells With Gene Variants Linked to Type 2 Diabetes.},
  url          = {http://dx.doi.org/10.2337/db11-1516},
  volume       = {61},
  year         = {2012},
}