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

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

doi:10.2337/db11-1516

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

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 McCarthyLeif Groop, S Albert Salehi, Anna L Gloyn, Erik Renström, Patrik Rorsman, Lena Eliasson

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	1726-1733
Journal	Diabetes
Volume	61
Issue number	7
DOIs	https://doi.org/10.2337/db11-1516
Publication status	Published - 2012

Subject classification (UKÄ)

Endocrinology and Diabetes

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/db11-1516

http://www.ncbi.nlm.nih.gov/pubmed/22492527?dopt=Abstract

2 Doctoral Thesis (compilation)

CFTR in pancreatic islets
Edlund, A., 2016, 150 ed. Lund: Lund University: Faculty of Medicine. 69 p.
Research output: Thesis › Doctoral Thesis (compilation)

File
Mechanisms of defective insulin secretion in type 2 diabetes
Mahdi, T., 2013, Islet patophysiology. 138 p.
Research output: Thesis › Doctoral Thesis (compilation)

File

Cite this

Rosengren, A., Braun, M., Mahdi, T., Andersson, S. A., Travers, M. E., Shigeto, M., Zhang, E., Almgren, P., Ladenvall, C., Axelsson, A., Edlund, A., Pedersen, M. G., Jonsson, A., Ramracheya, R., Tang, Y., Walker, J. N., Barrett, A., Johnson, P. R. V., Lyssenko, V., ... Eliasson, L. (2012). Reduced Insulin Exocytosis in Human Pancreatic β-cells With Gene Variants Linked to Type 2 Diabetes. Diabetes, 61(7), 1726-1733. https://doi.org/10.2337/db11-1516

@article{c0434fddac4a4e7a9b90560137d8cf31,

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

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 = "Anders Rosengren and Matthias Braun and Taman Mahdi and Andersson, {Sofia A} and Travers, {Mary E} and Makoto Shigeto and Enming Zhang and Peter Almgren and Claes Ladenvall and Annika Axelsson and Anna Edlund and Pedersen, {Morten Gram} and Anna Jonsson and Reshma Ramracheya and Yunzhao Tang and Walker, {Jonathan N} and Amy Barrett and Johnson, {Paul R V} and Valeriya Lyssenko and McCarthy, {Mark I} and Leif Groop and Salehi, {S Albert} and Gloyn, {Anna L} and Erik Renstr{\"o}m and Patrik Rorsman and Lena Eliasson",

year = "2012",

doi = "10.2337/db11-1516",

language = "English",

volume = "61",

pages = "1726--1733",

journal = "Diabetes",

issn = "1939-327X",

publisher = "American Diabetes Association Inc.",

number = "7",

}

Rosengren, A, Braun, M, Mahdi, T, Andersson, SA, Travers, ME, Shigeto, M, Zhang, E, Almgren, P, Ladenvall, C, Axelsson, A, Edlund, A, Pedersen, MG, Jonsson, A, Ramracheya, R, Tang, Y, Walker, JN, Barrett, A, Johnson, PRV, Lyssenko, V, McCarthy, MI, Groop, L, Salehi, SA, Gloyn, AL, Renström, E, Rorsman, P & Eliasson, L 2012, 'Reduced Insulin Exocytosis in Human Pancreatic β-cells With Gene Variants Linked to Type 2 Diabetes.', Diabetes, vol. 61, no. 7, pp. 1726-1733. https://doi.org/10.2337/db11-1516

TY - JOUR

T1 - Reduced Insulin Exocytosis in Human Pancreatic β-cells With Gene Variants Linked to Type 2 Diabetes.

AU - Rosengren, Anders

AU - Braun, Matthias

AU - Mahdi, Taman

AU - Andersson, Sofia A

AU - Travers, Mary E

AU - Shigeto, Makoto

AU - Zhang, Enming

AU - Almgren, Peter

AU - Ladenvall, Claes

AU - Axelsson, Annika

AU - Edlund, Anna

AU - Pedersen, Morten Gram

AU - Jonsson, Anna

AU - Ramracheya, Reshma

AU - Tang, Yunzhao

AU - Walker, Jonathan N

AU - Barrett, Amy

AU - Johnson, Paul R V

AU - Lyssenko, Valeriya

AU - McCarthy, Mark I

AU - Groop, Leif

AU - Salehi, S Albert

AU - Gloyn, Anna L

AU - Renström, Erik

AU - Rorsman, Patrik

AU - Eliasson, Lena

PY - 2012

Y1 - 2012

N2 - 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.

AB - 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.

U2 - 10.2337/db11-1516

DO - 10.2337/db11-1516

M3 - Article

C2 - 22492527

SN - 1939-327X

VL - 61

SP - 1726

EP - 1733

JO - Diabetes

JF - Diabetes

IS - 7

ER -

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

Abstract

Subject classification (UKÄ)

UN SDGs

Access to Document

Fingerprint

Research output

CFTR in pancreatic islets

Mechanisms of defective insulin secretion in type 2 diabetes

Cite this