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Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

Ingelsson, Erik; Langenberg, Claudia; Hivert, Marie-France; Prokopenko, Inga; Lyssenko, Valeriya LU ; Dupuis, Josee; Maegi, Reedik; Sharp, Stephen; Jackson, Anne U. and Assimes, Themistocles L., et al. (2010) 59th Annual Meeting of the American-Society-of-Human-Genetics In Diabetes 59(5). p.1266-1275
Abstract
OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084).... (More)
OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010 (Less)
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Chapter in Book/Report/Conference proceeding
publication status
published
subject
in
Diabetes
volume
59
issue
5
pages
1266 - 1275
publisher
American Diabetes Association
conference name
59th Annual Meeting of the American-Society-of-Human-Genetics
external identifiers
  • wos:000277554700019
  • scopus:77951858557
ISSN
0012-1797
DOI
10.2337/DB09-1568
language
English
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yes
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1a233bbf-acba-4587-a63b-d8f429355d18 (old id 1617932)
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http://www.ncbi.nlm.nih.gov/pubmed/20185807
date added to LUP
2010-06-21 08:51:48
date last changed
2018-06-24 04:08:52
@inproceedings{1a233bbf-acba-4587-a63b-d8f429355d18,
  abstract     = {OBJECTIVE-Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS-We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS-The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS-Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes. Diabetes 59:1266-1275, 2010},
  author       = {Ingelsson, Erik and Langenberg, Claudia and Hivert, Marie-France and Prokopenko, Inga and Lyssenko, Valeriya and Dupuis, Josee and Maegi, Reedik and Sharp, Stephen and Jackson, Anne U. and Assimes, Themistocles L. and Shrader, Peter and Knowles, Joshua W. and Zethelius, Bjorn and Abbasi, Fahim A. and Bergman, Richard N. and Bergmann, Antje and Berne, Christian and Boehnke, Michael and Bonnycastle, Lori L. and Bornstein, Stefan R. and Buchanan, Thomas A. and Bumpstead, Suzannah J. and Boettcher, Yvonne and Chines, Peter and Collins, Francis S. and Cooper, Cyrus C. and Dennison, Elaine M. and Erdos, Michael R. and Ferrannini, Ele and Fox, Caroline S. and Graessler, Juergen and Hao, Ke and Isomaa, Bo and Jameson, Karen A. and Kovacs, Peter and Kuusisto, Johanna and Laakso, Markku and Ladenvall, Claes and Mohlke, Karen L. and Morken, Mario A. and Narisu, Narisu and Nathan, David M. and Pascoe, Laura and Payne, Felicity and Petrie, John R. and Sayer, Avan A. and Schwarz, Peter E. H. and Scott, Laura J. and Stringham, Heather M. and Stumvoll, Michael and Swift, Amy J. and Syvanen, Ann-Christine and Tuomi, Tiinamaija and Tuomilehto, Jaakko and Tonjes, Anke and Valle, Timo T. and Williams, Gordon H. and Lind, Lars and Barroso, Ines and Quertermous, Thomas and Walker, Mark and Wareham, Nicholas J. and Meigs, James B. and McCarthy, Mark I. and Groop, Leif and Watanabe, Richard M. and Florez, Jose C.},
  booktitle    = {Diabetes},
  issn         = {0012-1797},
  language     = {eng},
  number       = {5},
  pages        = {1266--1275},
  publisher    = {American Diabetes Association},
  title        = {Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans},
  url          = {http://dx.doi.org/10.2337/DB09-1568},
  volume       = {59},
  year         = {2010},
}