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

Lookup NU author(s): Professor Mark Walker


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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

Publication metadata

Author(s): Walker M; Ingelsson E; Langenberg C; Hivert MF; Prokopenko I; Lyssenko V; Dupuis J; Magi R; Sharp S; Jackson AU; Assimes TL; Shrader P; Knowles JW; Zethelius B; Abbasi FA; Bergman RN; Bergmann A; Berne C; Boehnke M; Bonnycastle LL; Bornstein SR; Buchanan TA; Bumpstead SJ; Bottcher Y; Chines P; Collins FS; Cooper CC; Dennison EM; Erdos MR; Ferrannini E; Fox CS; Graessler J; Hao K; Isomaa B; Jameson KA; Kovacs P; Kuusisto J; Laakso M; Ladenval C; Mohlke KL; Morken MA; Narisu N; Nathan DM; Pascoe L; Payne F; Petrie JR; Sayer AA; Schwarz PEH; Scott LJ; Stringham HM; Stumvoll M; Swift AJ; Syvanen AC; Tuomi T; Tuomilehto J; Tonjes A; Valle TT; Williams GH; Lind L; Barroso I; Quertermous T; Wareham NJ; Meigs JB; McCarthy MI; Groop L; Watanabe RM; Florez JC

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2010

Volume: 59

Issue: 5

Pages: 1266-1275

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/DB09-1568

Notes: 59th Annual Meeting of the American Society of Human Genetics. Honolulu, Hawaii, USA. 20-24 October 2009.


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Funder referenceFunder name
G0701863Medical Research Council
MC_U106179471Medical Research Council
MC_UP_A620_1015Medical Research Council
MC_U147574213Medical Research Council
MC_U147574239Medical Research Council
MC_UP_A620_1014Medical Research Council