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PMID: 18719881 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles.

Diabetologia ·Vol. 51 ·No. 11 ·2008-11-00 ·Pages 1989-92

Pascoe L, Frayling TM, Weedon MN, Mari A, Tura A, Ferrannini E, Walker M, RISC Consortium

Abstract

Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min(-1) m(-2) (mmol/l)(-1), p = 1.51 x 10(-6)). The same was seen for the 30 min insulin response (p = 4.17 x 10(-7)). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively). This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals.

MeSH Terms
Adult Blood Glucose/metabolism Body Mass Index Cyclin-Dependent Kinase 5/genetics Diabetes Mellitus/epidemiology,genetics Genetic Predisposition to Disease Glucose/pharmacology Glucose Tolerance Test Homeodomain Proteins/genetics Humans Insulin/blood Insulin-Secreting Cells/drug effects,physiology Polymorphism, Single Nucleotide Risk Factors TCF Transcription Factors/genetics Transcription Factor 7-Like 2 Protein Transcription Factors/genetics tRNA Methyltransferases
Chemicals
Blood Glucose HHEX protein, human Homeodomain Proteins Insulin TCF Transcription Factors TCF7L2 protein, human Transcription Factor 7-Like 2 Protein Transcription Factors tRNA Methyltransferases Cyclin-Dependent Kinase 5 CDKAL1 protein, human Glucose
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Pascoe L
The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
Frayling T M
Weedon M N
Mari A
Tura A
Ferrannini E
Walker M
RISC Consortium
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Article Info
Journal
Diabetologia
Abbr.
Diabetologia
ISSN
0012-186X
DOI
10.1007/s00125-008-1124-7
Published
2008-11-00
Epub
2008-00-22
Pages
1989-92
Language
English
Region
Germany
NLM ID
0006777
Subset
IM
External Links
PubMed source DOI: 10.1007/s00125-008-1124-7 View journal details
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