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Genetic Factors and Insulin Secretion

Gene Variants in the IGF Genes

¹ Deparment of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands
² Department of Internal Medicine, Universitätsklinikum Tübingen, Tübingen, Germany
³ Department of Epidemiology and Biostatistics, Genetic Epidemiology Unit, Erasmus University Medical Center, Rotterdam, the Netherlands
⁴ Institute for Research in Extramural Medicine, Free University Medical Center, Amsterdam, the Netherlands
⁵ Department of Internal Medicine, University Medical Center, Utrecht, the Netherlands

IGFs are important regulators of pancreatic ß-cell development, growth, and maintenance. Mutations in the IGF genes have been found to be associated with type 2 diabetes, myocardial infarction, birth weight, and obesity. These associations could result from changes in insulin secretion. We have analyzed glucose-stimulated insulin secretion using hyperglycemic clamps in carriers of a CA repeat in the IGF-I promoter and an ApaI polymorphism in the IGF-II gene. Normal and impaired glucose-tolerant subjects (n = 237) were independently recruited from three different populations in the Netherlands and Germany to allow independent replication of associations. Both first- and second-phase insulin secretion were not significantly different between the various IGF-I or IGF-II genotypes. Remarkably, noncarriers of the IGF-I CA repeat allele had both a reduced insulin sensitivity index (ISI) and disposition index (DI), suggesting an altered balance between insulin secretion and insulin action. Other diabetes-related parameters were not significantly different for both the IGF-I and IGF-II gene variant. We conclude that gene variants in the IGF-I and IGF-II genes are not associated with detectable variations in glucose-stimulated insulin secretion in these three independent populations. Further studies are needed to examine the exact contributions of the IGF-I CA repeat alleles to variations in ISI and DI.

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