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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Adult, Aged, Alleles, Body Mass Index, Diabetes Mellitus, Type 2, Female, Genotype, Germany, Glucose, Glucose Clamp Technique, Glucose Intolerance, Humans, Hyperglycemia, Insulin, Male, Middle Aged, Netherlands, Polymorphism, Single Nucleotide, Reference Values, Risk Assessment, Risk Factors.
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Is combined risk allele score of eight type 2 diabetes genes associated with reduced first-phase glucose-stimulated insulin secretion during hyperglycemic clamps? Context: At least 20 type 2 diabetes loci have now been identified, and several of these are associated with altered beta-cell function. In this study, we have investigated the combined effects of eight known beta-cell loci on insulin secretion stimulated by three different secretagogues during hyperglycemic clamps. A total of 447 subjects originating from four independent studies in the Netherlands and Germany (256 with normal glucose tolerance [NGT]/191 with impaired glucose tolerance [IGT]) underwent a hyperglycemic clamp. A subset had an extended clamp with additional glucagon-like peptide (GLP)-1 and arginine (n = 224). We next genotyped single nucleotide polymorphisms in TCF7L2, KCNJ11, CDKAL1, IGF2BP2, HHEX/IDE, CDKN2A/B, SLC30A8, and MTNR1B and calculated a risk allele score by risk allele counting. The risk allele score was associated with lower first-phase glucose-stimulated insulin secretion (GSIS) (P = 7.1 x 10(-6)). The effect size was equal in subjects with NGT and IGT. We also noted an inverse correlation with the disposition index (P = 1.6 x 10(-3)). When we stratified the study population according to the number of risk alleles into three groups, those with a medium- or high-risk allele score had 9 and 23% lower first-phase GSIS. Second-phase GSIS, insulin sensitivity index and GLP-1, or arginine-stimulated insulin release were not significantly different.
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A combined risk allele score for eight known beta-cell genes is associated with the rapid first-phase GSIS and the disposition index. The slower second-phase GSIS, GLP-1, and arginine-stimulated insulin secretion are not associated, suggesting that especially processes involved in rapid granule recruitment and exocytosis are affected in the majority of risk loci. Final Decision: yes