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Objective: 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., Research Design and Methods: 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., Results: 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., Conclusions: 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.

IGFs are important regulators of pancreatic beta-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.

The mitochondrial (mt) 3243 DNA mutation is an underlying cause of maternally inherited diabetes and deafness (MIDD) syndrome and the syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). We report an affected German MIDD pedigree with maternal lineage over three generations. The index patient, her mother, her maternal aunt and her maternal grandmother all suffered from diabetes and premature hearing loss and were positive on testing for the mt 3243 DNA mutation. The 27-year-old index patient had a history of grand mal seizures. As sequela of abdominal ultrasound and confirmed by magnetic resonance cholangio-pancreaticography, she was diagnosed with chronic pancreatitis with pancreatic calcifications and pancreatic duct dilation, although she was completely asymptomatic and with no signs of steatorrhoea. She did not have gallstones and the common bile duct was normal. A possible etiopathogenic pathway for pancreatitis could be a suppressive effect of the mt 3243 mutation on the oxidative phosphorylation in affected mitochondria. Although pancreatitis and pancreatic dysfunction in association with the mt 3243 mutation, especially in patients with comorbidity of MELAS and diabetes, has previously been described as a rare manifestation, this case is specific because of the discrepancy of advanced morphological pancreatic alterations and complete lack of pancreatogenic symptoms.