Polymorphisms in beta-cell transcription factor genes, Ala45Thr in the NeuroD1 gene and Arg121Trp in the Pax4 gene, have been reported. To clarify the role of these mutations in the pathogenesis of late-onset diabetes, we examined the insulin secretion and sensitivity in diabetic patients carrying the homozygous mutation in the NeuroD1 gene or Pax4 gene. We screened for the polymorphisms in NeuroD1 and Pax4 genes in 296 late-onset diabetic patients and 177 unrelated control subjects over 60 years of age. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) followed by direct sequencing. Acute insulin secretion was evaluated using a 2-compartment model analysis of C-peptide kinetics after intravenous glucose load (CS1). Insulin sensitivity was estimated by the insulin-modified minimal model analysis (Si). Four diabetic patients carried the homozygous mutation (Thr/Thr) in the NeuroD1 gene and 3 patients carried the homozygous mutation (Trp/Trp) in the Pax4 gene, while both homozygous mutations were not detected in the control subjects. In patients A, B, C, and D with homozygous mutations in NeuroD1, CS1 (normal range, 6.8 to 18.5 ng/mL/min) was 0.508, 1.481, 1.223, and 1.584 ng/mL/min, respectively, and Si (normal range, 2.6 to 7.6 x 10(-4)/min/[microU/mL]) was 0.727, 3.31, 3.79, and 0.00 x 10(-4)/min/(microU/mL), respectively. In patients X, Y, and Z with homozygous mutation in Pax4, CS was 0.418, 0.208, and 1.279 ng/mL/min, respectively, and Si was 1.11, 2.88, and 0.00 x 10(-4)/min/(microU/mL), respectively. Since acute insulin secretion in response to glucose was markedly impaired and insulin resistance was varied in the patients carrying the homozygous mutations in the NeuroD1 and Pax4 genes, the mutations are ones of the factors involved in the beta-cell dysfunction and do not relate to the insulin resistance. These homozygous mutations appear to play a part in the pathogenesis of beta-cell defect in about 2.5% of Japanese patients with late-onset diabetes.
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