Single-nucleotide Polymorphism rs7754840 of CDKAL1 Is Associated With Impaired Insulin Secretion in Nondiabetic Offspring of Type 2 Diabetic Subjects and in a Large Sample of Men With Normal Glucose Tolerance

J Clin Endocrinol Metab. 2008 May;93(5):1924-30. doi: 10.1210/jc.2007-2218. Epub 2008 Feb 19.

Abstract

Context: CDKAL1 is a recently discovered susceptibility gene for type 2 diabetes.

Objective: Our objective was to investigate the impact of rs7754840 of CDKAL1 on insulin secretion, insulin sensitivity, and risk of type 2 diabetes.

Design and settings: Study 1 (the EUGENE2 study) was a cross-sectional study including subjects from five white populations in Europe (Denmark, Finland, Germany, Italy, and Sweden). Study 2 is an ongoing prospective study of Finnish men.

Participants: In study 1, 846 nondiabetic offspring of type 2 diabetic patients (age 40 +/- 10 yr; body mass index 26.7 +/- 5.0 kg/m(2)) participated. In study 2, subjects included 3900 middle-aged men (533 type 2 diabetic and 3367 nondiabetic subjects).

Interventions: INTERVENTIONS included iv glucose-tolerance test (IVGTT), oral glucose-tolerance test (OGTT), and euglycemic-hyperinsulinemic clamp in study 1 and OGTT in study 2.

Main outcome measures: Parameters of insulin secretion, insulin resistance, and glucose tolerance status were assessed.

Results: In study 1, carriers of the GC and CC genotypes of rs7754840 had 11 and 24% lower first-phase insulin release in an IVGTT compared with that in carriers of the GG genotype (P = 0.002). The C allele was also associated with higher glucose area under the curve in an OGTT (P = 0.016). In study 2, rs7754840 was significantly associated with type 2 diabetes (P = 0.022) and markers of impaired insulin release [insulinogenic index (IGI), P = 0.012] in 2405 men with normal glucose tolerance.

Conclusions: rs7754840 of CDKAL1 was associated with markers of impaired insulin secretion in two independent studies. Furthermore, rs7754840 was associated with type 2 diabetes in Finnish men (study 2). Therefore, CDKAL1 is likely to increase the risk of type 2 diabetes by impairing insulin secretion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Cyclin-Dependent Kinase 5 / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Glucose Tolerance Test*
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance
  • Insulin Secretion
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide*
  • tRNA Methyltransferases

Substances

  • Insulin
  • tRNA Methyltransferases
  • Cyclin-Dependent Kinase 5
  • CDKAL1 protein, human