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.

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.