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

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.

Author information

1
Department of Medicine, University of Kuopio and University Hospital, 70210 Kuopio, Finland.

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.

PMID:
18285412
DOI:
10.1210/jc.2007-2218
[Indexed for MEDLINE]

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