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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

Alena Stanáková, Jussi Pihlajamäki, Johanna Kuusisto, Norbert Stefan, Andreas Fritsche, Hans Häring, Francesco Andreozzi, Elena Succurro, Giorgio Sesti, Trine Welløv Boesgaard, Torben Hansen, Oluf Pedersen, Per Anders Jansson, Ann Hammarstedt, Ulf Smith, Markku Laakso for the EUGENE2 Consortium

Department of Medicine (A.S., J.P., J.K., M.L.), University of Kuopio and Kuopio University Hospital, 70210 Kuopio, Finland; Department of Internal Medicine (N.S., A.F., H.H.), Division of Endocrinology, Diabetology, Nephrology, Vascular Medicine, and Clinical Chemistry, University of Tubingen, D-72076 Tubingen, Germany; Department of Experimental and Clinical Medicine (F.A., E.S., G.S.), University Magna Græcia of Catanzaro, 88100 Catanzaro, Italy; Steno Diabetes Centre (T.W.B., T.H., O.P.), DK-2820 Gentofte Copenhagen, Denmark; and The Lundberg Laboratory for Diabetes Research (P.A.J., A.H., U.S.), Department of Internal Medicine, Sahlgrenska University Hospital, SE-413 45 Gothenburg, Sweden

Adress all correspondence and requests for reprints to: Markku Laakso, M.D., Academy Professor, Department of Medicine, University of Kuopio, 70210 Kuopio, Finland. E-mail: markku.laakso{at}uku.fi.

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/m²) 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.