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

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Alena Stancáková, 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, EUGENE2 Consortium

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.
Original languageEnglish
JournalJournal of Clinical Endocrinology and Metabolism
Volume93
Issue number5
Pages (from-to)1924-30
Number of pages6
ISSN0021-972X
DOIs
Publication statusPublished - 2008

Bibliographical note

Keywords: Adult; Cyclin-Dependent Kinase 5; Diabetes Mellitus, Type 2; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Polymorphism, Single Nucleotide

ID: 10001187