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

• Published in: The journal of clinical endocrinology and metabolism 2008-05, Vol.93 (5), p.1924-1930
• Main Authors: Stančáková, Alena, Pihlajamäki, Jussi, Kuusisto, Johanna, Stefan, Norbert, Fritsche, Andreas, Häring, Hans, Andreozzi, Francesco, Succurro, Elena, Sesti, Giorgio, Boesgaard, Trine Welløv, Hansen, Torben, Pedersen, Oluf, Jansson, Per Anders, Hammarstedt, Ann, Smith, Ulf, Laakso, Markku
• Format: Article
• Language: English
• Subjects: Adult; Biological and medical sciences; Cyclin-Dependent Kinase 5 - genetics; Diabetes Mellitus; Diabetes Mellitus, Type 2 - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Glucose Tolerance Test; Humans; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Male; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Polymorphism; Polymorphism, Single Nucleotide; Single Nucleotide; tRNA Methyltransferases; Type 2/genetics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2007-2218

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.