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Submitted on October 3, 2007
Accepted on February 8, 2008
Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland; Department of Internal Medicine, Division of Endocrinology, Diabetology, Nephrology, Vascular Medicine and Clinical Chemistry, University of Tubingen, Tubingen, Germany; Department of Experimental and Clinical Medicine, University Magna Græcia of Catanzaro, Catanzaro, Italy; Steno Diabetes Centre, Copenhagen, Denmark; The Lundberg Laboratory for Diabetes Research, Department of Internal Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
* To whom correspondence should be addressed. E-mail: markku.laakso{at}uku.fi.
Context: CDKAL1 is a recently discovered susceptibility gene for type 2 diabetes.
Objective: To investigate the impact of rs7754840 of CDKAL1 on insulin secretion, insulin sensitivity and risk of type 2 diabetes.
Design and Settings: Study I (the EUGENE2 study): Cross-sectional study including subjects from five white populations in Europe (Denmark, Finland, Germany, Italy and Sweden). Study II: Ongoing prospective study of Finnish men.
Participants: Study I: 846 non-diabetic offspring of type 2 diabetic patients (age 40±10 years; BMI 26.7±5.0 kg/m2). Study II: 3900 middle-aged men (533 type 2 diabetic and 3367 non-diabetic subjects).
Interventions: Study I: intravenous glucose-tolerance test (IVGTT), oral glucose-tolerance test (OGTT), euglycemic hyperinsulinemic clamp. Study II: OGTT.
Main outcome measures: Parameters of insulin secretion, insulin resistance, and glucose tolerance status.
Results: Study I: Carriers of the GC and CC genotypes of rs7754840 had 11% and 24% lower first-phase insulin release in an IVGTT compared to 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). Study II: rs7754840 was significantly associated with type 2 diabetes (P=0.022), and markers of impaired insulin release (insulinogenic index, 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 II). Therefore, CDKAL1 is likely to increase the risk of type 2 diabetes by impairing insulin secretion.
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