The Prevalent Glu23Lys Polymorphism in the Potassium Inward Rectifier 6.2 (KIR6.2) Gene Is Associated With Impaired Glucagon Suppression in Response to Hyperglycemia
- Otto Tschritter,
- Michael Stumvoll,
- Fausto Machicao,
- Martin Holzwarth,
- Melanie Weisser,
- Elke Maerker,
- Anna Teigeler,
- Hans Häring and
- Andreas Fritsche
- From the Department of Endocrinology, Metabolism and Pathobiochemistry, Medizinische Klinik, Eberhard-Karls-Universität, Tübingen, Germany
Genetic factors play an important role in the pathogenesis of type 2 diabetes. The relevance to type 2 diabetes of the common polymorphism Glu23Lys in the potassium inward rectifier 6.2 (KIR6.2) gene is still controversial. The aim of this study was to assess whether this polymorphism influences β-cell function, α-cell function, or insulin action. We therefore studied 298 nondiabetic subjects using an oral glucose tolerance test (OGTT) and 75 nondiabetic subjects using a hyperglycemic clamp (10 mmol/l) with additional glucagon-like peptide (GLP)-1 and arginine stimulation. The prevalence of the Lys allele was ∼37%, and the Lys allele was associated with higher incremental plasma glucose during the OGTT (P = 0.03, ANOVA). Neither first- nor second-phase glucose-stimulated C-peptide secretion was affected by the presence of the polymorphism; nor were maximal glucose-, GLP-1-, or arginine-induced C-peptide secretion rates; nor was insulin sensitivity (all P > 0.7). However, the relative decrease in plasma glucagon concentrations during the 10 min after the glucose challenge was reduced in carriers of the Lys allele (10 ± 3% decrease from baseline in Lys/Lys, 18 ± 2% in Glu/Lys, and 20 ± 2% in Glu/Glu; P = 0.01, ANOVA). In conclusion, our findings suggest that the common Glu23Lys polymorphism in KIR6.2 is not necessarily associated with β-cell dysfunction or insulin resistance but with diminished suppression of glucagon secretion in response to hyperglycemia. Our findings thus confirm its functional relevance for glucose metabolism in humans.
Address correspondence and reprint requests to Professor Dr. med. Hans-Ulrich Häring, Medizinische Universitätsklinik, Otfried-Müller-Str. 10, D-72076 Tübingen, Germany. E-mail:.
Received for publication 18 January 2002 and accepted in revised form 4 June 2002.
AUCinc, incremental area under the curve; GLP, glucagon-like peptide; IGT, impaired glucose tolerance; KATP channel, ATP-sensitive K+ channel; KIR6.2, potassium inward rectifier 6.2; NGT, normal glucose tolerance; OGTT, oral glucose tolerance test; SUR1, sulfonylurea receptor; WHR, waist-to-hip ratio.