The prevalent Glu23Lys polymorphism in the potassium inward rectifier 6.2 (KIR6.2) gene is associated with impaired glucagon suppression in response to hyperglycemia.

Abstract

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 beta-cell function, alpha-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 approximately 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 beta-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.

• Authors: Otto Tschritter, Michael Stumvoll, Fausto Machicao, Martin Holzwarth, Melanie Weisser, Elke Maerker, Anna Teigeler, Hans Häring, Andreas Fritsche
• Journal: Diabetes (Diabetes) Vol. 51 Issue 9 Pg. 2854-60 (Sep 2002) ISSN: 0012-1797 [Print] United States
• PMID: 12196481 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Insulin
• Potassium Channels, Inwardly Rectifying
• Glutamic Acid
• Glucagon
• Lysine

Topics

• Adult
• Alleles
• Female
• Gene Frequency
• Glucagon (antagonists & inhibitors, blood)
• Glutamic Acid
• Humans
• Hyperglycemia (genetics, metabolism, physiopathology)
• Insulin (metabolism, physiology)
• Insulin Secretion
• Islets of Langerhans (physiopathology)
• Lysine
• Male
• Polymorphism, Genetic (physiology)
• Potassium Channels, Inwardly Rectifying (genetics)