Amino acid polymorphisms in the ATP-regulatable inward rectifier Kir6.2 and their relationships to glucose- and tolbutamide-induced insulin secretion, the insulin sensitivity index, and NIDDM

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 3; pp. 508 - 512
• Main Authors: HANSEN, L, ECHWALD, S. M, HANSEN, T, URHAMMER, S. A, CLAUSEN, J. O, PEDERSEN, O
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.03.1997
• Subjects: Adenosine triphosphate; Adenosine Triphosphate - metabolism; Adult; ATP (Adenosine triphosphate); Biological and medical sciences; Blood Glucose - metabolism; C-Peptide - blood; Cohort Studies; Denmark; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - physiopathology; Diabetes. Impaired glucose tolerance; DNA Primers; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; European Continental Ancestry Group; Female; Genetic aspects; Glucose Tolerance Test; Humans; Hypoglycemic Agents - pharmacology; Insulin - blood; Insulin - metabolism; Insulin resistance; Insulin Secretion; Male; Medical sciences; Physiological aspects; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Single-Stranded Conformational; Potassium channels; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels, Inwardly Rectifying; Reference Values; Tolbutamide - pharmacology; Type 2 diabetes; Denmark; Endocrinopathy; Human; Pancreatic hormone; Genetic inheritance; Non insulin dependent diabetes; Epidemiology; Insulin; Endocrine secretion; Target tissue resistance; Aminoacid; Race; Caucasoid; Polymorphism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diab.46.3.508

Kir6.2 is an inwardly rectifying potassium channel that is expressed in pancreatic beta-cells and cardiac and skeletal muscle. Expressed together with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling the native beta-cell channel. The objective of this study was to search for mutations in the Kir6.2 gene that might be associated with NIDDM or related to altered insulin secretion, insulin action, or glucose metabolism in healthy subjects. Using polymerase chain reaction-single-strand conformation polymorphism analysis (PCR-SSCP) on genomic DNA from 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved codons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CTC/CTG), Leu-->Leu; codon 270 (CTG/GTG), Leu-->Val; codon 337 (ATC/GTC), Ile-->Val; codon 381 (AAG/AAA), Lys-->Lys. The codon 23 and codon 337 amino acid polymorphisms were always coupled. The allelic frequencies of the polymorphisms were similar in NIDDM patients and control subjects. The amino acid polymorphisms were not associated with altered insulin secretion after intravenous glucose or tolbutamide injections or with altered glucose effectiveness in a phenotype study of 346 young healthy subjects. However, carriers of the maximal load of amino acid variants, the compound homozygous codon 23/337 and heterozygous codon 270, had on average a 62% higher insulin sensitivity index (P = 0.006), compared with noncarriers. We conclude that a combination of common Kir6.2 amino acid variants may contribute to the genetic background behind the large variation of the insulin sensitivity index in the general population.