AMINO-ACID POLYMORPHISMS IN THE ATP-REGULATABLE INWARD RECTIFIER KIR6.2 AND THEIR RELATIONSHIPS TO GLUCOSE-INDUCED AND TOLBUTAMIDE-INDUCED INSULIN-SECRETION, THE INSULIN SENSITIVITY INDEX, AND NIDDM

Kir6.2 is an inwardly rectifying potassium channel that is expressed i n pancreatic beta-cells and cardiac and skeletal muscle. Expressed tog ether with the high-affinity sulphonylurea receptor, it reconstitutes a sulphonylurea- and also ATP-sensitive potassium channel resembling t he 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 me tabolism in healthy subjects. Using polymerase chain reaction-single-s trand conformation polymorphism analysis (PCR-SSCP) on genomic DNA fro m 69 Danish NIDDM patients and 66 matched control subjects, we report the finding of three missense polymorphisms in otherwise conserved cod ons and three silent polymorphisms in the gene encoding Kir6.2: codon 23 (GAG/AAG), Glu-->Lys; codon 190 (GCT/GCC), Ala-->Ala; codon 267 (CT C/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 33 7 amino acid polymorphisms were always coupled. The allelic frequencie s of the polymorphisms were similar in NIDDM patients and control subj ects. The amino acid polymorphisms were not associated with altered in sulin 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 be hind the large variation of the insulin sensitivity index in the gener al population.