title: ABCC8 polymorphism (Ser1369Ala): influence on severe hypoglycemia due to sulfonylureas.
abstract: OBJECTIVE
  Sulfonylureas are categorized according to their binding sites of the ATP-sensitive K+ channel (K(ATP) channel) complex in pancreatic β-cells. The binding sites are classified as A, B and A + B site (both A and B sites), respectively. The Ser1369Ala variant in the sulfonylurea receptor gene ABCC8 which encodes a subunit of the K(ATP) channel complex has been demonstrated to be associated with the hypoglycemic effect of gliclazide, which binds to the A site. However, the hypoglycemic effect of the Ser1369Ala variant on treatment with A + B binding site sulfonylureas, such as glimepiride or glibenclamide, is still uncertain.
  
  
  METHODS
  In a case-control study, 32 patients with Type 2 diabetes admitted to hospital with severe hypoglycemia and 125 consecutive Type 2 diabetic outpatients without severe hypoglycemia were enrolled. We determined the genotypes of the ABCC8 polymorphism (Ser1369Ala) in the patients with or without severe hypoglycemia. All of the patients were taking glimepiride or glibenclamide.
  
  
  RESULTS
  In the patients treated with glimepiride or glibenclamide, we found no significant differences in the distribution of the Ser1369Ala genotype between patients with or without severe hypoglycemia (p = 0.26). Moreover, the Ala1369 minor allele tended to be less frequent in the hypoglycemic group (31 vs 43%; OR: 1.65; 95% CI: 0.92-2.96; p = 0.09).
  
  
  CONCLUSIONS
  Our findings suggest that the Ser1369Ala variant is not a major predictive factor of severe hypoglycemia due to glimepiride or glibenclamide, both of which bind to the A + B site. It is likely that severe hypoglycemia due to A + B binding site sulfonylureas will be mediated by other factors, and not the Ala1369 minor allele.
authors.affiliation: Department of Endocrinology & Metabolism, Hamamatsu University School of Medicine, Hamamatsu, Japan. ryos@hama-med.ac.jp
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Sato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Rieko
authors.initials: R
authors.lastname: Genma
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Masato
authors.initials: M
authors.lastname: Maekawa
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Nakamura
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D016022:Case-Control Studies; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007003:Hypoglycemia / Q000139:chemically induced* / Q000235:genetics; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012306:Risk; D012720:Severity of Illness Index; D013453:Sulfonylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use; D064233:Sulfonylurea Receptors
chemical_list: D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D004247:DNA