title: K(ATP) channel knockout mice crossbred with transgenic mice expressing a dominant-negative form of human insulin receptor have glucose intolerance but not diabetes.
abstract: Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
authors.affiliation: Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Kanezaki
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Obata
authors.forename: Rie
authors.initials: R
authors.lastname: Matsushima
authors.forename: Asako
authors.initials: A
authors.lastname: Minami
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Yuasa
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kishi
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Bando
authors.forename: Hisanori
authors.initials: H
authors.lastname: Uehara
authors.forename: Keisuke
authors.initials: K
authors.lastname: Izumi
authors.forename: Tasuku
authors.initials: T
authors.lastname: Mitani
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yukari
authors.initials: Y
authors.lastname: Takeshita
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Yousuke
authors.initials: Y
authors.lastname: Ebina
mesh_terms: D000273:Adipose Tissue / Q000473:pathology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004789:Enzyme Activation; D004822:Epididymis / Q000473:pathology; D005215:Fasting / Q000097:blood; D005799:Genes, Dominant; D005838:Genotype; D005947:Glucose / Q000493:pharmacokinetics; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D000078790:Insulin Secretion; D020738:Leptin / Q000097:blood; D008099:Liver / Q000201:enzymology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009929:Organ Size; D019518:Postprandial Period; D024661:Potassium Channels, Inwardly Rectifying / Q000172:deficiency*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin / Q000235:genetics* / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D001786:Blood Glucose; D005947:Glucose; D007328:Insulin; D020738:Leptin; D024661:Potassium Channels, Inwardly Rectifying; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; D000099161:Kcnj11 Channel