KATP Channel Knockout Mice Crossbred with Transgenic Mice Expressing a Dominant-negative Form of Human Insulin Receptor Have Glucose Intolerance but not Diabetes

Yoshiko KANEZAKI; Toshiyuki OBATA; Rie MATSUSHIMA; Asako MINAMI; Tomoyuki YUASA; Kazuhiro KISHI; Yoshimi BANDO; Hisanori UEHARA; Keisuke IZUMI; Tasuku MITANI; Mitsuru MATSUMOTO; Yukari TAKESHITA; Yutaka NAKAYA; Toshio MATSUMOTO; Yousuke EBINA

doi:10.1507/endocrj.51.133

ORIGINALS

K_ATP Channel Knockout Mice Crossbred with Transgenic Mice Expressing a Dominant-negative Form of Human Insulin Receptor Have Glucose Intolerance but not Diabetes

Yoshiko KANEZAKI, Toshiyuki OBATA, Rie MATSUSHIMA, Asako MINAMI, Tomoyuki YUASA, Kazuhiro KISHI, Yoshimi BANDO, Hisanori UEHARA, Keisuke IZUMI, Tasuku MITANI, Mitsuru MATSUMOTO, Yukari TAKESHITA, Yutaka NAKAYA, Toshio MATSUMOTO, Yousuke EBINA

Author information

Yoshiko KANEZAKI
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Department of Medicine and Bioregulatory Sciences, School of Medicine, The University of Tokushima
Toshiyuki OBATA
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Rie MATSUSHIMA
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Department of Nutrition, School of Medicine, The University of Tokushima
Asako MINAMI
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Tomoyuki YUASA
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Kazuhiro KISHI
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima
Yoshimi BANDO
Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima
Hisanori UEHARA
Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima
Keisuke IZUMI
Department of Molecular and Environmental Pathology, School of Medicine, The University of Tokushima
Tasuku MITANI
Division of Molecular Immunology, Institute for Enzyme Research, The University of Tokushima
Mitsuru MATSUMOTO
Division of Molecular Immunology, Institute for Enzyme Research, The University of Tokushima
Yukari TAKESHITA
Department of Nutrition, School of Medicine, The University of Tokushima
Yutaka NAKAYA
Department of Nutrition, School of Medicine, The University of Tokushima
Toshio MATSUMOTO
Department of Medicine and Bioregulatory Sciences, School of Medicine, The University of Tokushima
Yousuke EBINA
Division of Molecular Genetics, Institute for Enzyme Research, The University of Tokushima

Keywords: K_ATP channel knockout mouse, Tyrosine kinase-deficient insulin receptor transgenic mouse, Impaired insulin secretion, Insulin resistance, Diabetes mellitus

JOURNAL FREE ACCESS

2004 Volume 51 Issue 2 Pages 133-144

DOI https://doi.org/10.1507/endocrj.51.133

Details

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^KMTG), 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^KMTG 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^KMTG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR^KMTG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR^KMTG or Kir6.2KO mice, while the hIR^KMTG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR^KMTG and hIR^KMTG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR^KMTG 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^KMTG) were not sufficient to lead to overt diabetes.

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