Article tools
Author information
Published in Volume 99, Issue 5 (March 1,1997)
J. Clin. Invest. 99(5): 861-866 (1997). doi:10.1172/JCI119250.
Copyright © 1997, The American Society for Clinical Investigation.

Research Article

Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. Genetic reconstitution of diabetes as a polygenic disease.

Y Terauchi, K Iwamoto, H Tamemoto, K Komeda, C Ishii, Y Kanazawa, N Asanuma, T Aizawa, Y Akanuma, K Yasuda, T Kodama, K Tobe, Y Yazaki and T Kadowaki

Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Japan.

Published March 1, 1997

Non-insulin-dependent diabetes mellitus (NIDDM) is considered a polygenic disorder in which insulin resistance and insulin secretory defect are the major etiologic factors. Homozygous mice with insulin receptor substrate-1 (IRS-1) gene knockout showed normal glucose tolerance associated with insulin resistance and compensatory hyperinsulinemia. Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose. To elucidate the interplay between insulin resistance and insulin secretory defect for the development of NIDDM, we generated double knockout mice with disruption of IRS-1 and beta cell GK genes by crossing the mice with each of the single gene knockout. The double knockout mice developed overt diabetes. Blood glucose levels 120 min after intraperitoneal glucose load (1.5 mg/g body wt) were 108 +/- 24 (wild type), 95 +/- 26 (IRS-1 knockout), 159 +/- 68 (GK knockout), and 210 +/- 38 (double knockout) mg/dl (mean +/- SD) (double versus wild type, IRS-1, or GK; P < 0.01). The double knockout mice showed fasting hyperinsulinemia and selective hyperplasia of the beta cells as the IRS-1 knockout mice (fasting insulin levels: 0.38 +/- 0.30 [double knockout], 0.35 +/- 0.27 [IRS-1 knockout] versus 0.25 +/- 0.12 [wild type] ng/ml) (proportion of areas of insulin-positive cells to the pancreas: 1.18 +/- 0.68%; P < 0.01 [double knockout], 1.20 +/- 0.93%; P < 0.05 [IRS-1 knockout] versus 0.54 +/- 0.26% [wild type]), but impaired insulin secretion to glucose (the ratio of increment of insulin to that of glucose during the first 30 min after load: 31 [double knockout] versus 163 [wild type] or 183 [IRS-1 knockout] ng insulin/mg glucose x 10(3)). In conclusion, the genetic abnormalities, each of which is nondiabetogenic by itself, cause overt diabetes if they coexist. This report provides the first genetic reconstitution of NIDDM as a polygenic disorder in mice.

This article Copyright © 1997, The American Society for Clinical Investigation.

Articles that cite
this article:

Altered function of insulin receptor substrate-1–deficient mouse islets and cultured β-cell lines
Rohit N. Kulkarni, Jonathon N. Winnay, Molly Daniels, Jens C. Brüning, Sarah N. Flier, Douglas Hanahan, C. Ronald Kahn
J Clin Invest 104(12):R69. [CrossRef]

Restored insulin-sensitivity in IRS-1–deficient mice treated by adenovirus-mediated gene therapy
Kohjiro Ueki, Toshimasa Yamauchi, Hiroyuki Tamemoto, Kazuyuki Tobe, Ritsuko Yamamoto-honda, Yasushi Kaburagi, Yasuo Akanuma, Yoshio Yazaki, Sininchi Aizawa, Ryozo Nagai
J Clin Invest 105(10):1437. [CrossRef]

Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
Johan Rung, Stéphane Cauchi, Anders Albrechtsen, Lishuang Shen, Ghislain Rocheleau, Christine Cavalcanti-proença, François Bacot, Beverley Balkau, Alexandre Belisle, Knut Borch-johnsen
Nat Genet [CrossRef]


Jack Leahy
CURR OPIN ENDOCRINOL DIABETES 6(2):127. [CrossRef]

Insulin receptor substrate 2 plays a crucial role in β cells and the hypothalamus
Naoto Kubota, Yasuo Terauchi, Kazuyuki Tobe, Wataru Yano, Ryo Suzuki, Kohjiro Ueki, Iseki Takamoto, Hidemi Satoh, Toshiyuki Maki, Tetsuya Kubota
J Clin Invest 114(7):917. [CrossRef]

Insights into insulin resistance and type 2 diabetes from knockout mouse models
Takashi Kadowaki
J Clin Invest 106(4):459. [CrossRef]

IRS2 takes center stage in the development of type 2 diabetes
Matthew J. Brady
J Clin Invest 114(7):886. [CrossRef]

Diabetes in midlife: Planting genetic time bombs
Stephen O'rahilly
Nat Med 3(10):1080. [CrossRef]

Fulminant type 1 diabetes mellitus observed in insulin receptor substrate 2 deficient mice
T. Arai, H. Hashimoto, K. Kawai, A. Mori, Y. Ohnishi, K. Hioki, M. Ito, M. Saito, Y. Ueyama, M. Ohsugi
Clin Exp Med 8(2):93. [CrossRef]

Genetics of type 2 diabetes mellitus: status and perspectives
Lars Hansen, Oluf Pedersen
Diabetes Obes Metab 7(2):122. [CrossRef]

Glucokinase and IRS-2 are required for compensatory   cell hyperplasia in response to high-fat diet-induced insulin resistance
Y. Terauchi, I. Takamoto, N. Kubota, J. Matsui, R. Suzuki, K. Komeda, A. Hara, Y. Toyoda, I. Miwa, S. Aizawa
J Clin Invest 117(1):246. [CrossRef]

Spatial compartmentalization of signal transduction in insulin action
Christian A. Baumann, Alan R. Saltiel
Bioessay 23(3):215. [CrossRef]

Experimental gene interaction studies with SERT mutant mice as models for human polygenic and epistatic traits and disorders
D. L. Murphy, G. R. Uhl, A. Holmes, R. Ren-patterson, F. S. Hall, I. Sora, S. Detera-wadleigh, K.-P. Lesch
Genes Brain Behav 2(6):350. [CrossRef]

The genetics of type 2 diabetes
Mark Mccarthy, Stephan Menzel
Br J Clin Pharmacol 51(3):195. [CrossRef]

Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance
Franck Mauvais-jarvis, Rohit N. Kulkarni, C. Ronald Kahn
Clin Endocrinol (Oxf) 57(1):1. [CrossRef]

Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus
Francesco S. Celi, Carlo Negri, Keith Tanner, Nina Raben, Flora De pablo, Adela Rovira, Luis F. Pallardo, Pilar Martin-vaquero, Michael P. Stern, Braxton D. Mitchell
Diabetes Metab Res Rev 16(5):370. [CrossRef]

Insulin receptor substrate polymorphisms and Type 2 diabetes mellitus
Giorgio Sesti
phgs 1(3):343. [CrossRef]

Genetically defined pancreatic beta cell failure
Jan WA Smit, Michaela Diamant
phgs 3(5):669. [CrossRef]

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
Endocr J 51(2):133. [CrossRef]

TRANSGENIC MICE IN THE ANALYSIS OF METABOLIC REGULATION
Fatima Bosch, Anna Pujol, Alfons Valera
Annu Rev Nutr 18(1):207. [CrossRef]

METABOLIC ENGINEERING WITH RECOMBINANT ADENOVIRUSES
Peter A. Antinozzi, Hal K. Berman, Robert M. O'doherty, Christopher B. Newgard
Annu Rev Nutr 19(1):511. [CrossRef]

Insights into Molecular Pathogenesis of Type 2 Diabetes from Knockout Mouse Models.
YASUO Terauchi, TAKASHI Kadowaki
Endocr J 49(3):247. [CrossRef]

Deletion of the von Hippel–Lindau gene in pancreatic β cells impairs glucose homeostasis in mice
James Cantley, Colin Selman, Deepa Shukla, Andrey Y. Abramov, Frauke Forstreuter, Miguel A. Esteban, Marc Claret, Steven J. Lingard, Melanie Clements, Sarah K. Harten
J Clin Invest [CrossRef]