Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Mar 1;99(5):861–866. doi: 10.1172/JCI119250

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 1, K Iwamoto 1, H Tamemoto 1, K Komeda 1, C Ishii 1, Y Kanazawa 1, N Asanuma 1, T Aizawa 1, Y Akanuma 1, K Yasuda 1, T Kodama 1, K Tobe 1, Y Yazaki 1, T Kadowaki 1
PMCID: PMC507893  PMID: 9062343

Abstract

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.

Full Text

The Full Text of this article is available as a PDF (388.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aizawa T., Asanuma N., Terauchi Y., Suzuki N., Komatsu M., Itoh N., Nakabayashi T., Hidaka H., Ohnota H., Yamauchi K. Analysis of the pancreatic beta cell in the mouse with targeted disruption of the pancreatic beta cell-specific glucokinase gene. Biochem Biophys Res Commun. 1996 Dec 13;229(2):460–465. doi: 10.1006/bbrc.1996.1826. [DOI] [PubMed] [Google Scholar]
  2. Aizawa T., Sato Y., Ishihara F., Taguchi N., Komatsu M., Suzuki N., Hashizume K., Yamada T. ATP-sensitive K+ channel-independent glucose action in rat pancreatic beta-cell. Am J Physiol. 1994 Mar;266(3 Pt 1):C622–C627. doi: 10.1152/ajpcell.1994.266.3.C622. [DOI] [PubMed] [Google Scholar]
  3. Araki E., Lipes M. A., Patti M. E., Brüning J. C., Haag B., 3rd, Johnson R. S., Kahn C. R. Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature. 1994 Nov 10;372(6502):186–190. doi: 10.1038/372186a0. [DOI] [PubMed] [Google Scholar]
  4. Bouwens L., Wang R. N., De Blay E., Pipeleers D. G., Klöppel G. Cytokeratins as markers of ductal cell differentiation and islet neogenesis in the neonatal rat pancreas. Diabetes. 1994 Nov;43(11):1279–1283. doi: 10.2337/diab.43.11.1279. [DOI] [PubMed] [Google Scholar]
  5. Galli J., Li L. S., Glaser A., Ostenson C. G., Jiao H., Fakhrai-Rad H., Jacob H. J., Lander E. S., Luthman H. Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet. 1996 Jan;12(1):31–37. doi: 10.1038/ng0196-31. [DOI] [PubMed] [Google Scholar]
  6. Gauguier D., Froguel P., Parent V., Bernard C., Bihoreau M. T., Portha B., James M. R., Penicaud L., Lathrop M., Ktorza A. Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet. 1996 Jan;12(1):38–43. doi: 10.1038/ng0196-38. [DOI] [PubMed] [Google Scholar]
  7. Haffner S. M., Miettinen H., Gaskill S. P., Stern M. P. Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes. 1995 Dec;44(12):1386–1391. doi: 10.2337/diab.44.12.1386. [DOI] [PubMed] [Google Scholar]
  8. Hanis C. L., Boerwinkle E., Chakraborty R., Ellsworth D. L., Concannon P., Stirling B., Morrison V. A., Wapelhorst B., Spielman R. S., Gogolin-Ewens K. J. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet. 1996 Jun;13(2):161–166. doi: 10.1038/ng0696-161. [DOI] [PubMed] [Google Scholar]
  9. Johnston C., Ward W. K., Beard J. C., McKnight B., Porte D., Jr Islet function and insulin sensitivity in the non-diabetic offspring of conjugal type 2 diabetic patients. Diabet Med. 1990 Feb;7(2):119–125. doi: 10.1111/j.1464-5491.1990.tb01345.x. [DOI] [PubMed] [Google Scholar]
  10. Kadowaki T., Miyake Y., Hagura R., Akanuma Y., Kajinuma H., Kuzuya N., Takaku F., Kosaka K. Risk factors for worsening to diabetes in subjects with impaired glucose tolerance. Diabetologia. 1984 Jan;26(1):44–49. doi: 10.1007/BF00252262. [DOI] [PubMed] [Google Scholar]
  11. Kawano K., Hirashima T., Mori S., Saitoh Y., Kurosumi M., Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992 Nov;41(11):1422–1428. doi: 10.2337/diab.41.11.1422. [DOI] [PubMed] [Google Scholar]
  12. Kimura K., Toyota T., Kakizaki M., Kudo M., Takebe K., Goto Y. Impaired insulin secretion in the spontaneous diabetes rats. Tohoku J Exp Med. 1982 Aug;137(4):453–459. doi: 10.1620/tjem.137.453. [DOI] [PubMed] [Google Scholar]
  13. Lillioja S., Mott D. M., Spraul M., Ferraro R., Foley J. E., Ravussin E., Knowler W. C., Bennett P. H., Bogardus C. Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus. Prospective studies of Pima Indians. N Engl J Med. 1993 Dec 30;329(27):1988–1992. doi: 10.1056/NEJM199312303292703. [DOI] [PubMed] [Google Scholar]
  14. Mahtani M. M., Widén E., Lehto M., Thomas J., McCarthy M., Brayer J., Bryant B., Chan G., Daly M., Forsblom C. Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet. 1996 Sep;14(1):90–94. doi: 10.1038/ng0996-90. [DOI] [PubMed] [Google Scholar]
  15. Martin B. C., Warram J. H., Krolewski A. S., Bergman R. N., Soeldner J. S., Kahn C. R. Role of glucose and insulin resistance in development of type 2 diabetes mellitus: results of a 25-year follow-up study. Lancet. 1992 Oct 17;340(8825):925–929. doi: 10.1016/0140-6736(92)92814-v. [DOI] [PubMed] [Google Scholar]
  16. Polonsky K. S., Sturis J., Bell G. I. Seminars in Medicine of the Beth Israel Hospital, Boston. Non-insulin-dependent diabetes mellitus - a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med. 1996 Mar 21;334(12):777–783. doi: 10.1056/NEJM199603213341207. [DOI] [PubMed] [Google Scholar]
  17. Sato Y., Aizawa T., Komatsu M., Okada N., Yamada T. Dual functional role of membrane depolarization/Ca2+ influx in rat pancreatic B-cell. Diabetes. 1992 Apr;41(4):438–443. doi: 10.2337/diab.41.4.438. [DOI] [PubMed] [Google Scholar]
  18. Tamemoto H., Kadowaki T., Tobe K., Yagi T., Sakura H., Hayakawa T., Terauchi Y., Ueki K., Kaburagi Y., Satoh S. Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature. 1994 Nov 10;372(6502):182–186. doi: 10.1038/372182a0. [DOI] [PubMed] [Google Scholar]
  19. Taylor S. I., Accili D., Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes. 1994 Jun;43(6):735–740. doi: 10.2337/diab.43.6.735. [DOI] [PubMed] [Google Scholar]
  20. Terauchi Y., Sakura H., Yasuda K., Iwamoto K., Takahashi N., Ito K., Kasai H., Suzuki H., Ueda O., Kamada N. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. J Biol Chem. 1995 Dec 22;270(51):30253–30256. doi: 10.1074/jbc.270.51.30253. [DOI] [PubMed] [Google Scholar]
  21. Yamauchi T., Tobe K., Tamemoto H., Ueki K., Kaburagi Y., Yamamoto-Honda R., Takahashi Y., Yoshizawa F., Aizawa S., Akanuma Y. Insulin signalling and insulin actions in the muscles and livers of insulin-resistant, insulin receptor substrate 1-deficient mice. Mol Cell Biol. 1996 Jun;16(6):3074–3084. doi: 10.1128/mcb.16.6.3074. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES