Skip to main content
SpringerLink
Log in

Insulin Resistance and the Pathogenesis of Non-Insulin Dependent Diabetes Mellitus: Cellular and Molecular Mechanisms

  • Chapter
New Concepts in the Pathogenesis of NIDDM

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 334))

Abstract

Non-insulin dependent diabetes mellitus (NIDDM) is a complex metabolic disorder of heterogeneous etiology (1–4). There is clearly a strong hereditary component to the disease, but the exact genetic abnormalities are likely to differ among different population groups (1,5). In addition, NIDDM is likely to be multigenic, in that more than one discrete gene defect needs to complement before the NIDDM phenotype manifests. Thus, from a genetic point of view, NIDDM is heterogeneous and polygenic making identification of “diabetes” genes particularly difficult. Numerous biochemical abnormalities have been identified in NIDDM and the relative contribution of different physiologic or cellular defects differs among different patient groups (6,7). Regardless of the exact pathophysiologic sequence in a particular patient, once full blown fasting hyperglycemia develops, a characteristic set of metabolic derangements can be identified in the great majority of NIDDM patients (Fig. 1). This consists of abnormalities at the level of the pancreatic islets, the liver, and peripheral insulin target tissues which, taken together, represent a final common metabolic pathway for the pathogenesis of hyperglycemia (1,8).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. J.M. Olefsky. Pathogenesis of non-insulin depednent diabetes (Type II), in: DeGroot: Endocrinology Second Edition. L.J. DeGroot. G.M. Besser. G.F. Cahill, J.C. Marshall, D.H. Nelson, W.D. Odell, J.T. Potts, Jr., A.H. Rubenstein, and E. Steinberger, W.B. Saunders Co., Philadelphia (1989).

    Google Scholar 

  2. R.A. DeFronzo, The triumvirate: B-cell, muscle, liver: A collusion responsible for NIDDM, Diabetes 37:667 (1988).

    PubMed  CAS  Google Scholar 

  3. G.M. Reaven, Role of insulin resistance in human disease, Diabetes 37:1495 (1988).

    Google Scholar 

  4. S. Efendic, R. Luft, and A. Wajngot, Aspects of the pathogenesis of Type 2 diabetes, Endoc. Rev. 5:395 (1984).

    Article  CAS  Google Scholar 

  5. J.L. Rotter, C.M. Vadheim, and D.L. Rimoin, Genetics of diabetes mellitus. in: Diabetes Mellitus: Theory and Practice, H. Rifkin, D. Prote, Jr., Elsevier, New York (1990).

    Google Scholar 

  6. J.M. Olefsky. Insulin action and insulin resistance in non-insulin dependent diabetes mellitus, in: Recent Advances in Insulin Action and its Disorders, Y. Shigeta, M. Kobayashi, and J.M. Olefsky), Excerpta Medica, Amsterdam (1991).

    Google Scholar 

  7. J.F. Caro, L.G. Dohm, W.J. Pries, and M.K. Sinha, Cellular alterations in liver, skeletal muscle, and adipose tissue responsible for insulin resistance in obesity and Type II diabetes, Diab/Metab Rev. 5:665 (1989).

    Article  CAS  Google Scholar 

  8. J.M. Olefsky. Diabetes mellitus, in: Cecil Textbook of Medicine, 18th Edition, Volume 2, Chapter 231, J.B. Wyngaarden, L.H. Smith, Jr., J.C. Bennett, and F. Plum, W.B. Saunders, Philadelphia, PA (1991).

    Google Scholar 

  9. O.G. Kolterman, R.S. Gray, J. Griffin, P. Burstein, J. Insel, J.A. Scarlett, and J.M. Olefsky, Receptor and post-receptor defects contribute to the insulin resistance in non-insulin dependent diabetes mellitus. J. Clin. Invest. 68:957 (1981).

    Article  PubMed  CAS  Google Scholar 

  10. R.R. Revers, R. Fink, J. Griffin, J.M. Olefsky, and O.G. Kolterman, Influence of hyperglycemia on insulin’s in vivo effects of Type II diabetes. J. Clin. Invest. 73:664 (1984).

    Article  PubMed  CAS  Google Scholar 

  11. C. Bogardus, S. Lillioja, B.V. Howard, G. Reaven, and D. Mott, Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and non-insulin-dependent diabetic subjects. J. Clin. Invest. 74:1238 (1984).

    Article  PubMed  CAS  Google Scholar 

  12. S. Dinneen, J. Gerich, and R. Rizza, Carbohydrate metabolism in non-insulin-dependent diabetes mellitus, N. Engl. J. Med. 327:707 (1992).

    Article  PubMed  CAS  Google Scholar 

  13. J.F. Caro, Clinical review 26: Insulin resistance in obese and nonobese man, J. Clin. Endocrin. Rev. 73:691 (1991).

    Article  CAS  Google Scholar 

  14. O. Hother-Nielsen, O. Schmitz, P.H. Andersen, H. Beck-Nielsen, and O. Pedersen, Metformin improves peripheral but not hepatic insulin action in obese patients with type I diabetes, Acta. Endocrinol. (Copenh.), 120:257 (1989).

    CAS  Google Scholar 

  15. R.C. Bonadonna, and R.A. DeFronzo, Glucose metabolism in obesity and Type 2 diabetes, Diab. & Metab. 17:112 (1991).

    CAS  Google Scholar 

  16. G.M. Reaven, Resistance to insulin-stimulated glucose uptake and hyperinsulinemia: Role in non-insulin-dependent diabetes. high blood pressure. dyslipidemia and coronary heart disease. Diab. & Metab (Paris) 17:78 (1991).

    CAS  Google Scholar 

  17. C. Bogardus, S. Lillioja, B.V. Howard, G. Reaven and D. Mott, Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in non-diabetic and non-insulin-dependent diabetic subjects, J. Clin. Invest. 74:1238 (1984).

    Article  PubMed  CAS  Google Scholar 

  18. W.K. Ward, J.C. Beard, J.B. Halter, M.A. Pfeifer, and D. Porte, Jr., Pathophysiology of insulin secretion in non-insulin-dependent diabetes mellitus, Diabetes Care 7:491 (1984).

    Article  PubMed  CAS  Google Scholar 

  19. W.T. Garvey, J.M. Olefsky, J. Griffin, R. Hammon, and O.G. Kolterman, The effects of insuin treatment on insulin secretion and action in Type II diabetes mellitus. Diabetes 34:222 (1985).

    Article  PubMed  CAS  Google Scholar 

  20. R.R. Henry, P. Wallace and J.M, Olefsky, The effects of weight loss on the mechanisms of hyperglycemia in obese noninsulin-dependent diabetes mellitus, Diabetes 35:990 (1986).

    Article  PubMed  CAS  Google Scholar 

  21. O.G. Kolterman, R.S. Gray, G. Shapiro, J.A. Scarlett, J. Griffin, and J.M. Olefsky, The acute an chronic effects of sulfonylurea therapy in Type II diabetics, Diabetes 33:346 (1984).

    Article  PubMed  CAS  Google Scholar 

  22. R.A. DeFronzo, and E. Ferrannini, The pathogenesis of non-insulin-dependent diabetes, Medicine 61:125 (1982).

    Article  PubMed  CAS  Google Scholar 

  23. G.M. Reaven, and J.M. Olefsky, Relationship between heterogeneity of insulin responses and insulin resistance in normal subjects, Diabetologia 13:201 (1977).

    Article  PubMed  CAS  Google Scholar 

  24. R.R. Henry, L. Scheaffer and J.M. Olefsky, Glycemic effects of short-term intensive dietary restriction and isocaloric refeeding in non-insulin dependent diabetes mellitus, J. Clin. Endocrinol. Metab. 61:917 (1985).

    Article  PubMed  CAS  Google Scholar 

  25. R.A. DeFronzo, J.D. Tobin, and R. Andres, Glucose clamp technique: A method for quantifying insulin secretion and resistance, Am. J. Physiol. 237:E214 (1979).

    PubMed  CAS  Google Scholar 

  26. O.M. Rosen, After insuin binds, Science 237:1452 (1987).

    Article  PubMed  CAS  Google Scholar 

  27. C.R. Kahn and M.F. White, The insulin receptor and the molecular mechanism of insulin action, J. Clin. Invest. 82:1151 (1988).

    Article  PubMed  CAS  Google Scholar 

  28. J.M. Olefsky, The insulin receptor: A multi-functional protein, Diabetes 39:1009 (1990).

    Article  PubMed  CAS  Google Scholar 

  29. H.U. Haring, The insulin receptor: Signalling mechanism and contribution to the pathogenesis of insulin resistance, Diabetologia 34:848 (1991).

    Article  PubMed  CAS  Google Scholar 

  30. M. Kasuga, F.A. Karlsson, and C.R. Kahn, Insulin stimulates the phosphorylation of the 95,000 Dalton subunit of its own receptor, Science 215:185 (1982).

    Article  PubMed  CAS  Google Scholar 

  31. H.E. Tornqvist, M.W. Pierce, and A.R. Frackelton, Identification of insulin receptor tyrosine residues autophosphorylated in vitro, J. Biol. Chem. 262:10212 (1987).

    PubMed  CAS  Google Scholar 

  32. M.F. White, S.E. Shoelson, H. Keutmann, and C.R. Kahn, A cascade of tyrosine autophosphorylation in the subunit activates the insulin receptor, J. Biol. Chem. 263:2969 (1988).

    PubMed  CAS  Google Scholar 

  33. R.I. Fink, P. Wallace, G. Brechtel, and J.M. Olefsky, Evidence that glucose transport is rate-limiting for in vivo glucose uptake, Metabolism 41:897 (1992).

    Article  PubMed  CAS  Google Scholar 

  34. J-P. Idstrom, M.J. Rennie, T. Schersten, and A-C. Bylund-Fellenius, Membrane transport in relation to net uptake of glucose in the perperfused rat hind-limb, Biochem. J. 233:131 (1986).

    PubMed  CAS  Google Scholar 

  35. K. Kubo, and J.E. Foley, Rate-limiting steps for in sulin-mediated glucose uptake into perfused rat hindlimb, Am. J. Physiol. 250:E100 (1986).

    PubMed  CAS  Google Scholar 

  36. J.E. Pessin, and G.I. Bell, Mammalian facilltative glucose transporter family: Structure and molecular regulation, Ann. Rev. Physiol. 84:911 (1992).

    Article  Google Scholar 

  37. M. Muckler, Family of glucose transporter genes, Diabetes 39:6 (1990).

    Article  Google Scholar 

  38. S.W. Cushman, and L.J. Wardzala, Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell, J. Cell Biochem. 255:4758 (1980).

    CAS  Google Scholar 

  39. T. Kono, K. Suzuki, L.E. Dansey, F.W. Robinson, and T.L. Blewis, Energy-dependent and protein synthesis-independent recycling of the insulin-sensitive glucose transport mechanism in fat cells, J. Biol. Chem. 256:6400 (1981).

    PubMed  CAS  Google Scholar 

  40. G.R. Freidenberg, R.R. Henry, H.H. Klein, D.R. Reichart, and J.M. Olefsky, Decreased kinase activity of insulin receptors from adipocytes of non-insulin dependent diabetic (NIDDM) subjects, J. Clin. Invest. 79:240 (1987).

    Article  PubMed  CAS  Google Scholar 

  41. J.F. Caro, O. Ittoop, W.J. Pories, D. Meelheim, E.G. Flickinger, F. Thomas, M. Jenquin, J.F. Silverman, P.G. Khazanie, and M.K. Sinha, Studies on the mechanism of insulin resistance in the liver from humans with non-insulin-dependent diabetes, J. Clin. Invest. 78:249 (1986).

    Article  PubMed  CAS  Google Scholar 

  42. J.F. Caro, M.K. Sinha, S.J. Raju, O. Ittoop, W.J. Pries, E.G. Flickinger, D. Meelheim, and G.L. Dohm, Insulin receptor kinase in human skeletal muscle from obese subjects with and without non-insulin-dependent diabetes, J. Clin. Invest. 79:1330, (1987).

    Article  PubMed  CAS  Google Scholar 

  43. P. Arner, T. Pollare, H. Lithell, and J.N. Livingston, Defective insulin receptor tyrosine kinase in human skeletal muscle in obesity and Type 2 (non-insulin-dependent) diabetes mellitus, Diabetologia 30:437 (1987).

    Article  PubMed  CAS  Google Scholar 

  44. R.J. Comi, G. Grunberger, and P. Gorden, The relationship of insulin binding and insulin-stimulated tyrosine kinase activity is altered in Type II diabetes, J. Clin. Invest. 79:453 (1987).

    Article  PubMed  CAS  Google Scholar 

  45. H. Maegawa, Y. Shigeta, K. Egawa, and M. Kobayashi, Impaired autophosphorylation of insulin receptors from abdominal skeletal uscles in nonobese subjects with NIDDM, Diabetes 40:815 (1991).

    Article  PubMed  CAS  Google Scholar 

  46. D.J. Brillon, G.R. Freidenberg, R.R. Henry, and J.M. Olefsky, Mechanism of defective insuln receptor kinase activity in NIDDM: Evidence for two receptor populations, Diabetes 38:397 (1989).

    Article  PubMed  CAS  Google Scholar 

  47. G.R. Freidenberg, D. Reichart, J.M. Olefsky, and R.R. Henry, Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin dependent diabetes mellitus: Effect of weight loss, J. Clin. Invest. 82:1398 (1988).

    Article  PubMed  CAS  Google Scholar 

  48. G.R. Freidenberg, D. Reichart, and J.M. Olefsky, Insulin receptor kinase activity is not reduced in fibroblsts from subjects with non-insulin dependent diabetes mellitus (NIDDM), Clin. Res. 38:119A (1990).

    Google Scholar 

  49. J. Kusari, U.S. Verma, J.B. Buse, R.R. Henry, and J.M. Olefsky, Analysis of the gene squences of the in sulin receptor and the insuln sensitive glucose transporter (Glut-4) in patients with common type non-insulin dependent diabetes mellitus, J. Clin. Invest. 88:1323 (1991).

    Article  PubMed  CAS  Google Scholar 

  50. S. O’Rahilly, W.H. Choi, P. Patel, R.C. Turner, J.S. Flier, and D.E. Moller, Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms, Diabetes 40:777 (1991).

    Article  PubMed  Google Scholar 

  51. S. Seino, M. Seino, S. Nishi, and G.I. Bell, Structure of the human insulin receptor gene and characterization of its promoter, Proc. Natl. Acad. Sci. U.S.A. 86:114 (1989).

    Article  PubMed  CAS  Google Scholar 

  52. T.P. Ciaraldi, O.G. Kolterman, J.A. Scarlett, M. Kao, and J.M. Olefsky, Role of th glucose transport system in the post-receptor defect of non-insulin dependent diabetes mellitus, Diabetes 31:1016 (1982).

    PubMed  CAS  Google Scholar 

  53. G.L. Dohm, E.B. Tapscott, W.J. Pories, D.J. Dabbs, E.G. Flickinger, D. Meelheim, T. Fushiki, S.M. Atkinson, C.W. Elton, and J.F. Caro, An in vitro human muscle preparation suitable for metabolic studies: Decreased insulin stimulation of glucose transport in muscle from morbidly obese and diabetic subjects, J. Clin. Invest. 82:486 (1988).

    Article  PubMed  CAS  Google Scholar 

  54. O. Pedersen, J.F. Bak, P.H. Andersen, S. Lund, D.E. Moller, J.S. Flier; and B.B. Kahn, Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM, Diabetes 39:865 (1990).

    Article  PubMed  CAS  Google Scholar 

  55. J. Eriksson, L. Koranyi, R. Bourey, C. Schalin-Jantti, E. Widen, M. Mueckler, A.M. Permutt, and L.C. Groop, Insulin resistance in type 2 (non-insulin-dependent) diabetic patients and their relatives is not associated with a defect in the expression of the insulin-responsive glucose transporte (GLUT-4) gene in human skeletal muscle, Diabetologia 35:143 (1992).

    Article  PubMed  CAS  Google Scholar 

  56. W.T. Garvey, L. Maianu, J.A. Hancock, A.M. Golichowski, and A. Baron, Gene expression of GLUT4 in skeletal muscle from insulin-resistant patients with obesity, IGT, GDM, and NIDDM, Diabetes 41:465 (1992).

    Article  PubMed  CAS  Google Scholar 

  57. A. Handberg, A. Vaag, P. Damsbo, H. Beck-Nielson, and J. Vinten, Expression of insulin regulatable glucose transporters in skeletal muscle from type 2 (non-insulin dependent) diabetic patients, Diabe-tologia 33:625 (1990).

    Article  CAS  Google Scholar 

  58. J.B. Buse, K. Yasuda, T.P. Lay, T.S. Seo, A.L. Olson, J.E. Pessin. J.H. Karam. S. Seino. and G.I. Bell. Human GLUT4/muscle-fat glucose transporter gene: Characterization and genetic variation, Diabetes (In press).

    Google Scholar 

  59. W-H. Choi, S. O’Rahilly, J.B. Buse, A. Rees, R. Morgan, J.S. Flier, and D.E. Moller, Molecular scanning of insulin-responsive glucose transporter (GLUT4) gene in NIDDM subjects, Diabetes 40:1712 (1991).

    Article  PubMed  CAS  Google Scholar 

  60. G.I. Bell, T. Kayano, J.B. Buse, C.F. Burant, J. Takeda, D. Lin, H. Fujumoto, and S. Seino, Molecular biology of mammalian glucose transporters, Diabetes Care 13:198 (1990).

    Article  PubMed  CAS  Google Scholar 

  61. H. Fukumoto, T. Kayano, J.B. Buse, Y. Edwards, P.F. Pilch, G.I. Bell and S. Seino, Cloning and characterization of the major insulin-redponsive glucose transporter expressed in human skeletal muscle and other insulin-responsive tissues, J. Biol. Chem. 264:7776 (1989).

    PubMed  CAS  Google Scholar 

  62. X. Kian, P. Rothenberg, C.R. Kahn, J.M. Backer, E. Araki, P.A. Wilden, D.A. Cahill, B.J. Goldstein, and M.F. White, Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein, Nature 35:73 (1991).

    Google Scholar 

  63. S.E. Shoelson, S. Chatterjee, M. Chaudhuri, and M.F. White, YMXM motifs of IRS-1 define substrate specificities of the insulin receptor kinase, Proc. Natl. Acad. Sci. 89:2027 (1992).

    Article  PubMed  CAS  Google Scholar 

  64. J.M. Backer, M.G. Myers, Jr., X-J. Sun, J. Schlessinger, and M.F. White, The insulin receptor substrate IRS-1 associates with and activates the phospha-tidylinositol 3-kinase. Diabetes 41(Suppl. 1):166 #582 (1992).

    Google Scholar 

  65. R.S. Thies, J.M. Molina, T.P. Ciaraldi, G.R. Freidenberg, and J.M. Olefsky, Insulin receptor autophos-phorylation and endogenous substrate phosphoryla-tion in human adipocytes from control, obese, and non-insulin dependent diabetic subjects, Diabetes 39:250 (1990).

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA

    Jerrold M. Olefsky

  2. Veterans Administration Medical Center Medical Service (111G), 3350 La Jolla Village Drive, San Diego, CA, 92161, USA

    Jerrold M. Olefsky

Authors
  1. Jerrold M. Olefsky
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Karolinska Hospital, Stockholm, Sweden

    Claes Göran Östenson  & Suad Efendić  & 

  2. University of Toronto, Toronto, Ontario, Canada

    Mladen Vranic

Rights and permissions

Reprints and permissions

Copyright information

© 1993 Springer Science+Business Media New York

About this chapter

Cite this chapter

Olefsky, J.M. (1993). Insulin Resistance and the Pathogenesis of Non-Insulin Dependent Diabetes Mellitus: Cellular and Molecular Mechanisms. In: Östenson, C.G., Efendić, S., Vranic, M. (eds) New Concepts in the Pathogenesis of NIDDM. Advances in Experimental Medicine and Biology, vol 334. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-2910-1_10

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-2910-1_10

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-6262-3

  • Online ISBN: 978-1-4615-2910-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation