Skip to main content
SpringerLink
Log in

Derangements of pyruvate dehydrogenase in circulating lymphocytes of NIDDM patients and their healthy offspring

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Pyruvate dehydrogenase (PDH) is poorly active in circulating lymphocytes of NID-DM patients; in vitro, it is unresponsive to insulin at 5 μU/ml and activated at 50 μU/ml, instead of activated and inhibited as in healthy controls. This study examines whether healthy offspring of NIDDM patients with a family history for this disease have these alterations. Twenty seven healthy offspring (23±10 yr, median 18 yr) and their parents (13 diabetic with a family history for NIDDM and 11 healthy without this history) were enrolled. Twenty healthy individuals without the history and matched for age and gender with the offspring served as controls. Minimum levels for enzyme activity before and after cell stimulation with insulin at 5 μU/ml were computed for a 95% CI with no more than 5% of the controls excluded. Increased or unvaried enzyme activity in response to insulin at 50 μU/ml was defined as abnormal. All NIDDM parents and 11/27 offspring had below normal enzyme activity and defective and reversed enzyme response to insulin at 5 and 50 μU/ml; three offspring had altered enzyme response to insulin at both concentrations, four to insulin at 5 μU/ml, three to insulin at 50 μU/ml and six, together with the healthy parents, had no alterations. We conclude that in healthy individuals a family history for NIDDM is frequently signaled, irrespective of age, by molecular derangements, with an apparent genetic background, in their circulating lymphocytes.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Rinaudo M.T., Curto M., Rabbone I., Piccinini M., Bruno R., Mioletti S., Gamba S. Effect of sulfonylurea agents on pyruvate dehydrogenase activity in circulating lymphocytes from patients with non-insulin-dependent diabetes mellitus (NIDDM). J. Diab. Comp. 1994, 8: 221–225.

    Article  CAS  Google Scholar 

  2. Curto M., Novi R.F., Rabbone I., Maurino M., Piccinini M., Mioletti S., Mostert M., Bruno R., Rinaudo M.T. Insulin resistance in obese subjects and newly diagnosed NIDDM patients and derangements of pyruvate dehydrogenase in their circulating lymphocytes. Int. J. Obes. 1997, 21: 1137–1142.

    Article  CAS  Google Scholar 

  3. Froguel P., Velho G., Cohen D., Passa P. Strategy for the collection of sibling-pair data for genetic studies in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 1991, 34: 658.

    Article  Google Scholar 

  4. Wieland O.H. The mammalian pyruvate dehydrogenase complex: Structure and regulation. Rev. Physiol. Biochem. Pharmacol. 1983, 96: 123–170.

    Article  CAS  PubMed  Google Scholar 

  5. Wieland O.H., Patzelt C., Löffler G. Active and inactive forms of pyruvate dehydrogenase in rat liver. Effect of starvation and refeeding and of insulin treatment on pyruvate dehydrogenase interconversion. Eur. J. Biochem. 1972, 26: 426–433.

    Article  CAS  PubMed  Google Scholar 

  6. Wieland O.H., Siess E., Schulze-Wethmar F.H., Von Funcke H.G., Winton B. Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney. Effect of diabetes, fasting, and refeeding on pyruvate dehydrogenase interconversion. Arch. Biochem. Biophys. 1971, 143: 593–601.

    Article  CAS  PubMed  Google Scholar 

  7. Stansbie D., Denton R.M., Bridges B.J., Pask H. T., Randle P.J. Regulation of pyruvate dehydrogenase and pyruvate dehydrogenase phosphate phosphatase activity in rat epididymal fat-pads. Biochem. J. 1976, 154: 225–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hughes W.A., Denton R.M. Incorporation of 32p; into pyruvate dehydrogenase phosphate in mitochondria from control and insulin-treated adipose tissue. Nature 1976, 264: 471–473.

    Article  CAS  PubMed  Google Scholar 

  9. Popp D.A., Kiechle F.L., Kotagal N., Jarett L. Insulin stimulation of pyruvate dehydrogenase in an isolated plasma membrane-mitochondrial mixture occurs by activation of pyruvate dehydrogenase phosphatase. J. Biol. Chem. 1980, 255: 7540–7543.

    CAS  PubMed  Google Scholar 

  10. Rutter G.A., Diggle T.A., Denton R.M. Regulation of pyruvate dehydrogenase by insulin and polyamines within electropermeabilized fat-cells and isolated mitochondria. Biochem. J. 1992, 285: 435–439.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Lilley K., Zhang C., Villar-Palasi C., Larner J., Huang L. Insulin mediator stimulation of pyruvate dehydroge-nase phosphatase. Arch. Biochem. Biophys. 1992, 296: 170–174.

    Article  CAS  PubMed  Google Scholar 

  12. Hagg S.A., Taylor S.I., Ruderman N.B. Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise. Biochem. J. 1976, 158: 203–210.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rinaudo M.T., Curto M., Bruno R., Marino C., Mostert M. Effects of insulin on pyruvate dehydrogenase in circulating lymphocytes from normal and diabetic rats. Int. J. Biochem. 1988, 20: 667–674.

    Article  CAS  PubMed  Google Scholar 

  14. Mondon C.E., Jones I.R., Azhar S., Hollenbech C.B., Reave G.M. Lactate production and pyruvate dehydrogenase activity in fat and skeletal muscle from diabetic rats. Diabetes 1992, 41: 1547–1554.

    Article  CAS  PubMed  Google Scholar 

  15. Kelley D.E., Mandarino L.J. Hyperglycemia normalizes insulin-stimulated skeletal muscle glucose oxidation and storage in non-insulin-dependent diabetes mellitus. J. Clin. Invest. 1990, 86: 1999–2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kelley D.E., Mokan M., Mandarino L.J. Intracellular defects in glucose metabolism in obese patients with NIDDM. Diabetes 1992, 1: 698–706.

    Article  Google Scholar 

  17. Mandarino L.J., Madar Z., Kolterman O.I., Bell J.M., Olefsky J.M. Adipocyte glycogen synthase and pyruvate dehydrogenase in obese and type II diabetic subjects. Am. J. Physiol. 1986, 251 (Endocrinol. Metab. 14): E489–E49.

    CAS  PubMed  Google Scholar 

  18. National Diabetes Data Group. Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. Diabetes 1979, 28: 1039–1045.

    Article  Google Scholar 

  19. Boyüm A. Separation of leucocytes from blood and bone marrow. Scand. J. Lab. Clin. Invest. 1979, 21 (Suppl. 97): 9–109.

    Google Scholar 

  20. Curto M., Piccinini M., Cerutti F., Rabbone I., Mostert M., Sacchetti C., Bruno R., Rinaudo M.T. The insulin signal and its effects on the pyruvate dehydrogenase complex in circulating lymphocytes of obese children. Int. J. Biochem. 1992, 24: 831–837.

    Article  CAS  PubMed  Google Scholar 

  21. Teague W.M., Pettit F.H., Wu T.L., Silberman S.R., Reed L.J. Purification and properties of pyruvate dehydrogenase phosphatase from bovine heart and kidney. Biochemistry 1982, 21: 5585–5592.

    Article  CAS  PubMed  Google Scholar 

  22. Allred D.B., Guy D.J. Determination of coenzyme A and acetyl-CoA in tissue extracts. Anal. Biochem. 1969, 29: 293–299.

    Article  CAS  PubMed  Google Scholar 

  23. International Federation of Clinical Chemistry. Provisional recommendation on the theory of reference value. Chim. Clin. Acta. 1978, 87: 459–465.

    Article  Google Scholar 

  24. Tango T. Estimation of normal ranges of clinical laboratory data. Statistics in Medicine 1986, 5 (4): 335–346.

    Article  CAS  PubMed  Google Scholar 

  25. Armitage P., Berry G.D. Statistical Methods in Medical Research. Blackwell Scientific Publications, London, Oxford, 1994, p. 154–174.

    Google Scholar 

  26. Jarett L., Seals J.R. Pyruvate dehydrogenase activation in adipocyte mitochondria by an insulin generated mediator from muscle. Science 1979, 206: 1407–1408.

    Article  CAS  PubMed  Google Scholar 

  27. Seals J.R., Jarett L. Activation of pyruvate dehydrogenase by direct addition of insulin to an isolated plasma membrane/mitochondria mixture: Evidence for the generation of insulin’s second messenger in a subcellular system. Proc. Natl. Acad. Sci. U.S.A. 1980, 77: 77–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Saltiel A.R., Siegel M.I., Jacobs S., Cuatrecasas P. Putative mediators of insulin action: Regulation of pyruvate dehydrogenase and adenylate cyclase activities. Proc. Natl. Acad. Sci. U.S.A. 1982, 79: 3513–3517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gottschalk W.K., Jarett L. The insulinomimetic effects of the polar head group of an insulin-sensitive glycophospholipid on pyruvate dehydrogenase in both subcellular and whole cell assays. Arch. Biochem. Biophys. 1988, 15: 175–185.

    Article  Google Scholar 

  30. Cheng K., Galasko G., Huang L., Kellog J., Larner J. Studies of the insulin mediator — II Separation of two antagonistic biologically active materials from fraction II. Diabetes 1980, 29: 659–661.

    Article  CAS  PubMed  Google Scholar 

  31. Saltiel A., Jacobs S., Siegel M., Cuatrecasas P. Insulin stimulates the release from liver plasma membranes of a chemical modulator of pyruvate dehydrogenase. Biochem. Biophys. Res. Commun. 1981, 102: 1041–1047.

    Article  CAS  PubMed  Google Scholar 

  32. Saltiel A.R. Second messengers of insulin action. Diabetes Care 1990, 13: 244–256.

    Article  CAS  PubMed  Google Scholar 

  33. Curto M., Piccinini M., Bruno R., Mostert M., Rinaudo M.T. Insulin modulation of pyruvate dehydrogenase in human circulating lymphocytes. Int. J. Biochem. 1988, 20: 1211–1217.

    Article  CAS  PubMed  Google Scholar 

  34. Rabbone I., Piccinini M., Curto M., Mostert M., Gamba S., Mioletti S., Bruno R., Rinaudo M.T. Molecular effects of sulfonylurea agents in circulating lymphocytes of patients with non-insulin-dependent diabetes mellitus. Br. J. Clin. Pharmacol. 1998, 45: 291–299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. White M.F., Kahn C.R. The insulin signaling system. J. Biol. Chem. 1994, 269: 1–4.

    CAS  PubMed  Google Scholar 

  36. Denton R.M., Tavare J.M. Does mitogen activated-protein kinase have a role in insulin action? The cases for and against. Eur. J. Biochem. 1995, 227: 597–611.

    Article  CAS  PubMed  Google Scholar 

  37. Heesom K.J., Harbeck M., Kahn C.R., Denton R.M. Insulin action on metabolism. Diabetologia 1997, 40: B3–B9.

    Article  PubMed  Google Scholar 

  38. Avruch J. A signal for β-cell failure. Nature 1998, 391: 846–847.

    Article  CAS  PubMed  Google Scholar 

  39. Vaag A., Henriksen J.E., Beck-Nielsen H. Decreased insulin activation of glycogen synthase in skeletal muscle in young nonobese. Caucasian firstdegree relatives of patients with non-insulin-dependent diabetes mellitus. J. Clin. Invest. 1993, 89: 782–788.

    Article  Google Scholar 

  40. Gulli G., Ferrannini E., Stem M., Haffner S., DeFronzo R.A. The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents. Diabetes 1992, 41: 1575–1586.

    Article  CAS  PubMed  Google Scholar 

  41. Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Scalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N. Engl. J. Med. 1989, 321: 337–343.

    Article  CAS  PubMed  Google Scholar 

  42. Schalin-Jäntti C., Härkönen M., Groop L.C. Impaired activation of glycogen synthase in people at increased risk for developing NIDDM. Diabetes 1992, 41: 598–604.

    Article  PubMed  Google Scholar 

  43. Larner J., Galasko G., Cheng K., DePaoli-Roach A. A., Huang L., Daggy P., Kellogg J. Generation by insulin of a chemical mediator that controls protein phosphorylation and dephosphorylation. Science 1979, 206: 1408–1410.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Scienze Pediatriche e dell’Adolescenza, Torino, Italy

    M. Mostert, I. Rabbone & A. Musso

  2. Department of Medicina e Oncologia Sperimentale, Sezione di Biochimica, University of Torino, Via Michelangelo 27/b, I-10126, Torino, Italy

    M. Piccinini, M. Curto &  M. T. Rinaudo

  3. Oncologia Pediatrica, University of Torino, Torino, Italy

    S. Vai

Authors
  1. M. Mostert
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. Rabbone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Piccinini
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Curto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Vai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Musso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M. T. Rinaudo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. T. Rinaudo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mostert, M., Rabbone, I., Piccinini, M. et al. Derangements of pyruvate dehydrogenase in circulating lymphocytes of NIDDM patients and their healthy offspring. J Endocrinol Invest 22, 519–526 (1999). https://doi.org/10.1007/BF03343603

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF03343603

Key-words

Search

Navigation