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Indirect Effects of Insulin in Regulating Glucose Fluxes

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New Concepts in the Pathogenesis of NIDDM

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

Abstract

Insulin can regulate glucose metabolism directly via its effects on glucose transport and metabolic pathways. However, these effects cannot account for all the metabolic events that occur following insulin secretion or administration. A number of laboratories, including our own, have suggested that many of the known effects of insulin on glucose metabolism may be exerted partially via indirect pathways1. Cumulative evidence indicates that the indirect actions of insulin not only contribute to, but sometimes may play a predominant role in the overall effects of insulin on glucose fluxes.

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References

  1. M. Vranic, Glucose turnover. A key to understanding the pathogenesis of diabetes. Indirect effects of insulin. The Banting Lecture, Diabetes 41:1188 (1992).

    Article  PubMed  CAS  Google Scholar 

  2. A. Klip, T. Ramlal, D.A. Young and J.O. Holloszy, Insulin-induced translocation of glucose transporters in rat hindlimb muscles, FEBS Lett 224:224 (1987).

    Article  PubMed  CAS  Google Scholar 

  3. L.J. Warzala and B. Jeanrenaud, Potential mechanism of insulin action on glucose transport in isolated diaphragm. Apparent translocation of intracellular transport units to the plasma membrane, J Biol Chem 256:7090 (1981).

    Google Scholar 

  4. A. Klip, A. Marette, D. Dimitrakoudis, T. Ramlal, A. Giacca, Z. Shi and M. Vranic, Effect of diabetes on glucoregulation. From glucose transporters to glucose metabolism in vivo, Diabetes Care 15(11): 1747 (1992).

    Article  PubMed  CAS  Google Scholar 

  5. A. Klip, T. Ramlal, P.J. Bilan, G.D. Cartee, E.A. Gulve and J.O. Holloszy, Recruitment of GLUT-4 glucose transporter by insulin in diabetic rat skeletal muscle, Biochem Biophys Res Cornm 172:728 (1990).

    Article  CAS  Google Scholar 

  6. A. Marette, E. Burdett, A. Douen, M. Vranic and A. Klip, Insulin induces the translocation of GLUT4 glucose transporters from a unique intracellular organelle to transverse tubules in rat skeletal muscle, Diabetes 41(12): 1562 (1992).

    Article  PubMed  CAS  Google Scholar 

  7. P.S. Walker, T. Ramlal, J.A. Donovan, T.P. Doering, A. Sandra, A. Klip and J.E. Pessin, Insulin and glucose-dependent regulation of the glucose trnaport system in the rat L6 skeletal muscle line, J Biol Chem 264:6587 (1989).

    PubMed  CAS  Google Scholar 

  8. S.W. Cushman and L.J. Warzala, Potential mechanism of insulin action on glucose transport in the isolated rat adipose cell. Apparent translocation of intracellular transport systems to the plasma membrane, J Biol Chem 255:4748 (1980).

    Google Scholar 

  9. A.P. Thomas and R.M. Denton, Use of toluene-permeabilized mitochondria to study the regulation of adipose tissue pyruvate dehydrogenase in situ, Biochem J 238:93 (1986).

    PubMed  CAS  Google Scholar 

  10. O. Bjorkman, P. Miles, D. Wasserman, L. Lickley and M. Vranic, Regulation of glucose turnover in pancreatectomized, totally insulin deficient dogs: effects of beta-adrenergic blockade, J Clin Invest 81:1759 (1988).

    Article  PubMed  CAS  Google Scholar 

  11. D.H. Wasserman, H.L.A. Lickley and M. Vranic, Role of beta-adrenergic mechanisms during exercise in poorly-controlled insulin deficient diabetes, J Appl Physiol 59:1282 (1985).

    PubMed  CAS  Google Scholar 

  12. K. Yamatani, Z. Shi, A. Giacca, R. Gupta, S. Fisher, L. Lickley and M. Vranic, Role of FFA-glucose cycle in glucoregulation during exercise in total absence of insulin, Am J Physiol 263:E646 (1992).

    PubMed  CAS  Google Scholar 

  13. A. Giacca, S. Fisher, Z.Q. Shi, R. Gupta, L. Lickley and M. Vranic, Importance of peripheral insulin levels for insulin-induced suppression of glucose production in depancreatized dogs, J Clin Invest 90:1769 (1992).

    Article  PubMed  CAS  Google Scholar 

  14. M. Ader and R.N. Bergman, Peripheral effects of insulin dominate suppression of fasting hepatic glucose production, Am J Physiol 245:E1020 (1990).

    Google Scholar 

  15. P. Miles, K. Yamatani, L. Lickley and M. Vranic, Mechanism of glucoregulatory responses to stress and their deficiency in diabetes, Proc Natl Acad Sci U. S. A. 88(4):1296 (1991).

    Article  PubMed  CAS  Google Scholar 

  16. J.D. McGarry and D.W. Foster, Ketogenesis, in:Diabetes mellitus: Theory and practice, H. Rifkin and D. Porte, eds., Elsevier Science Publishing Co., Inc., New York (1990).pp.292.

    Google Scholar 

  17. L.V. Basso and R.J. Havel, Hepatic metabolism of free fatty acids in normal and diabetic dog, J Clin Invest 49:537 (1970).

    Article  PubMed  CAS  Google Scholar 

  18. M. Vranic, R. Kawamori, S. Pek, N. Kovacevic and G. Wrenshall, The essentiality of insulin and the role of glucagon in regulating glucose utilization and production during strenuous exercise in dogs, J Clin Invest 57:245 (1976).

    Article  PubMed  CAS  Google Scholar 

  19. D.H. Wasserman, J.L. Bupp, J.L. Johnson, D. Bracy and D.B. Lacy, Glucoregulation during rest and exercise in depancreatized dogs: role of the acute presence of insulin, Am J Physiol 262:E574 (1992).

    PubMed  CAS  Google Scholar 

  20. T. Ploug, H. Galbo, J. Vinten, M. Jorgensen and E. Richter, Kinetics of glucose transport in rat muscle: effects of insulin and contractions, Am J Physiol 253:E12 (1987).

    PubMed  CAS  Google Scholar 

  21. H. Wallberg-Henriksson, S.H. Constable, D.A. Young and J.O. Holloszy, Glucose transport into rat skeletal muscle: interaction between exercise and insulin, J Appl Physiol 65:909 (1988).

    PubMed  CAS  Google Scholar 

  22. R. Nesher, I.E. Karl and K.M. Kipnis, Dissociation of the effect(s) of insulin and contraction on glucose transport in rat epitrochlearis muscle, Am J Physiol 249:C226 (1985).

    PubMed  CAS  Google Scholar 

  23. D.H. Wasserman, H.L.A. Lickley and M. Vranic, Important role of glucagon during exercise and diabetes, J Appl Physiol 59:1272 (1985).

    PubMed  CAS  Google Scholar 

  24. P.J. Randle, E.A. Newsholme and P.B. Garland, Regulation of glucose uptake by muscle. 8. Effects of fatty acids and ketone bodies and pyruvate, and of alloxan-diabetes and starvation on the uptake and metabolic fate of glucose in rat heart and diaphragm muscle, Biochem J 93:652 (1964).

    PubMed  CAS  Google Scholar 

  25. P.J. Randle, P.B. Garland, C.N. Hales and E.A. Newsholme, The glucose-fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus, Lancet 1:785 (1963).

    Article  PubMed  CAS  Google Scholar 

  26. M.J. Rennie and J.O. Holloszy, Inhibition of glucose uptake and glycogenolysis by availability of oleate in well-oxygenated perfused skeletal muscle, Biochem J 168:161 (1977).

    PubMed  CAS  Google Scholar 

  27. D. Thiebaud, R.A. DeFronzo, E. Jacot, A. Golay, K. Acheson, E. Maeder, E. Jecquier and J.P. Felber, Effect of long chain triglyceride infusion on glucose metabolism in man, Metab 31:1128 (1982).

    Article  CAS  Google Scholar 

  28. P.J. Randle, Molecular mechanisms regulating fuel selection in muscle, in:Biochemistry of exercise, J.R. Poortsman and G. Niset, eds., Baltimore University Park Press, Baltimore (1983).pp.13.

    Google Scholar 

  29. P.J. Randle, Interaction of fatty acid and glucose metabolism, in:Diabetes 1988, R. Larkins, P. Zimmet and D. Chisholm, eds., Elsevier Science Publishers B.V. (Biomedical Division), (1989).pp.163.

    Google Scholar 

  30. B.M. Wolfe, S. Klein, E.J. Peters, B.F. Schmidt and R.R. Wolfe, Effect of elevated free fatty acids on glucose oxidation in normal humans, Metab 37(4):323 (1988).

    Article  CAS  Google Scholar 

  31. G.F. Tutwiler, R. Mohrbecker and W. Ho, Methyl 2-tetradecylglycidate, an orally effective hyperglycemie agent that inhibits long chain fatty acid oxidation selectively, Diabetes 28:242 (1979).

    PubMed  CAS  Google Scholar 

  32. J.C. Young, J.E. Bryan and S.H. Constable, Effects of the oral hypoglycemic agent methyl palmoxirate on exercise capacity of rats, Can J Physiol Pharmacol 62:815 (1984).

    Article  PubMed  CAS  Google Scholar 

  33. J.W. Bailey, M.D. Jensen and J.M. Miles, Effects of intravenous methyl palmoxirate on the turnover and oxidation of fatty acids in conscious dogs, Metab 40(4):428 (1991).

    Article  CAS  Google Scholar 

  34. R.W. Tuman, G.F. Tutwiler, J.M. Joseph and N.H. Wallace, Hypoglycemie and hypoketonemic effects of single and repeated oral doses of methyl palmoxirate (methyl 2-tetradecylglycidate) in streptozotoic/alloxan-induced diabetic dogs, Br J Pharmacol 94:130 (1991).

    Article  Google Scholar 

  35. G.F. Tutwiler and H.J. Brentzel, Relation of oxidation of long-chain fatty acids to gluconeogenesis in the perfused liver of the guinea pig: effect of 2-tetradecylglycidic acid (McN-3802), Eur J Biochem 124:465 (1982).

    Article  PubMed  CAS  Google Scholar 

  36. L. Mandarino, E. Tsalikian, S. Bartold, H. Marsh, A. Carney, E. Buerklin, G. Tutwiler, M. Haymond, B. Handwerger and R. Rizza, Mechanism of hyperglycemia and response to treatment with an inhibitor of fatty acid oxidation in a patient with insulin resistance due to antiinsulin receptor antibodies, J Clin Endocrinol Metab 59:658 (1984).

    Article  PubMed  CAS  Google Scholar 

  37. A. Consoli, N. Nurjhan, F. Capani and J. Gerich, Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM, Diabetes 38:550 (1989).

    Article  PubMed  CAS  Google Scholar 

  38. R.W. Stevenson, P.E. Williams and A.D. Cherrington, Role of glucagon suppression on gluconeogenesis during insulin treatment of the conscious diabetic dog, Diabetologia 30:782 (1987).

    Article  PubMed  CAS  Google Scholar 

  39. J. Radziuk and H.L.A. Lickley, The metabolic clearance of glucose: measurment and meaning, Diabetologia 28:315 (1985).

    Article  PubMed  CAS  Google Scholar 

  40. Z.Q. Shi, A. Giacca, K. Yamatani, P.D.G. Miles, S. Fisher, M. Van Delangeryt, L. Lickely and M. Vranic, Glucose uptake in exercise and stress: The indirect role of insulin, in:Proceedings of the Diabetes Mellitus and Exercise Symposium, J. Devlin, E.S. Horton and M. Vranic, eds., Smith-Gordon and Company Ltd, London (1992).pp.101.

    Google Scholar 

  41. D.J. Wasserman, R.J. Geer, D.E. Rice, D. Bracy, P.J. Flakoll, L.L. Brown, J.O. Hill and N.N. Abumrad, Interaction of exercise and insulin action in humans, Am J Physiol 260:E37 (1991).

    PubMed  CAS  Google Scholar 

  42. Z.Q. Shi, A. Giacca, K. Yamatani, S. Fisher, L. Lickley and M. Vranic, Effects of subbasal insulin infusion on resting and exercise-induced glucose uptake in depancreatized dogs, Am J Physiol 264:E334 (1993).

    PubMed  CAS  Google Scholar 

  43. R.A. DeFronzo, R.C. Bonadonna and E. Ferrannini, Pathogenesis of NIDDM: A balanced overview, Diabetes Care 15(3):318 (1992).

    Article  PubMed  CAS  Google Scholar 

  44. D. Dimitrakoudis, T. Ramlal, S. Rastogi, M. Vranic and A. Klip, Glycemia regulates the glucose transporter number in the plasma membrane of rat skeletal muscle, Biochem J 284(2):341 (1992).

    PubMed  CAS  Google Scholar 

  45. L. Rossetti, D. Smith, G.L. Shuman, D. Papachristou and R.A. DeFronzo, Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats, J Clin Invest 79:1510 (1987).

    Article  PubMed  CAS  Google Scholar 

  46. S. Efendic, S. Karlander and M. Vranic, Mild type II diabetes markedly increases glucose cycling in the postabsorptive state and during glucose infusion irrespective of obesity, J Clin Invest 81: 1953 (1988).

    Article  PubMed  CAS  Google Scholar 

  47. B. Issekutz, Studies on hepatic glucose cycles in normal and methylprednisolone-treated dogs, Metab 26:157 (1977).

    Article  CAS  Google Scholar 

  48. H.L.A. Lickley, G.G. Ross and M. Vranic, Effects of selective insulin or glucagon deficiency on glucose turnover, Am J Physiol 236:E255 (1979).

    PubMed  CAS  Google Scholar 

  49. S. Efendic, A. Wajngot and M. Vranic, Increased activity of the glucose cycle in the liver: Early characteristic of type 2 diabetes, Proc Natl Acad Sci U. S. A. 82:2965 (1985).

    Article  PubMed  CAS  Google Scholar 

  50. A. Giacca, Z.Q. Shi, S.J. Fisher, G. van de Werve and M. Vranic, Acute correction of both hyperglycemia and hypoinsulinemia decreases elevated glucose cycling in diabetes, Diabetes 41(suppl.):(1992).(Abstract).

    Google Scholar 

  51. H. Sasaki, s. Marubashi, Y. Yawata and et al, Neuropeptides and glucose metabolism, in:The brain as an endcrine organ, Endocrinology and Metabolism III, Progrss in Research and Clinical Practice, M.P. Cohen and P.P. Foa, eds., Springer-Verlag, New York (1988).pp.150.

    Google Scholar 

  52. M.R. Brown and L.A. Fisher, Corticotropin-releasing factor: effects on the autonomie nervous system and visceral systems, Fed Proc 44:243 (1985).

    PubMed  CAS  Google Scholar 

  53. M.R. Brown, L.A. Fisher, J. Spiess, J. Rivier, C. Rivier and W. Vale, Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism, Endocrinol 111:928 (1982).

    Article  CAS  Google Scholar 

  54. D.A. Fisher and M.R. Brown, Somatostatin analog: Plasma catecholamine suppression mediated by the central nervous system, Endocrinol 107:714 (1980).

    Article  CAS  Google Scholar 

  55. F.W. Kemmer, R. Bisping, H.J. Steingruber, H. Baar, F. Hartman, R. Schlagheche and M. Berger, Psychological stress and metabolic control in patients with type 1 diabetes mellitus, N Engl J Med 314:1078 (1986).

    Article  PubMed  CAS  Google Scholar 

  56. N.J. Christensen and O. Brandesborg, The relationship between plasma catecholamine concentration and pulse rate during exercise and standing, Eur J Clin Invest 3:299 (1973).

    Article  PubMed  CAS  Google Scholar 

  57. D.W. Wilmore, C.A. Lindsey, J.A. Moylan, G.R. Faloona, B.A. Pruitt and R.H. Unger, Hyperglucagonemia after burns, Lancet 1:73 (1974).

    Article  PubMed  CAS  Google Scholar 

  58. D.W. Wilmore, J.M. Long and A.D. Mason, Catecholamines: mediator of the hypermetabolic response to thermal injury, Ann Surg 180:653 (1974).

    Article  PubMed  CAS  Google Scholar 

  59. W.J. Kraemer, J.F. Patton, H.G. Knuttgen, L.J. Marchitalli, C. Cruthirds, A. Damokosh, E. Harman, P. Frykman and J.E. Dziados, Hypothalamic-pituitary-adrenal responses to short-duration high-intensity cycle exercise, J Appl Physiol 66(1): 161 (1989).

    Article  PubMed  CAS  Google Scholar 

  60. A.J.W. Scheurink, A.B. Steffens, H. Bouritius, G.H. Dreteler, R. Bruntink, R. Remie and J. Zaagsma, Sympathoadrenal influence of glucose, FFA, and insulin levels in exercising rats, Am J Physiol 25:R161 (1989).

    Google Scholar 

  61. J. Vissing, G.A. Iwamoto, K.J. Rybicki, H. Galbo and J.H. Mitchell, Mobilization of glucoregulatory hormones and glucose by hypothalamic locomotor centers, Am J Physiol 20:E722 (1989).

    Google Scholar 

  62. P.D.G. Miles, K. Yamatani, H.L.A. Lickley and M. Vranic, The intracerebroventricular injection of a somatostatin analog (ODT8-SS) suppresses the stress response in normal and diabetic dogs, Program of International Symposium on Somatostatin Montreal, Canada abstract #68:64 (1989).(Abstract).

    Google Scholar 

  63. D.E. Gray, H.L.A. Lickley and M. Vranic, Physiologic effects of epinephrine on glucose turnover and plasma free fatty acid concentrations mediated independently of glucagon, Diabetes 29:600 (1980).

    Article  PubMed  CAS  Google Scholar 

  64. R.A. Rizza, M. Haymond, P. Cryer and J. Gerich, Differential effects of epinephrine on glucose production and disposal in man, Am J Physiol 237:E356 (1979).

    PubMed  CAS  Google Scholar 

  65. K.M.A. El-Tayeb, P.L. Brubaker, M. Vranic and H.L.A. Lickley, Beta-endorphin modulation of the glucoregulatory effects of repeated epinephrine infusion in normal dogs, Diabetes 34:1293 (1985).

    Article  PubMed  CAS  Google Scholar 

  66. Y. Minokoshi, M. Sudo and T. Shinazu, Neural control of glucose uptake in peripheral tissues, Diabetes 40(suppl. 1):153A (1991).(Abstract).

    Google Scholar 

  67. A. Marette and L. Bukowiecki, Stimulation of glucose transport by insulin and norepinephrine in isolated rat brown adipocytes, Am J Physiol 257:C714 (1989).

    PubMed  CAS  Google Scholar 

  68. I. Bihler, P.C. Sawh and I.G. Sloan, Dual effect of adrenalin on sugar transport in rat diaphragm muscle, Biochem Biophys Acta 510:349 (1978).

    Article  PubMed  CAS  Google Scholar 

  69. I.G. Sloan, P.C. Sawh and I. Bihler, Influence of adrenalin on sugar transport in soleus, a red skeletal muscle, Mol Cell Endorinol 10:3 (1978).

    Article  CAS  Google Scholar 

  70. J.L. Chiasson, H. Shikama, D.T.W. Chu and J.H. Exton, Inhibitory effect of epinephrine on insulin-stimulated glucose uptake by rat skeletal muscle, J Clin Invest 68:706 (1981).

    Article  PubMed  CAS  Google Scholar 

  71. D.A. Young, H. Wallberg-Henriksson, J. Cranshaw, M. Chen and J.O. Holloszy, Effects of catecholamine on glucose uptake and glycogenolysis in rat, Am J Physiol 248:C406 (1985).

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Physiology, University of Toronto, Toronto, Ontario, Canada, M5S 1A8

    Z. Q. Shi, A. Giacca, S. J. Fisher, M. Lekas, D. Bilinski, M. Van Delangeryt & M. Vranic

  2. Department of Surgery, University of Toronto, Toronto, Ontario, Canada, M5S 1A8

    H. L. A. Lickley

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  1. Z. Q. Shi
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  2. A. Giacca
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  3. S. J. Fisher
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  4. M. Lekas
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  5. D. Bilinski
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  6. M. Van Delangeryt
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  7. H. L. A. Lickley
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  1. Karolinska Hospital, Stockholm, Sweden

    Claes Göran Östenson  & Suad Efendić  & 

  2. University of Toronto, Toronto, Ontario, Canada

    Mladen Vranic

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Shi, Z.Q. et al. (1993). Indirect Effects of Insulin in Regulating Glucose Fluxes. 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_11

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