Advertisement

European Journal of Clinical Pharmacology

, Volume 48, Issue 5, pp 327–332 | Cite as

Dysfunction in the β2-adrenergic signal pathway in patients with insulin dependent diabetes mellitus (IDDM) and unawareness of hypoglycaemia

  • T. S. Trovik
  • A. Vaartun
  • G. Sager
  • R. Jorde
Pharmacodynamics

Abstract

The majority of the impaired symptoms in hypoglycaemia unawareness, such as palpitations, tachycardia and tremor, are caused by increased release of adrenaline (ADR) and noradrenaline (NA), and induced by stimulation of β-adrenergic receptors. Binding of ADR or NA to the β-adrenergic receptor generates a signal, transmitted via a guanine nucleotide binding protein complex (G-protein), which in turn activates adenylate cyclase with increased production of cAMP. The aim of this study was to show whether IDDM-patients with hypoglycaemia unawareness had deficient coupling between β2-adrenergic receptors and G-proteinscompared to IDDM-patients with hypoglycaemia awareness and healthy controls. The IDDM-patients were subgrouped as hypoglycaemia aware or unaware based on questionnaire answers, clinical information and the results of isoprenaline sensitivity tests. Mononuclear leukocytes (MNL) were isolated from venous blood. By saturation binding experiments, using [125I]-(-)-iodopindolol ((-)-IPIN), total receptor number (Bmax) and affinity (Kd) were determined. By displacement experiments the relative number of low-and high-affinity receptors for the β-adrenergic agonist (-)-isoprenaline ((-)-ISO) were determined. We found no difference in Bmax- or Kd-values for (-)-IPIN between the subgroups. However, there was a reduced capability to form high-affinity binding complexes with (-)-ISO in MNL from IDDM-patients with hypoglycaemia unawareness. It was concluded that hypoglycaemia unawareness in IDDM was associated with dysfunction of the proximal β2-adrenergic signal pathway.

Key words

Hypoglycaemia unawareness Diabetes mellitus β-adrenergic sensitivity β-adrenergic receptor affinity isoprenaline catecholamines G-proteins 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Berlin I, Grimaldi A, Landault C, Zoghbi F, Thervet F, Puech J, Legrand JC (1988) Lack of hypoglycemic symptoms and decreased β-adrenergic sensitivity in insulin-dependent patients. J Clin Endocrin Metabol 66:273–278Google Scholar
  2. 2.
    Berlin I, Grimaldi A, Payan C, Sachon C, Bosquet F, Thervet F, Peuch AJ (1987) Hypoglycemic symptoms and decreased β-adrenergic sensitivity in insulin-dependent diabetic patients. Diabetes Care 10:742–747Google Scholar
  3. 3.
    Trovik TS, Jæger R, Jorde R, Sager G (1994) Reduced sensitivity to β-adrenoceptor stimulation and blockade in insulin dependent diabetic patients with hypoglycemia unawareness. Br J Clin Pharmacol 38:5,427–432Google Scholar
  4. 4.
    Serusclat P, Rosen SG, Smith EB, Shah SD, Clutter WE, Cryer PE (1983) Mononuclear leucocyte β2-adrenergic receptors and adenylate cyclase sensitivity in insulin-dependent diabetes mellitus. Diabetes 32:825–829Google Scholar
  5. 5.
    Sager G, Slørdal L, Huseby N-E, Florholmen J (1991) β-Adrenoceptor regulation in insulin-dependent diabetes mellitus. Scand J Clin Lab Invest 51:283–288Google Scholar
  6. 6.
    Gerich JE, Mokan M, Veneman T, Korytkowski M, Mitrakou A (1991) Hypoglycemia unawareness. Endocrine Rev 12:4,356–371Google Scholar
  7. 7.
    Lefkowitz RJ, Cotecchia S, Samama P, Costa T (1993) Constitutive activity of receptors coupled to guanine nucleotide regulatory proteins. Trends Pharmacol Sci 14:303–307Google Scholar
  8. 8.
    Birnbaumer L (1990) Transduction of receptor signal into modulation of effector activity by G proteins: the first 20 years or so. FASEB J 4:3068–3078Google Scholar
  9. 9.
    George CF, Conolly ME, Fenyvesi T, Briant R, Dollery CT (1972) Intravenously administered isoproterenol sulfate doseresponse curves in man. Arch Intern Med 130:361–364Google Scholar
  10. 10.
    Bøyum A (1968) Isolation of mononuclear cells and granulo cytes from human blood. Scand J Clin Lab Invest 21 [Suppl 97]:77–89Google Scholar
  11. 11.
    Kent RS, DeLean A, Lefkowitz RJ (1980) A quantitative analysis of beta-adrenergic receptor interactions: resolution of high and low affinity states of the receptor by computer modeling of ligand binding data. Mol Pharmacol 17:14–23Google Scholar
  12. 12.
    DeLean A, Stadel J, Lefkowitz RJ (1980) A ternary complex model explains the agonist-specific binding properties of the adenylate cyclase-coupled β-adrenergic receptor. J Biol Chem 255:7108–7117Google Scholar
  13. 13.
    Sager G (1990) Types of β-adrenergic binding sites on plasma proteins and blood cells. In: Belpaire F, Bogaert M, Tillement JP Verbeeck R (eds) Plasma binding of drugs and its consequences. Academia Press, Ghent, pp 43–53Google Scholar
  14. 14.
    Widom B, Simonson D (1990) Glycemic control, neuropsycologic function during hypoglycemia in patients with insulindependent diabetes. Ann Intern Med 112:904–912Google Scholar
  15. 15.
    Mokan M, Mitrakou A, Raptis G, Platanisiotis D, Grannakopoulos F, Korytkowski M, Cryer P, Gerich J (1991) Differential effects of duration of diabetes and glycemic control on thresholds and magnitudes of responses to hypoglycemia. Diabetes 40 [Suppl 1]:556AGoogle Scholar
  16. 16.
    Boyle P, Schwartz N, Shah S, Clutter W, Cryer P (1988) Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 318:1487–1492Google Scholar
  17. 17.
    Lohse MJ, Benovic JL, Caron MG, Lefkowitz RJ (1990) Multiple pathways of rapid β2-adrenergic receptor desensitization. J Biol Chem 265:3202–3209Google Scholar
  18. 18.
    Lynch CJ, Exton JH (1992) Alterations in G-protein-mediated cell signalling in diabetes mellitus. In: Milligan G, Wakelam M (eds) G-proteins. Signal, Transduction and Disease. Academic Press, London, pp 87–108Google Scholar
  19. 19.
    Kampa IS, Frascella DW, Hundertmark JM, Rosenberg JM, Reid V (1981) The effect of hyperthermic stress on blood glucagon levels in normal and diabetic rats. Horm Metab Res 13:122–122Google Scholar
  20. 20.
    Chang AY, Noble RE, Wyse BM (1977) Comparison of highly inbred diabetic and nondiabetic lines in the Upjohn colony of Chinese hamsters. Diabetes 26:1063–1071Google Scholar
  21. 21.
    Christensen NJ (1974) Plasma norepinephrine and epinephrine in untreated diabetics, during fasting and after insulin administration. Diabetes 23:1–8Google Scholar
  22. 22.
    Tamborlane WV, Sherwin RS, Koivisto V, Hendler R, Genel M, Felig P (1979) Normalization of the growth hormone and catecholamine response to exercise in juvenile-onset diabetic subjects treated with a portable insulin infusion pump. Diabetes 28:785–788Google Scholar
  23. 23.
    Wasserman DH, Lickley HLA, Vranic M (1985) Role of beta-adrenergic mechanisms during exercise in poorly controlled diabetes. J Appl Physiol 59:1272–1281Google Scholar
  24. 24.
    Hayford JT, Danney MM, Hendrix JA, Thompson RG (1980) Integrated concentration of growth hormone in juvenile-onset diabetes. Diabetes 29:391–398Google Scholar
  25. 25.
    Topper E, Gertner S, Amiel S, Press M, Genel M, Tamborlane WV (1985) Deranged alpha-adrenergic regulation of growth hormone secretion in poorly controlled diabetes; reversal of the exaggerated response to clonidine after continuous subcutaneous insulin infusion. Pediatr Res 19:534–536Google Scholar
  26. 26.
    Ingebretsen WR, Peralta C, Monsher M, Wagner LK, Ingebretsen CG (1981) Diabetes alters the myocardial cAMP-protein kinase cascade system. Am J Physiol 240:H375-H382Google Scholar
  27. 27.
    Miller TB Jr, Pradeiro M, Wolleben C, Bullman J (1981) A hypersensitivity of glycogen phosphorylase activation in hearts of diabetic rats. J Biol Chem 256:1748–1753Google Scholar
  28. 28.
    Miller TB Jr (1984) Phosphorylase activation hypersensitivity in hearts of diabetic rats. Am J Physiol 246: E134-E140Google Scholar
  29. 29.
    Grimaldi A, Bosquet F, Davidoff P, Digy J, Landault C, Therver F, Zoghbr F, Legrand J (1990) Unawareness of hypoglycemia by insulin-dependent diabetics. Horm Metab Res 22:90–95Google Scholar
  30. 30.
    Hepburn D, Patrick A, Eadington D, Ewing D, Frier B (1990) Unawareness of hypoglycemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabetic Med 7:711–717Google Scholar
  31. 31.
    Heller S, Herbert M, MacDonald I, Tatterstall R (1987) Influence of sympathetic nervous system on hypoglycemic warning symptoms. Lancet II:359–363Google Scholar
  32. 32.
    Keen H (1976) Glucose intolerance, diabetes mellitus, atherosclerosis; prospects for prevention. Postgrad Med J 52:445–451Google Scholar
  33. 33.
    Hoeldtke RD, Boden G, Shuman CR, Owen OE (1982) Reduced epinephrine secretion and hypoglycemia unawareness in diabetic autonomic neuropathy. Ann Intern Med 96:459–462Google Scholar
  34. 34.
    Editorial (1987) Awareness of hypoglycemia in diabetes. Lancet II:371–372Google Scholar
  35. 35.
    The diabetes control and complications trial research group (1991) Epidemiology of severe hypoglycemia in the diabetes control and complications trial. Am J Med 90:450–459Google Scholar
  36. 36.
    Cryer PE (1992) Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM: a vicious circle. Diabetes 41:255–260Google Scholar
  37. 37.
    Fanelli CG, Epifano L, Rambotti AM, Pampanelli S, DiVincenzo A, Modarelli F, Lepore M, Annibale B, Ciofetta M, Bottini P, Porcellati F, Scionti L, Santeusanio F, Brunetti P, Bolli GB (1993) Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. Diabetes 42:1683–1689Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • T. S. Trovik
    • 1
  • A. Vaartun
    • 1
  • G. Sager
    • 1
  • R. Jorde
    • 2
  1. 1.Department of Pharmacology, Institute of Medical BiologyUniversity of TromsøTromsøNorway
  2. 2.Department of Internal MedicineUniversity Hospital of TromsøTromsøNorway

Personalised recommendations