Diabetologia

, Volume 37, Issue 12, pp 1265–1276

Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of rational, intensive insulin therapy in IDDM

  • C. Fanelli
  • S. Pampanelli
  • L. Epifano
  • A. M. Rambotti
  • A. Di Vincenzo
  • F. Modarelli
  • M. Ciofetta
  • M. Lepore
  • B. Annibale
  • E. Torlone
  • G. Perriello
  • P. De Feo
  • F. Santeusanio
  • P. Brunetti
  • G. B. Bolli
Originals

Summary

Hypoglycaemia unawareness, is a major risk factor for severe hypoglycaemia and a contraindication to the therapeutic goal of near-normoglycaemia in IDDM. We tested two hypotheses, first, that hypoglycaemia unawareness is reversible as long as hypoglycaemia is meticulously prevented by careful intensive insulin therapy in patients with short and long IDDM duration, and that such a result can be maintained long-term. Second, that intensive insulin therapy which strictly prevents hypoglycaemia, can maintain long-term near-normoglycaemia. We studied 21 IDDM patients with hypoglycaemia unawareness and frequent mild/severe hypoglycaemia episodes while on “conventional” insulin therapy, and 20 nondiabetic control subjects. Neuroendocrine and symptom responses, and deterioration in cognitive function were assessed in a stepped hypoglycaemia clamp before, and again after 2 weeks, 3 months and 1 year of either intensive insulin therapy which meticulously prevented hypoglycaemia (based on physiologic insulin replacement and continuous education, experimental group, EXP, n=16), or maintenance of the original “conventional” therapy (control group, CON, n=5). At entry to the study, all 21 IDDM-patients had subnormal neuroendocrine and symptom responses, and less deterioration of cognitive function during hypoglycaemia. After intensive insulin therapy in EXP, the frequency of hypoglycaemia decreased from 0.5±0.05 to 0.045±0.02 episodes/patient-day; HbA1C increased from 5.83±0.18 to 6.94±0.13% (range in non-diabetic subjects 3.8–5.5%) over a 1-year period; all counterregulatory hormone and symptom responses to hypoglycaemia improved between 2 weeks and 3 months, with the exception of glucagon which improved at 1 year; and cognitive function deteriorated further as early as 2 weeks (p<0.05). The improvement in responses was maintained at 1 year. The improvement in plasma adrenaline and symptom responses inversely correlated with IDDM duration. In contrast, in CON, neither frequency of hypoglycaemia, nor neuroendocrine responses to hypoglycaemia improved. Thus, meticulous prevention of hypoglycaemia by intensive insulin therapy reverses hypoglycaemia unawareness even in patients with long-term IDDM, and is compatible with long-term near-normoglycaemia. Because carefully conducted intensive insulin therapy reduces, not increases the frequency of moderate/severe hypoglycaemia, intensive insulin therapy should be extended to the majority of IDDM patients in whom it is desirable to prevent/delay the onset/progression of microvascular complications.

Key words

Autonomic neuropathy intensive insulin therapy hypoglycaemia unawareness glucose counterregulation catecholamines 

Abbreviations

IDDM

Insulin-dependent diabetes mellitus

IIT

intensive insulin therapy

HU

hypoglycaemia unawareness

EXP

experimental patient group

CON

control group

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Gerich J, Mokan M, Veneman T, Korytkowski M, Mitrakou A (1991) Hypoglycemia unawareness. Endo Rev 12: 356–371Google Scholar
  2. 2.
    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. Diabet Med 7: 711PubMedGoogle Scholar
  3. 3.
    Mokan M, Mitrakou A, Veneman T et al. (in press) Hypoglycemia unawareness in insulin-dependent diabetes mellitus. Diabetes Care (in press)Google Scholar
  4. 4.
    Dagogo-Jack SE, Cryer PE (1993) Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest 91: 819PubMedGoogle Scholar
  5. 5.
    White N, Skor D, Cryer P et al. (1983) Identification of type 1 diabetic patients at increased risk for hypoglycemia during intensive therapy. N Engl J Med 308: 485–491PubMedGoogle Scholar
  6. 6.
    Bolli G, De Feo P, De Cosmo S et al. (1984) A reliable and reproducible test for adequate glucose counterregulation in type 1 diabetes mellitus. Diabetes 33: 732–737PubMedGoogle Scholar
  7. 7.
    Cryer P, Gerich J (1985) Glucose counterregulation, hypoglycemia, and intensive insulin therapy in diabetes mellitus. N Engl J Med 313: 232–241PubMedGoogle Scholar
  8. 8.
    The Diabetes Control and Complications Trial Research Group (1993) The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 329: 977–986Google Scholar
  9. 9.
    Reichard P, Nilsson B-Y, Rosenquist U (1993) The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 329: 304–309Google Scholar
  10. 10.
    Brinchmann-Hansen O, Dahl-Jorgensen K, Sandvik L, Hanssen K (1992) Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. BMJ 304: 19–22PubMedGoogle Scholar
  11. 11.
    Heller S, Herbert M, MacDonald I, Tattersall R (1987) Influence of sympathetic nervous system on hypoglycemic warning symptoms. Lancet II: 359–363Google Scholar
  12. 12.
    Amiel S, Sherwin R, Simonson R et al. (1988) Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37: 901–907PubMedGoogle Scholar
  13. 13.
    Cryer PE (1992) Iatrogenic hypoglycemia as a cause of hypoglycemia-associated autonomic failure in IDDM. A vicious circle. Diabetes 41: 255–260PubMedGoogle Scholar
  14. 14.
    Heller S, Cryer P (1991) Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in nondiabetic humans. Diabetes 40: 223–226PubMedGoogle Scholar
  15. 15.
    Davis M, Shamoon H (1991) Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endocrinol Metab 73: 995–1001PubMedGoogle Scholar
  16. 16.
    Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993) Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 42: 1233–1237PubMedGoogle Scholar
  17. 17.
    Widom B, Simonson DC (1992) Intermittent hypoglycemia impairs glucose counterregulation. Diabetes 41: 1597–1602PubMedGoogle Scholar
  18. 18.
    Lingefelser T, Renn W, Sommerwerck U et al. (1993) Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients. Diabetes 42: 610–618PubMedGoogle Scholar
  19. 19.
    Maran A, Taylor J, MacDonald I, Amiel S (1992) Evidence for reversibility of defective counterregulation in a patient with insulinoma. Diabet Med 9: 765–768PubMedGoogle Scholar
  20. 20.
    Mitrakou A, Fanelli C, Veneman T et al. (1993) Reversibility of unawareness of hypoglycemia in patients with insulinomas. N Engl J Med 329: 834–839Google Scholar
  21. 21.
    Lingefelser T, Renn W, Eggstein M, Reinauer M (1993) Restoration of impaired Counterregulatory hormone response, symptom perception and cerebral function by short-term euglycemia in IDDM. Diabetes 42: 243A (Abstract)Google Scholar
  22. 22.
    Liu D, McManus R, Toth E, Ryan E (1993) Improved hormonal and symptomatic responses to hypoglycemia in IDDM patients after three months of less strict glucose control. Diabetes 42: 17A (Abstract)Google Scholar
  23. 23.
    Davis M, Mellman M, Friedman S, Shamoon H (1993) Enhanced epinephrine responses during hypoglycemia in IDDM patients on conventional therapy following intensive insulin therapy. Diabetes 42: 80A (Abstract)Google Scholar
  24. 24.
    Fanelli C, Epifano L, Rambotti AM et al. (1993) Meticulous prevention of hypoglycemia (near-)normalizes magnitude and glycemic thresholds of neuroendocrine responses to, symptoms of, and cognitive function during hypoglycemia in intensively treated patients with IDDM of short duration. Diabetes 42: 1683–1689PubMedGoogle Scholar
  25. 25.
    Bolli GB, Perriello G, Fanelli C, De Feo P (1993) Nocturnal blood glucose control in type 1 diabetes mellitus. Diabetes Care 16 [Suppl 1]: 71–89PubMedGoogle Scholar
  26. 26.
    Ewing DJ, Clarke BF (1982) Diagnosis and management of diabetic autonomic neuropathy. BMJ 285: 916–918PubMedGoogle Scholar
  27. 27.
    Mitrakou A, Ryan C, Veneman T et al. (1991) Hierarchy of glycemic thresholds for Counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am J Physiol 260: E67–E74PubMedGoogle Scholar
  28. 28.
    Fanelli C, Modarelli F, Rambotti AM et al. (1994) Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in, hypoglycaemia in humans. Diabetologia 37: 797–807PubMedGoogle Scholar
  29. 29.
    Perriello G, Torlone E, Di Santo S et al. (1988) Effects of storage temperature of insulin on pharmacokinetics and pharmacodynamics of insulin mixtures injected subcutaneously in subjects with IDDM. Diabetologia 31: 811–815CrossRefPubMedGoogle Scholar
  30. 30.
    Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic thresholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777–781PubMedGoogle Scholar
  31. 31.
    Fanelli C, De Feo P, Porcellati F et al. (1992) Adrenergic mechanisms contribute to the late phase of hypoglycemic glucose counterregulation in humans by stimulating lipolysis. J Clin Invest 89: 2005–2013PubMedGoogle Scholar
  32. 32.
    Kohn A, Annibale B, Suriano G et al. (1985) Gastric acid and pancreatic polypeptide responses to modified sham feeding: indication of an increased basal vagal tone in a subgroup of duodenal ulcer patients. Gut 26: 776–782PubMedGoogle Scholar
  33. 33.
    Zar J (1984) Biostatistical analysis. Prentice Hall, Englewood CliffsGoogle Scholar
  34. 34.
    McCall A, Fixman L, Fleming N et al. (1986) Chronic hypoglycemia increases brain glucose transport. Am J Physiol 251: E442–E447PubMedGoogle Scholar
  35. 35.
    Boyle PJ, Nagy R, O'Connor AM et al. (in press) Adaptation in brain glucose uptake following recurrent hypoglycemia. Proc Natl Acad Sci USA (in press)Google Scholar
  36. 36.
    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: 1487–1492PubMedGoogle Scholar
  37. 37.
    De Feo P, Gallai V, Mazzotta G, et al. (1988) Modest decrements in plasma glucose concentration cause early impairment in cognitive function and later activation of glucose counterregulation in the absence of hypoglycemic symptoms in normal man. J Clin Invest 82: 436–434PubMedGoogle Scholar
  38. 38.
    Widom B, Simonson DC (1990) Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Ann Intern Med 112: 904–912PubMedGoogle Scholar
  39. 39.
    Maran A, Lomas J, MacDonald I, Amiel S (1993) Lack of protection of cerebral function in well controlled diabetic patients with hypoglycemia unawareness. Diabetes 42: 17A (Abstract)Google Scholar
  40. 40.
    Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA (1994) Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 344: 283–287PubMedGoogle Scholar
  41. 41.
    Clarke WL, Gonder-Frederick LA, Richards FE, Cryer PE (1991) Multifactorial origin of hypoglycemia unawareness in IDDM: association with defective glucose counterregulation and better glycemic control. Diabetes 40: 680–685PubMedGoogle Scholar
  42. 42.
    Heller S, McDonald I (1991) Physiological disturbances in hypoglycaemia: effect on subjective awareness. Clin Sci 81: 1–9PubMedGoogle Scholar
  43. 43.
    Ginsburg J, Paton A (1956) Effects of insulin after adrenalectomy. Lancet 2: 491–494CrossRefGoogle Scholar
  44. 44.
    Hilsted J, Richter E, Madsbad S et al. (1987) Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy. N Engl J Med 317: 421–426Google Scholar
  45. 45.
    Dagogo-Jack S, Rattarasarn C, Cryer P Reversal of hypoglycemia unawareness, but not glucose counterregulation, in insulin dependent diabetes mellitus. Diabetes (in press)Google Scholar
  46. 46.
    Gerich J, Langlois M, Noacco C et al. (1973) Lack of glucagon response to hypoglycemia in diabetes: evidence for an intrinsic pancreatic alpha-cell defect. Science 182: 171–173PubMedGoogle Scholar
  47. 47.
    Bolli GB, De Feo P, Compagnucci P et al. (1983) Abnormal glucose counterregulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes 32: 134–141PubMedGoogle Scholar
  48. 48.
    Bolli G, Dimitriadis G, Pehling G et al. (1984) Abnormal glucose counterregulation after subcutaneous insulin in insulin-dependent diabetes mellitus. N Engl J Med 310: 1706–1711PubMedGoogle Scholar
  49. 49.
    Diamond M, Hallarman L, Starick-Zych K et al. (1991) Suppression of counterregulatory hormone response to hypoglycemia by insulin per se. J Clin Endocrinol Metab 72: 1388–1390PubMedGoogle Scholar
  50. 50.
    Liu D, Moberg E, Kollind M, Lins P-E, Adamson U (1991) A high concentration of insulin suppresses the glucagon response to hypoglycemia in man. J Clin Endocrinol Metab 73: 1123–1128PubMedGoogle Scholar
  51. 51.
    Liu D, Adamson U, Lins P-E, et al. (1992) Inhibitory effect of circulating insulin on glucagon secretion during hypoglycaemia in type I diabetes. Diabetes Care 15: 59–65Google Scholar
  52. 52.
    The DCCT Research Group (1991) Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med 90: 450–459Google Scholar
  53. 53.
    Binder C, Lauritzen T, Faber O, Pramming O (1984) Insulin pharmacokinetics. Diabetes Care 3: 188–199Google Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • C. Fanelli
    • 1
  • S. Pampanelli
    • 1
  • L. Epifano
    • 1
  • A. M. Rambotti
    • 1
  • A. Di Vincenzo
    • 1
  • F. Modarelli
    • 1
  • M. Ciofetta
    • 1
  • M. Lepore
    • 1
  • B. Annibale
    • 2
  • E. Torlone
    • 1
  • G. Perriello
    • 1
  • P. De Feo
    • 1
  • F. Santeusanio
    • 1
  • P. Brunetti
    • 1
  • G. B. Bolli
    • 1
  1. 1.Dipartimento di Medicina Interna e Scienze Endocrine e MetabolicheUniversità degli Studi di PerugiaItaly
  2. 2.Cattedra di GastroenterologiaUniversità La SapienzaRomeItaly

Personalised recommendations