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Long-term intensive insulin therapy in IDDM: effects on HbA1c, risk for severe and mild hypoglycaemia, status of counterregulation and awareness of hypoglycaemia

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Summary

The present studies were designed to assess the percentage of HbA1c, frequency, and awareness of hypoglycaemia (H) during long-term intensive therapy (IT) of insulin-dependent diabetes mellitus (IDDM). From 1981 to 1994, 112 IDDM patients were on IT. HbA1c was 7.17±0.16% (non-diabetic subjects 3.8–5.5%), the frequency of severe H 0.01±0.009 episodes/patient-year, frequency of mild symptomatic H 35.6±2.9 episodes/patient-year. IDDM patients with HbA1c ≤ 5.5% (Group I, n=10), between 6.1–7.0% (Group II, n=12), and ≥ 7.6% (Group III, n=11) were studied to assess responses of counterregulatory hormones, symptoms and cognitive function during experimental, stepped H. Compared to 18 non-diabetic subjects, Group I exhibited high thresholds (plasma glucose had to decrease more than normal to evoke responses), and impaired responses of adrenaline, unawareness of H and delayed onset of cognitive dysfunction at the lowest glycaemic plateau (2.3 mmol/l). Group II had normal thresholds and responses, whereas Group III had low thresholds. Frequency of mild H was higher in Group I (54.5±1.9 episodes/patient-year) than in Group II and III (33.7±3.5 and 20.4±2.5 episodes/ patient-year, respectively, p<0.001) and correlated with percentage of HbA1c (r=−0.82). In conclusion: IT can maintain near-normal HbA1c and is compatible with low frequency of severe H. However, if HbA1c is less than 6.0%, mild, symptomatic H is excessively frequent and causes impaired counterregulation and H unawareness. Efforts should be made not only to maintain HbA1c ≤ 7.0%, but also to prevent, recognize and reverse iatrogenic H unawarenes during long-term IT of IDDM by maintaining HbA1c>6.0%.

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Abbreviations

IDDM:

Insulin-dependent diabetes mellitus

DCCT:

Diabetes Control and Complications Trial

References

  1. Brinchmann-Hansen O, Dahl-Jorgensen K, Sandivik L et al. (1992) Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. BMJ 304: 19–22

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 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: 304–309

    Article  CAS  PubMed  Google Scholar 

  3. 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: 977–986

    Article  Google Scholar 

  4. Simonson D, Tamborlane W, De Fronzo R, Sherwin R (1985) Intensive insulin therapy reduces the counterregulatory hormone response to hypoglycemia in patients with type 1 diabetes. Arch Intern Med 103: 184–190

    CAS  Google Scholar 

  5. Amiel S, Sherwin R, Simonson D, Tamborlane W (1988) Effect of intensive insulin therapy on glycemic thresholds for counterregulatory hormone release. Diabetes 37: 901–907

    Article  CAS  PubMed  Google Scholar 

  6. 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: 1683–1689

    Article  CAS  PubMed  Google Scholar 

  7. Fanelli C, Pampanelli S, Epifano L et al. (1994) Long-term recovery from unawareness, deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia, following institution of a rational, intensive insulin therapy in IDDM. Diabetologia 37: 1265–1276

    Article  CAS  PubMed  Google Scholar 

  8. Cryer PE (1992) Iatrogenic hypoglycemia as cause of hypoglycemia-associated autonomic failure in IDDM. A vicious circle. Diabetes 41: 255–260

    Article  CAS  PubMed  Google Scholar 

  9. Ewing DJ, Clarke BF (1982) Diagnosis and management of diabetic autonomic neuropathy. BMJ 285: 916–918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Bolli GB (1989) The pharmacokinetic basis of insulin therapy. Diab Res Clin Prac 6: S3–S16

    Article  CAS  Google Scholar 

  11. Dimitriadis G, Gerich J (1983) Importance of timing of preprandial subcutaneous insulin administration in the management of diabetes mellitus. Diabetes Care 6: 374–377

    Article  CAS  PubMed  Google Scholar 

  12. Pampanelli S, Torlone E, Lalli C et al. (1995) Improved post-prandial metabolic control after subcutaneous injection of a short-acting insulin analogue in IDDM of short duration with residual pancreatic Β-cell function. Diabetes Care 18: 1452–1459

    Article  CAS  PubMed  Google Scholar 

  13. Bolli GB, Perriello G, Fanelli C, De Feo P (1993) Nocturnal blood glucose control in type 1 diabetes mellitus. Diabetes Care [Suppl 3] 16: 71–89

    Article  PubMed  Google Scholar 

  14. The DCCT Research Group (1991) Epidemiology of severe hypoglycemia in the Diabetes Control Complications Trial. Am J Med 90: 450–459

    Article  Google Scholar 

  15. Fanelli C, Pampanelli S, Epifano L 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 male and female humans. Diabetologia 37: 797–807

    Article  CAS  PubMed  Google Scholar 

  16. De Feo P, Perriello G, Ventura MM et al. (1986) Studies on overnight insulin requirements and metabolic clearance rate of insulin in normal and diabetic man: relevance to the pathogenesis of the dawn phenomenon. Diabetologia 29: 475–480

    Article  PubMed  Google Scholar 

  17. McGuire E, Helderman J, Tobin R, Andres R, Berman M (1976) Effects of arterial versus venous sampling on analysis of glucose kinetics in man. J Appl Physiol 41: 565–573

    CAS  PubMed  Google Scholar 

  18. Schwartz N, Clutter W, Shah S, Cryer P (1987) Glycemic threholds for activation of glucose counterregulatory systems are higher than the thresholds for symptoms. J Clin Invest 79: 777–781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Towler DA, Havlin CE, Craft S, Cryer PH (1993) Mechanisms of awareness of hypoglycemia. Perception of neurogenic (predominantly cholinergic) rather than neuro-glycopenic symptoms. Diabetes 42: 1791–1798

    Article  CAS  PubMed  Google Scholar 

  20. Fanelli C, De Feo P, Porcellati F et al. (1992) Adenergic mechanisms contribute to the late phase of hypolgycemic glucose counterregulation in humans by stimulating lipolysis. J Clin Invest 89: 2005–2013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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: 776–782

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 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 type 1 (insulin-dependent) diabetes mellitus. Diabetologia 31: 811–815

    Article  CAS  PubMed  Google Scholar 

  23. Zar J (1984) Biostatistical analysis. Englewood Cliffs, Prentice Hall

    Google Scholar 

  24. The Diabetes Control and Complication Trial Research Group (1995) The relation of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 44: 968–983

    Article  Google Scholar 

  25. Heller S, Cryer P (1991) Reducedneuroendocrine and symptomatic responses to subsequent hypoglycemia after one episode of hypoglycemia in humans. Diabetes 40: 223–226

    Article  CAS  PubMed  Google Scholar 

  26. Davis M, Shamoon H (1991) Counterregulatory adaptation to recurrent hypoglycemia in normal humans. J Clin Endo-crinol Metab 73: 995–1001

    Article  CAS  Google Scholar 

  27. Widom B, Simonson DC (1990) Glycemic control and neuropsychologic function during hypoglycemia in patients with insulin-dependent diabetes mellitus. Ann Intern Med 112: 904–912

    Article  CAS  PubMed  Google Scholar 

  28. Lingenfelser T, Renn W, Sommerwerck U et al. (1993) Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypolgycemia in IDDM patients. Diabetes 42: 610–618

    Article  CAS  PubMed  Google Scholar 

  29. Veneman T, Mitrakou A, Mokan M, Cryer P, Gerich J (1993) Induction of hypoglycemia unawareness by asymptomatic nocturnal hypoglycemia. Diabetes 42: 1233–1237

    Article  CAS  PubMed  Google Scholar 

  30. De Fronzo R, Hendler R, Christensen N (1980) Stimulation of counterregulatory hormonal response in diabetic man by a fall in glucose concentration. Diabetes 29: 125–131

    Article  Google Scholar 

  31. Boyle PJ, Shwartz NS, Shah SD, Clutter WE, Cryer PE (1988) Plasma glucose concentrations at the onset of hypoglycemic symptoms in patients with poorly controlled diabetes and in nondiabetics. N Engl J Med 318: 1487–1492

    Article  CAS  PubMed  Google Scholar 

  32. Jacob RJ, Weber AB, Dziura J, Morgen J, Sherwin RS (1995) Brainstem dysfunction is provoked by less pronounced hypoglycemic stimulus in diabetic BB rats. Diabetes 44: 900–905

    Article  CAS  PubMed  Google Scholar 

  33. Gjedde A, Crone C (1981) Blood-brain glucose transfer: repression in chronic hyperglycemia. Science 214: 456–457

    Article  CAS  PubMed  Google Scholar 

  34. McCall A, Fixman L, Fleming N et al. (1986) Chronic hypoglycemia increases brain glucose transport. Am J Physiol 251: E 442–E-447

    CAS  Google Scholar 

  35. Boyle P, Kempers S, O'Connor AM, Nagy RJ (1995) Brain glucose uptake and hypoglycemia unwareness in patients with insulin-dependent diabetes mellitus. N Engl J Med 333: 1726–1731

    Article  CAS  PubMed  Google Scholar 

  36. Schattenberg S, Bott U, Overmann H et al. (1995) Translation of intensified insulin therapy into routine diabetes care: lowering HbA1c without increase in the risk of severe hypoglycaemia. Diabetologia 38 [Suppl 1]: A18 (Abstract)

    Google Scholar 

  37. 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: 134–141

    Article  CAS  PubMed  Google Scholar 

  38. Cranston I, Lomas J, Maran A, MacDonald J, Amiel SA (1994) Restoration of hypoglycaemia unawareness in patients with long-duration of insulin-dependent diabetes. Lancet 344: 283–287

    Article  CAS  PubMed  Google Scholar 

  39. Dagogo-Jack S, Rattarasarn C, Cryer P (1994) Reversal of hypoglycemia unawareness, but not glucose counterregulation, in insulin dependent diabetes mellitus. Diabetes 43: 1426–1434

    Article  CAS  PubMed  Google Scholar 

  40. De Feo P, Perriello G, Torlone E et al. (1991) Evidence against important catecholamine compensation for absent glucagon counterregulation. Am J Physiol 260: E 203–E212

    Google Scholar 

  41. Bottini P, Boschetti E, Pampanelli S et al. (1995) Response of plasma adrenaline to hypoglycaemia and exercise in IDDM with or without autonomic neuropathy. Diabetologia 38 [Suppl 1]: A203

    Google Scholar 

  42. 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: 819–828

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Schwartz TW (1983) Pancreatic polypeptide: a hormone under vagal control. Gastroenterology 85: 1411–1425

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Dipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, University of Perugia, Perugia, Italy

    S. Pampanelli, C. Fanelli, C. Lalli, M. Ciofetta, P. Del Sindaco, M. Lepore, F. Modarelli, A. M. Rambotti, L. Epifano, A. Di Vincenzo, L. Bartocci, P. Brunetti & G. B. Bolli

  2. Cattedra di Gastroenterologia, II Clinica Medica, University “La Sapienza”, Rome, Italy

    B. Annibale

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  1. S. Pampanelli
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  2. C. Fanelli
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  3. C. Lalli
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  8. A. M. Rambotti
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  9. L. Epifano
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  14. G. B. Bolli
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Pampanelli, S., Fanelli, C., Lalli, C. et al. Long-term intensive insulin therapy in IDDM: effects on HbA1c, risk for severe and mild hypoglycaemia, status of counterregulation and awareness of hypoglycaemia. Diabetologia 39, 677–686 (1996). https://doi.org/10.1007/BF00418539

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  • DOI: https://doi.org/10.1007/BF00418539

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