Originals

Diabetologia

, Volume 37, Issue 12, pp 1265-1276

First online:

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

  • C. FanelliAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , S. PampanelliAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , L. EpifanoAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , A. M. RambottiAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , A. Di VincenzoAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , F. ModarelliAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , M. CiofettaAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , M. LeporeAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
  • , B. AnnibaleAffiliated withCattedra di Gastroenterologia, Università La Sapienza
    • , E. TorloneAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
    • , G. PerrielloAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
    • , P. De FeoAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
    • , F. SanteusanioAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
    • , P. BrunettiAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia
    • , G. B. BolliAffiliated withDipartimento di Medicina Interna e Scienze Endocrine e Metaboliche, Università degli Studi di Perugia

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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