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

Abstract

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 i 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 EXR the frequency of hypoglycaemia decreased from 0.5 + 0.05 to 0.045 _+ 0.02 episodes/patient-day; HbAlc 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 i 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.

The effects of acute hypoglycaemia on memory acquisition and recall and prospective memory in type 1 diabetes

“…Evidence has accumulated to show that recurrent exposure to hypoglycaemia in people with type 1 diabetes results in cerebral adaptation, such that cognitive performance is relatively preserved during hypoglycaemia [22][23][24][25][26][27]. Repeated exposure to hypoglycaemia can also result in impaired hypoglycaemia awareness, and a shared mechanism for the two phenomena has been proposed [28].…”

Recovery of Hypoglycemia Awareness in Long-standing Type 1 Diabetes: A Multicenter 2 × 2 Factorial Randomized Controlled Trial Comparing Insulin Pump With Multiple Daily Injections and Continuous With Conventional Glucose Self-monitoring (HypoCOMPaSS)

“…Single-center studies in adults with type 1 diabetes and SH have shown that rigorous biochemical hypoglycemia avoidance can restore awareness (16)(17)(18)(19). In a 24-week pilot study in this high-risk group, we compared optimized analog MDI and CSII interventions with a control group in which the current insulin regimen was maintained with relaxation of self-monitored blood-glucose targets.…”

Defining and Reporting Hypoglycemia in Diabetes

“…That concept has been extended recently to include exercise-and sleeprelated hypoglycemia-associated autonomic failure (11). Thus, hypoglycemia unawareness is reversible in most affected patients, and the reduced epinephrine component of defective glucose counterregulation is variably improved, by as little as 2-3 weeks of scrupulous avoidance of iatrogenic hypoglycemia (15)(16)(17)(18)(19). Importantly, antecedent plasma glucose levels as high as 70 mg/dl (3.9 mmol/l) cause reduced sympathoadrenal responses to subsequent hypoglycemia (20).…”