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Research methodologies in hypoglycaemia: counterregulation phenomena and nerve/brain dysfunction
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EVIDENCE FOR REVERSIBILITY OF DEFECTIVE COUNTERREGULATION IN A PATIENT WITH INSULINOMA
No full textTo investigate her unheralded neuroglycopenia, a 45-year-old woman was studied before and 3 months after removal of her insulinoma. Hypoglycaemia was induced and reversed by glucose infusion during 4-h insulin infusions (1.5 mU kg-1 min-1). Postoperatively,the low preoperative adrenaline, noradrenaline, growth hormone, and cortisol responses increased by 490, 152, 64, and 178 %, respectively, and started at higher glucose levels (2.7 vs 1.9 mmol l-1 for adrenaline), with a four-fold increase in autonomic symptoms and more profound psychomotor dysfunction. We conclude that the syndrome of recurrent severe hypoglycaemia with defective warning symptoms and hormonal responses, in this case induced by an insulin-secreting tumour, is reversible, perhaps by the removal of the hypoglycaemia, a finding which may be relevant to other patients with recurrent severe hypoglycaemia
LACK OF PRESERVATION OF HIGHER BRAIN-FUNCTION DURING HYPOGLYCEMIA IN PATIENTS WITH INTENSIVELY-TREATED IDDM
No full textAbstract: Severe hypoglycaemia with cognitive dysfunction is 3 times more common in intensively, rather than conventionally, treated insulin-dependent diabetes mellitus (IDDM). To investigate the effect of diabetes control on higher brain function during acute hypoglycaemia, we studied one of-the earliest detectable changes in cognitive function, i.e. the four-choice reaction time, and symptomatic and hormonal responses during euglycaemic and hypoglycaemic clamping in human subjects. There were no changes in symptoms or counterregulatory hormones and four-choice reaction time was stable during 220 min of euglycaemic insulin clamping in five men with IDDM, with a coefficient of variation of less than 2.2% (1% for accuracy) for the cognitive function test. During stepped hypoglycaemic clamping however, hormonal responses and subjective awareness of hypoglycaemia occurred in all groups but started at much lower blood glucose concentrations in eight intensively-treated diabetic subjects (Group 1) than in ten conventionally-treated (Group 2) or in eight non-diabetic subjects (Group 3). For example, for adrenaline, plasma glucose thresholds were 2.7 +/- 0.2 vs 3.4 +/- 0.2 and 3.2 +/- 0.1 mmol/l, respectively, p < 0.05, Group 1 vs Groups 2 or 3 and for subjective awareness of hypoglycaemia 2.3 +/- 0.2 vs 3.0 +/- 0.1 and 3.2 +/- 0.1 mmol/l, p less than or equal to 0.003), as in previous studies. In contrast, deterioration in reaction time occurred at 3.2 +/- 0.3, 3.2 +/- 0.2 and 3.0 +/- 0.2 mmol/l, respectively (p = NS), thus occurring at higher glucose levels than subjective awareness in the intensively-treated subjects only. The altered hierarchy of responses to hypoglycaemia in well-controlled intensively-treated diabetes explains the increased risk of severe hypoglycaemia without warning seen in such patients
RESTORATION OF HYPOGLYCEMIA AWARENESS IN PATIENTS WITH LONG-DURATION INSULIN-DEPENDENT DIABETES
No full textAbstract: Hypoglycaemia without warning is a dangerous complication of insulin-dependent diabetes mellitus and it limits the use of intensified insulin therapy to reduce chronic diabetic complications.
To investigate the possibility of restoring awareness; symptomatic, cognitive, and hormonal responses to controlled hypoglycaemia were studied in insulin-dependent diabetic patients with long disease duration (6 with good glycaemic control and 6 with poor control) before and after hypoglycaemia avoidance. At the start of the study, all had loss of hypoglycaemia awareness. Responses to the initial challenge were small (pooled area under curve [AUC] adrenaline 5.75 [SE 0.07] nmol/L per 260 min, pooled AUC symptom score 80 [1.3]) and only started when plasma glucose was significantly lower than the 2.8 (0.1) mmol/L at which cognitive function deteriorated. After 4.1 (1.1) months' scrupulous hypoglycaemia avoidance, hormone and symptom responses to the challenge were increased (AUC adrenaline 15.9 [0.1] nmol/L per 260 min, p = 0.01; AUC symptom score 275 [7], p < 0.001), starting at plasma glucose concentrations significantly higher than that causing cognitive dysfunction. Glycosylated haemoglobin did not deteriorate significantly.
We conclude that the normal hierarchy of subjective awareness before cognitive dysfunction during hypoglycaemia can be restored by avoiding hypoglycaemia. This is independent of disease duration or initial metabolic control
GENDER DIFFERENCES IN COUNTERREGULATION TO HYPOGLYCEMIA
Full text linkAbstract: To investigate the effect of gender on catecholamine responses to hypoglycaemia, single-step euglycaemic-hypoglycaemic clamps have been performed in 14 healthy men and 17 women. Adrenaline responses were 44 % lower in females (p < 0.01) and noradrenaline 17% lower (p = 0.08). In response to low-dose intravenous insulin infusion (0.3 mU - kg-1 . min-1), plasma glucose fall and counterregulation in seven men and seven women had a different course (p < 0.001), with different glucose kinetics. In men, endogenous glucose output recovered quickly to levels that exceeded basal; in women suppression of endogenous glucose output was more prolonged, without rates ever exceeding basal (p < 0,05). Peripheral glucose uptake was stimulated in men only. The hormones of acute glucose counterregulation (catecholamines and glucagon) did not differ between the sexes during this challenge, the catecholamine response in the women being supported by the continuous fall in plasma glucose. These results suggest that: 1) catecholamine responses to moderately controlled hypoglycaemia are diminished in women, and 2) peripheral insulin sensitivity in men is enhanced over that of women but hepatic sensitivity to insulin may be greater in women
LACTATE DELAYS COUNTERREGULATION AND PROTECTS COGNITIVE FUNCTION DURING HYPOGLYCEMIA IN MAN
No full textPROTECTION BY LACTATE OF CEREBRAL FUNCTION DURING HYPOGLYCEMIA
No full textAbstract: Severe hypoglycaemia with brain dysfunction limits intensified therapy in patients with insulin-dependent diabetes mellitus, despite evidence that such therapy reduces the risk of chronic complications of the disease. We have investigated the effect of infusing lactate (a potential non-glucose fuel for brain metabolism) on protective, symptomatic neurohumoral responses and on brain function during hypoglycaemia in seven healthy men.
Elevation of lactate (within a physiological range) substantially diminished catecholamines, growth hormone, cortisol, and symptomatic responses to hypoglycaemia and lowered the glucose level at which these responses began. Glucagon responses were unaffected. Lactate was also associated with a significant lowering of the glucose level at which brain function deteriorated, suggesting that brain function was protected during the hypoglycaemia.
The defect in counter-regulation is similar to that seen in hypoglycaemia-prone diabetic patients. Initiation of the protective responses to hypoglycaemia (except glucagon) can be delayed by supporting-metabolism with an alternative metabolic fuel. Cerebral cortical dysfunction of severe hypoglycaemia is also delayed. Our demonstration that higher brain function can be protected during hypoglycaemia may have therapeutic potential
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