Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state

Abstract

Aims/hypothesis. The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. Methods. We studied 11 subjects with Type I (insulindependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1±0.003 mmol· min -1 ·l -1 (fast fall), on the other at the rate of 0.03±0.001 mmol·min -1 ·l -1 (slow fall). Subjects underwent a control euglycaemic clamp study as well. Results. In response to fast-fall as compared to slowfall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: TrailMaking B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8±0.5 vs 3.5±0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5±1.0 vs 5.2±0.4 pmol·min -1 ·100 ml -1 , p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. Conclusion/interpretation. In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia. [Diabetologia (2003) 46:53-64] Keywords Type I diabetes mellitus, postprandial hypoglycaemia, glucose counterregulation, cognitive dysfunction, forearm noradrenaline spillover. acting insulin analogue as compared to human regular insulin, the technique of s.c. injection, insulin sensitivity and meal size and composition, are usually considered the most important determinants of the rate of decreasing postprandial blood glucose concentrations. After s.c. injection of rapid-acting insulin analogues [1], the rate of decreasing blood glucose is greater than after injecting human regular insulin [2,3]. Therefore, it is expected that when hypoglycaemia is induced by mealtime administration of rapid-acting insulin analogue, the rate of decreasing blood glucose is greater than after injecting human regular insulin. In theory, different rates of decreasing blood glucose in the postprandial condition might result in different reWhen patients with Type I (insulin-dependent) diabetes mellitus experience hypoglycaemia after a subcutaneous (s.c.) injection of rapid-acting insulin at mealtime, blood glucose decreases to below normal concentrations at rates which can differ on different occasions. Among several factors, the injection of a rapid-

The Locus for Hypoglycemic Detection Shifts With the Rate of Fall in Glycemia

“…Thus, it is possible that CNS glucose sensors only respond to catastrophic drops in glycemia and normally rely on peripheral input for glycemic detection. Consistent with this idea, Fanelli et al (32) observed that cognitive function was impaired to a greater extent when hypoglycemia ensued rapidly as opposed to a slow fall. It is now recognized that glucose-sensing neurons in the CNS respond to a variety of metabolic and hormonal inputs relevant to overall energy homeostasis (2,33).…”

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

“…A 'hangover' effect of hypoglycaemia is unlikely to be responsible, as delayed recall was tested 50 min after restoration of euglycaemia. The only robust study to show residual cognitive impairment demonstrated this 20 min after hypoglycaemia [35]; earlier studies reported impaired cognitive function 45-90 min after hypoglycaemia [8,[36][37][38][39][40], but each had a methodological deficiency, such as failure to test statistical significance or the absence of a euglycaemia control arm.…”

Effect of Oral Amino Acids on Counterregulatory Responses and Cognitive Function During Insulin-Induced Hypoglycemia in Nondiabetic and Type 1 Diabetic People

“…Surprisingly, to the best of our knowledge, no study so far has examined whether amino acids given orally may stimulate glucagon response during insulin-induced hypoglycemia in type 1 diabetes. This hypothesis might be interesting, because previous studies have shown that the failure of glucagon response to hypoglycemia in type 1 diabetes recovers after food intake (14,15). This has led to the hypothesis that it is the protein component of the meal that induces such an effect (15).…”