Hierarchy of Physiological Responses to Hypoglycemia: Relevance to Clinical Hypoglycemia in Type I (Insulin Dependent) Diabetes Mellitus*

Abstract

Hypoglycemia elicits a characteristic sequence of responses in healthy humans. These responses (and their arterialized venous glycemic thresholds) include: 1) Decreased insulin secretion (approximately 4.5 mmol/L). 2) Increased glucose counterregulatory hormone (glucagon, epinephrine, growth hormone and cortisol) secretion (approximately 3.6-3.8 mmol/L). 3) Symptoms of hypoglycemia (approximately 3.0 mmol/L). 4) Cognitive dysfunction (approximately 2.6 mmol/L). Thus, insulin secretion decreases as plasma glucose levels fall within the physiological range, and counterregulatory hormone secretion increases as plasma glucose levels fall just below the physiological range at substantially higher glucose levels than those required to produce symptoms and impair cognitive function. These data are entirely consistent with the body of evidence that insulin, glucagon and epinephrine stand high in the hierarchy of redundant glucoregulatory factors that prevent, as well as correct, hypoglycemia. When the same methods are used, these thresholds are remarkably reproducible from laboratory to laboratory. Nonetheless, the glycemic thresholds are dynamic rather than static. They vary in relation to recent antecedent glycemia. For example, lower plasma glucose concentrations are required to elicit autonomic, including epinephrine, and symptomatic responses in patients with well controlled IDDM, a phenomenon best attributed to recent antecedent iatrogenic hypoglycemia. This is the basis of the clinical syndrome of hypoglycemia unawareness, which is now known to be reversible with scrupulous avoidance of iatrogenic hypoglycemia. The latter also at least partially reverses reduced epinephrine responses to hypoglycemia, a key component (in the setting of absent glucagon responses) of the syndrome of defective glucose counterregulation. While perhaps seemingly adaptive, these threshold shifts appear to be maladaptive since both defective glucose counterregulation and hypoglycemia unawareness are associated with substantially increased rates of severe iatrogenic hypoglycemia in people with IDDM.

Synergistic effect of portal glucose and glucagon-like peptide-1 to lower systemic glucose and stimulate counter-regulatory hormones

“…However, during hypoglycaemia counterregulatory mechanisms will override the glucagon suppression [41]. In our study, the hypoglycaemic threshold of about 4 mmol/l that has been established for counterregulation [42] was only reached in one animal, while the average values, though below basal, remained above the threshold. However, it has been reported that a non-hyperinsulinaemic-induced decrease in glucose of 0.6 mmol/l to 5.2 mmol/l can result in a fall of plasma insulin and an increase in glucagon, indicating that in the dog the pancreatic alpha cell is very sensitive to a drop in glucose [43].…”

Low-dose glucose infusion after achieving critical hypoglycemia during insulin tolerance testing: effects on time of hypoglycemia, neuroendocrine stress response and patient’s discomfort in a pilot study

“…They described a significant correlation with the value of glucose nadir and the response of cortisol and growth hormone. Cryer et al (18) proved in several studies investigating diabetic patients that the absolute value of glucose nadir determines the extent of counterregulatory responses. The studies of Landon et al and Cryer et al support our hypothesis, that the duration of hypoglycemia in the insulin tolerance test can be shortened by early glucose intervention without affecting the response of cortisol and growth hormone if the glucose nadir is maintained.…”

Secrets of the lac Operon

“…Our proposal is quite consistent with this hypothesis, since hypoglycemia is a classic inducer of the stress response. Thus, for example, reduction of blood glucose stimulates secretion of glucocorticoids (a classic stress response) in mice [126], rats [127] and humans [128]. Similarly, reduction of blood glucose activates the sympathetic nervous system, also a classic stress response, in mice [129], rats [127] and humans [128].…”

“…Thus, for example, reduction of blood glucose stimulates secretion of glucocorticoids (a classic stress response) in mice [126], rats [127] and humans [128]. Similarly, reduction of blood glucose activates the sympathetic nervous system, also a classic stress response, in mice [129], rats [127] and humans [128]. Indeed, hypoglycemia even produces homotypic densitization, a classic feature of stress responses, in mice [129], rats [127] and humans [130].…”