Responses to Hypoglycemia Relevant to Iatrogenic Hypoglycemia in Type 1 Diabetes
Decrements in insulin, increments in glucagon, and, absent the latter, increments in epinephrine stand high in the hierarchy of redundant glucose counterregulatory factors that normally prevent or rapidly correct hypoglycemia (1). Despite the actions of other potentially important glucose-raising hormones, neurotransmitters, and substrates, hypoglycemia develops or progresses when glucagon and epinephrine are deficient and insulin is present. The secretion of all three of these key hormones is typically altered in patients with established (i.e. C-peptide negative) T1DM (1). Insulin levels do not decrease and glucagon levels do not increase as plasma glucose concentrations fall. Thus, the first and second physiological defenses against hypoglycemia are lost, leaving the patient largely dependent on the third defense, increases in epinephrine. However, the epinephrine response is often attenuated. That is a critical pathophysiological event. Patients with combined deficiencies of their glucagon and epinephrine responses to falling plasma glucose concentrations have been shown to be at 25-fold or greater higher risk of severe iatrogenic hypoglycemia than those with deficient glucagon but normal epinephrine responses during intensive therapy of T1DM (6, 7). They have the clinical syndrome of defective glucose counterregulation.
Loss of the warning, largely neurogenic (autonomic) symptoms of developing hypoglycemia constitutes the clinical syndrome of hypoglycemia unawareness (or impaired awareness of hypoglycemia, as some prefer, because the loss can be partial) (1). Absent these warning symptoms, the first manifestation of a hypoglycemic episode is neuroglycopenia, and that is often too late for the patient to recognize and self-treat (i.e. to make the appropriate behavioral response such as ingestion of carbohydrate) the episode. Hypoglycemia unawareness is also associated with a high frequency of severe iatrogenic hypoglycemia in T1DM.
Reduced responsiveness of the sympathochromaffin system—the adrenal medullae, which release epinephrine and some norepinephrine into the circulation, and the sympathetic nervous system, which releases norepinephrine and acetylcholine from its postganglionic neurons—to falling glucose concentrations is a key pathophysiological feature of both defective glucose counterregulation and hypoglycemia unawareness (1). These reduced responses to a given level of hypoglycemia are the result of shifts of their glycemic thresholds to lower plasma glucose concentrations. Responses can be elicited, but lower glucose concentrations are required. Although classical diabetic autonomic neuropathy may contribute to the reduced sympathochromaffin responses in affected patients (8), these responses are typically reduced in the absence of that complication (9). They are now known to be the result of recent antecedent hypoglycemia. Recent antecedent hypoglycemia has been shown to reduce autonomic and symptomatic responses, among other neuroendocrine responses, to a given level of hypoglycemia in nondiabetic individuals (10, 11) and in patients with T1DM (9). It shifts the glycemic thresholds for these responses to lower plasma glucose concentrations.
The concept of hypoglycemia-associated autonomic failure in T1DM (1, 9), a functional disorder distinct from classical diabetic autonomic neuropathy, posits that: 1) periods of relative or absolute therapeutic insulin excess in the setting of absent glucagon responses lead to episodes of hypoglycemia; 2) these episodes, in turn, cause reduced autonomic (including epinephrine) responses to falling glucose concentrations on subsequent occasions; and 3) these reduced autonomic responses result in both reduced symptoms of developing hypoglycemia (i.e. hypoglycemia unawareness) and—because epinephrine responses are reduced in the setting of absent glucagon responses—impaired physiological defenses against developing hypoglycemia (i.e. defective glucose counterregulation). Thus, a vicious cycle of recurrent hypoglycemia is created and perpetuated. Perhaps the most compelling support for this functional construct is the finding, in three independent laboratories, that hypoglycemia unawareness and, at least in part, the reduced epinephrine component of defective glucose counterregulation are reversible in many affected patients with T1DM after as little as 2 weeks of scrupulous avoidance of iatrogenic hypoglycemia (12, 13, 14).