Effects of Recent, Short-Term Hyperglycemia on Responses to Hypoglycemia in Humans: Relevance to the Pathogenesis of Hypoglycemia Unawareness and Hyperglycemia-Induced Insulin Resistance

A single episode of recent hypoglycemia increases, whereas long-term hyperglycemia decreases, the glycemic thresholds of responses of counterregulatory hormone and symptoms to subsequent hypoglycemia in humans. To assess whether short-term, antecedent hyperglycemia exerts effects opposite to those observed after acute hypoglycemia, seven normal, nondiabetic subjects and eight insulin-dependent diabetes mellitus (IDDM) patients were studied during hyperinsulinemic-hypoglycemic clamp (sequential, 90-min plateaus of plasma glucose [PG] of 4.3, 3.7, 3.0, and 2.4 mmol/l). Nondiabetic subjects were studied the morning after either 6-h clamped hyperglycemia (PG ∼ 13.5 mmol/l) or euglycemia (PG ∼5 mmol/l) between 1600 and 2200 the previous day (glucose and insulin infused on both occasions), as well as after nocturnal hyperglycemia (PG ∼ 13.5 mmol/l) or euglycemia between 2300 and 0500. The IDDM patients were studied after 15 h of euglycemia or hyperglycemia (∼ 17 mmol/l) but identical hyperinsulinemia (∼ 225 pmol/l) between 1600 and 0700. Neither PG thresholds of counterregulatory hormone, symptoms, onset of cognitive dysfunction to hypoglycemia, nor maximal responses were affected by antecedent, short-term hyperglycemia in normal nondiabetic subjects and IDDM patients (NS). However, the rate of glucose infusion required to maintain hypoglycemic plateaus during hypoglycemia was lower after hyperglycemia (nondiabetic subjects 31.2 ± 3.4 vs. 36.7 ± 4 ³mol · kg⁻¹·min⁻¹, IDDM patients 33 ± 3.1 vs. 42.5 ± 3.9 ³mol · kg⁻¹ · min⁻¹; P < 0.05) indicating greater insulin resistance induced by antecedent hyperglycemia. In conclusion, in contrast to acute hypoglycemia and long-term hyperglycemia, recent, short-term hyperglycemia does not affect physiological responses to hypoglycemia. However, recent, short-term hyperglycemia induces insulin resistance that contributes to glucose counterregulation. This is relevant to IDDM patients who have deficient glucagon and adrenaline responses to hypoglycemia.