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 similar to 13.5 mmol/l) or euglycemia (PG similar to 5 mmol/l) between 1600 and 2200 the previous day (glucose and insulin infused on both occasions), as well as after nocturnal hyperglycemia CPG similar to 13.5 mmol/l) or euglycemia between 2300 and 0500. The IDDM patients were studied after 15 h of euglycemia or hyperglycemia (similar to 17 mmol/l) but identical hyperinsulinemia (similar to 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 mu mol . kg(-1) . min(-1), IDDM patients 33 +/- 3.1 vs. 42.5 +/- 3.9 mu mol . 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 counter-regulation. This is relevant to IDDM patients who have deficient glucagon and adrenaline responses to hypoglycemia.