Gender-related differences in counterregulatory responses to antecedent hypoglycemia in normal humans

Compared to men, inherent counterregulatory responses are reduced in health y and type 1 diabetic women. Despite this, the prevalence of hypoglycemia i n patients with type 1 diabetes (type 1 DM) is gender neutral. The aim of t his study was to determine the in vivo mechanism(s) responsible for this ap parent clinical paradox. The central importance of antecedent hypoglycemia in causing subsequent counterregulatory failure is now established. We, the refore, hypothesized that a gender-related difference to the blunting effec ts of prior hypoglycemia may exist, and this could explain why type 1 DM wo men do not have an increased prevalence of hypoglycemia despite reduced cou nterregulatory responses. Fifteen healthy male and female individuals (eigh t men and seven women) underwent four separate a-day experimental protocols in a randomized fashion. Day 1 involved identical morning and afternoon 2- h hyperinsulinemic (9 pmol/kg.min) glucose clamp studies with 5.1 +/- 0.1, 3.9 +/- 0.1, 3.3 +/- 0.1, or 2.9 +/- 0.1 mmol/L. Day 2 consisted of a singl e 2-h hypoglycemic clamp of 2.9 +/- 0.1 mmol/L. Insulin levels mere similar on both days of each protocol in men and women. After day 1 euglycemia (5. 1 +/- 0.1 mmol/L), day 2 counterregulatory responses were significantly inc reased (P < 0.01) in men relative to women. In women, counterregulatory res ponses were resistant to the effects of day 1 hypoglycemia. Antecedent hypo glycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L produced 3 +/- 2%, 5 +/- 2%, a nd 25 +/- 4% aggregate reductions in day 2 neuroendocrine, muscle sympathet ic nerve activity, and metabolic counterregulatory responses. In marked con trast, identical day 1 hypoglycemia of 3.9, 3.3, and 2.9 +/- 0.1 mmol/L in men produced significantly greater reductions in day 2 counterregulatory re sponses of 30 +/- 6%, 39 +/- 6%, and 52 +/- 6%, respectively. The net effec t of the differential gender effects of antecedent hypoglycemia was to over come the usually increased (50%) sympathetic nervous system (SNS) counterre gulatory responses to hypoglycemia found in men. We conclude that I) antece dent hypoglycemia produces less blunting of counterregulatory responses to subsequent hypoglycemia in women relative to men; 2) two episodes of antece dent hypoglycemia can overcome the greater SNS response to hypoglycemia usu ally found in men; and 3) the reduced susceptibility of women to the blunti ng effects of antecedent hypoglycemia may be the mechanism explaining why, despite inherently reduced SNS counterregulatory responses, female type 1 D M patients have a similar prevalence of hypoglycemia compared to men.