Physiological levels of cortisol have been found to blunt neuroendocrine and metabolic responses to subsequent hypoglycemia in humans. The aim of this study was to determine whether cortisol acts directly on the brain to elicit this effect. A total of 41 conscious unrestrained Sprague-Dawley rats were studied during 2-day experiments. Day 1 consisted of two episodes of clamped 2-h hyperinsulinemic (30 pmol ⅐ kg ؊1 ⅐ min ؊1 ) hypoglycemia (2.8 ؎ 0.1 mmol/l; n ‫؍‬ 12; ANTE HYPO), euglycemia (6.2 ؎ 0.1 mmol/l; n ‫؍‬ 12; ANTE EUG), or euglycemia (6.2 ؎ 0.1 mmol/l) plus simultaneous intracerebroventricular (ICV) infusion of cortisol (25 g/h; n ‫؍‬ 9; ANTE EUG؉Cort) or saline (24 l/h; n ‫؍‬ 8; ANTE EUG؉Sal). For all groups, day 2 consisted of a 2-h hyperinsulinemic (30 pmol ⅐ kg ؊1 ⅐ min ؊1 ) hypoglycemic (2.9 ؎ 0.2 mmol/l) clamp. Plasma epinephrine and glucagon incremental area under the curve (⌬AUC) responses were significantly less in ANTE EUG؉Cort and ANTE HYPO versus both ANTE EUG and ANTE EUG؉Sal (P < 0.05). The ⌬AUC responses of plasma norepinephrine were significantly lower in ANTE EUG؉Cort versus both ANTE EUG and ANTE EUG؉Sal (P < 0.05). Endogenous glucose production was significantly less in ANTE HYPO and ANTE EUG؉Cort versus the other groups (P < 0.05). Lastly, the glucose infusion rate to maintain the desired hypoglycemia was significantly greater in ANTE EUG؉Cort and ANTE HYPO versus the other two groups (P < 0.05). In summary, ICV infusion of cortisol significantly blunted norepinephrine, epinephrine, glucagon, and endogenous glucose production responses to next-day hypoglycemia. We conclude that cortisol can act directly on the central nervous system to blunt counterregulatory responses to subsequent hypoglycemia in the conscious rat. Diabetes 52:2198 -2204, 2003 I ntensive glucose control in type 1 diabetic patients can slow the progression or prevent complications of diabetes such as retinopathy, nephropathy, or neuropathy (1). Unfortunately, it is also well established that intensive glucose treatment increases the frequency of severe hypoglycemia (2). The mechanism for the increased frequency of hypoglycemia may not be simply due to insulin excess. It has been clearly established (3-5) that repeated exposure to hypoglycemia can reduce neuroendocrine (catecholamine, glucagon, and growth hormone) and metabolic (endogenous glucose production [EGP], lactate, and glycerol) counterregulatory responses to subsequent hypoglycemia by as much as 50% in healthy humans and type 1 diabetic subjects (6,7). Thus, blunted counterregulatory responses make type 1 diabetic patients susceptible to an increased vicious cycle of hypoglycemia.Cortisol has been proposed to play a role in blunting neuroendocrine and metabolic responses to subsequent hypoglycemia (8,9). Similar to antecedent hypoglycemia, antecedent elevations of cortisol through infusion of cortisol (9) or adrenocorticotropic hormone (ACTH) (10) blunted neuroendocrine and metabolic counterregulatory responses to subsequent day 2 hypoglycemia in nondiabetic...

After antecedent hypoglycemia, counterregulatory responses to subsequent hypoglycemia exhibit greater blunting in men than in women. Because physical exercise and hypoglycemia share multiple counterregulatory mechanisms, we hypothesized that prior exercise may also result in gender-specific blunting of counterregulatory responses to subsequent hypoglycemia. Thirty healthy subjects (15 women and 15 men; age, 28 +/- 3 yr; body mass index, 23 +/- 1 kg/m2) were studied during 2-d experiments. Day 1 consisted of either identical 90-min morning and afternoon cycle exercise at 50% maximum oxygen expenditure or two 2-h episodes of hyperinsulinemic euglycemia. Day 2 consisted of a 2-h morning hyperinsulinemic-hypoglycemic clamp. Endogenous glucose production was measured using [3-(3)H]glucose. Muscle sympathetic nerve activity was measured using microneurography. Day 2 insulin (540 +/- 36 pmol/liter) and plasma glucose (2.9 +/- 0.06 pmol/liter) levels were similar in men and women during the last 30 min of hypoglycemia. Compared with antecedent euglycemia, d 1 exercise produced significant blunting of d 2 counterregulatory responses to hypoglycemia. Several key d 2 counterregulatory responses were blunted to a greater extent in men than in women: glucagon (men, -105 +/- 14; women, -25 +/- 7 ng/liter; P < 0.0001), epinephrine (men, -2625 +/- 257 pmol/liter; women, -212 +/- 573; P < 0.001), norepinephrine (men, -0.50 +/- 0.12 nmol/liter; women, -0 +/- 0.11; P < 0.001), and muscle sympathetic nerve activity (men, -13 +/- 4; women, -4 +/- 4 bursts/min; P < 0.01). Cardiovascular responses (heart rate and systolic and mean arterial blood pressures) were also more blunted by antecedent exercise in men than in women. After d 1 exercise, the amount of glucose infused during d 2 hypoglycemia in men was increased 6-fold compared with that after d 1 euglycemia. This amount was significantly increased (P < 0.01) compared with the 2-fold (P < 0.01) increment in glucose infusion that was required in women after d 1 exercise. Lipolysis was unaffected by d 1 exercise in women, but was significantly blunted during d 2 hypoglycemia in men. In summary, two bouts of prolonged, moderate exercise (90 min at 50% maximum oxygen expenditure) induced a marked sexual dimorphism in key neuroendocrine (glucagon, catecholamines, and muscle sympathetic nerve activity) and metabolic (glucose kinetic, lipolysis) responses to next day hypoglycemia.

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