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The Effects of Dehydroepiandrosterone Sulfate on Counterregulatory Responses During Repeated Hypoglycemia in Conscious Normal Rats

From the Department of Medicine, Vanderbilt University School of Medicine, and Nashville Veterans Affairs Medical Center, Nashville, Tennessee

We previously determined that both antecedent hypoglycemia and elevated cortisol levels blunt neuroendocrine and metabolic responses to subsequent hypoglycemia in conscious, unrestrained rats. The adrenal steroid dehydroepiandrosterone sulfate (DHEA-S) has been shown in several studies to oppose corticosteroid action. The purpose of this study was to determine if DHEA-S could preserve counterregulatory responses during repeated hypoglycemia. We studied 40 male Sprague-Dawley rats during a series of 2-day protocols. Day 1 consisted of two 2-h episodes of 1) hyperinsulinemic (30 pmol · kg^-1 · min^-1) euglycemia (6.2 ± 0.2 mmol/l; n = 12; ANTE EUG), 2) hyperinsulinemic euglycemia (6.0 ± 0.1 mmol/l; n = 8) plus simultaneous intravenous infusion of DHEA-S (30 mg/kg; ANTE EUG + DHEA-S), 3) hyperinsulinemic hypoglycemia (2.8 ± 0.1 mmol/l; n = 12; ANTE HYPO), or 4) hyperinsulinemic hypoglycemia (2.8 ± 0.1 mmol/l; n = 8) with simultaneous intravenous infusion of DHEA-S (30 mg/kg; ANTE HYPO + DHEA-S). Day 2 consisted of a single 2-h hyperinsulinemic hypoglycemic (2.8 ± 0.1 mmol/l) clamp. During the final 30 min of day 2, hypoglycemia norepinephrine levels were significantly lower in the ANTE HYPO group versus the ANTE HYPO + DHEA-S group (2.0 ± 0.2 vs. 3.3 ± 0.6 nmol/l; P < 0.05). In addition, epinephrine (8 ± 1 vs. 17 ± 2, 14 ± 3, and 15 ± 3 nmol/l), glucagon (91 ± 8 vs. 273 ± 36, 231 ± 42, and 297 ± 48 ng/l), and corticosterone (1,255 ± 193 vs. 1,915 ± 212, 1,557 ± 112, and 1,668 ± 119 pmol/l) were significantly lower in the ANTE HYPO group versus the ANTE EUG, ANTE EUG + DHEA-S, and ANTE HYPO + DHEA-S groups (P < 0.05). Endogenous glucose production was also significantly less in the ANTE HYPO group versus the ANTE EUG, ANTE EUG + DHEA-S, and ANTE HYPO + DHEA-S groups (13 ± 5 vs. 32 ± 3, 38 ± 7, and 29 ± 8 µmol/l · kg^-1 · min^-1; P < 0.05). Consequently, the amount of exogenous glucose needed to maintain the glycemic level during the clamp studies was significantly higher in the ANTE HYPO versus the ANTE EUG, ANTE EUG + DHEA-S, and ANTE HYPO + DHEA-S groups (57 ± 8 vs. 22 ± 5, 18 ± 6, and 18 ± 3 µmol/l · kg^-1 · min^-1; P < 0.05). In summary, day-1 antecedent hypoglycemia blunted neuroendocrine and metabolic responses to next-day hypoglycemia. However, simultaneous DHEA-S infusion during antecedent hypoglycemia preserved neuroendocrine and metabolic counterregulatory responses during subsequent hypoglycemia in conscious rats.

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