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

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The Effects of Dehydroepiandrosterone Sulfate on Counterregulatory Responses During Repeated Hypoglycemia in Conscious Normal Rats Darleen A The Effects of Dehydroepiandrosterone Sulfate on Counterregulatory Responses During Repeated Hypoglycemia in Conscious Normal Rats Darleen A. Sandoval, Ling Ping, Ray Anthony Neill, Sachiko Morrey, and Stephen N. Davis ␮ ⅐ ؊1 ⅐ ؊1 We previously determined that both antecedent hy- mol/l kg min ; P < 0.05). In summary, day-1 poglycemia and elevated cortisol levels blunt neu- antecedent hypoglycemia blunted neuroendocrine and roendocrine and metabolic responses to subsequent metabolic responses to next-day hypoglycemia. How- hypoglycemia in conscious, unrestrained rats. The adre- ever, simultaneous DHEA-S infusion during antecedent nal steroid dehydroepiandrosterone sulfate (DHEA-S) hypoglycemia preserved neuroendocrine and metabolic has been shown in several studies to oppose corticoste- counterregulatory responses during subsequent hypo- roid action. The purpose of this study was to determine glycemia in conscious rats. Diabetes 53:679–686, 2004 if DHEA-S could preserve counterregulatory responses during repeated hypoglycemia. We studied 40 male Sprague-Dawley rats during a series of 2-day protocols. he Diabetes Control and Complications Trial Day 1 consisted of two 2-h episodes of 1) hyperinsuline- mic (30 pmol ⅐ kg؊1 ⅐ min؊1) euglycemia (6.2 ؎ 0.2 established that intensive glucose control in type ANTE EUG), 2) hyperinsulinemic eug- 1 diabetic patients can slow the progression or ;12 ؍ mmol/l; n -plus simultaneous Tsignificantly reduce the onset of diabetic micro (8 ؍ lycemia (6.0 ؎ 0.1 mmol/l; n intravenous infusion of DHEA-S (30 mg/kg; ANTE EUG vascular complications (e.g., retinopathy, nephropathy, ؉ DHEA-S), 3) hyperinsulinemic hypoglycemia (2.8 ؎ neuropathy) (1). Unfortunately, the study also established ANTE HYPO), or 4) hyperinsulinemic that intensive glucose treatment causes an approximate ;12 ؍ mmol/l; n 0.1 -with simulta- threefold increase in the frequency of severe hypoglyce (8 ؍ hypoglycemia (2.8 ؎ 0.1 mmol/l; n neous intravenous infusion of DHEA-S (30 mg/kg; ANTE mia (2). This increased frequency of hypoglycemia is at HYPO ؉ DHEA-S). Day 2 consisted of a single 2-h least partially caused by deficient autonomic nervous ؎ hyperinsulinemic hypoglycemic (2.8 0.1 mmol/l) system (ANS) counterregulatory responses to hypoglyce- clamp. During the final 30 min of day 2, hypoglycemia norepinephrine levels were significantly lower in the mia (3–5). Repeated exposure to hypoglycemia reduces ANTE HYPO group versus the ANTE HYPO ؉ DHEA-S neuroendocrine, ANS, and metabolic (endogenous glucose group (2.0 ؎ 0.2 vs. 3.3 ؎ 0.6 nmol/l; P < 0.05). In production [EGP], lactate, and glycerol) counterregulatory addition, epinephrine (8 ؎ 1 vs. 17 ؎ 2, 14 ؎ 3, and 15 ؎ responses to subsequent hypoglycemia by as much as 50% nmol/l), glucagon (91 ؎ 8 vs. 273 ؎ 36, 231 ؎ 42, and in nondiabetic and type 1 diabetic subjects (6–9). These 3 -ng/l), and corticosterone (1,255 ؎ 193 vs. blunted counterregulatory responses are significant con 48 ؎ 297 and 1,668 ؎ 119 pmol/l) were tributing factors to a vicious cycle of hypoglycemia for ,112 ؎ 1,557 ,212 ؎ 1,915 significantly lower in the ANTE HYPO group versus the type 1 diabetic patients (9). ؉ ؉ ANTE EUG, ANTE EUG DHEA-S, and ANTE HYPO The mechanisms responsible for the blunted counter- DHEA-S groups (P < 0.05). Endogenous glucose produc- regulatory responses seen after antecedent hypoglycemia tion was also significantly less in the ANTE HYPO group versus the ANTE EUG, ANTE EUG ؉ DHEA-S, and are not fully understood. Controversy exists regarding the ANTE HYPO ؉ DHEA-S groups (13 ؎ 5 vs. 32 ؎ 3, 38 ؎ role played by corticosteroids in the pathophysiology of ؊ ؊ -and 29 ؎ 8 ␮mol/l ⅐ kg 1 ⅐ min 1; P < 0.05). Conse- blunted ANS responses during hypoglycemia (10–14). Re ,7 quently, the amount of exogenous glucose needed to ports in rodents (12) and humans (15) have demonstrated maintain the glycemic level during the clamp studies that, similar to antecedent hypoglycemia, antecedent was significantly higher in the ANTE HYPO versus the increases of cortisol can blunt neuroendocrine and meta- -ANTE EUG, ANTE EUG ؉ DHEA-S, and ANTE HYPO ؉ bolic counterregulatory responses to next day hypoglyce DHEA-S groups (57 ؎ 8 vs. 22 ؎ 5, 18 ؎ 6, and 18 ؎ 3 mia. In addition, patients with adrenocortical failure have preserved catecholamine, pancreatic polypeptide, gluca- From the Department of Medicine, Vanderbilt University School of Medicine, gon, growth hormone, and muscle sympathetic nerve and Nashville Veterans Affairs Medical Center, Nashville, Tennessee. activity responses to hypoglycemia after antecedent hy- Address correspondence and reprint requests to Darleen Sandoval, poglycemia (16). Other animal studies have found that PhD, 715 PRB II Division of Diabetes & Endocrinology, Vanderbilt Univer- sity Medical School, Nashville, TN 37232-6303. E-mail: darleen.sandoval@ corticosteroids can blunt catecholamine responses to a vanderbilt.edu. variety of stressors, including insulin-induced hypoglyce- Received for publication 30 April 2003 and accepted in revised form 2 December 2003. mia in sheep (17) and immobilization stress in rats (18,19). ANS, autonomic nervous system; DHEA, dehydroepiandrosterone; DHEA-S, However, in contrast to the above studies, three other DHEA sulfate; EGP, endogenous glucose production; GABA, ␥-aminobutyric reports have indicated that prior corticosterone adminis- acid; HPLC, high-performance liquid chromatography; NMDA, N-methyl-D- aspartate. tration has little or no effect on ANS responses to subse- © 2004 by the American Diabetes Association. quent hypoglycemia in the conscious rat (10,13,14). DIABETES, VOL. 53, MARCH 2004 679 EFFECTS OF DEHYDROEPIANDROSTERONE DURING HYPOGLYCEMIA FIG. 1. Protocol for the 2-day studies in four groups of conscious rats. Dehydroepiandrosterone (DHEA) and its corresponding Vanderbilt University Animal Care Facility. All procedures for animal use sulfate ester (dehydroepiandrosterone sulfate; DHEA-S) were approved by the Institutional Animal Care and Use Committee at Vanderbilt University. are steroid hormones secreted from the adrenal gland. At 1 week before experiments, catheters were placed in the rats’ carotid After being orally or intravenously administered, the two artery (for blood sampling) and the external jugular vein (for infusions) under hormones are interconverted at a high rate and have a general anesthesia mixture (5 mg/kg acepromazine, 10 mg/kg xylazine, and similar physiological effects (20,21). Little is known about 50 mg/kg ketamine). Catheter lines were kept patent by flushing them with 150 their biological significance, but many studies have shown unit/ml of heparin every 3 days. Rats had free access to rat diet on the days that they work contrary to corticosteroid actions. For ex- preceding surgery and the experiments. All rats used for the 2-day experi- ments maintained Ͼ90% of their presurgery body weight. ample, in rats, a simultaneous infusion of DHEA-S coun- Four groups of rats were studied after an overnight fast during a 2-day teracts the detrimental effects of corticosterone on neuronal experimental protocol, as outlined in Fig. 1. Rats were fasted overnight before function (22) and neurogenesis (23) in the dentate gyrus. each day of the 2-day study and remained conscious and unrestrained In Zucker rats, simultaneous infusion of DHEA and dexa- throughout the 2-day protocols. The morning of each study day, extensions were placed on the exteriorized catheters for ease of access and were methasone prevents the dexamethasone-induced increase removed between day-1 and -2 studies. At t ϭ 0 min, rats were moved to an in hepatic tyrosine aminotransferase activity (24). In addi- experimental cage and allowed to become acclimated to the surroundings. tion, intracerebroventricular infusion of DHEA has been Day-1 procedures. Day 1 consisted of two 2-h (120–240 and 360–480 min) shown to increase norepinephrine and epinephrine levels hyperinsulinemic-euglycemic clamps (ANTE EUG; n ϭ 12), hyperinsulinemic- in the paraventricular nucleus and ventromedial hypothal- hypoglycemic clamps (ANTE HYPO; n ϭ 12), hyperinsulinemic-euglycemic clamps plus infusion of DHEA-S (30 mg/kg) (ANTE EUG ϩ DHEA-S; n ϭ 8) or amus in obese Zucker rats (25). Although corticosteroids hyperinsulinemic-hypoglycemic clamps plus DHEA-S infusion (ANTE HYPO have been found to increase gluconeogenesis (26), prote- ϩ DHEA-S; n ϭ 8). The DHEA-S was continuously infused into the jugular olysis (27), and net fat deposition in humans (28), DHEA vein starting at t ϭ 0 min throughout day-1 procedures. DHEA-S rather than has been found to elicit the opposite effect on these met- DHEA was infused because of the former’s water solubility. DHEA-S (30 mg/kg) was dissolved in 1.5 ml of normal saline and infused at a rate of 3 abolic processes (29–32). Based on the wealth of existing ␮l/min. This dosage of DHEA-S was chosen because it has been previously studies, we therefore hypothesized that if DHEA-S can shown to have anticorticosteroid effects on the brain (22). At the conclusion antagonize corticosteroid actions, it may also prevent any of day-1 procedures, rats were fed 5–8 g of rat diet. To maintain hematocrit, corticosteroid-induced inhibition of neuroendocrine and after each blood draw the rats’ own erythrocytes plus normal saline were metabolic responses to repeated hypoglycemia. Thus, the reinfused through the jugular cannula. If a rat’s hematocrit was Ͻ40% at the beginning of the day-2 studies, that rat was removed from the study. Plasma aim of this study was to determine if peripheral infusion of measurements of glucose were taken every 5 min during the clamp periods DHEA-S during antecedent hypoglycemia could preserve and at t ϭ 240 and 480 min for insulin levels. Between morning and afternoon counterregulatory responses during a subsequent bout of clamps, plasma glucose was measured every 15–30 min and glucose infusion hypoglycemia in conscious, unrestrained rats. was adjusted to maintain euglycemia at 6.1 mmol/l. Day-2 procedures. At t ϭ 0 min, rats were moved to an experimental cage and allowed to become acclimated to the surroundings.
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