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

Abstract

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. T he Diabetes Control and Complications Trial established that intensive glucose control in type 1 diabetic patients can slow the progression or significantly reduce the onset of diabetic microvascular complications (e.g., retinopathy, nephropathy, neuropathy) (1). Unfortunately, the study also established that intensive glucose treatment causes an approximate threefold increase in the frequency of severe hypoglycemia (2). This increased frequency of hypoglycemia is at least partially caused by deficient autonomic nervous system (ANS) counterregulatory responses to hypoglycemia (3-5). Repeated exposure to hypoglycemia reduces neuroendocrine, ANS, and metabolic (endogenous glucose production [EGP], lactate, and glycerol) counterregulatory responses to subsequent hypoglycemia by as much as 50% in nondiabetic and type 1 diabetic subjects (6 -9). These blunted counterregulatory responses are significant contributing factors to a vicious cycle of hypoglycemia for type 1 diabetic patients (9).The mechanisms responsible for the blunted counterregulatory responses seen after antecedent hypoglycemia are not fully understood. Controversy exists regarding the role played by corticosteroids in the pathophysiology of blunted ANS responses during hypoglycemia (10 -14). Reports in rodents (12) and humans (15) have demonstrated that, similar to antecedent hypoglycemia, antecedent increases of cortisol can blunt neuroendocrine and metabolic counterregulatory responses to next day hypoglycemia. In addition, patients with adrenocortical failure have preserved catecholamine, pancreatic polypeptide, glucagon, growth hormone, and muscle sympathetic nerve activity responses to hypoglycemia after antecedent hypoglycemia (16). Other animal studies have found that corticosteroids can blunt catecholamine responses to a variety of stressors, including insulin-induced hypoglycemia in sheep (17) and immobilization stress in rats (18,19). However, in contrast to the above studies, three other reports have indicated that prior corticosterone administration has little or no effect on ANS responses to subsequent hypoglycemia in the conscious rat (10,13,14).

Glucagon and Cyclic AMP: Time to Turn the Page?

“…Blood glucagon concentrations in the rat (mean ± sem) vary between a statistical minimum of 0.030 ± 0.004 nM (10 -10.5 M) postprandially to a maximum of 0.085 ± 0.032 nM (10 -10.1 M) during starvation-, exercise-, or insulin-induced hypoglycemia [average from refs. [30][31][32][33][34][35][36][37][38][39]. The blood concentration range in the human is similar: 0.035 ± 0.005 -0.064 ± 0.012 nM [average from refs.…”

“…All curves are composites compiled from multiple reports: A) [13,[23][24][25][26][27]; B) [63][64][65][66][67][68][69][70][71][72]; and C) [24,69,[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103]. The shaded area is the average glucagon blood range in the rat, from references [30][31][32][33][34][35][36][37][38][39]. so that the threshold concentration of the signal curve nearly or completely exceeds peak physiological blood concentrations.…”

Antecedent short-term central nervous system administration of estrogen and progesterone alters counterregulatory responses to hypoglycemia in conscious male rats

“…Rates of glucose appearance, endogenous glucose production (EGP), and glucose utilization were calculated according to the methods of Wall et al (43) and as described previously (37).…”

Insulin-like stimulation of cardiac fuel metabolism by physiological levels of glucagon: involvement of PI3K but not cAMP

“…In contrast, the left-hand curve reveals a dose-dependent stimulation of glycolysis that occurred over a much lower concentration range, between 10 Ϫ11 and 10 Ϫ10 M with an estimated EC 50 value of 2.8 ϫ 10 Ϫ11 M, in the absence of any observable changes in LVP. The position of the curve overlapped the normal blood concentration range, which is nearly identical in rodents and humans (8,36). The wide separation of the two curves suggested strongly that the metabolic response did not involve stimulation of AC/cAMP.…”