Antecedent moderate-intensity exercise has been shown to blunt autonomic, neuroendocrine, and metabolic counterregulatory responses to subsequent hypoglycemia in nondiabetic individuals. The aims of the current study were to determine 1) whether this occurs in type 1 diabetic patients and 2) whether the degree of blunting is dependent on exercise intensity. Twentyseven type 1 diabetic patients (13 women and 14 men) were studied during a single-step, 2-h hyperinsulinemic (9 pmol ⅐ kg ؊1 ⅐ min ؊1 )-hypoglycemic (ϳ2.8 mmol/l) clamp 1 day after two 90-min exercise bouts at 30% (n ؍ 11) or at 50% (n ؍ 11) VO 2max or after no prior stress (control subjects, n ؍ 25). After prior exercise at both 30 and 50% VO 2max , epinephrine (1,959 ؎ 553 and 1,528 ؎ 424 vs. 3,420 ؎ 424 pmol/l, respectively; P < 0.05) and pancreatic polypeptide (97 ؎ 32 and 98 ؎ 8 vs. 223 ؎ 32 pmol/l, respectively; P < 0.05) responses to subsequent hypoglycemia were significantly lower compared with those of control subjects. Endogenous glucose production was significantly lower, while glucose utilization and, consequently, the exogenous glucose infusion rate needed to maintain hypoglycemia were significantly greater after both exercise intensities compared with that of control subjects. Muscle sympathetic nerve activity was significantly reduced by prior exercise of both intensities at baseline (16 ؎ 4 and 22 ؎ 4 vs. 31 ؎ 3 bursts/min) and during hypoglycemia (22 ؎ 4 and 27 ؎ 5 vs. 41 ؎ 3 bursts/min) compared with that of control subjects (P < 0.05). Total hypoglycemic symptoms were also significantly lower (P < 0.05) in both exercise groups compared with the control group. In summary, repeated episodes of prolonged exercise of both low and moderate intensities blunted key autonomic (epinephrine and pancreatic polypeptide) and metabolic (endogenous glucose production and peripheral glucose uptake) counterregulatory responses to next-day hypoglycemia in type 1 diabetes. Diabetes 53: 1798 -1806, 2004 I ntensive maintenance of normal glucose levels delays or prevents the development of microvascular complications associated with diabetes (1,2). Unfortunately, an approximate threefold increase in severe hypoglycemia in these intensively treated patients (1) limits the widespread implementation of this treatment paradigm. Although excess insulin is an important contributing factor to increased hypoglycemia, with increased duration of the disease, glucagon responses to hypoglycemia in type 1 diabetes are absent (3). This leaves type 1 diabetic patients dependent on epinephrine to counter falling glucose levels. However, recent antecedent episodes of hypoglycemia have significantly reduced autonomic counterregulatory responses to subsequent hypoglycemia in nondiabetic and type 1 diabetic patients (4 -7). This has been termed hypoglycemia-associated autonomic failure (8,9) and is proposed to create a vicious cycle of hypoglycemia for the type 1 diabetic patient.Exercise has numerous therapeutic benefits. Despite this, exercise often results in hypogly...
This study tested the hypothesis that estrogen is the mechanism responsible for the sexual dimorphism present in the neuroendocrine and metabolic responses to hypoglycemia. Postmenopausal women receiving (E2; n ؍ 8) or not receiving (NO E2; n ؍ 9) estrogen replacement were compared with age-and BMI-matched male subjects (n ؍ 8) during a single-step 2-h hyperinsulinemic-hypoglycemic clamp. Plasma insulin (599 ؎ 28 pmol/l) and glucose (2.9 ؎ 0.03 mmol/l) levels were similar among all groups during the glucose clamp. In response to hypoglycemia, epinephrine (2.8 ؎ 0.6 vs. 5.8 ؎ 0.8 and 4.4 ؎ 0.5 nmol/l), glucagon (57 ؎ 8 vs. 77 ؎ 8 and 126 ؎ 18 ng/l), and endogenous glucose production (2 ؎ 2 vs. 10 ؎ 2 and 6 ؎ 3 mol ⅐ kg ؊1 ⅐ min ؊1 ) were significantly lower in E2 vs. both NO E2 and male subjects (P < 0.05). These reduced counterregulatory responses resulted in significantly greater glucose infusion rates (16 ؎ 2 vs. 6 ؎ 2 and 6 ؎ 3 mol ⅐ kg ؊1 ⅐ min ؊1 ; P < 0.01) in E2 vs. both NO E2 and male subjects. Pancreatic polypeptide was significantly lower (P < 0.05) in both the E2 and NO E2 groups compared with the male subjects (136 ؎ 20 and 136 ؎ 23 vs. 194 ؎ 16 pmol/l). Last, glycerol (36 ؎ 3 vs. 47 ؎ 5 mol/l; P < 0.05), lactate (1.4 ؎ 0.1 vs. 1.8 ؎ 0.2 mmol/l; P < 0.05), and muscle sympathetic nerve activity (19 ؎ 4 to 27 ؎ 4 vs. 27 ؎ 5 to 42 ؎ 6 bursts/min; P < 0.05) responses to hypoglycemia were all significantly lower in E2 vs. NO E2 subjects. We conclude that estrogen appears to play a major role in the sexual dimorphism present in counterregulatory responses to hypoglycemia in healthy humans. Diabetes 52:1749 -1755, 2003 M en and women respond differently to an acute bout of hypoglycemia. We have previously shown that healthy and type 1 diabetic women, compared with men, have lower catecholamine, glucagon, cortisol, growth hormone, endogenous glucose production (EGP), and lactate responses, and they have increased glycerol responses to hypoglycemia (1,2). This sexual dimorphism also appears to be present in a wide variety of physiological stresses. For example, women have been found to have reduced neuroendocrine and increased lipolytic responses to exercise (3-5) and reduced sympathetic nervous system responses to cognitive stress (6).The physiological mechanism(s) responsible for sexually dimorphic responses to stress in humans remains unknown, although it seems likely that one or more of the reproductive hormones may be responsible. Animal studies suggest that estrogen may play an important role. Estrogen administration has been shown to independently reduce catecholamine levels, either by increasing norepinephrine degradation in the brain (and thereby reducing sympathetic system drive) (7) or by decreasing secretion from the adrenal medulla (8,9). Metabolically, estrogen has been found to increase lipolysis (10), glycogen deposition (11), and glucose uptake during exercise in rats (10). Recent studies in mice even suggest that estrogen, specifically estrone sulfate, may have a direct effect on reduc...
. Acute, sameday effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab 290: E1331-E1338, 2006. First published January 31, 2006 doi:10.1152/ajpendo.00283.2005.-Exercise-induced hypoglycemia can occur within hours after exercise in type 1 diabetes mellitus (T1DM) patients. This study tested the hypothesis that an acute exercise bout causes (within hours) blunted autonomic and metabolic responses to subsequent hypoglycemia in patients with T1DM. Twelve T1DM patients (3 W/9 M) were studied during a single-step, 2-h hyperinsulinemic (572 Ϯ 4 pmol/l) hypoglycemic (2.8 Ϯ 0.1 mmol/l) clamp 2 h after either a hyperinsulinemic euglycemic (AM EUG) or hypoglycemic clamp (AM HYPO) or after sitting in a chair with basal insulin infusion (AM CON) or 90 min of moderate-intensity exercise (50% V O2 max, AM EX). Both AM HYPO and AM EX significantly blunted epinephrine responses and muscle sympathetic nerve activity responses to subsequent hypoglycemia compared with both control groups. Endogenous glucose production was significantly lower and the exogenous glucose infusion rate needed to maintain the hypoglycemic level was significantly greater during subsequent hypoglycemia in AM EX vs. CON. Rate of glucose disposal (Rd) was significantly reduced following AM HYPO. In summary, within 2.5 h, both moderate-intensity AM EX and AM HYPO blunted key autonomic counterregulatory responses. Despite this, glucose Rd was reduced during afternoon hypoglycemia following morning hypoglycemia, indicating posthypoglycemic insulin resistance. After morning exercise, endogenous glucose production was blunted, but glucose Rd was maintained during afternoon hypoglycemia, thereby indicating reduced metabolic defenses against hypoglycemia. These data suggest that exercise-induced counterregulatory failure can occur very rapidly, increasing the risk for hypoglycemia in T1DM within hours. sympathetic nervous system; hormones ANTECEDENT EPISODES OF HYPOGLYCEMIA occurring 24 h before exercise have been found to blunt autonomic counterregulatory responses to subsequent prolonged moderate-intensity exercise (90 min at 50% V O 2 max ) by ϳ50% in both nondiabetic (8) and type 1 diabetes mellitus (T1DM) (19) individuals. In fact, it seems that this relationship is reciprocal; that is, recent antecedent episodes of prolonged moderate-intensity exercise have also been found to blunt autonomic counterregulatory responses during subsequent hypoglycemia occurring 24 h later in healthy (17, 30) and T1DM subjects (33). However, clinically, exercise-induced hypoglycemia has been reported to occur within 2 h after exercise.Although acute exercise-induced hypoglycemia in T1DM may at least partially stem from iatrogenic causes (i.e., in balance of subcutaneous insulin and metabolic needs), we (13) have demonstrated that morning hypoglycemia could acutely reduce neuroendocrine and symptom responses to subsequent, same-day, afternoon hypoglycemia in nondiabetic individuals. Des...
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