To assess the roles of decrements in insulin and increments in glucagon in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal young men were studied during somatostatin infusions with insulin and glucagon infused to 1) hold insulin and glucagon levels constant, 2) decrease insulin, 3) increase glucagon, and 4) decrease insulin and increase glucagon during exercise. In contrast to a comparison study (saline infusion), when insulin and glucagon were held constant, glucose production did not increase and plasma glucose decreased from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.001) initially during exercise. Notably, plasma glucose then plateaued and was 3.3 +/- 0.2 mmol/l at the end of exercise. This decrease was at most only delayed when either insulin was decreased or glucagon was increased independently. However, when insulin was decreased and glucagon was increased simultaneously, there was an initial increase in glucose production, and the glucose level was 4.5 +/- 0.2 mmol/l at 60 min, a value not different from that in the comparison study. Thus we conclude that both decrements in insulin and increments in glucagon play important roles in the prevention of hypoglycemia during exercise and do so by signaling increments in glucose production. However, since hypoglycemia did not develop during exercise when changes in insulin and glucagon were prevented, an additional counterregulatory factor, such as epinephrine, must be involved in the prevention of hypoglycemia during exercise, at least when the primary factors, insulin and glucagon, are inoperative.
To assess the role of catecholamines in the prevention of hypoglycemia during moderate exercise (approximately 60% peak O2 consumption for 60 min), normal humans were studied with combined alpha- and beta-adrenergic blockade and with adrenergic blockade while changes in insulin and glucagon were prevented with the islet clamp technique (somatostatin infusion with insulin and glucagon infused at fixed rates). The results were compared with those from an islet clamp alone study. In contrast to a comparison study (saline infusion), adrenergic blockade resulted in a small initial decrease in plasma glucose during exercise, from 5.0 +/- 0.2 to 4.4 +/- 0.2 mmol/l (P less than 0.01), but the level then plateaued. There was a substantial exercise-associated decrement in plasma glucose when insulin and glucagon were held constant, i.e., from 5.5 +/- 0.2 to 3.4 +/- 0.2 mmol/l (P less than 0.0001), but the level again plateaued. However, when insulin and glucagon were held constant and catecholamine actions were blocked simultaneously, progressive hypoglycemia, to 2.6 +/- 0.6 mmol/l (P less than 0.001), developed during exercise. Hypoglycemia was the result of an absent increase in glucose production and an exaggerated initial increase in glucose utilization. Thus we conclude that sympathochromaffin activation plays a minor role when insulin and glucagon are operative, but a catecholamine, probably epinephrine, becomes critical to the prevention of hypoglycemia during exercise when changes in insulin and glucagon do not occur.
IntroductionTo examine putative relationships between adrenergic receptors on accessible circulating cells and relatively inaccessible extravascular catecholamine target tissues, we measured mononuclear leukocyte (MNL) and lung fl-adrenergic receptors and platelet and lung a-adrenergic receptors in tissues obtained from 15 patients undergoing pulmonary resection. Plasma catecholamine concentrations were measured concurrently to explore potential regulatory relationships between the activity of the sympathochromaffin system and both intravascular and extravascular adrenergic receptors. MNL and lung membrane 0-adrenergic receptor densities were correlated highly (r = 0.845, P < 0.001 The pharmacology, physiology, biochemistry, and cellular and molecular biology of the adrenergic receptors (adrenoceptors) that mediate the diverse actions of the catecholamines have been studied extensively in vitro and to a lesser extent in vivo in animals (1-3). Application of this data base to the study of adrenergic receptor regulation in humans is limited by the relative inaccessibility of relevant catecholamine target tissues such as heart, lung, etc. Therefore, most investigators studying human adrenergic receptors have measured these on accessible intravascular tissues, circulating mononuclear leukocytes (12-adrenergic receptors), platelets (a2-adrenergic receptors), or both, and used these measurements as indices of adrenergic receptor status on extravascular target tissues (3), i.e., those tissues that are not exposed directly to the intravascular compartment. This approach rests on the critical assumption that adrenergic receptor status on circulating cells reflects faithfully that on catecholamine target cells throughout the body. Although one can marshal a body of evidence to support this assumption, certain apparent exceptions led one of us to urge caution (4). For example, estrogen administration has been reported to decrease platelet but increase myometrial a-adrenergic receptor density in rabbits (5, 6), and thyroid hormone excess has been reported to increase human mononuclear leukocyte (7) and rat myocardial (8) fl-adrenergic receptor densities but decrease rat hepatic j3-adrenergic receptor density (9). Furthermore, regulation of extravascular adrenergic receptors by catecholamines has been found to be tissue and receptor subtype selective (10, 1 1). To our knowledge, the only published direct comparison ofadrenergic receptors on circulating and extravascular cells in humans is the report of Brodde et al. (12) that human myocardial and intact mononuclear leukocyte ,B-adrenergic receptor densities are correlated.There is considerable evidence that catecholamines modulate adrenergic receptors ( 1-4). The most extensively studied pattern is an inverse relationship between agonist levels and adrenergic receptor function. For example, high catecholamine levels generally lead to desensitization of the tissue response to ,B-adrenergic agonists; among other possibilities, this involves uncoupling of,B-adrenergic ...
We assessed simplified approaches to measurement of steady-state norepinephrine (NE) kinetics (short, nonprimed infusions of [3H]NE or of unlabeled NE and arterialized venous sampling), then reexamined the kinetic mechanism(s) of the age-associated increase in plasma NE, and tested the hypothesis that the latter is the result of a sedentary lifestyle. We studied 17 young (21-28 yr) and 21 elderly (60-76 yr) subjects and a subset (n = 8) of the latter again after 1 yr of physical training. NE appearance rates (Ra) and NE metabolic clearance rates (MCRs), calculated from arterialized venous data, were not significantly different from those calculated from arterial data, whereas those calculated from venous data were substantially (approximately 50%) higher. NE Ra and NE MCR, determined from infusions of unlabeled NE were approximately 20% higher than those determined with [3H]NE, a finding plausibly attributed to approximately 20% suppression of endogenous NE appearance. Arterialized venous plasma NE concentrations were significantly higher in the elderly as a result of significantly higher NE Ra and lower NE MCR. However, arterial NE Ra was not increased, and venous NE MCR was not decreased significantly in the elderly. In the subset of elderly subjects, 1 yr of physical training, which increased peak O2 consumption by 24%, did not decrease plasma NE or NE Ra or increase NE MCR. Therefore, 1) arterial sampling provides no practical advantage over arterialized venous sampling in the measurement of NE kinetics. 2) The use of unlabeled NE infusions to determine NE kinetics overestimates NE Ra and NE MCR by approximately 20%.(ABSTRACT TRUNCATED AT 250 WORDS)
Advanced age is a risk factor for hypoglycemia caused by sulfonylureas (and insulin) used to treat diabetes mellitus. Therefore, we hypothesized that there is an age-associated impairment of glucose counterregulation and further that this is the result of a sedentary life-style. To test these hypotheses, glycemic and neuroendocrine responses to hypoglycemia, produced by 0.05 U/kg body wt insulin i.v. were measured in nondiabetic elderly subjects (age 65.1 +/- 0.9 yr n = 23)--and in a subset (n = 11) again after 1 yr of physical training (which increased VO2 max by 5.2 +/- 0.9 ml.kg-1.min-1, P less than 0.05)--and compared with these responses in nondiabetic young subjects (23.8 +/- 0.6 yr, n = 18). Recovery from hypoglycemia was attenuated (analysis of variance P less than 0.001) in the elderly (plasma glucose recovery rate 29.4 +/- 2.2 vs. 42.7 +/- 5.0 microM/min, P less than 0.02). This attenuation was the result of a smaller counterregulatory increment in glucose production (maximum increment 13.3 +/- 1.1 vs. 17.2 +/- 1.1 mumol.kg-1.min-1; P less than 0.05) rather than a greater increment in glucose utilization in the elderly. The attenuated glucose recovery was associated with higher plasma insulin concentrations (maximum increment 1385 +/- 122 vs. 940 +/- 72 pM, P less than 0.01) and reduced glucagon responses to hypoglycemia (maximum increment 43 +/- 6 vs. 66 +/- 12 ng/L). The epinephrine, norepinephrine, cortisol, and growth hormone responses were similar, although the epinephrine response was slightly delayed and the growth hormone response appeared smaller in the elderly.(ABSTRACT TRUNCATED AT 250 WORDS)
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