Citations

To determine whether the sensitivity of adipose tissue lipolysis to catecholamines is increased in poorly controlled insulin-dependent diabetes, the lipolytic response to epinephrine was measured in seven nondiabetic volunteers and seven poorly controlled diabetic subjects with use of [1-(14)C]palmitate as a tracer. Subjects received sequential 1-h infusions of epinephrine, which produced epinephrine concentrations of approximately 1,000, approximately 1,750, approximately 3,500, and approximately 6,000 pmol/l. A pancreatic clamp was used to maintain constant plasma hormone levels. Concentration-response curves were constructed for each subject from the integrated lipolytic response during each epinephrine infusion. There was no difference in maximal lipolytic response (117 +/- 19 vs. 152 +/- 11 mumol.kg-1.h-1) or in maximally effective (3,171 +/- 267 vs. 3,357 +/- 349 pmol/l) or half-maximally effective (1,081 +/- 109 vs. 1,015 +/- 120 pmol/l) epinephrine concentrations between nondiabetic and diabetic subjects, respectively (all P = NS). In control subjects, maximum beta-hydroxybutyrate concentrations were achieved at lower epinephrine concentrations than those required for a maximum lipolytic effect. Thus, under pancreatic clamp conditions, the lipolytic response to epinephrine in nondiabetic and diabetic subjects was similar.

Upper-body and lower-body adipocytes respond differently to physiological catecholamines in vitro. It is not known whether this is true in vivo or whether gender differences exist in the regional adipose tissue responses to epinephrine. These studies were therefore conducted to examine free fatty acid (FFA) release ([3H]palmitate) from lower-body (leg), splanchnic, and upper-body adipose tissue in normal-weight adult men (n = 8) and women (n = 7). In response to intravenous epinephrine (10 ng.kg-1.min-1), palmitate release increased (P < 0.01) in both men (168 +/- 10 to 221 +/- 15 mumol/min) and women (177 +/- 12 to 234 +/- 18 mumol/min). Basal leg palmitate release was similar in women and men (16.8 +/- 2.9 and 12.4 +/- 1.3 mumol/min, P = not significant) but doubled (P < 0.01) in response to epinephrine in men and was virtually unchanged in women. Splanchnic palmitate release increased (P < 0.05) in men (n = 6) but not in women (n = 6), whereas nonsplanchnic upper-body palmitate release increased more in women than in men. Upper-body (splanchnic and nonsplanchnic) palmitate release increased (P < 0.05) in both men and women in response to epinephrine. In summary, lower-body adipose tissue FFA release increased in response to epinephrine in men but not women, whereas upper-body palmitate release increased in both groups. These findings are consistent with some in vitro findings and suggest that catecholamine action may play a role in determining gender-based differences in body fat distribution.

To determine whether fasting alters the ability of insulin to suppress endogenous glucose production or proteolysis, isotopic flux measurements of glucose, leucine, alpha-keto-isocaproate, and alanine were made in 13 normal volunteers after a 14-h (day 1) and an 84-h (day 4) fast. Using the “pancreatic clamp” technique, we achieved small increments in plasma insulin concentrations, as well as constant and identical plasma hormone and glucose concentrations, on both study days in seven subjects. The remaining six subjects were infused with saline and served as controls. Leucine rate of appearance (an index of proteolysis) was greater on day 4 than on day 1 (P less than 0.001), but decreased to equal values during the pancreatic clamp on each study day. During the pancreatic clamp, endogenous glucose production decreased to lesser (P less than 0.005) values on day 4 than on day 1. In conclusion, insulin suppresses proteolysis equally well before and after brief fasting, and endogenous glucose production is more completely suppressed by insulin after brief fasting than after an overnight fast.

To determine the relative contribution of splanchnic and leg tissues to postprandial thermogenesis, systemic and regional oxygen consumption rates were measured in nine women and eight men before and for 6 h after the consumption of a mixed meal that provided one-third of the daily energy needs. In women, the increase in splanchnic oxygen uptake accounted for 63 +/- 12% of the postprandial increase in oxygen consumption, whereas in men it accounted for 35 +/- 14% (P = not significant between women and men). Leg oxygen uptake accounted for 11 +/- 4 and 10 +/- 3% of the increase in postprandial oxygen consumption in women and men, respectively. The combined data suggest that approximately 48% of postprandial thermogenesis over 6 h occurs in splanchnic tissues, whereas 30-35% occurs in skeletal muscle. Thus the increase in oxygen consumption after a mixed meal is primarily localized to splanchnic tissues, and major reductions in postprandial thermogenesis are unlikely to be attributable solely to abnormalities of skeletal muscle metabolism.

To determine whether estrogen directly affects effective adipose lipolysis, palmitate rate of appearances ([14C]palmitate) was measured in 15 postmenopausal women. Each volunteer was studied after > or = 2 mo of estrogen treatment and again after > or = 2 mo of estrogen deficiency. Plasma hormone concentrations were controlled and identical on the 2 study days with use of the pancreatic clamp technique, and the lipolytic response to epinephrine and epinephrine + phentolamine was assessed. Results showed that overall palmitate flux was greater (10-20%, P < 0.05) during the estrogen-deficient than during the estrogen-replete study. Adrenergic stimulation of lipolysis was not specifically influenced by estrogen treatment, and control of plasma hormone concentrations did not eliminate the difference in palmitate flux between the estrogen-deficient and estrogen-replete study days. We conclude that estrogen deficiency is associated with increased plasma free fatty acid availability and that estrogen likely has direct, albeit small, effects on adipose tissue lipolysis.

In man, a decrease in plasma glucose concentration results in a compensatory increase in hepatic glucose release. Studies in vitro have suggested that a low glucose concentration per se may directly stimulate hepatic glucose release, an effect often referred to as autoregulation. Whether autoregulation occurs in man in response to a physiologic decrement in blood glucose is not known. Therefore, seven healthy, nonobese subjects were studied on two occasions to determine the role of autoregulation in mediating the increase in glucose production that accompanies a physiologic decrement in plasma glucose concentration. On both occasions, plasma glucose concentrations were clamped successively at 95, 65, and 95 mg/dl for 2 h each. Insulin (∼14 μU/ml) and glucagon (∼70 pg/ml) were maintained constant on both occasions by an infusion of somatostatin and insulin. Phentolamine and propranolol also were infused on one occasion to produce combined alpha- and beta-adrenergic blockade. In the absence of adrenergic blockade, glucose production increased by approximately 1.3 mg/kg min when the plasma glucose concentration was decreased from 95 to 65 mg/dl and decreased by approximately 1.5 mg/kg min when glucose was increased from 65 to 95 mg/dl. In the presence of adrenergic blockade, the increase and decrease in glucose production averaged 0 and 0.5 mg/kg·min, respectively, representing 70–100% inhibition. We conclude that, in the presence of low physiologic insulin concentrations, autoregulation is not a major contributor to the hepatic response to a physiologic decrement in plasma glucose concentration in man.

To determine whether glucose-mediated as well as insulin-mediated regulation of glucose utilization and glucose production is impaired in patients with insulindependent diabetes mellitus (IDDM), six nonobese, diabetic patients and seven age-, sex-, and weightmatched nondiabetic subjects were studied. Despite slightly higher free insulin concentrations in the diabetic patients than in the nondiabetic subjects during 0.2 mU/kg · min (22 ± 3 versus 15 ± 2 μU'ml) and 1.0 mU'kg · min (98 ± 10 versus 75 μU/ml) insulin infusions, glucose utilization at plasma glucose concentrations of 95, 135, and 175 mg/dl was lower in the diabetic patients than in the nondiabetic subjects. The increment in glucose utilization per increment in plasma glucose (i.e., slope) in the diabetic and nondiabetic subjects, respectively, did not differ significantly during either the 0.2 (1.7 ±1.3 versus 1.4 ± 0.5 dl/kg · min) or 1.0 (4.4 ±1.1 versus 6.2 ±1.0 dl/kg · min) mU/kg · min insulin infusions, although they tended to be higher in the nondiabetic subjects during the latter infusion. Thus, although stimulation of glucose utilization by insulin is impaired in patients with IDDM, the ability of an increase in glucose concentration to increase glucose utilization does not appear to differ from that present in nondiabetic subjects, at insulin concentrations in the low physiologic range. Whether differences exist in the high physiologic range remains to be determined.

Glucagon normally plays a primary role in promoting glucose recovery from insulin-induced hypoglycemia. Epinephrine compensates largely for deficient glucagon secretion. Glucose recovery from hypoglycemia fails to occur only in the absence of both glucagon and epinephrine. Perhaps as a relatively early feature of autonomic neuropathy, patients with insulin-dependent diabetes mellitus commonly have blunted or absent glucagon secretory responses to hypoglycemia. However, this deficient response is commonly compensated for by epinephrine and glucose recovery occurs. In some patients, progression of adrenergic neuropathy to the point of deficient epinephrine secretory responses to hypoglycemia, coupled with deficient glucagon responses, leads to frequent, severe, and prolonged hypoglycemia. Thus, these glucose counterregulatory systems are of critical importance to patients with insulindependent diabetes mellitus. The efficacy of glucose counterregulation in a given patient may determine the degree to which euglycemia can be achieved with aggressive insulin therapy in that patient.