To determine the effect of thyroid hormone excess on insulin secretion, metabolism and action in humans, we examined intravenous glucose tolerance, glucose-induced insulin secretion, insulin clearance, monocyte insulin receptor binding, and the dose-response characteristics for the effects of insulin on glucose production, uptake, oxidation, and nonoxidative disposal in 10 normal volunteers for 14 days before and after oral administration of triiodothyronine (T3) in doses that increased plasma T3 to levels observed in spontaneous thyrotoxicosis (P less than 0.001). After T3 postabsorptive plasma glucose (P less than 0.05) and insulin (P less than 0.05) both increased; intravenous glucose tolerance was unaffected, but plasma insulin responses were increased (P less than 0.01); basal glucose production, uptake, and oxidation all increased (all P less than 0.05), whereas nonoxidative glucose disposal was unaffected (P = NS); monocyte insulin receptor binding increased (P less than 0.01) due to increased receptor affinity (P less than 0.05); and receptor number was not significantly altered (P = NS). Insulin clearance was increased. Insulin-induced suppression of glucose production was impaired (Km 22 +/- 3 vs. 37 +/- 7 microU/ml, P less than 0.02); maximal insulin-induced glucose uptake (10.7 +/- 0.6 vs. 13.0 +/- 0.9 mg X kg-1 X min-1, P less than 0.001) and oxidation (3.41 +/- 0.30 vs. 5.34 +/- 0.59 mg X kg-1 X min-1, P less than 0.001) were increased without a significant change in Km. However, submaximal rates of nonoxidative glucose disposal and glucose uptake were inappropriately low for the increased insulin receptor binding.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term growth hormone excess is associated with impaired hepatic and extrahepatic responses to insulin in the absence of a change in insulin binding. To determine whether similar defects occur after chronic growth hormone excess, insulin dose-response curves for stimulation of glucose utilization and suppression of glucose production and monocyte and erythrocyte insulin binding were determined in five acromegalic patients and six healthy volunteers of comparable age, sex, and obesity. During infusion of insulin, glucose infusion rates required to maintain euglycemia were significantly lower (P less than 0.02 all) in the acromegalic patients than in the control subjects. Suppression of glucose production was impaired in the acromegalic subjects at insulin concentrations in the physiological range but not at insulin concentrations in the supraphysiological range. In contrast stimulation of glucose utilization was decreased in the acromegalic subjects at both physiological and supraphysiological insulin concentrations. Neither monocyte nor erythrocyte insulin binding differed significantly in the acromegalic and control subjects. These data indicate that chronic growth hormone excess is associated with a defect in both hepatic and extrahepatic insulin action. The decrease in glucose utilization at supraphysiological insulin concentrations in the acromegalic subjects and the normal monocyte and erythrocyte insulin binding suggest a postbinding alteration in insulin action.

As bstract. Prolonged exposure to glucocorticoids in pharmacologic amounts results in muscle wasting, but whether changes in plasma cortisol within the physiologic range affect amino acid and protein metabolism in man has not been determined. To determine whether a physiologic increase in plasma cortisol increases proteolysis and the de novo synthesis ofalanine, seven normal subjects were studied on two occasions during an 8-h infusion ofeither hydrocortisone sodium succinate (2 1g

These studies were designed to determine whether the insulin resistance of fasting extends to its antilipolytic effects and whether fasting enhances the lipolytic effects ofadrenergic stimulation independent of changes in plasma hormone and substrate concentrations. Palmitate flux was determined isotopically (il-'4Cjpalmitate) before and during epinephrine infusion in normal volunteers after a 14-h (day 1) and an 84-h (day 4) fast. Using a pancreatic clamp, constant plasma hormone and glucose concentrations were achieved on both study days in seven subjects. Six subjects were infused with saline and served as controls. During the pancreatic clamp, palmitate flux was greater (P < 0.01) on day 4 than day 1, despite similar plasma insulin, glucagon, growth hormone, cortisol, epinephrine, norepinephrine, and glucose concentrations. The lipolytic response to epinephrine was greater (P < 0.05) on day 4 than day 1 in both groups of subjects. In conclusion, lipolysis during fasting is less completely suppressed by insulin and more readily stimulated by epinephrine.

IntroductionTo assess the mechanisms responsible for increased gluconeogenesis in noninsulin-dependent diabetes mellitus (NIDDM), we infused 13-14Cjlactate, 13-13Cjalanine, and 16-3Hjglucose in 10 postabsorptive NIDDM subjects and in 9 age-and weightmatched nondiabetic volunteers and measured systemic appearance of alanine and lactate, their release from forearm tissues, and their conversion into plasma glucosq (corrected for Krebs cycle carbon exchange). Systemic appearance of lactate and alanine were both significantly greater in diabetic subjects (18.2±0.9 and 5.8±0.4 ,mol/kg/min, respectively) than in the nondiabetic volunteers (12.6±0.7 and 4.2±0.3 ,umol/kg/min, respectively, P < 0.001 and P < 0.01). Conversions of lactate and alanine to glucose were also both significantly greater in NIDDM subjects (8.6±0.5 and 2.4±0.1 Mmole/kg/min, respectively) than in nondiabetic volunteers (4.2±0.4 and 1.8±0.1 ;mol/kg/min, respectively, P < 0.001 and P < 0.025).The proportion of systemic alanine appearance converted to glucose was not increased in NIDDM subjects (42.7±1.9 vs. 44.2±2.9% in nondiabetic volunteers), whereas the proportion of systemic lactate appearance converted to glucose was increased in NIDDM subjects (48.3±3.8 vs. 34.2±3.8% in nondiabetic volunteers, P < 0.025); the latter increased hepatic efficiency accounted for 40% of the increased lactate conversion to glucose. Neither forearm nor total body muscle lactate and alanine release was significantly different in NIDDM and nondiabetic volunteers. Therefore, we conclude that increased substrate delivery to the liver and increased efficiency of intrahepatic substrate conversion to glucose are both important factors for the increased gluconeogenesis of NIDDM and that tissues other than muscle are responsible for the increased delivery of gluconeogenic precursors to the liver. (J.