Peripheral glucose metabolism in human hyperthyroidism

The present study was designed to determine the effect of spontaneous hyperthyroidism on the forearm muscle glucose uptake and oxidation during the postabsorptive state and after an oral glucose challenge. Ten normal subjects and 11 hyperthyroid patients were studied after an overnight fast (12-14 h) and for 3 h after ingestion of 75 g glucose. Peripheral glucose metabolism was analyzed by the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Increased forearm glucose uptake was observed in the hyperthyroid patients compared to that in the normal subjects (1286 +/- 212 vs. 677 +/- 88 mumol/100 mL forearm.3 h) with enhanced glucose oxidation (443 +/- 40 vs. 147 +/- 29 mumol/100 mL forearm.3 h). Nonoxidative glucose metabolism was also greater in hyperthyroid patients than in normal subjects (842 +/- 234 vs. 529 +/- 90 mumol/100 mL forearm.3 h). Basal serum FFA levels were significantly higher in hyperthyroid than in normal subjects (0.252 +/- 0.025 vs. 0.182 +/- 0.022 g/L), as were the basal lipid oxidation rates in the forearm muscles of the thyrotoxic individuals (0.290 +/- 0.066 vs. 0.088 +/- 0.016 mg/100 mL forearm.min). After glucose ingestion, serum FFA levels and lipid oxidation rates declined significantly to equivalent values in both groups of subjects, and the similar basal insulin concentrations increased to significantly higher levels in the hyperthyroid patients. In conclusion, spontaneous human hyperthyroidism increases glucose uptake by the forearm muscles in the postabsorptive state and during an oral glucose challenge, with augmented fluxes of glucose through the oxidative and nonoxidative pathways.     

Effect of 50 and 100 g glucose loads on peripheral muscle glucose metabolism in normal man.

The present study was designed to determine the effects of 50 and 100 g glucose loads on forearm muscle glucose uptake, oxidation and nonoxidative glucose metabolism in normal man. Ten healthy male subjects were studied during the postabsorptive state (12-14 h overnight fast) and for 3 hours following glucose ingestion. Peripheral glucose metabolism was analysed by the use of the forearm technique to estimate muscle exchange of substrate combined with indirect calorimetry. Greater forearm muscle uptake and nonoxidative metabolism of glucose were observed in the subjects during the G.100 study than during the G.50 study (G.100 = 178.9 +/- 19.7 and 155.3 +/- 23.0 vs 103.5 +/- 16.6 and 85.2 +/- 16.7 mg/100 g forearm muscle. 3 h, respectively). the muscle glucose oxidation did not show significant difference after the two glucose loads. Insulin levels reached after 100 g glucose ingestion were significantly higher than after the 50 g glucose load. In conclusion, this study revealed a dose-dependent metabolic response in the muscular tissue of normal subjects to oral glucose loads of 50 and 100 g, with respect to forearm muscle glucose uptake and nonoxidative glucose metabolism. The oxidative responses of the muscle tissue to the oral glucose challenges seem not to be directly proportional to the ingested meals.     

Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation

We tested whether FFAs influence glucose uptake by human peripheral tissues in vivo. Whole body glucose uptake, FFA turnover, energy expenditure and substrate oxidation rates, forearm glucose and FFA uptake, and nonoxidative glycolysis (net release of alanine and lactate) were measured in 14 normal male subjects in the basal state (0-240 min; serum insulin, approximately 5 microU/mL) and during euglycemic hyperinsulinemia (240-360 min; approximately 75 microU/mL) on 2 separate occasions, once during elevation of plasma FFA by infusions of Intralipid and heparin (plasma FFA, 4.6 +/- 0.1 vs. 4.2 +/- 0.4 mmol/L; 180-240 vs. 300-360 min) and once during infusion of saline (plasma FFA, 0.50 +/- 0.07 vs. 0.02 +/- 0.07 mmol/L, respectively). In the basal state, whole body glucose disposal remained unchanged, but the fate of glucose was significantly altered toward diminished oxidation (7.3 +/- 0.8 vs. 5.6 +/- 0.5 mumol/kg.min; P less than 0.05, saline vs. Intralipid) and increased nonoxidative glycolysis (P less than 0.05). Elevation of plasma FFA significantly increased forearm glucose uptake (1.0 +/- 0.6 vs. 2.4 +/- 0.7 mumol/kg.min; P less than 0.01) and nonoxidative glycolysis (net release of alanine and lactate, 0.4 +/- 0.5 vs. 1.2 +/- 0.4 mumol glucose equivalents/kg.min; P less than 0.05). During hyperinsulinemia, FFA decreased whole body glucose disposal (38 +/- 2 vs. 30 +/- 3 mumol/kg.min; P less than 0.001) due to a decrease in glucose oxidation (13 +/- 1 vs. 7 +/- 1 mumol/kg.min; P less than 0.01, saline vs. Intralipid), and forearm glucose uptake (31 +/- 4 vs. 24 +/- 6 mumol/kg.min; P less than 0.01, saline vs. Intralipid). Under these conditions, 7 +/- 2% and 3 +/- 1% (P less than 0.05) of forearm glucose uptake could be accounted for by nonoxidative glycolysis in the Intralipid and saline studies, respectively. In summary, 1) elevation of plasma FFA concentrations suppresses the rate of carbohydrate oxidation to a rate that, both basally and during hyperinsulinemia, is similar to that reported for insulin-independent glucose oxidation in the brain; 2) basally, forearm glucose uptake is increased by FFA; and 3) during hyperinsulinemia, FFA inhibit glucose uptake by forearm tissues. We conclude that the interaction between glucose and FFA fuels in human forearm tissues is dependent upon the ambient insulin concentration; the increase in basal glucose uptake would be compatible with the increase need of glucose for FFA reesterification; the decrease in insulin-stimulated glucose uptake supports operation of the glucose-FFA cycle in human forearm tissues.     

Mechanisms of hepatic and peripheral insulin resistance during acute infections in humans.

To examine mechanisms of insulin resistance, nine patients (age 33 +/- 4 yr, body mass index 22 +/- 1 kg/m2) with acute bacterial or viral infections and in six matched normal subjects were studied. Endogenous glucose appearance (Ra), glucose disappearance (Rd), and recycling, the percentage of plasma lactate originating from plasma glucose, total glucose oxidation, and whole body and forearm muscle Rd were measured after an overnight fast in the basal state and during physiological hyperinsulinemia (serum insulin approximately 215 pmol/L). Basally Ra, Rd, glucose recycling, and oxidation were similar in both groups. During hyperinsulinemia, insulin stimulated plasma Rd approximately 35% less (17.6 +/- 1.3 vs. 26.8 +/- 3.6 mumol/kg.min, P less than 0.01, patients vs. normal subjects), and inhibited endogenous Ra less in the patients (from 13.3 +/- 0.8 to 5.3 +/- 0.8 mumol/kg.min) than in the normal subjects (from 12.8 +/- 1.0 to 2.1 +/- 1.2 mumol/kg.min, P less than 0.01). The decrease in whole body Rd was largely explained by a approximately 75% reduction in muscle Rd (5.6 +/- 1.5 vs. 20.8 +/- 3.3 mumol/kg muscle.min, P less than 0.01, patients vs. normal subjects). The defect in Rd was confined to nonoxidative (4.8 +/- 1.1 vs. 11.0 +/- 3.0 mumol/kg.min, P less than 0.01, patients vs. normal subjects) but not to oxidative glucose metabolism. The percentage of plasma lactate derived from plasma glucose during hyperinsulinemia averaged 63 +/- 6% in the patients and 79 +/- 5% in the normal subjects, indicating that glycogenolysis did not excessively dilute glycolytic carbons in the patients. We conclude that during natural infections in humans, abnormal glucose metabolism is confined to the insulin-stimulated state and involves a marked defect in muscle glucose uptake and glycogen synthesis, as well as a less marked hepatic defect.     

Study of glucose and lipid metabolism by continuous indirect calorimetry in Graves' disease: effect of an oral glucose load

Glucose and lipid metabolism were studied in 12 patients with hyperthyroid Graves' disease for 3 h during an oral glucose tolerance test (100 g) by continuous indirect calorimetry. In the postabsorptive state, glucose oxidation was not different from that in normal subjects, but lipid oxidation was significantly increased. Impaired glucose tolerance was found, but total glucose oxidation increased after the glucose load to 47.1 +/- 2.0 (+/- SEM) vs. 33.4 +/- 1.4 g/3 h in the control group (P less than 0.001). Total glucose oxidation corresponded, in hyperthyroid patients, to the highest rate obtained with progressively increasing insulin and glucose administration in normal man. Glucose storage was clearly lower in hyperthyroid patients. After treatment in 7 patients, glucose tolerance improved significantly, and the metabolic patterns almost normalized. In the 12 hyperthyroid patients and the 7 patients after treatment (n = 19), a correlation was found between total serum T3 concentration and both basal lipid oxidation and suprabasal glucose oxidation. It is concluded that the decrease in glucose tolerance in hyperthyroidism cannot be explained by an alteration in glucose oxidation, but, rather, by a defect in nonoxidative glucose uptake in the periphery.     

Reversal of steroid-induced insulin resistance by a nicotinic-acid derivative in man.

A recent report suggested that the glucose-free fatty acid (FFA) cycle may contribute to steroid-induced insulin resistance in rats, and that glucose tolerance could be restored to normal when FFA levels were lowered with nicotinic acid. To test this hypothesis in man, we measured insulin sensitivity (by euglycemic insulin clamp in combination with indirect calorimetry and infusion of tritiated glucose) before and after short-term administration of a nicotinic-acid derivative (Acipimox) in 10 steroid-treated, kidney transplant patients with insulin resistance. Thirty-five healthy subjects served as controls. Six of them received Acipimox. Total body glucose metabolism was reduced in steroid-treated patients compared with control subjects (41.7 +/- 3.3 v 50.0 +/- 2.2 mumol/kg lean body mass [LBM].min, P less than .05). The reduction in insulin-stimulated glucose uptake was mainly due to an impairment in nonoxidative glucose metabolism (primarily glucose storage as glycogen) (18.3 +/- 2.8 v 27.2 +/- 2.2 mumol/kg LBM.min, P less than .01). Acipimox lowered basal FFA concentrations (from 672 +/- 63 to 114 +/- 11 mumol/L, P less than .05) and the rate of lipid oxidation measured in the basal state (1.5 +/- 0.2 to 0.6 +/- 0.1 mumol/kg LBM.min, P less than .01) and during the clamp (0.7 +/- 0.2 to 0.03 +/- 0.2 mumol/kg LBM.min, P less than .05). In addition, Acipimox administration normalized total glucose disposal (to 54.4 +/- 4.4 mumol/kg LBM.min), mainly due to enhanced nonoxidative glucose metabolism (to 28.9 +/- 3.9 mumol/kg LBM.min) in steroid-treated patients (both P less than .05 v before Acipimox).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of a physiological growth hormone pulse on substrate metabolism in insulin-dependent (type 1) diabetic subjects.

When present in inappropriate amounts GH induces substantial insulin resistance and it has furthermore been suggested that modest nocturnal surges of GH may precipitate the emergence of the dawn phenomenon. To characterize the metabolic effects of physiologically relevant, small-scale GH exposure, six type 1 diabetic subjects were studied for 5 h in the postabsorptive state after an iv pulse of either 210 micrograms GH or saline. Identical amounts of insulin were infused on both occasions to maintain a prevailing blood glucose concentration of 125 +/- 12 mg/100 ml. The GH bolus caused an increase in serum GH levels to a peak value of 22 +/- 2 micrograms/L after 10 min, a 70% increase in serum FFA (from 570 +/- 80 to 980 +/- 60 mumol/L) and a 400% increase in blood 3-hydroxybutyrate (3-OHB) (from 100 +/- 15 to 420 +/- 35 mumol/l) concentrations after 180 and 240 min respectively (P less than 0.05). Blood glycerol and forearm uptake of 3-OHB rose in parallel (P less than 0.01). Plasma glucose, isotopically measured glucose turnover and forearm glucose uptake was not affected by GH. Blood lactate concentrations increased (P less than 0.05) and nonoxidative glucose use and lipid oxidation tended to increase with GH. Energy expenditure remained unaffected. These results suggest that under everyday conditions GH acts as an important regulator of fuel fluxes in type 1 diabetic subjects, the main effect being a transient stimulation of lipolysis. Since no significant effect on glucose metabolism was recorded, we do not presently find evidence to support a primary role for small surges of GH in the pathogenesis of the dawn phenomenon.     

Sex-related differences in peripheral glucose metabolism in normal subjects

The metabolic response of muscle tissue to glucose ingestion was studied in 10 normal men (M) and women (F) by using the forearm balance technique and indirect calorimetry simultaneously. During the 3 hours after a 75 g--oral glucose load, glucose uptake per unit muscle mass was significantly higher in women than in men, F = 187.3 +/- 26.9 vs M = 116.7 +/- 9.5 mg/100 g forearm muscle (P less than 0.05). A significant difference in muscle glucose fate was also observed since the amount of glucose utilized through a nonoxidative pathway was significantly higher in women, F = 84.5 +/- 2.6% (161.8 +/- 27.3 mg/100 g forearm muscle) vs M = 75.3 +/- 2.2% (87.2 +/- 8.6 mg/100 g forearm muscle) (P less than 0.05), whereas the amount of glucose oxidized in relation to glucose uptake was significantly higher in men, M = 24.7 +/- 2.2% (28.2 +/- 3.2 mg/100 g forearm muscle) vs F = 15.5 +/- 2.6% (27.8 +/- 5.4 mg/100 g forearm muscle) (P less than 0.05). No significant differences in insulin response to glucose ingestion were detected between groups. The women showed greater suppression of serum free fatty acids (FFA) levels in relation to basal levels than men. We conclude that: 1) after ingesting 75 g glucose, normal women showed greater glucose uptake per unit muscle mass than normal men, 2) for 3 hours after the ingestion of 75 g glucose, the predominant tendency toward utilizing glucose by a nonoxidative pathway is more marked in normal women than in normal men, and 3) the higher glucose uptake per unit muscle mass in the female group in the presence of an insulin response not significantly different from that of the male group suggests that muscle insulin sensitivity is greater in normal women.     

Effect of weight loss on glucose disposal in obese and obese diabetic patients

The purpose of the study was to examine the effect of short-term weight loss on glucose disposal and lipid oxidation in obese patients. Twenty-six obese patients were divided into three groups according to their degree of glucose intolerance: normal glucose tolerance = Gp I; impaired glucose tolerance without diabetes = Gp II; diabetes = Gp III. The patients submitted to an hypocaloric, high-protein diet for 8 to 45 weeks. Respiratory exchange measurements were performed by means of continuous indirect calorimetry during a 100 g, 3 h oral glucose tolerance test (OGTT) before weight loss and were repeated at the end of the weight loss period, 3 to 8 weeks after the reintroduction of a balanced isocaloric diet. Glucose tolerance, which was decreased in Gps II and III, improved after weight loss. Glucose oxidation, which was decreased in Gps II and III showed improvement after weight reduction in both Gp II (30.9 +/- 2.3 after weight loss vs 24.2 +/- 2.0 g/3 h before, P less than 0.025) and in Gp III (33.1 +/- 1.6 vs 25.8 +/- 4.1, ns). In the diabetic group (Gp III), before weight loss, a decrease in nonoxidative glucose uptake was observed, which was probably due both to a decrease in glucose storage and to the inhibition of splanchnic glucose output. After weight loss, it increased significantly from 27.7 +/- 5.2 to 56.9 +/- 2.3 g/3 h (P less than 0.001). Postabsorptive plasma insulin levels decreased in all groups following weight reduction. When exaggerated the insulin response to the glucose load fell to normal values whereas the insulin response increased in the diabetic patients in whom it was initially blunted. Lipid oxidation rates, both preload and postload, were markedly elevated before weight loss in all three groups. They were substantially reduced after weight loss. This study shows that a weight loss of 10 to 33 kg in obese patients promoted an increase in the subnormal glucose oxidation rate in Gp II as well as an improvement of the low nonoxidative glucose uptake in the diabetic group, thus improving their glucose tolerance. There was a simultaneous reduction in lipid oxidation in both groups. Furthermore, the insulin response to the glucose load, whether elevated or decreased before weight loss, tended towards normalization after weight reduction.     

The effect of starvation on insulin-induced glucose disposal and thermogenesis in humans

The effect of 48-hour starvation on glucose metabolism was studied in six non-diabetic, normal weight men using a hyperinsulinemic (100 mU/min/m2) glucose clamp (3.5 mmol/L). The rate of glucose oxidation was calculated from measurements of respiratory gas exchange, after allowing for the oxidation of ketones and of protein. During the glucose clamp, the whole body glucose disposal rate decreased from 39.8 (SEM 4.6) mumol/kg/min in the fed state to 24.1 (2.1) mumol/kg/min in the starved state (P less than .01), consistent with insulin "resistance." The glucose oxidation rate decreased from 21.8 (1.3) to 3.9 (1.4) mumol/kg/min with starvation (P less than .001), but the nonoxidative glucose disposal rate was unchanged (18.0 [3.9] mumol/kg/min normally fed, and 20.2 [1.2] mumol/kg/min starved). With starvation, the rate of glucose uptake in the forearm during the glucose clamp was reduced from 59.4 to 15.4 mumol/min/L forearm (SE 5.6, P less than .01, ANOVA). There was a significant net increase in thermogenesis during the glucose clamp in the normally fed state (0.27 [0.08] kJ/min, P less than .01, ANOVA), but not following starvation (0.11 [0.09] kJ/min, NS, ANOVA). Therefore, starvation caused decreases in oxidative glucose disposal and in forearm glucose uptake; despite the whole body nonoxidative disposal rate of glucose being unchanged, the associated net thermogenic response was diminished.     

Basal- and insulin-stimulated substrate metabolism in patients with active acromegaly before and after adenomectomy.

Active acromegaly is characterized by inappropriate tissue growth, increased mortality, and perturbations of intermediary metabolism. It is, in general, not well described to which extent these disturbances are normalized after treatment of the disease. To further assess basal and insulin stimulated fuel metabolism in acromegaly six patients with monotropic GH excess were each studied approximately 1 month prior to and 2 months after successful selective pituitary adenomectomy and compared to a control population of seven subjects. The studies consisted of a 3-h basal postabsorptive period and a 2-h hyperinsulinaemic (0.4 mU/kg/min) euglycemic clamp and the methods employed included isotopical measurement of glucose turnover, indirect calorimetry, and the forearm technique. When compared to the control subjects the patients with acromegaly were preoperatively and in the basal state characterized by: 1) increased circulating concentrations of GH, insulin, and C-peptide (P less than 0.05); 2) increased plasma glucose (5.9 +/- 0.2 vs. 5.2 +/- 0.2 mmol/L), blood lactate (710 +/- 90 vs. 580 +/- 70 mumol/L), glucose turnover (2.34 +/- 0.12 vs. 1.93 +/- 0.12 mg/kg/min), and plasma lipid intermediates and a decreased forearm glucose uptake (0.06 +/- 0.02 vs. 0.19 +/- 0.04 mmol/L) (P less than 0.05); and 3) a 20% increase in energy expenditure, a 50% elevation of lipid oxidation rates, and a 130% elevation of nonoxidative glucose turnover (P less than 0.05). During the clamp the patients with active acromegaly were substantially resistant to the actions of insulin on both glucose and lipid metabolism. Following pituitary surgery all of these metabolic abnormalities were abolished. We conclude that active acromegaly is characterized by profound disturbances of not only glucose but also lipid metabolism, which in theory may precipitate the increased mortality in this disease. By showing that these abnormalities and the concomitant overall insulin resistance can be completely reversed our results may also have important implications for other insulin-resistant states and for the potential therapeutic use of GH.     

Quantitation of forearm glucose and free fatty acid (FFA) disposal in normal subjects and type II diabetic patients: evidence against an essential role for FFA in the pathogenesis of insulin resistance

This study was designed to quantitate glucose and FFA disposal by muscle tissue in patients with type II diabetes and to investigate the relationship between FFA metabolism and insulin resistance. The forearm perfusion technique was used in six normal subjects and two groups of normal weight diabetic patients, i.e. untreated (n = 8) and insulin-treated (n = 6). The latter received 2 weeks of intensive insulin therapy before the study. Plasma insulin levels were raised acutely [950-1110 pmol/L) (130-150 microU/mL)], while the blood glucose concentration was clamped at its basal value [4.9 +/- 0.1 (+/- SE) mmol/L in the normal subjects, 5.7 +/- 0.5 in the insulin-treated diabetic patients, and 5.5 +/- 0.3 in the untreated diabetic patients] by a variable glucose infusion. During the control period, arterial FFA concentrations were similar in the three groups, and they decreased to a comparable extent (less than 0.1 mmol/L) in response to insulin infusion. During the control period, the mean forearm FFA uptake was 2.5 +/- 0.5 mumol/L.min in the normal subjects, 2.9 +/- 0.5 in the insulin-treated patients, and 2.1 +/- 0.5 in the untreated diabetic patients. During the insulin infusion, FFA uptake was profoundly suppressed to similar levels in the normal subjects (0.9 +/- 0.1 mumol/L.min), the insulin-treated diabetic patients (1.1 +/- 0.3), and the untreated diabetic patients (0.9 +/- 0.1; P less than 0.001). Forearm glucose uptake was similar in the three groups during the control period. It increased during the insulin infusion, but the response in both diabetic groups was less than that in the normal subjects. The total amounts of glucose taken up by the forearm during the study period were 5.2 +/- 0.7, 2.6 +/- 0.5, and 2.1 +/- 0.6 mmol/L.min in the normal subjects, the insulin-treated diabetic patients, and the untreated diabetic patients, respectively (P less than 0.01). We conclude that 1) insulin-mediated glucose uptake by forearm skeletal muscle is markedly impaired in type II diabetes and improves only marginally after 2 weeks of intensive insulin therapy; 2) in contrast, no appreciable abnormality in forearm FFA metabolism is demonstrable in insulin-treated type II diabetic patients; and 3) FFA do not contribute to the insulin-treated skeletal muscle insulin resistance that occurs in patients with type II diabetes mellitus.     

Muscle sympathetic nerve activity in patients with acromegaly

Muscle sympathetic nerve activity was measured in nine acromegalic patients (age, 35 +/- 4 yr; body mass index, 28 +/- 2 kg/m2) and eight healthy subjects (age, 32 +/- 3 yr; body mass index, 25 +/- 2 kg/m2) by combining the forearm arterial-venous difference technique with the tracer method [infusion of tritiated norepinephrine (NE)]. Muscle NE release was quantified both at rest and during physiological hyperinsulinemia while maintaining euglycemia (approximately 90 mg/dL) by means of the euglycemic clamp. Arterial plasma NE was similar in the two groups at rest (197 +/- 28 and 200 +/- 27 pg/mL (-1) and slightly increased during insulin infusion. Forearm NE release was 2.33 +/- 0.55 ng x liter(-1) x min(-1) in healthy subjects and 2.67 +/- 0.61 ng x liter(-1) x min(-1) in acromegalic subjects in the basal state and increased to a similar extent during insulin infusion in both groups (3.13 +/- 0.71 and 3.32 +/- 0.75 ng x L(-1) x min(-1), P < 0.05 vs. basal), indicating a normal stimulatory effect of insulin on muscle sympathetic activity. In contrast, insulin-stimulated forearm glucose uptake was markedly lower in acromegalic patients (2.3 +/- 0.4 mg x L(-1) x min(-1)) than in control subjects (7.9 +/- 1.3 mg x L(-1) x min(-1), P < 0.001), indicating the presence of severe insulin resistance involving glucose metabolism. Our data demonstrate that patients with long-term acromegaly have normal sympathetic activity in the skeletal muscle in the basal, postabsorptive state and normal increments in NE spillover in response to the sympatho-excitatory effect of insulin. Thus, the presence of severe insulin resistance in acromegaly is not accounted for by adrenergic mechanisms.     

Interaction of lipid and carbohydrate metabolism after infusions of lipids or of lipid lowering agents: lack of a direct relationship between free fatty acid concentrations and glucose disposal.

The present work was planned to study the effects of changes in lipid metabolism irrespective of FFA concentrations (FFA) on the regulation of oxidative and nonoxidative disposal of a glucose infusion during hyperinsulinaemia. Fifteen normal volunteers participated in the 3 protocols, in which 1) Intralipid 2) beta-pyridylcarbinol or 3) isotonic saline were infused during 2 hours. Thereafter, these infusions were discontinued and a two-hour euglycaemic hyperinsulinaemic clamp was performed. All three studies were carried out in combination with indirect calorimetry to measure glucose uptake, and oxidative and nonoxidative glucose disposal (corresponding essentially to glucose storage). Plasma FFA concentrations were 508 +/- 34, 601 +/- 43 and 546 +/- 45 mumol/l in the basal state during the Intralipid, beta-pyridylcarbinol and control protocols. It increased to 960 +/- 71 mumol/l after the Intralipid infusion, fell to 246 +/- 17 mumol/l after the beta-pyridylcarbinol infusion, vs 600 +/- 48 mumol/l in the control. At the end of the glucose-insulin clamp the values were low in the 3 protocols: 263 +/- 17, 233 +/- 19 and 204 +/- 14 mumol/l. Intralipid infusion prior to the clamp protocol induced a suppression of both insulin-mediated glucose uptake (4.91 +/- 0.46 (Intralipid) vs 6.83 +/- 0.63 mg.kg-1.min-1 (saline)) and storage (1.61 +/- 0.34 vs 2.99 +/- 0.53 mg.kg-1.min-1) while beta-pyridylcarbinol infusion induced an increased insulin-mediated glucose uptake (8.58 +/- 0.37 mg.kg-1.min-1) and in glucose storage (4.29 +/- 0.31 mg.kg-1.min-1) (p less than 0.5 vs Intralipid). These changes occurred even though FFA plasma concentrations were similar in the 3 experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum leptin levels in patients with acromegaly before and after correction of hypersomatotropism by trans-sphenoidal surgery

It has been shown that GH excess is associated with decreased leptin levels and decreased body fat mass. Reports regarding the effect of GH on serum leptin levels are inconsistent. We studied leptin secretion in 20 acromegalics before and 2 months after trans-sphenoidal surgery and in 20 gender-, age-, and body mass index (BMI)-matched control subjects. The mean 8-h leptin concentration for each subject was measured from a pool formed of samples collected hourly beginning at 2200 h until 0600 h the next morning. In a subgroup of 10 acromegalics, leptin pulsatility was assessed for the same period of time in 10-min sampling intervals. Basal GH, insulin-like growth factor-I (IGF-I), insulin, glucose, and lipids levels were measured. Area under the curve for insulin (AUCins) during oral glucose tolerance test was calculated. Control subjects and acromegalics had similar BMI, but patients with active acromegaly had significantly lower mean leptin level (mean +/- SEM; in men, 2.6+/-0.4 vs. 7.1+/-1.1 microg/L, P = 0.003; in women, 16.0+/-3.4 vs. 23.5+/-3.1 microg/L; P = 0.036). Mean 8-h leptin correlated with BMI (r = 0.57, P = 0.007, in controls; r = 0.70, P = 0.001, in patients). In stepwise regression analysis with mean 8-h leptin as a dependent variable, BMI (P<0.001) and gender (P = 0.01) in acromegalics entered the equation, whereas in control subjects gender, free fatty acids, insulin, and age accounted for 99.3% in leptin variability. After surgery, BMI did not change significantly; and glucose (P = 0.014), GH (P<0.001), and IGF-I (P<0.001) levels together with AUCins (P = 0.002) decreased, whereas mean leptin concentration rose significantly and attained normal levels (4.1+/-0.8 microg/L, P = 0.028) in acromegalic men and (23.6+/-4.7 microg/L, P = 0.003) in acromegalic women. Correlation between leptin level and BMI was preserved after surgery (r = 0.62, P = 0.005). In stepwise regression analysis, free fatty acids (P = 0.04) contributed to 26.8% of the variance in corrected-leptin (for BMI and gender). Leptin concentration peak height and interpeak nadir level rose significantly (P = 0.033 and P = 0.037) after surgery by Cluster analysis, without significant changes in leptin pulse frequency and incremental peak amplitude. Nocturnal rise of leptin (mathematically described by a cubic curve) was characterized by an acrophase just after midnight, before and after surgery. The amplitude and the average leptin concentration of the cubic fit increased significantly after surgery (P = 0.028 and P< 0.001). In conclusion in acromegalic patients: 1) leptin secretion maintains the pulsatility and nocturnal rise; 2) the gender-based leptin differences are preserved; 3) GH-IGF-I normalization leads to a rise in leptin that is not related to changes in BMI; and 4) the possible role of rise in leptin levels when assessing clinical and metabolic outcome of therapy in acromegalic patients deserves additional studies.     

Severity, duration, and mechanisms of insulin resistance during acute infections

Acute infections provoke insulin resistance. These experiments were designed to study the severity, duration, and mechanisms of insulin resistance caused by acute infections. First, we studied eight patients [mean age, 29 +/- 11 (+/- SD) yr; body mass index, 23 +/- 2 kg/m2] with acute viral or bacterial infections during the acute stage of their infection and 1-3 months after recovery. The rate of glucose infusion required to maintain normoglycemia during hyperinsulinemia (approximately 500 pmol/L) was used as a measure of insulin action. During infection, the glucose requirements in the patients [21 +/- 2 (+/- SE) mumol/kg.min] were 52% less than those in weight- and age-matched normal subjects (44 +/- 2 mumol/kg.min; P less than 0.001). Compared to data from a large group of normal subjects, the resistance to insulin during infection corresponded to that predicted for a weight-matched 84-yr-old normal person or an age-matched obese person with a body mass index of 37 kg/m2. One to 3 months after recovery, the patients' glucose requirements were still significantly lower (37 +/- 3 mumol/kg.min; P less than 0.02) than those in matched normal subjects. To assess the mechanism of insulin resistance, seven additional patients were studied during the acute stage of infection using a low dose insulin infusion (plasma insulin, 215 pmol/L) combined with a [3-3H]glucose infusion and indirect calorimetry. Again, the glucose requirements were 59% lower in the patients (14 +/- 2 mumol/kg.min) than in matched normal subjects (34 +/- 2 mumol/kg.min; P less than 0.001). This decrease was due to a defect in glucose utilization (18 +/- 2 vs. 37 +/- 1 mumol/kg.min; P less than 0.001, patients vs. normal subjects) rather than impaired suppression of glucose production (4 +/- 1 vs. 3 +/- 1 mumol/kg.min, respectively). Total carbohydrate oxidation rates were similar in both groups (16 +/- 2 vs. 14 +/- 1 mumol/kg.min, respectively), whereas the apparent glucose storage was neglible in the patients (2 +/- 1 mumol/kg.min) compared to that in normal subjects (22 +/- 2 mumol/kg.min; P less than 0.001). We conclude that acute infections induce severe and long-lasting insulin resistance, which is localized to glucose-utilizing pathways. The rate of carbohydrate oxidation is normal during infections, whereas the rate of nonoxidative glucose disposal, as determined by indirect calorimetry, is nearly zero. The apparent blockade in glucose storage could result from diminished glycogen synthesis, accelerated glycogenolysis, or both.     

Impact of octreotide, a long-acting somatostatin analogue, on glucose tolerance and insulin sensitivity in acromegaly

OBJECTIVE: We aimed to investigate the impact of a long-acting somatostatin analogue, octreotide, on glucose tolerance and on insulin sensitivity in acromegaly. DESIGN: We performed a non-randomized controlled trial. PATIENTS: Seven patients with active acromegaly were assessed before and during octreotide therapy given in a dose of 500 micrograms three times daily subcutaneously. MEASUREMENTS: The effects of octreotide on carbohydrate metabolism were assessed by performing a glucose tolerance test and a euglycaemic hyperinsulinaemic clamp. These latter tests were undertaken 8 hours after the last dose, allowing GH and glucagon to return to pretreatment levels during the study. RESULTS: Octreotide significantly reduced (P less than 0.05) mean +/- SEM 12-h GH (from 42 +/- 13 to 10 +/- 3 mIU/I) and IGF-I (from 4.2 +/- 0.5 to 2.1 +/- 0.5 U/ml) concentrations. Glucose tolerance was normalized in four of five patients with impaired glucose tolerance without a significant change in mean insulin concentrations. The improvement in fasting and mean blood glucose during glucose tolerance testing was dependent on the pretherapy blood glucose concentrations (r = -0.95, P = 0.002). The glucose infusion rate during the hyperinsulinaemic (5 U/h) clamp was significantly increased (P less than 0.05, 15.3 +/- 1.8 vs 24.2 +/- 5.4 mumol/kg min) following octreotide treatment. Insulin infusion during the glucose clamp completely suppressed hepatic glucose production during but not before octreotide treatment (7.9 +/- 2.4 vs 0.7 +/- 2.2 mumol/kg min, P = 0.02). Insulin-mediated stimulation of peripheral glucose uptake was unaffected by treatment. Mean GH and glucagon levels during both clamp studies were not significantly different. CONCLUSIONS: Octreotide improves whole body insulin sensitivity by an increased ability of insulin to suppress hepatic glucose production without affecting the substantial impairment of peripheral insulin action. Octreotide has beneficial effects on carbohydrate metabolism in acromegalic patients with glucose intolerance.     

Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly

OBJECTIVE: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. DESIGN AND METHODS: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test--oral glucose tolerance test (OGTT) and the GH provocation test--ghrelin test (1 microg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. RESULTS: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 microg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 microg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (+/-s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 +/- 0.2 microg/l vs 20.1 +/- 2.4 microg/l vs 31.1 +/- 2.5 microg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. CONCLUSIONS: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.     

Relationship among peripheral glucose uptake, oxygen consumption, and glucose turnover in postabsorptive man

To assess the importance of glucose uptake by muscle in determining total glucose utilization in the basal state, forearm glucose uptake (FGU), reflecting mainly skeletal muscle metabolism, and glucose turnover using [3-3H]glucose were studied simultaneously in 17 postabsorptive normal men. Mean +/- SE glucose disappearance was 2.36 +/- 0.14 mg/kg X min, amounting to 170 +/- 9 mg/min, while FGU was 0.049 +/- 0.009 mg/100 ml forearm X min. When the latter was calculated in terms of skeletal muscle in the body as a whole, muscle glucose utilization was found to be 24.7 +/- 4.5 mg/min, comprising only 13.5 +/- 1.9% of the total glucose disappearance. Forearm oxygen consumption was 6.6 +/- 0.5 mumol/100 ml forearm X min, of which only 26 +/- 5% could be accounted for by concurrent glucose uptake. These results suggest that in the basal state, glucose uptake by skeletal muscle accounts for 1) only a small percentage of total glucose disappearance and 2) only a minor proportion of peripheral oxygen consumption, which may be more dependent on lipid oxidation.     

Role of the splanchnic tissues in the pathogenesis of altered carbohydrate metabolism in patients with chronic renal failure

To evaluate the contribution of the splanchnic area to the carbohydrate abnormalities associated with chronic uremia, the splanchnic exchange of glucose and gluconeogenic substrates was quantitated basally and after an iv glucose load in nine uremic patients with impaired glucose tolerance and seven control subjects. In the basal state, blood glucose and splanchnic glucose production were similar in the two groups. During glucose infusion (33 mumol/kg.min for 90 min), blood glucose reached significantly higher levels in the uremic patients than in controls (P less than 0.02). Plasma insulin increased slightly more in uremic patients than in controls (P less than 0.05 at 15 min). Both basal and postglucose glucagon levels were 2- to 3-fold higher in uremic patients than in normal subjects (P less than 0.05-0.02). In both groups, splanchnic glucose balance switched from net output in the basal state (-9.4 +/- 0.5 and -8.0 +/- 1.1 mumol/kg.min in normals and uremics, respectively) to net uptake with glucose infusion. However, this response was less marked in the uremic patients than in normal subjects (P less than 0.05-0.02 at 30 and 90 min). The cumulative net splanchnic glucose balance over the 90-min study period was 538 +/- 55 mumol/kg in normal subjects and 279 +/- 89 in uremic subjects (P less than 0.05). A net splanchnic lactate uptake was present in the basal state in normal (4.2 +/- 0.5 mumol/kg.min) and uremic subjects (3.4 +/- 0.5). During glucose infusion, in normal subjects splanchnic lactate exchange switched to a net output (-4.0 +/- 1.6 mumol/kg.min), whereas in the uremic group it remained as a net uptake (1.1 +/- 0.7) throughout the study period. Splanchnic gluconeogenic amino acid uptake was similar in the two groups in the basal state (1.8 +/- 0.1 mumol/kg.min and 2.2 +/- 0.2 in normal and uremic subjects, respectively). Glucose infusion caused a marked fall in amino acid uptake by liver in normal subjects, whereas no change was observed in the uremic group (0.9 +/- 0.3 and 1.9 +/- 0.2 mumol/kg.min, respectively). Splanchnic glycerol uptake was not different in the two groups in the basal state (0.75 +/- 0.2 and 1.1 +/- 0.2 mumol/kg.min) and decreased to a similar extent during glucose infusion. We conclude the following. 1) In uremic patients with glucose intolerance but normal fasting glycemia, the splanchnic metabolism of glucose and gluconeogenic substrates is normal in the postabsorptive state.(ABSTRACT TRUNCATED AT 400 WORDS)