Measurement of free GH and bioactive IGF-I in non-diabetic haemodialysis patients treated with GH for 7 days.

BACKGROUND: End-stage renal failure (ESRF) patients demonstrate augmented growth hormone (GH) secretion, but normal insulin-like growth factor-I (IGF-I) concentrations, indicating a state of GH resistance. To test this hypothesis, we compared the IGF-I response with exogenous GH in haemodialysis patients and healthy controls, with special focus on free GH and bioactive IGF-I. METHODS: Ultrafiltered free GH and total GH were measured in serum collected hourly for 24 h at baseline and after 7 days of recombinant human (rh) GH (50 µg/kg/day) treatment in 11 non-diabetic haemodialysis patients and 10 matched controls. Serum levels of bioactive IGF-I (determined by cell-based IGF-I receptor activation assay), total IGF-I and the GH-binding protein (GHBP) were assayed twice daily. RESULTS: At baseline, patients showed elevated total GH (24 ± 5 versus 9 ± 1 µg/L × h, P < 0.02), free GH (21 ± 5 versus 7 ± 1 µg/L × h, P < 0.02), reduced GHBP (1.5 ± 0.3 versus 2.5 ± 0.2 nmol/L, P < 0.01), high-normal total IGF-I (173 ± 18 versus 135 ± 14 µg/L, P = 0.12) and subnormal bioactive IGF-I (2.1 ± 0.3 versus 2.8 ± 0.2 µg/L, P < 0.05) when compared with controls. After 7 days of rhGH treatment, there was a greater GH increase in the non-diabetic haemodialysis patients than in controls (total GH: 293 ± 33 versus 166 ± 13 µg/L × h, P < 0.001; free GH: 284 ± 40 versus 126 ± 15 µg/L × h, P < 0.001). GHB remained unaffected and total IGF-I increased to the same extent in patients and controls (701 ± 87 versus 572 ± 33 µg/L, P = 0.17), whereas bioactive IGF-I tended to be lower in patients (5.37 ± 0.55 versus 6.63 ± 0.25 µg/L, P < 0.10). When adjusting for the actual increments in plasma GH, the ability of exogenous GH to stimulate bioactive IGF-I levels was reduced by ~50% in ESRF (P < 0.02), whereas the response of total IGF-I remained normal (74%; P= 0.18) CONCLUSIONS: The study demonstrates that ESRF is associated with markedly elevated serum levels of free GH. Furthermore changes in bioactive, but not immunoreactive, IGF-I indicated that the hepatic sensitivity to GH was reduced by 50% in ESRF patients. Clearly, the physiological importance of our observations awaits further studies, but they suggest that changes in total IGF-I may not necessarily reflect changes in the endogenous activity of IGF-I in ESRF patients on GH treatment.

OPPORTUNITY™: a large-scale randomized clinical trial of growth hormone in hemodialysis patients.

BACKGROUND: Adult maintenance hemodialysis (MHD) patients experience high mortality and morbidity and poor quality of life (QoL). Markers of protein-energy wasting are associated with these poor outcomes. The OPPORTUNITY™ Trial examined whether recombinant human growth hormone (hGH) reduces mortality in hypoalbuminemic MHD patients. Secondary end points were effects on number of hospitalizations, cardiovascular events, lean body mass (LBM), serum proteins, exercise capacity, QoL and adverse events. METHODS: We performed a randomized, double-blind, placebo-controlled, multicenter multinational trial stratified for diabetic status. Clinically, stable adult MHD patients with serum albumin <4.0 g/dL were randomized to subcutaneous injections of hGH, 20 µg/kg/day, or placebo. Planned treatment duration was 24 months for 2500 patients. The trial was terminated early due to slow recruitment. RESULTS: Seven hundred and twelve patients were randomized until trial termination; 695 patients received at least one dose of trial medication. Mean treatment duration was 20 weeks (no completers). There were no differences between groups in all-cause mortality, cardiovascular morbidity or mortality, serum albumin, LBM, physical exercise capacity or QoL. The hGH group, compared to placebo, displayed a reduction in body weight, total body fat, serum high-sensitivity C-reactive protein and possibly homocysteine and an increase in serum high-density lipoprotein-cholesterol and transferrin levels. CONCLUSIONS: Although the OPPORTUNITY™ Trial was terminated early, treatment with hGH, compared to placebo, improved certain cardiovascular risk factors but did not reduce mortality, cardiovascular events or improve nutritional factors or QoL. The power for showing differences was substantially reduced due to the marked decrease in treatment duration and sample size.

Cost-effectiveness of somatropin for the treatment of short children born small for gestational age.

BACKGROUND: Short children born small for gestational age (SGA) may be at increased risk for long-term morbidity and reduced health-related quality of life (HRQoL) due to their short stature. Normalization of height in childhood and adolescence is possible in such children via the use of the recombinant human growth hormone somatropin. OBJECTIVE: The aim of this study was to determine whether somatropin was a cost-effective treatment option in short children born SGA. METHODS: A decision analytic model was constructed to calculate the cost-effectiveness of somatropin treatment versus no treatment over the lifetime of a short individual born SGA, from the perspective of the UK National Health Service (NHS). The model was based on patient-level data from a multicenter, double-blind, randomized controlled trial that reported the effects of somatropin on final (adult) height in short children born SGA. Health care resource and drug costs associated with each of the treatment arms were considered, and published utility scores were used to calculate improvement in HRQoL. The model calculated incremental costs and incremental quality-adjusted life-years (QALYs) associated with somatropin treatment compared with no treatment. Cost-effectiveness was expressed as incremental cost per QALY and cost per centimeter of height gained. RESULTS: Over a patient's lifetime, somatropin (0.033 mg/kg/d) treatment was associated with a height gain of 16.12 cm and a cost per centimeter of height gained of pound4359 compared with no treatment. The incremental cost of somatropin treatment was pound70,263, with a QALY gain of 2.95, resulting in an incremental cost per QALY of pound23,807-below the widely accepted cost-effectiveness threshold in the United Kingdom of pound30,000. CONCLUSION: In this model, somatropin was a cost-effective treatment option for short children born SGA from the perspective of the UK NHS.

The cost-effectiveness of somatropin treatment for short children born small for gestational age (SGA) and children with growth hormone deficiency (GHD) in Sweden.

OBJECTIVE: Reduction in health-related quality of life is common in children born small for gestational age (SGA) or children with growth hormone deficiency (GHD). Growth hormone treatment with somatropin in these children leads to normalisation of height. The aim of this study was to determine whether somatropin is a cost-effective treatment option for short children born SGA and GHD children in Sweden. METHODS: A Markov decision-tree model was used to calculate the relative costs and health benefits associated with somatropin treatment over the lifetime of SGA and GHD children, compared with no treatment. The analysis was undertaken from a Swedish Health Service perspective. As quality-adjusted life-year (QALY) data were not obtained directly in the clinical studies, a degree of uncertainty is related to these results. Sensitivity analyses assessed the degree of uncertainty surrounding central parameters. RESULTS: For short children born SGA, somatropin treatment was associated with an additional 3.29 QALYs at an incremental cost of 792,489 SEK (Swedish Krona), compared with no treatment. For GHD, somatropin treatment resulted in 3.25 additional QALYs at an incremental cost of 391,291 SEK. This equates to an incremental cost per QALY of 240,831 SEK and 120,494 SEK for SGA and GHD, respectively, below a cost-effectiveness threshold of 500,000-600,000 SEK/QALY. CONCLUSIONS: Somatropin is a cost-effective treatment strategy in Sweden for children with GHD and SGA. To overcome present study limitations future clinical research should incorporate appropriate quality of life questionnaires.

OPPORTUNITY: a randomized clinical trial of growth hormone on outcome in hemodialysis patients.

BACKGROUND: The mortality rate of maintenance hemodialysis (MHD) patients remains high. Measures of protein-energy wasting, including hypoalbuminemia, are strongly associated with their high mortality. Growth hormone (GH) may improve lean body mass (LBM) and serum albumin levels, and health-related quality of life (HRQoL), which are significantly and positively associated with survival in MHD patients. The OPPORTUNITY Trial will examine whether GH reduces mortality and morbidity and improves overall health in hypoalbuminemic MHD patients. HYPOTHESIS: The primary hypothesis is that daily recombinant human GH injections, compared with placebo, improve survival in hypoalbuminemic MHD patients. Secondary hypotheses are that GH improves morbidity and health, including number of hospitalized days, time to cardiovascular events, LBM, serum protein and inflammatory marker levels, exercise capacity, and HRQoL, and has a favorable safety profile. DESIGN/MEASUREMENTS: This is a prospective, double-blind, multicenter, randomized clinical trial involving 2500 MHD patients, up to 50% with diabetes mellitus, from 22 countries. Patients are randomized in a 1:1 ratio to receive daily injections of GH (20 microg/kg per day) or placebo for 104 weeks. Key inclusion criteria include clinically stable and well-dialyzed (Kt/V > or =1.2) adult MHD patients with serum albumin <4.0 g/dl. Exclusion criteria include active malignancy, active proliferative or severe nonproliferative diabetic retinopathy, uncontrolled hypertension, chronic use of high-dose glucocorticoids, or immunosuppressive agents and pregnancy. CONCLUSIONS: The OPPORTUNITY Trial is the first large-scale randomized clinical trial in adult MHD patients evaluating the response to GH of such clinical endpoints as mortality, morbidity, markers of body protein mass, inflammation, exercise capacity, and HRQoL.

Acute effects of ghrelin administration on glucose and lipid metabolism.

CONTEXT: Ghrelin infusion increases plasma glucose and nonesterified fatty acids, but it is uncertain whether this is secondary to the concomitant release of GH. OBJECTIVE: Our objective was to study direct effects of ghrelin on substrate metabolism. DESIGN: This was a randomized, single-blind, placebo-controlled two-period crossover study. SETTING: The study was performed in a university clinical research laboratory. PARTICIPANTS: Eight healthy men aged 27.2 +/- 0.9 yr with a body mass index of 23.4 +/- 0.5 kg/m(2) were included in the study. INTERVENTION: Subjects received infusion of ghrelin (5 pmol x kg(-1) x min(-1)) or placebo for 5 h together with a pancreatic clamp (somatostatin 330 microg x h(-1), insulin 0.1 mU x kg(-1) x min(-1), GH 2 ng x kg(-1) x min(-1), and glucagon 0.5 ng.kg(-1) x min(-1)). A hyperinsulinemic (0.6 mU x kg(-1) x min(-1)) euglycemic clamp was performed during the final 2 h of each infusion. RESULTS: Basal and insulin-stimulated glucose disposal decreased with ghrelin [basal: 1.9 +/- 0.1 (ghrelin) vs. 2.3 +/- 0.1 mg x kg(-1) x min(-1), P = 0.03; clamp: 3.9 +/- 0.6 (ghrelin) vs. 6.1 +/- 0.5 mg x kg(-1) x min(-1), P = 0.02], whereas endogenous glucose production was similar. Glucose infusion rate during the clamp was reduced by ghrelin [4.0 +/- 0.7 (ghrelin) vs. 6.9 +/- 0.9 mg.kg(-1) x min(-1); P = 0.007], whereas nonesterified fatty acid flux increased [131 +/- 26 (ghrelin) vs. 69 +/- 5 micromol/min; P = 0.048] in the basal period. Regional lipolysis (skeletal muscle, sc fat) increased insignificantly with ghrelin infusion. Energy expenditure during the clamp decreased after ghrelin infusion [1539 +/- 28 (ghrelin) vs. 1608 +/- 32 kcal/24 h; P = 0.048], but the respiratory quotient did not differ. Minor but significant elevations in serum levels of GH and cortisol were observed after ghrelin infusion. CONCLUSIONS: Administration of exogenous ghrelin causes insulin resistance in muscle and stimulates lipolysis; these effects are likely to be direct, although a small contribution of GH and cortisol cannot be excluded.

Effects of cortisol on carbohydrate, lipid, and protein metabolism: studies of acute cortisol withdrawal in adrenocortical failure.

CONTEXT: Cortisol is an important catabolic hormone, but little is known about the metabolic effects of acute cortisol deficiency. OBJECTIVE: The objective of the study was to test whether clinical symptoms of weight loss, fatigue, and hypoglycemia could be explained by altered energy expenditure, protein metabolism, and insulin sensitivity during cortisol withdrawal in adrenocortical failure. DESIGN, PARTICIPANTS, AND INTERVENTION: We studied seven women after 24-h cortisol withdrawal and during replacement control during a 3-h basal period and a 3-h glucose clamp. RESULTS: Cortisol withdrawal generated cortisol levels close to zero, a 10% decrease in basal energy expenditure, increased TSH and T(3) levels, and increased glucose oxidation. Whole-body glucose and phenylalanine turnover were unaltered, but forearm phenylalanine turnover was increased. During the clamp glucose, infusion rates rose by 70%, glucose oxidation rates increased, and endogenous glucose production decreased. Urinary urea excretion decreased by 40% over the 6-h study period. CONCLUSIONS: Cortisol withdrawal increased insulin sensitivity in terms of increased glucose oxidation and decreased endogenous glucose production; this may induce hypoglycemia in adrenocortical failure. Energy expenditure and urea loss decreased, indicating that weight and muscle loss in Addison's disease is caused by other mechanisms, such as decreased appetite. Increased muscle protein breakdown may amplify the loss of muscle protein.

Continuous subcutaneous glucose monitoring shows a close correlation between mean glucose and time spent in hyperglycemia and hemoglobin A1c.

BACKGROUND: The Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study highlighted hemoglobin A1c (HbA1c) as the main predictor of diabetic complications. Currently, diabetes is managed by frequent capillary spot glucose measurements, but continuous monitoring systems may have the capacity of improving diabetic control. The SCGM 1 system is microdialysis based and allows for monitoring of changes in interstitial fluid glucose levels every minute. The aim of this study was to evaluate the correlation between HbA1c and short-term glucose excursions in patients with type 1 diabetes. MATERIAL AND METHODS: We investigated 91 patients with type 1 diabetes (mean +/- standard deviation (SD); age 34 +/- 10 years, body mass index 24.2 +/- 4.1 kg/m2) with a duration of diabetes of 17 +/- 11 years for 4.8 +/- 0.4 days. The average HbA1c was 7.9 +/- 1.4%. From the monitoring profiles we determined individual mean glucose, the SD of glucose, and the relative time spent in hyperglycemia and hypoglycemia calculated as the area under the curve (AUC) with arbitrary cutoffs of 180 and 70 mg/dl, respectively. RESULTS: Mean glucose, SD glucose, and hyperglycemic and hypoglycemic AUC all correlated with HbA1c, but with decreasing statistical power. In multiple linear regression analysis, mean glucose was the sole independent variable (r = 0.626, p < 0.0001). A close correlation between HbA1c and various measures of short-term hyperglycemic values was observed. There was a close correlation between mean glucose and SD glucose, pointing toward increased variability with increasing mean glucose. CONCLUSIONS: Mean glucose generated after short-term continuous monitoring is the main predictor of HbA1c and reveals increased lability of glucose with increasing mean glucose and HbA1c.

Clinical and epidemiological description of aortic dissection in Turner's syndrome.

BACKGROUND: Women with Turner's syndrome have an increased risk of congenital cardiac malformations, ischaemic heart disease, hypertension and stroke. Aortic dissection seems to occur with increased frequency. AIM: To describe in more detail aortic dissection as encountered in Turner's syndrome, giving attention to clinical, histological and epidemiological aspects. MATERIALS AND METHODS: Based on a retrospective study, we describe the clinical, karyotypic, and epidemiological aspects of aortic dissection as encountered in cases of Turner's syndrome seen in Denmark and Sweden. RESULTS: The median age at onset of aortic dissection in 18 women was 35 years, ranging from 18 to 61 years. Fourteen of 18 women had a 45,X karyotype, while 2 patients had 45,X/45,XY, and 2 had the 45,X/46,X+r(X) complement, respectively. Echocardiography was performed in 10 of 18 patients before their acute illness, and showed signs of congenital cardiac disease, with either bifoliate aortic valves, dilation of the aortic root, or previous aortic coarctation evident in most patients. In 5 patients evidence of a bifoliate aortic valve was conclusive. Hypertension was present in 5 of 18 patients, while 10 of the patients died from aortic dissection, of so-called type A in 6, type B in 3, while in the final case the origin of dissection could not be determined. Biochemical analysis showed altered ratio between type I and type III collagen. Histology showed cystic medial necrosis in 3 of 7 cases. We estimated an incidence of dissection of 36 per 100,000 Turner's syndrome years, compared with an incidence of 6 per 100,000 in the general population, and a cumulated rate of incidence of 14, 73, 78, and 50 per 100,000 among 0-19, 20-29, 30-39, and 40+ year olds, respectively. CONCLUSION: Aortic dissection is extremely common in the setting of Turner's syndrome, and occurs early in life. Patients with Turner's syndrome should be offered a protocol for clinical follow-up similar to that provided for patients with Marfan syndrome, and each clinic should embrace a programme for follow-up.

Continuous glucose monitoring in interstitial subcutaneous adipose tissue and skeletal muscle reflects excursions in cerebral cortex.

Continuous glucose monitoring (CGM) is being explored using several types of glucose sensors. Some are designed for subcutaneous adipose tissue. It is important to determine to which extent these glucose fluctuations in different tissues reflect changes taking place in the central nervous system, where glucose sensing is thought to occur. We studied the ability of subcutaneous adipose interstitial fluid measurements to parallel glucose propagations in blood, muscle, and central nervous system (CNS) during hyper- and hypoglycemia. A subcutaneous CGM system was applied in the CNS, subcutaneous adipose tissue, and skeletal muscle of nine Vietnamese potbellied pigs, and data were compared with frequent sampling in blood. Alterations in glucose levels were induced with intravenous glucose and insulin. During hyperglycemia, no difference was detected in delay between blood and interstitial glucose levels in subcutaneous adipose tissue (18.0 +/- 0.8 min), muscle (18.0 +/- 0.9 min), and CNS (20.3 +/- 1.2 min), respectively. During hypoglycemia, we found no time difference between interstitial parameters in the three tissues. However, the amplitude of glucose changes varied considerably, with a smaller magnitude of glucose change taking place in the brain. The timing of glucose excursions in subcutaneous adipose tissue and muscle reflect excursions in CNS. The reduced magnitude of glucose excursions in the brain suggests that different mechanisms of glucose transport are operative in CNS compared with subcutaneous adipose tissue and muscle.

Evidence against a role for insulin-signaling proteins PI 3-kinase and Akt in insulin resistance in human skeletal muscle induced by short-term GH infusion.

Prolonged growth hormone (GH) excess is known to be associated with insulin resistance, but the underlying mechanisms remain unknown. The aim of this study was to assess the impact of GH on insulin-stimulated glucose metabolism and insulin signaling in human skeletal muscle. In a cross-over design, eight healthy male subjects (age 26.0 +/- 0.8 yr and body mass index 24.1 +/- 0.5 kg/m2) were infused for 360 min with either GH (Norditropin, 45 ng.kg(-1).min(-1)) or saline. During the final 180 min of the infusion, a hyperinsulinemic euglycemic clamp was performed (insulin infusion rate: 1.2 mU.kg(-1).min(-1)). Muscle biopsies from vastus lateralis were taken before GH/saline administration and after 60 min of hyperinsulinemia. GLUT4 content and insulin signaling, as assessed by insulin receptor substrate (IRS)-1-associated phosphatidylinositol 3-kinase and Akt activity were determined. GH levels increased to a mean (+/-SE) level of 20.0 +/- 2.3 vs. 0.5 +/- 0.2 microg/l after saline infusion (P < 0.01). During GH infusion, the glucose infusion rate during hyperinsulinemia was reduced by 38% (P < 0.01). In both conditions, free fatty acids were markedly suppressed during hyperinsulinemia. Despite skeletal muscle insulin resistance, insulin still induced a similar approximately 3-fold rise in IRS-1-associated PI 3-kinase activity (269 +/- 105 and 311 +/- 71% compared with baseline, GH vs. saline). GH infusion did not change Akt protein expression, and insulin caused an approximately 13-fold increase in Akt activity (1,309 +/- 327 and 1,287 +/- 173%) after both GH and saline infusion. No difference in total GLUT4 content was noted (114.7 +/- 7.4 and 107.6 +/- 16.7 arbitrary units, GH vs. saline, compared with baseline). In conclusion, insulin resistance in skeletal muscle induced by short-term GH administration is not associated with detectable changes in the upstream insulin-signaling cascade or reduction in total GLUT4. Yet unknown mechanisms in insulin signaling downstream of Akt may be responsible.

Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia.

This study assessed whether glucose-dependent insulin secretion and overall counterregulatory response are preserved during hypoglycemia in the presence of exenatide. Twelve healthy fasted volunteers were randomized in a triple-blind crossover study to receive either intravenous exenatide (0.066 pmol. kg(-1). min(-1)) or placebo during a 270-min stepwise hyperinsulinemic-hypoglycemic clamp (insulin infusion 0.8 mU. kg(-1). min(-1)). Plasma glucose was clamped sequentially at 5.0 (0-120 min), 4.0 (120-180 min), 3.2 (180-240 min), and 2.7 mmol/l (240-270 min). At 270 min, insulin infusion was terminated and plasma glucose increased to approximately 3.2 mmol/l. The time to achieve plasma glucose >/=4 mmol/l thereafter was recorded. Insulin secretory rates (ISRs) and counterregulatory hormones were measured throughout. Glucose profiles were superimposable between the exenatide and placebo arms. In the presence of euglycemic hyperinsulinemia, ISRs in the exenatide arm were approximately 3.5-fold higher than in the placebo arm (353 +/- 29 vs. 100 +/- 29 pmol/min [least-square means +/- SE]). However, ISRs declined similarly and rapidly at all hypoglycemic steps (

Effects of growth hormone on lipid metabolism in humans.

The most immediate effect of growth hormone (GH) administration in humans is a significant increase in free fatty acids after 1-2 h, reflecting stimulation of lipolysis and ketogenesis. This stimulation represents an important physiological adaptation to stress and fasting. When the capacity of GH to increase lipolysis is blocked, the protein-retaining and insulin-antagonistic effects of GH on glucose metabolism are either abolished or weakened dramatically, compatible with a key role for lipolysis in orchestrating the metabolic actions of GH.

Effects of GH on urea, glucose and lipid metabolism, and insulin sensitivity during fasting in GH-deficient patients.

Fasting-related states of distress pose major health problems, and growth hormone (GH) plays a key role in this context. The present study was designed to assess the effects of GH on substrate metabolism and insulin sensitivity during short-term fasting. Six GH-deficient adults underwent 42.5 h of fasting on two occasions, with and without concomitant GH replacement. Palmitate and urea fluxes were measured with the steady-state isotope dilution technique after infusion of [9,10-3H]palmitate and [13C]urea. During fasting with GH replacement, palmitate concentrations and fluxes increased by 50% [palmitate: 378 +/- 42 (GH) vs. 244 +/- 12 micromol/l, P < 0.05; palmitate: 412 +/- 58 (GH) vs. 276 +/- 42 microM, P = 0.05], and urea turnover and excretion decreased by 30-35% [urea rate of appearance: 336 +/- 22 (GH) vs. 439 +/- 43 micromol. kg-1. h-1, P < 0.01; urea excretion: 445 +/- 43 (GH) vs. 602 +/- 74 mmol/24 h, P < 0.05]. Insulin sensitivity (determined by a euglycemic hyperinsulinemic clamp) was significantly decreased [M value: 1.26 +/- 0.06 (GH) vs. 2.07 +/- 0.22 mg. kg-1. min-1, P < 0.01] during fasting with GH replacement. In conclusion, continued GH replacement during fasting in GH-deficient adults decreases insulin sensitivity, increases lipid utilization, and conserves protein.

Elevated regional lipolysis in hyperthyroidism.

Hyperthyroidism is characterized by increased levels of circulating free fatty acids (FFA) and increased lipid oxidation, but it is uncertain which regional fat depots contribute. The present study was designed to define the participation of femoral and abdominal fat stores in the overall stimulation of lipolysis in hyperthyroidism in the basal state and during insulin stimulation. We studied nine women with newly diagnosed hyperthyroidism (HT) and after (euthyroidism, ET) medical treatment with methimazol and compared with eight control subjects (CTR). All subjects were studied in the postabsorptive state and during a 3-h hyperinsulinemic euglycemic clamp with microdialysis catheters sc in the abdominal and femoral adipose tissue. Before treatment, patients had elevated circulating concentrations of triiodthyronine, FFA, and glycerol. Levels of interstitial glycerol ( micro mol/liter) in abdominal adipose tissue [485 +/- 24 (HT), 226 +/- 20 (ET) (P < 0.001), 265 +/- 34 (CTR) (P < 0.001)] and in femoral adipose tissue [468 +/- 41(HT), 245 +/- 29 (ET) (P < 0.01), 278 +/- 31(CTR) (P < 0.005)] were elevated in the basal hyperthyroid state, and these differences prevailed during the glucose clamp [230 +/- 23 (HT), 113 +/- 13 (ET) (P < 0.01), 132 +/- 22(CTR) (P < 0.01) and 303 +/- 39 (HT), 122 +/- 15 (ET) (P < 0.01), 166 +/- 21(CTR) (P < 0.01)]. These results suggest that femoral and abdominal adipose tissue contribute equally to the excessive rate of lipolysis in hyperthyroidism and that both tissues are resistant to the actions of insulin.