Influence of hyperthyroidism on splanchnic exchange of glucose and gluconeogenic precursors.

Arterial concentrations and splanchnic exchange of glucose, amino acids, lactate, pyruvate, and glycerol were determined in 14 hyperthyroid patients and 12 healthy controls. Seven of the patients were restudied after 5-12 mo of medical management at which time there was chemical and clinical evidence of a euthyroid state. The arterial level of glucose was slightly higher (+10%) in the patient group and the glycerol concentration was three times greater among the patients. The plasma levels of the glycogenic amino acids, alanine, glycine, and serine were decreased by 20-30%, while the concentrations of leucine, isoleucine, and tyrosine were increased by 20-80%. The levels of lactate and pyruvate were similar in patients and controls as were insulin and glucagon concentrations. Splanchnic glucose output in the patient group was 35% lower than in controls. However, total splanchnic uptake of glucogenic precursors was 100% higher than in controls and showed a direct linear correlation with serum triiodothyronine. Total precursor uptake could account for 75% of splanchnic glucose output in the patients, compared to 26% in controls. The increase in uptake of lactate, alanine, and other amino acids was due to a 35-80% rise in splanchnic fractional extraction plus a 20% rise in estimated hepatic blood flow. When the patients were restudied after medical treatment splanchnic exchange of glucose and glucose precursors had reverted to normal values. The present findings demonstrate that in hyperthyroidism (a) total splanchnic glucose output is reduced in relation to controls, (b) splanchnic uptake of gluconeogenic precursors is accelerated, largely due to a rise in fractional extraction of precursor substrates and to a smaller extent, as a result of an increase in hepatic blood flow, and (c) these changes revert to normal when a euthyroid state has been achieved.

Influence of thyroid hormone level on insulin action in human adipose tissue.

The relationship between the levels of circulating thyroid hormones and the action of insulin on adipose tissue was investigated in 6 hypothyroid patients and 6 hyperthyroid patients, all untreated, and 8 healthy control subjects. All were matched for age, body weight, and fat cell size. Gluteal s.c. adipose tissue was used. The insulin receptor number in isolated adipocytes was increased by 70% in hypothyroidism and decreased by 40% in hyperthyroidism. The sensitivities of the effects of insulin on lipolysis and glucose oxidation were increased fourfold in hypothyroidism and decreased fivefold in hyperthyroidism. The maximum insulin-induced glucose oxidation (insulin responsiveness) was inhibited by 60% in hypothyroidism and enhanced by 180% in hyperthyroidism. The thyroid hormone concentration was significantly correlated with insulin receptor number (r = -0.72), insulin responsiveness (r = 0.71), and insulin sensitivity (r = -0.75). It is suggested that thyroid hormones regulate the effect of insulin on adipose tissue, which occurs at the receptor and postreceptor levels of insulin action.

Influence of hyper- and hypothyroidism on subcutaneous adipose tissue blood flow in man.

Subcutaneous adipose tissue (AT) blood flow (BF) in the abdomen, thigh, and arm was determined by measuring the local clearance of [133]Xe in patients with untreated hyper- or hypothyroidism (n = 10, n = 7); six patients in each group were reexamined after treatment when they were euthyroid. Abdominal ATBF before treatment was 5.5 +/- 0.8 (SE) ml/min X 100 g AT in the hyperthyroid patients and 1.3 +/- 0.3 ml/min X 100 g AT in those who were hypothyroid. After therapy abdominal ATBF was 60% lower (P less than 0.05) in the hyperthyroid group and 80% higher (P less than 0.05) in the hypothyroid group. Similarly, ATBF in the thigh and arm was significantly reduced and increased, respectively, after treatment in the two groups. The blood glycerol level in the hyperthyroid group was 128 +/- 24 mumol/liter initially and was 50% lower (P less than 0.05) after therapy, whereas in the hypothyroid group blood glycerol levels were similar before (46 +/- 4 mumol/liter) and after therapy. Body fat, expressed as a percentage of body weight, was similar in the two groups before and after treatment. There was a positive correlation (P less than 0.001) between ATBF and serum T3 and T4 levels and an inverse correlation (P less than 0.01) between ATBF and plasma norepinephrine levels. Mean arterial blood pressure was similar in the two groups indicating that the alterations in ATBF were due to changes in vascular resistance. The results of this study suggest that thyroid hormones regulate sc ATBF in man.

Regulation of lipolysis by human adipose tissue in hyperthyroidism.

The effects of noradrenaline (NA) and isopropyl-noradrenaline (ISNA) on glycerol release and cAMP levels in sc adipose tissue were studied in vitro in 27 patients with hyperthyroidism. In 11 patients, the studies were repeated after 6--12 months of treatment for hyperthyroidism. A third group comprised 21 euthyroid patients otherwise healthy except for morbid obesity. The lipolytic response to ISNA, observed in untreated thyrotoxic patients, was found to be reduced by 30% when the patients were reexamined after treatment for thyrotoxicosis. This reduction was attributable to a decrease in the cAMP level. This was observed whether adipose tissue was incubated in the presence or absence of a phosphodiesterase inhibitor, theophylline. Both NA and ISNA induced 50% more rapid glycerol release and 4 times higher cAMP levels in adipose tissue of the thyrotoxic subjects than in the obese euthyroid patients. A positive correlation between tissue cAMP and glycerol release, on one hand, and mean fat cell size, on the other hand, was observed in treated thyrotoxic patients and obese euthyroid patients but was not recorded in the untreated hyperthyroid patients. The basal rate of lipolysis was not altered in thyrotoxicosis. The results suggest that the enhanced lipolytic response to catecholamines in adipose tissue of hyperthyroid patients is due to increased beta-adrenergic responsiveness. In addition, a disruption in subsequent stages of the regulatory pathway at the level of protein kinase or hormone-sensitive lipase also seems possible.

Changes in the effects of insulin on human adipose tissue metabolism in hyperthyroidism.

The in vitro effects of insulin on glycerol release and glucose incorporation into neutral lipids (lipogenesis) were studied in segments of sc adipose tissue obtained from 9 control subjects and 11 patients with hyperthyroidism; 6 patients were reinvestigated after treatment. In untreated hyperthyroidism, there was a decreased sensitivity to the antilipolytic effect of insulin, since the dose-response curve was shifted to the right; 250 microU/ml insulin were required for 50% of the maximal effect compared to 25 microU/ml in the controls. During antithyroid therapy, the dose-response curve normalized. Insulin caused a 25% increase in lipogenesis in the untreated hyperthyroid patients, but no consistent effect was seen in the control subject or in hyperthyroid patients during treatment.

Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients.

The influence of thyroid hormones on the adrenergic regulation of lipolysis was studied in isolated adipocytes removed from the gluteal region of hyper- and hypothyroid women and compared in adipocytes from euthyroid normal women. Noradrenaline significantly enhanced lipolysis in hyperthyroid patients, whereas noradrenaline inhibited lipolysis in hypothyroid patients compared to that in controls. Moreover, beta-adrenergic sensitivity and responsiveness were 10- and 2-fold increased, respectively, in hyperthyroid patients. In hypothyroid patients, beta-adrenoceptor responsiveness was reduced by 50%, whereas beta-adrenergic sensitivity remained unchanged compared with that in controls. Furthermore, the alpha 2-adrenergic and adenosine-induced antilipolytic effects were similar in all thyroid states. The lowered beta-adrenergic responsiveness seen in hypothyroidism could be mimicked by agents acting at the levels of phosphodiesterase (enprofylline), adenylate cyclase (forskolin) and protein kinase (dibutyryl cAMP). In hyperthyroidism, the increased beta-adrenergic sensitivity and responsiveness were not seen when lipolysis was stimulated at the adenylate cyclase, phosphodiesterase, or protein kinase levels. There was no change in the numbers of adipocyte beta- and alpha 2-adrenoceptors in hypothyroidism. However, the number of beta-adrenergic binding sites was doubled, whereas the fraction and affinities of isoprenaline high affinity sites remained unchanged in hyperthyroidism. Thus, the influence of thyroid hormone on catecholamine-stimulated lipolysis in man acts through different mechanisms when adipocytes are exposed to high or low levels of thyroid hormones. In hyperthyroidism, lipolysis adapts to increasing energy demands through an increase in the beta-adrenoceptor number and, thus, a more effective coupling of the adenylate-cyclase complex. In hypothyroidism, the low lipolytic effect of catecholamines seems to be mainly due to an impairment at the protein kinase level or to the hormone-sensitive lipase itself.

Splanchnic extraction of 3,3'-diiodothyronine and 3',5'-diiodothyronine in hyperthyroidism.

The splanchnic extraction of 3,3'-diiodothyronine (3,3'-T2) and 3',5'-diiodothyronine (3',5'-T2) was studied in 7 hyperthyroid patients and 20 normal subjects employing the hepatic venous catheterization technique. A significant net uptake by splanchnic tissues was found for both diiodothyronines . The fractional splanchnic extraction calculated as the arterio-hepatic venous plasma concentration difference divided by the arterial concentration was unaffected by hyperthyroidism as compared to normal values. There was a close positive correlation between the arterio-hepatic venous concentration difference and arterial concentration, 3,3'-T2: r = 0.988, and 3',5'-T2: r = 0.932 (P less than 0.001). The splanchnic extraction was nonsaturable at endogenous plasma concentrations of 3,3'-T2 up to at least 17.0 ng/dl and of 3',5'-T2 up to at least 15.2 ng/dl. The data suggest that the splanchnic extraction of 3,3'-T2 and 3',5'-T2 obeys first order kinetics, the fractional extraction being unaffected by hyperthyroidism. Furthermore, changes in the net splanchnic extraction of 3,3'-T2 and 3',5'-T2 do not seem to contribute to changes in circulating levels of these iodothyronines. It is suggested that tissues other than the liver contribute significantly to the deiodination process both in normal and in hyperthyroid man.

Hepatic glucose production and splanchnic glucose exchange in hyperthyroidism.

Hepatic glucose production (HGP) and net splanchnic glucose balance (NSGB) were simultaneously determined in the basal state in 8 hyperthyroid patients and 10 normal subjects using iv infusion of [3H]3-glucose and the hepatic venous catheter technique. Splanchnic glucose uptake (SGU) was calculated as the difference between the HGP and NSGB. SGU was also measured by determining the splanchnic extraction ratio of [3H]3-glucose across the splanchnic bed. In 5 hyperthyroid patients and 5 normal subjects a renal vein was also catheterized in the basal state. The influence of increased endogenous insulin secretion [stimulated by a low rate iv infusion of glucose (2 mg/kg . min)] on splanchnic and hepatic glucose exchange was also examined. Basal HGP (measured with [3H]3-glucose) was increased by 20% in the hyperthyroid patients [14.2 +/- 0.6 (SEM) mumol/kg . min] as compared to normal subjects (11.9 +/- 0.6, P less than 0.02). In marked contrast, NSGB output was slightly but not significantly decreased in the hyperthyroid group. SGU in the hyperthyroid patients, as determined with both techniques, was more than 2-fold higher than in the normal group (P less than 0.02-P less than 0.005). Splanchnic uptake of gluconeogenic precursors (lactate, pyruvate, glycerol) was increased by 20-120% in the patient group. During iv infusion of glucose, plasma insulin levels increased more in the hyperthyroid group (66% vs. 37%, P less than 0.05). Nevertheless, HGP and NSGB were less markedly suppressed in the patients as compared to the normal subjects (P less than 0.01), whereas the augmented SGU in the hyperthyroid patients reverted to normal. Splanchnic uptake of gluconeogenic precursors was unchanged in both groups. No net renal glucose production could be demonstrated in either group in the basal state. We conclude that in hyperthyroidism, increased HGP occurs in the face of an unchanged or slightly reduced rate of net glucose delivery to extrasplanchnic tissue. This discrepancy can be ascribed to augmented splanchnic uptake of glucose. These findings raise the possibility of futile cycling of glucose in the liver as a mechanism of increased oxygen consumption in hyperthyroidism. The data also demonstrate a diminished inhibitory effect of endogenous insulin on splanchnic glucose production, suggesting the presence of hepatic resistance to insulin in hyperthyroidism.

Adrenergic regulation of lipolysis in human adipocytes: findings in hyper- and hypothyroidism.

In isolated sc adipocytes removed from hyperthyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol was greater than that in adipocytes from normal subjects. Based on Scatchard analysis of the [125I] iodocyanopindolol data, this difference was due to a significant (P less than 0.01) increase in adrenoceptor number, which was 1.72 +/- 0.18 (+/- SEM) pmol/10(7) cells in the hyperthyroid patients and 0.94 +/- 0.16 pmol/10(7) cells in the normal subjects. When the patients were restudied when they were euthyroid, a significant decrease in the specific binding of the two radioligands was found. In hyperthyroidism, the lipolytic responsiveness (maximum effect) to norepinephrine was increased 5-fold, and that to isopropylnorepinephrine was increased 2-fold. No changes in either the binding of [3H]yohimbine or the antilipolytic effect of clonidine were found. In isolated adipocytes from hypothyroid patients, the specific binding of [3H]dihydroalprenolol and [125I]iodocyanopindolol did not differ from that in the normal subjects. The basal rate of lipolysis (P less than 0.025) and the lipolytic responsiveness to isopropylnorepinephrine (P less than 0.025) were significantly lower than normal, and the response to norepinephrine was almost completely abolished in the hypothyroid state. The sensitivity and responsiveness to clonidine were comparable in the adipocytes of the hypothyroid patients and normal subjects. There was no difference between hypothyroid patients and normal subjects in the binding of [3H]yohimbine. We conclude that the sc adipocytes in hyperthyroidism have beta-adrenergic, but not alpha 2-adrenergic abnormalities. Although there was a moderate increase in the beta-adrenoceptor density in hyperthyroidism, the most important abnormality, namely the increased responsiveness to the catecholamines, seems to be located beyond the receptor level. On the other hand, in hypothyroidism, there was no evidence of changes in either the alpha 2- or the beta-adrenoceptors. The chief abnormality in hypothyroidism, decreased responsiveness to beta-adrenergic agonists, also would appear to be localized beyond the adrenoceptor level.

Phosphodiesterase activity in human subcutaneous adipose tissue in hyper- and hypothyroidism.

Phosphodiesterase (PDE) activity was determined in sc adipose tissue from 12 patients with untreated hyperthyroidism, 8 patients with untreated hypothyroidism, and 10 healthy nonobese subjects. Eight of the hyperthyroid group were reexamined after treatment when they were euthyroid. The apparent Vmax of the low Km form of PDE was 25% lower in untreated hyperthyroidism (P less than 0.05) and 100% higher in untreated hypothyroidism (P less than 0.01) than in the controls; treatment of the hyperthyroidism resulted in normalization of the value. There was a positive correlation between the mean fat cell volume and the Vmax of the low Km PDE in all conditions (r = 0.64-0.85). As regards the high Km form of PDE, the Vmax values for both hyper- and hypothyroid patients did not differ from those for the control group. The results of this study suggest that in man, the apparent Vmax for the PDE with low Km is determined by the thyroid hormones.

Fructose-6-phosphate cycling and the pentose cycle in hyperthyroidism.

Hepatic fructose-6-phosphate (fructose-6-P) cycling and pentose cycle activity were quantified in hyperthyroid patients. A measure of the fructose-6-P cycle was the incorporation of 14C, on administering [3-3H,6-14C]galactose, into carbon 1 of blood glucose and the 3H/14C ratio in blood glucose. The measure of the pentose cycle was the randomization of 14C to carbon 1 of blood glucose on administering [2-14C]galactose. [2-3H]Galactose was also administered, so the 3H/14C ratio in blood glucose measured the extent of equilibration of glucose-6-P with fructose-6-P. Patients given [3-3H,6-14C]galactose were restudied when euthyroid. Of the 14C from [3-3H,6-14C]galactose, 7.7-9.5% was in carbon 1 of glucose in both states. 3H/14C ratios were also the same in both states. Fructose-6-P cycling was estimated to be 13 +/- 1% the rate of glucose turnover in the euthyroid and 15 +/- 1% that in the hyperthyroid state. The pentose cycle contributed about 2% to glucose utilization, similar to previous estimates in healthy humans. As in healthy individuals, about 25% of 3H was retained in the conversion of [2-3H]glucose-6-P to glucose. Thus, the fractions of glucose turnover participating in hepatic fructose-6-P and pentose cycling are similar in hyperthyroid and healthy subjects. As a result, augmented fructose-6-P cycling does not substantially contribute to increased hepatic oxygen consumption in hyperthyroidism.

Adrenergic regulation of human adipose tissue metabolism in situ during mental stress.

The adrenergic regulation of adipose tissue lipolysis and glucose metabolism was investigated in situ during a standardized mental stress test in 11 nonobese, healthy subjects, using microdialysis of the extracellular water space in sc adipose tissue. Microdialysis probes were inserted in the abdominal sc fat, and were perfused using solvents with or without adrenoceptor blocking agents. The tissue dialysate concentrations of glycerol (lipolysis index) glucose, lactate, and pyruvate were determined. The glycerol concentration in adipose tissue increased markedly during the stress test and decreased in the poststress period. A similar kinetic pattern was observed in blood. In situ administration of the nonselective beta-adrenoceptor blocking agent propranolol almost completely prevented the stress-induced increase in adipose tissue glycerol levels, whereas a nonselective alpha-adrenoceptor blocking agent (phentolamine) was ineffective in this respect. Plasma levels of glucose and lactate remained unaltered during and after the stress test; at the same time plasma pyruvate decreased moderately. By contrast, glucose, lactate, and pyruvate in adipose tissue increased by 25-30% during or after the stress (P < 0.05). The increase in lactate and pyruvate in adipose tissue after the stress was completely off-set by alpha-adrenoceptor blockade in situ, whereas beta-adrenoceptor blockade in situ did not influence the kinetic pattern of these metabolites. It is concluded that the lipolytic activity in human adipose tissue is markedly enhanced during mental stress, owing to adrenergic mechanisms that are mediated via beta-adrenoceptors. After mental stress, adipose tissue glucose utilization is decreased and routed toward nonoxidative pathways. The latter seems to involve adrenergic effects that are mediated via alpha-adrenoceptors.

Effects of mental stress on lipolysis in humans.

Lipid mobilization was investigated in subcutaneous adipose tissue specimens obtained before and after a standardized mental-stress test in 14 non-obese healthy subjects. All participants responded with an increased heart rate and elevation of plasma glycerol levels. Plasma norepinephrine concentrations remained unchanged throughout the test. In six subjects, mental stress induced a significant increase in plasma epinephrine levels, to more than 0.26 nmol/L (responders), while the remaining eight individuals showed a response of less than 0.12 nmol/L (nonresponders). In the responders, a 30% increase in catecholamine-stimulated in vitro lipolysis was found after the mental-stress test, while the lipolytic response in isolated fat cells in vitro decreased slightly in the nonresponders after mental stress. A strong correlation (r = .84) was observed between the increased in vitro lipolytic responsiveness due to mental stress and circulating plasma epinephrine levels. In vitro data suggest that the augmentation in lipolytic activity induced by acute mental stress was caused by alterations between the beta-adrenoceptor and adenylate cyclase, ie, probably an increased coupling between beta-receptors and the stimulatory guanosine triphosphate [GTP]-binding protein (G2). This, in combination with elevated levels of circulating epinephrine, may explain the increased lipolysis during mental stress in some individuals (ie, responders). However, other parallel mechanisms for activation of lipolysis during mental stress must also exist in certain individuals (ie, nonresponders), and seem not to involve the adrenergic system.

Adrenoceptor occupancy in isolated human fat cells and its relationship with lipolysis rate.

The relationship between lipolysis and adrenoceptor occupancy was determined in isolated human fat cells, which possess both lipolytic beta-adrenoceptors and antilipolytic alpha 2-adrenoceptors. The beta-adrenoceptor agonist, isoprenaline, and the alpha 2-adrenoceptor agonist, clonidine, had lower affinities to compete with antagonist radioligands (Ki) than to affect the rate of lipolysis (Ka). At 1 min of incubation human fat cells bound isoprenaline and clonidine with high affinity to beta- and alpha 2-adrenoceptors, respectively, but this high-affinity binding rapidly converted to a low-affinity state. The relationship between lipolysis and adrenoceptor occupancy was also assessed after long-lasting receptor inactivation. The inactivation of a small receptor fraction shifted the dose-response curves for isoprenaline and clonidine to the right but did not alter the maximum effect of the agonists (responsiveness). These results suggest that alpha 2- and beta-adrenoceptors are coupled to lipolysis according to similar models. There is a non-linear relationship between receptor and effector for both receptors, which can be explained by the co-existence of spare receptors and a transient high-affinity state of the receptors for agonists.

Impact of hypoxaemia on neuroendocrine function and catecholamine secretion in chronic obstructive pulmonary disease (COPD). Effects of long-term oxygen treatment.

The aim of the study was to investigate the effects of chronic hypoxaemia on neuroendocrine function in hypoxaemic chronic obstructive pulmonary disease (COPD). The stress level was assessed by measurement of daytime plasma catecholamine and nocturnal urinary catecholamine levels and endocrine function was assessed by measuring serum gonadotropins, peripheral sex hormones and peripheral thyroid hormones, and by measuring thyroid stimulating hormone (TSH), prolactin and growth hormone before and after thyroid releasing hormone challenge in 12 male, stable, hypoxaemic COPD patients before and after at least 4 months of long-term oxygen treatment (LTOT). Mean pre-treatment PaO2 was 7.39 +/- 0.78 kPa and mean nocturnal arterial oxygen saturation (MSaO2) was 86.6 +/- 3.2%. Plasma norepinephrine (NE) levels were higher than normal, while all other pre-treatment hormone levels were within normal range. Low forced expiratory volume in 1 sec (FEV1) was associated with low basal and stimulated TSH (P < 0.01). Urinary NE excretion correlated positively to nocturnal time spent with SaO2<85% (P<0.05). In similarity with normal controls, positive correlations were found between sex hormone binding globulin and testosterone both before and after LTOT (P<0.01). No significant hormonal changes were noted following an average of 8 months of LTOT for the entire study group. However, in a subgroup (n = 6) with an increase in MSaO2 exceeding 7% points following LTOT, nocturnal excretion of NE and epinephrine were reduced by 30% (P<0.05) and S-free thyroxin by 20% (P<0.05). In conclusion, patients with chronic hypoxaemia secondary to COPD exhibit elevated plasma NE levels but otherwise normal endocrine levels, including a normal hypothalamic-pituitary testicular axis. The severity of airway obstruction is associated with reduced basal and stimulated TSH. The endocrine function is not significantly changed following LTOT except for a subgroup with severe nocturnal hypoxaemia, where elevated nocturnal NE excretion was noted, which was reduced only if whole night oxygenation was normalized during oxygen therapy.

Pituitary reactivity, androgens and catecholamines in obstructive sleep apnoea. Effects of continuous positive airway pressure treatment (CPAP).

We studied the effects of chronic nocturnal hypoxaemia due to obstructive sleep apnoea syndrome (OSAS) on the hypothalamic-pituitary-thyroid and hypothalamic-pituitary-testicular axes and on catecholamine and cortisol secretion. We investigated whether hormones other than catecholamines may serve as markers for chronic hypoxic stress and the possible effects of nasal continuous positive airway pressure (nCPAP) treatment on endocrine status. Nocturnal oximetry was performed in 16 male patients with OSAS diagnosed by polysomnography, immediately before nCPAP treatment and in 11 of the patients the oximetry was repeated after 7 months of nCPAP therapy. Plasma and urinary catecholamines, luteinizing hormone (LH) testosterone, cortisol, thyroid stimulating hormone (TSH), prolactin (PRL), and the response of TSH and PRL to a thyroid releasing hormone (TRH) challenge test were measured immediately before and after 7 months of nCPAP treatment. Subnormal LH and TSH and elevated serum cortisol as well as increased nocturnal urinary norepinephrine levels were found in patients prior to treatment; otherwise endocrine values were normal. There was a significant correlation between low pretreatment nocturnal arterial oxygen saturation and high plasma and urinary norepinephrine levels. The nCPAP treatment caused significant reduction in serum prolactin and TSH, and significant reduction in plasma epinephrine and urinary norepinephrine. The reduction in serum TSH and urinary norepinephrine was most pronounced in the subjects with the worst pretreatment nocturnal hypoxaemia. No other significant changes were found in basal hormone levels. The response to TRH challenge was normal before and after treatment and was not influenced by CPAP therapy. OSAS is associated with elevated catecholamine and cortisol and decreased TSH and LH levels but a normal response to TRH challenge and a normal androgen status. Apart from catecholamines, none of the hormones studied is likely to serve as a specific marker for chronic hypoxic stress.

Variation in serum levels of T3, T4, FT4 and TSH during thyroxine replacement therapy.

Serum levels of T3, T4, FT4 and TSH were determined in 9 euthyroid patients during 6 h after intake of morning thyroxine replacement medication. Four hypothyroid patients were studied in the same way after the intake of 50 micrograms thyroxine. In the euthyroid patients the FT4 level increased by 31%, while the increase of T4 was 16% and the increase of T3 11%. In the hypothyroid patients levels of T3, T4 and FT4 did not change after ingestion of 50 micrograms thyroxine, while the TSH level was decreased by 30%. It is concluded that during thyroxine replacement therapy hormone analysis must be interpreted in relation to the time of thyroxine administration.

Antilipolytic effects of insulin and adenylate cyclase inhibitors on isolated human fat cells.

Antilipolysis induced by insulin by adenylate cyclase inhibitors was compared in isolated human fat cells when lipolysis was activated at well-defined steps in the cyclic AMP system. The latter was achieved with isoprenaline (beta-adrenoreceptor agonist), cholera toxin and pertussis toxin (acting on the GTP-sensitive coupling proteins), forskolin (stimulating the catalytic component of adenylate cyclase), enprofylline (selective phosphodiesterase inhibitor) and N6-monobutyryl-cyclic-AMP or 8-bromo cyclic-AMP (cyclic AMP analogues which are resistant or sensitive to phosphodiesterase, respectively). Clonidine (alpha 2-adrenoreceptor agonist), prostaglandin E2 and N6-(phenylisopropyl) adenosine (adenosine analogue) failed to inhibit lipolysis stimulated by cholera toxin or pertussis toxin, but were effective under all other conditions. Insulin failed to inhibit lipolysis stimulated by enprofylline or N6-monobutyryl cyclic AMP, but was effective under all other circumstances. In conclusion, insulin and adenylate cyclase inhibitors are antilipolytic in human fat cells through different mechanisms. Adenylate cyclase inhibitors act predominantly on the GTP-sensitive coupling proteins and, to a minor extent, at some yet unidentified distal step in the lipolytic machinery. As regards insulin, the major site of the antilipolytic action is phosphodiesterase.

Relationship between circulating leptin and peripheral fat distribution in obese subjects.

BACKGROUND: Abdominal obesity is an important risk factor for the development of non-insulin dependent diabetes mellitus and other atherogenic disorders. The recently discovered fat-derived hormone leptin has been proposed to regulate adiposity through stimulation of satiety and increased energy expenditure. This study was undertaken to examine the relationship between fasting plasma leptin, body fat distribution and atherogenic complications in markedly obese adult subjects. SUBJECTS: The study comprised 29 women and 26 men who all were obese but otherwise healthy (body mass index, BMI, 33-60 kg/m2). RESULTS: In 37 of the obese subjects, who were characterized in detail, the fasting plasma leptin levels correlated with plasma insulin (-0.34) but not in a significant way with blood pressure, insulin sensitivity, plasma glucose tolerance or circulating concentrations of glucose, lipoproteins, catecholamines or plasminogen activator inhibitor-1. In the whole patient material the fasting plasma leptin levels were two times higher in women than in men who had similar body mass index values (P < 0.0001). In spite of the fact that all subjects were massively obese, the plasma leptin values correlated positively with BMI (r = 0.39, P = 0.004). On the other hand, there was a negative correlation between plasma leptin and waist-to-hip ratio (r = 0.65, P = 0.0001), which was independent of BMI. CONCLUSION: Except for a quite weak relationship with fasting plasma insulin, leptin appears not to be associated with classical metabolic atherogenic complications to obesity. Instead, it may protect obese subjects with a gynoid fat distribution from metabolic complications. About 40% of the variation in leptin in massively obese subjects could in fact be explained by peripheral fat distribution.