The Joint Asia Diabetes Evaluation (JADE) Program: a web-based program to translate evidence to clinical practice in Type 2 diabetes.

AIMS: The Joint Asia Diabetes Evaluation (JADE) Program is the first web-based program incorporating a comprehensive risk engine, care protocols, clinical decision and self-management support to improve ambulatory diabetes care. The aim was to validate the risk stratification system of the JADE Program using a large prospective cohort. METHODS: The JADE interactive risk engine stratifies patients into different risk levels using results from an annual comprehensive assessment of complications and risk factors. We used a prospective registry consisting of 7534 Type 2 diabetic patients [45.6% men, median (range) age 57 years (13-92)] to perform internal validation of the risk engine. RESULTS: The JADE Risk Engine categorized patients into four risk levels (from low to high): level 1, n = 4520 (6%); level 2, n = 1468 (19.5%); level 3, n = 4476 (59.4%); and level 4, n = 1138 (15.1%). After a median follow-up period of 5.5 years (mean +/- sd 5.4 +/- 2.81 years), 763 (10.1%) died, 1129 (14.9%) developed cardiovascular disease (CVD), 282 (3.7%) developed end-stage renal disease and 1400 (18.6%) had at least one of these events. Compared with risk level 1, levels 2, 3 and 4 were associated with 2.8-, 4.7- and 8.6-fold increased risk of clinical end-points. Risk levels 3 and 4 were, respectively, associated with 2.2- and 3.9-fold increased risk for all-cause death and 4.8- and 12.1-fold increased CVD risks. CONCLUSION: Based on results from a comprehensive assessment, the JADE Risk Engine successfully categorizes patients into different risk levels to guide clinical management.

Metabolic effects of oestrogens: impact of the route of administration.

To investigate whether oestrogen modulates GH secretion and action in adult life, we studied the impact of oestrogen replacement on circulating GH and IGF-I levels in post-menopausal women. Since the liver is the major source of circulating IGF-I and the oral route of oestrogen delivery causes non-physiologic effects on hepatic proteins, we compared the effects of oral and transdermal route of delivery. Oral ethinyl oestradiol administration resulted in a significant fall in mean IGF-I levels and a 3-fold increase in mean 24h GH. Transdermal administration of 17beta oestradiol resulted in a slight increase in serum IGF-I but no change in mean 24h GH levels. To determine whether differences in oestrogen type rather than in the route of delivery caused the different effects on the GH/IGF-I axis, we compared the effects of three oral oestrogen formulations. Ethinyl oestradiol, conjugated equine oestrogen and oestradiol valerate each induced a fall in IGF-I and a rise of mean 24h GH levels in post-menopausal women. To determine the metabolic significance of oestrogen-induced changes on GH/ IGF-I, we compared the effects of 24 weeks each of oral and transdermal oestrogen on energy metabolism and body composition in 18 post menopausal women in an open-label randomised cross-over study. When compared to the transdermal route, oral oestrogen reduced lipid oxidation, increased fat mass and reduced lean body mass. Oestrogen causes distinct, route dependent effects on the somatotrophic axis. The dissociation of the GH/IGF-I axis by the oral route is likely to arise from impaired hepatic IGF-I production which causes increased GH secretion through reduced feedback inhibition. The route of oestrogen therapy confers divergent effects on substrate oxidation and body composition. The suppression of lipid oxidation during oral oestrogen therapy may increase fat mass while the fall in IGF-I may lead to a loss of lean body mass. The route dependent changes in body composition observed during oestrogen replacement therapy may have important implications for post-menopausal health and oestrogen use in general.

Transition to raloxifene with and without low-dose estrogen therapy in postmenopausal women: effects on serum lipids and fibrinogen - a pilot study.

OBJECTIVE: To compare the effects of transferring from low-dose transdermal estrogen to raloxifene (RLX), with a phase of alternate-day RLX therapy with or without low-dose transdermal estrogen, on serum lipids and fibrinogen in postmenopausal women previously administered estrogen plus progestogen therapy. METHODS: Sixty postmenopausal women (mean age 55 years) were randomized to one of two treatment groups: RLX + low-dose transdermal estrogen (RLX + E) or RLX + placebo. The study consisted of four 8-week phases: phase I (all subjects low-dose transdermal estrogen 25 microg/day), phase II (double-blind RLX 60 mg every 2nd day in combination with either low-dose transdermal estrogen or placebo), phase III (all subjects RLX 60 mg every 2nd day + placebo) and phase IV (all subjects RLX 60 mg/day + placebo). RESULTS: No significant differences existed between groups for baseline measurements prior to phase I. In phase I, for all subjects combined, total cholesterol and low-density lipoprotein cholesterol both showed a significant increase (median increase of 0.2 mmol/l, p = 0.008 and 0.4 mmol/l, p< 0.001, respectively), while triglycerides decreased significantly (median decrease of 0.2 mmol/l, p< 0.001). For the primary analysis (phase II to phase IV), the mean change from baseline observations showed no significant differences between the therapy groups for serum lipids, fibrinogen, vital signs or weight. In the comparison phase (phase II), changes in serum lipids, fibrinogen, vital signs and weight were not significantly different between groups. CONCLUSION: Gradual conversion to RLX from low-dose transdermal estrogen, with a phase of alternate-day RLX therapy with or without low-dose transdermal estrogen, does not have any effect on the serum lipid profile or fibrinogen level.

Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-deficient women.

We have determined whether oral estrogen reduces the biological effects of growth hormone (GH) in GH-deficient (GHD) women compared with transdermal estrogen treatment. In two separate studies, eight GHD women randomly received either oral or transdermal estrogen for 8 wk before crossing over to the alternate route of administration. The first study assessed the effects of incremental doses of GH (0.5, 1.0, 2.0 IU/day for 1 wk each) on insulin-like growth factor I (IGF-I) levels during each estrogen treatment phase. The second study assessed the effects of GH (2 IU/day) on lipid oxidation and on protein metabolism using the whole body leucine turnover technique. Mean IGF-I level was significantly lower during oral estrogen treatment (P < 0.05) and rose dose dependently during GH administration by a lesser magnitude (P < 0.05) compared with transdermal treatment. Postprandial lipid oxidation was significantly lower with oral estrogen treatment, both before (P < 0.05) and during (P < 0.05) GH administration, compared with transdermal treatment. Protein synthesis was lower during oral estrogen both before and during GH administration (P < 0.05). Oral estrogen antagonizes several of the metabolic actions of GH. It may aggravate body composition abnormalities already present in GHD women and attenuate the beneficial effects of GH therapy. Estrogen replacement in GHD women should be administered by a nonoral route.

No influence of prednisolone on IGFBP-3 proteolysis in healthy young men.

AIMS: The impact of growth hormone (GH) and prednisolone on the GH/insulin-like growth factor (IGF) axis with special emphasis on IGF binding protein-3 (IGFBP-3) proteolysis was studied in 8 healthy adults in a double-blind cross-over study with four periods: (1) placebo; (2) s.c. GH 0.1 IU/kg/day; (3) oral prednisolone 50 mg/day, and (4) co-administration of GH and prednisolone. METHODS: Each treatment period lasted for 4 days followed by a washout period of 10 days. We measured IGF-I, IGF-II, IGFBP-1, IGFBP-2, IGFBP-3 by immunoassays, IGFBP-3 by Western ligand blotting (WLB) and finally in vitro IGFBP-3 proteolysis by a (125)I-IGFBP-3 degradation assay. RESULTS: IGF-I levels increased by 99% during GH administration and 67% during co-administration of GH and prednisolone (p < 0.0005), whereas no significant change was seen during prednisolone alone. IGFBP-1 levels decreased 55% during the prednisolone period (p < 0.002), but the between period changes were not significant (p < 0.1). IGFBP-2 decreased 33% during co-administration of GH and prednisolone (p < 0.002). IGFBP-3 increased 12% during GH and 7% during co-administration of GH and prednisolone (p < 0.003 and p < 0.03 compared to placebo, respectively), whereas prednisolone alone induced no significant changes. IGFBP-3 measured by WLB did not change significantly, neither did IGFBP-3 proteolysis. CONCLUSIONS: Prednisolone administration induces only minimal changes in circulating components of the IGF axis and is not accompanied by alterations in IGFBP-3 proteolysis. This indicates that the metabolic effects of glucocorticoids do not depend on serum IGF-I.

Effects of budesonide and prednisolone on hepatic kinetics for urea synthesis.

BACKGROUND/AIMS: Glucocorticoids upregulate hepatic urea synthesis and cause protein breakdown to prevail over synthesis, releasing amino acids into the blood stream and increasing the substrate supply for hepatic urea synthesis. Budesonide is a new generation glucocorticoid that may be used for treatment of inflammatory diseases, e.g. Crohn's disease and autoimmune hepatitis. Due to its extensive first-pass metabolism in the liver, it has a potential adverse effect profile superior to that of prednisolone. Little attention has been directed towards differences in nitrogen catabolic properties between budesonide and prednisolone. METHODS: Eight normal male subjects (age 20-44 years; BMI 21.6-28.2 kg/m2) were randomly studied 3 times: 1) At baseline, 2) after 6 days of prednisolone (50 mg/day), and 3) after 6 days of budesonide (9 mg/ day). We measured urea nitrogen synthesis rates (UNSR) and blood alpha-amino-nitrogen (N) levels before, during, and after a 3-h constant infusion of alanine (2 mmol/(kg BW x h)). UNSR was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between UNSR and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance (FHNC). RESULTS: Prenisolone, but not budesonide, administration increased basal blood and amino nitrogen concentrations (3.5 +/- 0.1 mmol/l (control) vs 3.8 +/- 0.1 mmol/l (prednisolone) (p<0.05) and 3.6 +/- 0.1 mmol/l (budesonide) (NS). Basal UNSR values were significantly increased following prednisolone (23.3 +/- 6.5 (control) vs 51.2 +/- 6.3 (prednisolone) (p<0.05)), while budesonide had no effect on basal UNSR (33.7 +/- 4.2 (budesonide) (NS)). Prednisolone administration increased FHNC (from 24.6 +/- 4.7 l/h (control) to 47.3 +/- 5.9 l/h (prednisolone) (p<0.05). Budesonide administration did not significantly increase FHNC (33.7 +/- 4.2 l/h (budesonide), (vs control; p=0.12, vs prednisolone: p<0.05)). CONCLUSIONS: Prednisolone administration led to increased levels of amino acids in blood and loss of N as urea, the latter in part due to a specific hepatic mechanism as shown by the increased FHNC. Budesonide led to unaltered levels of amino acids in blood, no changes in loss of N as urea, and unaltered hepatic kinetics for urea synthesis. Thus, oral budesonide administration had very limited effects on the hepatic contribution to nitrogen homeostasis and metabolism via urea synthesis, making treatment with budesonide superior to that of conventional glucocorticoids in this respect.

Hepatic amino- to urea-N clearance and forearm amino-N exchange during hypoglycemic and euglycemic hyperinsulinemia in normal man.

BACKGROUND/AIMS: Hypoglycemia has well-described effects on glucose metabolism, whereas the possible effects on hepatic amino nitrogen conversion in relation to muscle amino nitrogen flux are more uncertain. METHODS: We studied six healthy young male subjects three times, i.e. for 6 h in the basal state, during a 6-h euglycemic hyperinsulinemic (1.5 mU/kg/min) clamp and during a 6-h hypoglycemic (plasma glucose below 2.8 mmol/l) clamp. Alanine (2 mmol/kg body weight/h) was infused for 3 h to describe the relationship between blood amino nitrogen concentrations and hepatic ureagenesis estimated from urea urine excretion and accumulation in body water. The slope of this relationship is denoted functional hepatic nitrogen clearance (FHNC) and quantifies substrate-independent alterations in hepatic amino nitrogen degradation. In parallel, amino nitrogen balances across muscles were estimated by the forearm flux method. RESULTS: Euglycemia decreased circulating glucagon values (100+/-25 ng/l vs. 160+/-30 ng/l), whereas hypoglycemia doubled glucagon (350+/-45 ng/l, p<0.05). Hepatic nitrogen clearance (FHNC) decreased during hyperinsulinemic euglycemia (19.5+/-3.4 l/h vs. 30.6+/-5.7 l/h, p<0.01), whereas forearm net uptake of amino nitrogen increased (130+/-40 nmol/100 ml x min vs. control: -10+/-4 nmol/100 ml x min). During hypoglycemia there was a 3-fold increase in hepatic nitrogen clearance up to 83.0+/-16.8 l/h (p<0.01) and increased release of amino nitrogen from the forearm (-100+/-30 nmol/100 ml x min, p<0.01). CONCLUSION: Hypoglycemia in man induces a marked increase in hepatic amino- to urea-N clearance. This catabolic response to hypoglycemia in the liver may be of primary importance for muscle amino acid release. Our data are compatible with the notion that liver and muscle together are responsible for catabolism during hypoglycemia, and that glucagon may be the primary mediator via its effect on liver metabolism.

Serum leptin concentrations during short-term administration of growth hormone and triiodothyronine in healthy adults: a randomised, double-blind placebo-controlled study.

The regulation of adipose tissue mass and energy expenditure is currently subject to intensive research, which primarily relates to the discovery of leptin. Leptin is a peptide, which is the product of the obese (ob) gene expressed in adipose tissue of several species icluding humans. Leptin is supposed to serve both as an index of fat mass and as a sensor of energy balance. Administration of recombinant murine leptin in ob/ob-mice, which do not produce leptin, decreases food intake and increases thermogenesis both of which result in a reduction in body weight and adipose tissue mass. The calorigenic effect of leptin presumably acts through an increase in sympathetic outflow which in turn activates the beta3 adrenergic receptor in brown adipose tissue. The regulation and action of endogenous leptin in humans are less well understood, and clinical grade recombinant human leptin is so far not available. Serum leptin correlates logarithmically with total body fat in both normal weight and obese subjects, which suggest insensitivity to leptin in obese patients. Furthermore, more rapid excursions in serum leptin have been reported following short-term changes in caloric intake and administration of insulin. Growth hormone (GH) exerts pronounced effects on lipid metabolism and resting energy expenditure. The lipolytic actions of GH appear to involve both increased sensitivity to the beta-adrenergic pathway, and a suppression of adipose tissue lipoprotein lipase activity. The calorigenic effects of GH have been shown not only to be secondary to changes in lean body mass. Growth hormone administration furthermore increases the peripheral conversion of thyroxine to triiodothyronine, which may contribute to the overall actions of GH on fuel and energy metabolism. So far, little is known about the effects of GH and iodothyronines on serum leptin levels in humans. We therefore measured serum leptin levels and energy expenditure before and after the administration of GH and triiodothyronine, alone and in combinaion, in a randomized double-blind placebo-controlled study in healthy young male adults. The dose of triiodothyronine was selected to obtain serum levels comparable to those seen after GH administration.

Effects of growth hormone on steroid-induced increase in ability of urea synthesis and urea enzyme mRNA levels.

Growth hormone (GH) reduces the catabolic side effects of steroid treatment due to its effects on tissue protein synthesis/degradation. Little attention is focused on hepatic amino acid degradation and urea synthesis. Five groups of rats were given 1) placebo, 2) prednisolone, 3) placebo, pair fed to the steroid group, 4) GH, and 5) prednisolone and GH. After 7 days, the in vivo capacity of urea N synthesis (CUNS) was determined by saturating alanine infusion, in parallel with measurements of liver mRNA levels of urea cycle enzymes, N contents of organs, N balance, and hormones. Prednisolone increased CUNS (micromol . min-1 . 100 g-1, mean +/- SE) from 9.1 +/- 1.0 (pair-fed controls) to 13.2 +/- 0.8 (P < 0.05), decreased basal blood alpha-amino N concentration from 4.2 +/- 0.5 to 3.1 +/- 0.3 mmol/l (P < 0.05), increased mRNA levels of the rate- and flux-limiting urea cycle enzymes by 20 and 65%, respectively (P < 0. 05), and decreased muscle N contents and N balance. In contrast, GH decreased CUNS from 6.1 +/- 0.9 (free-fed controls) to 4.2 +/- 0.5 (P < 0.05), decreased basal blood alpha-amino N concentration from 3. 8 +/- 0.3 to 3.2 +/- 0.2, decreased mRNA levels of the rate- and flux-limiting urea cycle enzymes to 60 and 40%, respectively (P < 0. 05), and increased organ N contents and N balance. Coadministration of GH abolished all steroid effects. We found that prednisolone increases the ability of amino N conversion into urea N and urea cycle gene expression. GH had the opposite effects and counteracted the N-wasting side effects of prednisolone.

Differential effects of growth hormone and prednisolone on energy metabolism and leptin levels in humans.

Short-term growth hormone (GH) exposure has been shown to stimulate energy expenditure (EE) without concomitant changes in body composition. To what extent this is related to thyroid function, sympathetic activity, hyperinsulinemia, or leptin secretion is unknown. It is also unknown whether the calorigenic effect of GH is influenced by glucocorticoids, which are known to antagonize the anabolic actions of GH. To pursue this, eight normal male subjects (aged 22 to 28 years; body mass index, 21.6 to 26.3 kg/m2) were randomly studied during four 4-day treatment periods with (1) daily subcutaneous (SC) placebo injections and placebo tablets, (2) daily SC GH injections (0.1 IU/kg x d) and placebo tablets, (3) daily prednisolone administration (25 mg morning and evening) plus placebo injections, and (4) daily GH injections plus prednisolone administration. GH administration decreased plasma epinephrine significantly (mean +/- SE, 34.7 +/- 5.7 ng/L for control v 24.8 +/- 5.8 for GH, P < .05), had no effect on plasma norepinephrine or serum leptin, and increased both free triiodothyronine (FT3) levels (5.7 +/- 0.3 pmol/L for control v 6.7 +/- 0.3 for GH, P < .05) and resting EE ([REE] 1,861 +/- 61 kcal/24 h for control v 1,996 +/- 69 for GH, P < .05). Prednisolone administration did not affect epinephrine and REE, decreased norepinephrine (116 +/- 13, P < .05) and FT3 (4.7 +/- 0.2, P < .05), and increased leptin (3.93 +/- 0.71, P < .05). Concomitant GH and prednisolone administration increased REE (2,068 +/- 85, P +/- .05) and leptin (4.82 +/- 0.93, P +/- .05), had no effect on either epinephrine or norepinephrine, and decreased FT3 (5.0 +/- 0.2, P < .05). Resting heart rate (HR) increased only during GH, whereas sympathetic nerve activity was unchanged in all studies. Our data suggest that (1) the calorigenic effect of GH is not mediated by changes in sympathetic activity or leptin secretion, (2) rapid elevations in leptin induced by glucocorticoids do not affect EE in humans, and (3) the acute calorigenic effects of GH are probably related to increased cardiac workload.

Blockade of the renin-angiotensin-aldosterone system prevents growth hormone-induced fluid retention in humans.

To test if the renin-angiotensin-aldosterone system (RAAS) is involved in growth hormone (GH)-associated fluid retention, we examined the effect of GH administration in the presence or absence of RAAS blockade at different levels on body fluid homeostasis. Eight subjects were examined in a controlled, randomized double-blinded trial. During four 6-day periods they received subcutaneous GH (6 IU-m-2) or placebo injections and tablets as follows: 1) placebo and placebo, 2) GH and placebo, 3) GH and captopril, and 4) GH and spironolactone. GH increased extracellular volume (liters; placebo 18.87 +/- 0.85; GH + placebo 20.43 +/- 1.01) but this effect was abolished by captopril (GH + captopril 18.82 +/- 0.67) and spironolactone (GH + spironolactone 18.99 +/- 0.85). Correspondingly, the GH-induced reduction in bioimpedance was blocked by captopril and spironolactone. Plasma renin and angiotensin II concentrations increased during all three GH treatment regimens, whereas plasma aldosterone was increased only after GH plus spironolactone. The data demonstrate that GH activates the RAAS and that blockade of the RAAS by two separate mechanisms prevents fluid retention normally encountered after GH exposure. These observations suggest that the RAAS plays a key role in GH-induced regulation of fluid homeostasis.

Effects of growth hormone and insulin-like growth factor-I singly and in combination on in vivo capacity of urea synthesis, gene expression of urea cycle enzymes, and organ nitrogen contents in rats.

Improvement of nitrogen balance is desirable in patients with acute or chronic illness. Both growth hormone (GH) and insulin-like growth factor-I (IGF-I) are promising anabolic agents, and their combined administration has been shown to reverse catabolism more efficiently than each of the peptides alone. This is believed to be mediated primarily through increased peripheral protein synthesis, whereas little attention has focused on a possible participation of amino acid metabolism in the liver. Four groups of rats were given: 1) placebo; 2) GH (200 micrograms/d); 3) IGF-I (300 micrograms/d); and 4) both GH and IGF-I. After 3 days, the maximum capacity of urea-nitrogen synthesis was determined by saturating infusion of alanine (n = 8 in each group), together with measurements of liver messenger RNA (mRNA) levels for urea cycle enzymes (n = 5 in each group) and N-contents of muscles, heart, and kidney. Basal plasma alpha-amino acid concentrations were similar in all groups. The capacity of urea-N synthesis [mumol/(min x 100 g body weight)] was reduced in a stepwise manner (placebo: 8.25 +/- 1.2; GH treatment: 6.52 +/- 0.8; IGF-I treatment: 5.5 +/- 0.6; and GH/IGF-I: 4.22 +/- 1.6 [P < .001 by ANOVA]), each step being lower than the former. Serum IGF-I increased stepwise from placebo (699 +/- 40 to 1,579 +/- 96 micrograms/L in the combined GH/IGF-I group), and was correlated negatively with the capacity of urea-nitrogen synthesis (P < .01). mRNA levels for urea cycle enzymes in the liver decreased after GH and IGF-I treatment, and the effect was more pronounced after the combined treatment in which the rate-limiting enzyme, argininosuccinate synthetase, was halved. Nitrogen contents of organs increased after both GH and IGF-I treatment, and even more so after the combination treatment, reaching an increase of 30% (P < .05). Data suggest that GH and IGF-I singly and, even more so in combination, additively inhibit urea synthesis. This is supposed to favor protein buildup in organs. We speculate that this inhibitory effect on the capacity of urea synthesis is caused by a decreased translation rate of the urea cycle enzymes caused by GH and IGF-I's down-regulatory effect on urea cycle enzyme gene transcription. The findings may indicate a novel mechanism of the protein anabolic action of GH and IGF-I.

Hepatic amino nitrogen conversion and organ N-contents in hypothyroidism, with thyroxine replacement, and in hyperthyroid rats.

BACKGROUND/AIMS: The role of thyroid hormones in the regulation of hepatic conversions of amino nitrogen to urea is unresolved. The present study was designed to assess ureagenesis in rats with experimentally well-established hypo- and hyperthyroidism. The possible role of propylthiuracil (PTU), used for induction of hypothyroidism, was ascertained during thyroxine replacement of PTU treated hypothyroid rats. METHODS: Basal blood amino nitrogen concentrations (AAN), the urea nitrogen synthesis rate (UNSR) and the maximal hepatic capacity for urea nitrogen synthesis (CUNS) obtained during alanine infusion were determined together with N-contents in the soleus muscle and kidneys in experimentally hypothyroid rats (n = 19), upon thyroxine replacement (n = 14) and in experimentally hyperthyroid rats (n = 19). Hypothyroidism was induced by adding propylthiouracil (0.05%) to the drinking water for 5 weeks. Hyperthyroidism was induced by thyroxine 100 micrograms/100 g body weight. RESULTS: During hyperthyroidism, T3 fell to less than 10%, food intake was halved, and body weight fell by 13%. Basal blood AAN fell by 25% (p < 0.01), UNSR more than doubled (p < 0.01), and CUNS rose by 45% (p < 0.05). N-contents of the soleus muscle fell by 13% and by 20% in kidneys, respectively (p < 0.05). Thyroxine replacement normalized AAN, UNSR, CUNS and reduced N-loss to 7% in the soleus muscle (NS) and kidneys (p < 0.05), respectively. During hyperthyroidism, T3 rose five-fold, food intake rose by two thirds, and body weight fell by 10%. Basal AAN rose by 20% (p < 0.05), UNSR doubled (p < 0.01), and CUNS rose by 25% (p < 0.05). N-contents of the soleus muscle decreased by 19%, whereas kidney N-contents increased by 25% (p < 0.05). Overall liver function assessed by galactose elimination capacity did not differ among groups. Both conditions increased the rate of urea synthesis; in the hypothyroid state the hepatic waste of amino-N was limited by low blood concentration of amino-N, probably due to lower proteolysis. In the hyperthyroid state hepatic amino-N loss was aggravated by higher blood concentration of amino-N, probably due to higher proteolysis. This difference may explain the markedly different dietary nitrogen economy between the two groups. CONCLUSIONS: The findings suggest that distinct hepatic acceleration of urea synthesis may contribute to the protein loss seen in both myxedema and in thyrotoxicosis in humans.

Moderate hyperthyroidism reduces liver amino nitrogen conversion, muscle nitrogen contents and overall nitrogen balance in rats.

There are conflicting data on the effect of thyroid hormones on nitrogen metabolism. We determined the basal blood amino nitrogen (amino-N) concentrations, the urea nitrogen (urea-N) synthesis rate and the maximum hepatic capacity of urea nitrogen synthesis during saturating infusion of alanine, in moderately acutely (24 h) and chronically (7 days) hyperthyroid rats and compared this with changes in organ nitrogen contents in muscles and kidney, nitrogen excretion and nitrogen balance. Forty-three rats were made acutely hyperthyroid through administration of 5 microg 100 g(-1) triiodothyronine twice daily (T3: 2.2 +/- 0.7 vs. 0.87 +/- 0.04 nmol L(-1), P < 0.01). Fifty-one rats were made chronically hyperthyroid through administration of 12.5 microg 100 g(-1) thyroxine twice daily (T3: 2.63 +/- 0.18 vs. 0.87 +/- 0.04 nmol L(-1), P < 0.01). Weight gain was halved in this group. Both acute and chronic hyperthyroidism increased basal blood amino-N concentration in both groups by 16% (4.5 +/- 0.15 vs. 3.9 +/- 0.13 mmol L(-1) and 4.7 +/- 0.12 vs. 3.9 +/- 0.13 mmol L(-1), respectively, P < 0.01), and decreased basal urea-N synthesis rate in both groups by 30% [2.7 +/- 0.3 vs. 4.1 +/- 0.3 micromol (min x 100 g)(-1) and 3.1 +/- 0.3 vs. 4.1 +/- 0.3 micromol (min x 100g)(-1), respectively, P < 0.01]. The capacity of urea-N synthesis during saturation fell in both groups by 35% compared with controls [6.5 +/- 0.4 vs. 9.3 +/- 0.5 micromol (min x 100 g)(-1) and 5.7 +/- 0.5 vs. 9.3 +/- 0.6 micromol (min x 100g)(-1), respectively, P < 0.01]. Nitrogen contents in the muscles, soleus and extensor digitorum longus, of chronically hyperthyroid rats decreased by 22% and 11%, respectively, whereas kidney N-content increased by 12% (P < 0.05). N-balance and urinary urea-N excretion fell by 30%, whereas faeces-N excretion increased by 80% in hyperthyroid rats. Overall liver function assessed by galactose elimination capacity did not differ among groups. Both acute and chronic moderate hyperthyroidism increase blood amino-N and decrease basal and maximum rate of urea formation. Furthermore, chronic hyperthyroidism reduces N-contents of muscles, urinary urea-N excretion and N-balance. Thyroid hormones thus mobilize muscle-N, whereas amino-N in the liver is spared from irretrievable conversion into urea.

Growth hormone prevents prednisolone-induced increase in functional hepatic nitrogen clearance in normal man.

BACKGROUND/AIMS: Glucocorticoid treatment increases urea excretion and leads to negative nitrogen balance. This effect is presumed mainly to reflect actions on tissue protein metabolism, but has been shown in rats to involve an hepatic element in the form of upregulation of the kinetics of ureagenesis. Likewise, the anabolic action of growth hormone administration has been shown to involve an hepatic element, just as growth hormone administration has been shown to prevent the protein catabolic side effects of prednisolone. Whether glucocorticoids increase the ability of the liver to convert amino-N to urea-N in man, and whether growth hormone counteracts any possible effect of glucocorticoid has not been studied. METHODS: We measured urea nitrogen synthesis rates and blood alpha-amino-N levels before, during, and after a 4-h constant i.v. infusion of alanine (2 mmol x kg BW(-1) x h(-1)). The urea nitrogen synthesis rate was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between urea nitrogen synthesis rate and amino-N concentration represents the hepatic kinetics of conversion of amino- to urea-N, and is denoted the functional hepatic nitrogen clearance. Eight normal male subjects (aged 22-28 years; BMI 21.6-26.3 kg/m2) were randomly studied four times: i) after 4 days of s.c. saline injections, ii) after 4 days of s.c. growth hormone injections (0.1 IU x kg(-1) x day(-1)), iii) after 4 days of glucocorticoid administration (50 mg/d) and iv) after 4 days of growth hormone and glucocorticoid administration. All injections were given at 20 00 hours and 25 mg prednisolone was given morning and evening. RESULTS: Growth hormone decreased functional hepatic nitrogen clearance (l/h) by 21% (from 38.8+/-1.8 l/h (control) to 30.5+/-2.7 l/h (4 d growth hormone) (mean+/-SE) (ANOVA; p<0.05)). Glucocorticoid increased functional hepatic nitrogen clearance by 23% (47.7+/-3.3 l/h, p<0.05), while growth hormone plus glucocorticoid offset any effect on functional hepatic nitrogen clearance (36.2+/-3.3 l/h, p=0.83). CONCLUSIONS: Glucocorticoid administration leads to loss of nitrogen as urea, in part due to a specific hepatic mechanism, as shown by the increased functional hepatic nitrogen clearance. Growth hormone has the opposite effect, and also neutralises the glucocorticoid effect when given together with prednisolone. This adds to the understanding of the development and treatment possibilities of steroid catabolism.

Effects of growth hormone on serum lipids and lipoproteins: possible significance of increased peripheral conversion of thyroxine to triiodothyronine.

The role of growth hormone (GH) and thyroid hormone in the regulation of lipid and lipoprotein metabolism is not fully established. Furthermore, the possible linkage between the well-known GH-induced increase in peripheral thyroxine (T4) to triiodothyronine (T3) generation and the effects of GH on lipid and lipoprotein metabolism has not been elucidated. In this double-blind placebo-controlled study, we compared the effects of GH and T3 administration alone and in combination on lipid and lipoprotein metabolism in a group of healthy young adults. The dose of T3 was selected to mimic the T2 increase seen during exogenous GH exposure. Eight normal male subjects (aged 21 to 27 years; body mass index, 21.11 to 27.17 kg/m2) were randomly studied during four 10-day treatment periods with (1) daily subcutaneous placebo injections and placebo injections and placebo tablets, (2) daily subcutaneous GH injections (0.1 IU/kg.d) and placebo tablets, (3) daily T3 administration (40 micrograms on even dates or 20 micrograms on uneven dates) plus placebo injections, and (4) daily GH injections plus T3 administration. GH administration increased free T3 (FT3) to the same level as during T3 administration. GH caused decreased levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol and increased levels of triglycerides (TG) and lipoprotein(a) (Lp(a)), but no changes in high-density lipoprotein (HDL) cholesterol and apolipoprotein B (apo B). T3 administration caused no alteration in these parameters, except for decreased levels of TC comparable to those seen after GH administration. Combined GH and T3 administration caused changes identical to those seen after GH administration, in addition to decreased apo B levels and a further decrease of TC levels. We conclude that GH and iodothyronines in the physiologic range exert distinct but disparate effects on lipids and lipoproteins, and do not support the hypothesis that the effects observed during GH administration are exclusively secondary to changes in peripheral T3 levels.

Calorigenic effects of growth hormone: the role of thyroid hormones.

GH administration increases energy expenditure, independent of changes in lean body mass, in healthy, obese, and GH-deficient subjects. This may be causally linked to the well known GH-induced increase in peripheral T4 to T3 generation, but experimental data are sparse. In this study we have addressed whether 1) the calorigenic effects of GH administration could be reproduced by oral supplementation of T3 in a dose selected to mimic the GH-induced increase in peripheral T3 levels; and 2) combined GH and T3 administration have a synergistic effect on resting energy expenditure (REE). Eight normal male subjects (aged 21-27 yr; body mass index, 21.11-27.17 kg/m2) were randomly studied during four 10-day treatment periods with 1) daily sc placebo injections and placebo tablets, 2) daily sc GH injections (0.1 IU/kg x day) and placebo tablets, 3) daily T3 administration (40 microg on even dates, 20 microg on uneven dates) plus placebo injections, and 4) daily GH injections plus T3 administration. GH administration increased both free T3 (FT3) levels [mean +/- SE, 6.2 +/- 0.3 (control) vs. 7.3 +/- 0.5 (GH) pmol/L; P < 0.05] and REE [mean +/- SE, 1959 +/- 67 (control) vs. 2164 +/- 55 (GH) Cal/24 h; P < 0.01]. T3 administration yielded comparable levels of FT3 (7.7 +/- 0.5 pmol/L; T3 vs. GH, P = 0.37), but did not increase REE (2015 +/- 48 Cal/24 h; T3 vs. control, P = 0.23). Combined GH and T3 administration increased REE to a level higher than that seen with T3 alone (2279 +/- 68 Cal/24 h; T3 vs. GH plus T3, P < 0.01). Significant increments in serum levels of insulin-like growth factor I and insulin were recorded with GH administration, but not with T3 alone. Resting heart rate increased to a similar degree after GH administration and T3 supplementation, respectively. Tympanic temperature remained unaltered in all four studies. The results suggest that the calorigenic effect of GH is not mediated solely through increased conversion of T4 to T3.

Effects of long-term growth hormone (GH) and triiodothyronine (T3) administration on functional hepatic nitrogen clearance in normal man.

BACKGROUND/AIMS: A decline in urea excretion is seen following long-term growth hormone administration, reflecting overall protein anabolism. Conversely, hyperthyroidism is characterized by increased urea synthesis and negative nitrogen metabolism. These seemingly opposite effects are presumed to reflect different actions on peripheral protein metabolism. The extent to which these hormonal systems have different direct effects on hepatic urea genesis has not been fully characterized. METHODS: We measured urea nitrogen synthesis rates and blood alanine levels concomitantly before, during, and after a 4-h constant intravenous infusion of alanine (2 mmol.kg bw-1.h-1). Urea nitrogen synthesis rate was estimated hourly as urinary excretion corrected for gut hydrolysis and accumulation in body water. The slope of the linear relationship between urea nitrogen synthesis rate and alanine concentration represents the liver function as to conversion of amino-N, and is denoted the functional hepatic nitrogen clearance. Eight normal male subjects (age 21-27 years; body mass index 22.4-27.0 kg/m2) were randomly studied four times: 1) after 10 days of subcutaneous saline injections, 2) after 10 days of subcutaneous growth hormone injections (0.1 IU/kg per day), 3) after 10 days of triiodothyronine administration (40 micrograms on even dates, 20 micrograms on uneven dates) and 4) after 10 days given 2)+3). All injections were given at 20 00 h. RESULTS: Growth hormone decreased functional hepatic nitrogen clearance (l/h) by 30% (from 33.8 +/- 3.2 l/h (control) to 23.8 +/- 1.5 l/h (10 days growth hormone) (mean +/- SE) (ANOVA; p < 0.01)). Triiodothyronine did not change functional hepatic nitrogen clearance (36.7 +/- 3.2 l/h), but triiodothyronine given together with growth hormone abolished the effect of growth hormone functional hepatic nitrogen clearance (38.8 +/- 4.8 l/h). CONCLUSIONS: The results show that long-term growth hormone administration acts on liver by decreasing functional hepatic nitrogen clearance, thereby retaining amino-N in the body. Triiodothyronine has no effect on functional hepatic nitrogen clearance, but given together with growth hormone, it abolishes the effect of growth hormone on functional hepatic nitrogen clearance. A possible mechanism is the known effect of thyroid hormones in reducing the bioavailability of insulin-like growth factor-I. Thus, the effects of growth hormone and triiodothyronine on amino-N homeostasis are interdependent and to some extent exerted via interplay in their regulation of liver function as to amino-N conversion.

Fuel metabolism in growth hormone-deficient adults.

Apart from being a stimulator of longitudinal growth, growth hormone (GH) regulates fuel metabolism in children and adults. A halfmark is mobilization of lipids, which involves an inhibition of lipoprotein lipase activity in adipose tissue and activation of the hormone sensitive lipase. Suppression of basal glucose oxidation and resistance to insulin are other important effects. This may cause concern during GH substitution in GH-deficient adults, some of whom may present with insulin resistance due to concomitant abdominal obesity. However, there are data to suggest that the GH-induced reduction in fat mass and increase in lean body mass may offset the insulin antagonistic actions of the hormone. The nitrogen-retaining effects of GH seem to involve a direct stimulation of protein synthesis in addition to secondary effects such as generation of insulin-like growth factor-I (IGF-I), hyperinsulinemia, and promotion of lipolysis. Thus, during periods of substrate affluence, GH acts in concert with insulin and IGF-I to promote protein anabolism. Postabsorptively, GH is primarily lipolytic and thereby indirectly protein-sparing. This effect becomes further accentuated with more prolonged fasting. In that sense, GH is unique by its preservation of protein during both feast and famine. These fuel metabolic effects add merit to the principle of GH substitution in hypopituitary adults.