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Unlabelled: Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure., Background: Chronic renal failure (CRF) results in major changes in the circulating growth hormone (GH)/insulin-like growth factor (IGF) system. However, there are only limited data on changes in free IGF-I in CRF., Methods: Matched groups of nondiabetic, nondialyzed patients with CRF (N = 25) and healthy controls (N = 13) were compared. The creatinine clearance (CCr) based on a 24-hour urine collection ranged from 3 to 59 and 89 to 148 ml/min/1.73 m2 in patients and controls, respectively. Overnight fasting serum samples were analyzed for free and total IGF-I and -II, and IGF-binding protein (IGFBP)-1, -2, and -3. Additionally, intact as well as proteolyzed IGFBP-3 was determined., Results: The patients had reduced serum-free IGF-I (-53%) and increased levels of total IGF-II (40%), IGFBP-1 (546%), and IGFBP-2 (270%, P < 0.05). Serum total IGF-I and free IGF-II were normal. Also, serum levels of immunoreactive IGFBP-3 were elevated (33%, P < 0.05), but this could be explained by an increased abundance of IGFBP-3 fragments, as ligand blotting showed no difference in levels of intact IGFBP-3. Accordingly, patients had an increased proteolysis of IGFBP-3 in vivo (17%) and in vitro (7%, P < 0.05). In patients, free IGF-I levels correlated positively with CCr (r2 = 0.38, P < 0.002) and inversely with IGFBP-1 (r2 = 0.69, P < 0. 0001) and IGFBP-2 (r2 = 0.41, P < 0.0007), whereas CCr was inversely correlated with levels of IGFBP-1 (r2 = 0.48, P < 0.0001) and IGFBP-2 (r2 = 0.63, P < 0.0001)., Conclusions: These data strongly support the hypothesis that CRF-related growth failure and tissue catabolism are caused by an increased concentration of circulating IGFBP-1 and -2, resulting in low serum levels of free IGF-I and thus IGF-I bioactivity. In addition, low levels of free IGF-I may explain the increased secretion of GH in CRF.

Ipamorelin is a new and potent synthetic pentapeptide which has distinct and specific growth hormone (GH)-releasing properties. With the objective of investigating the effects on longitudinal bone growth rate (LGR), body weight (BW), and GH release, ipamorelin in different doses (0, 18, 90 and 450 microg/day) was injected s.c. three times daily for 15 days to adult female rats. After intravital tetracycline labelling on days 0, 6, and 13, LGR was determined by measuring the distance between the respective fluorescent bands in the proximal tibia metaphysis. Ipamorelin dose-dependently increased LGR from 42 microm/day in the vehicle group to 44, 50, and 52 microm/day in the treatment groups (P<0.0001). There was also a pronounced and dose-dependent effect on BW gain. The treatment did not affect total IGF-I levels, IGFBPs, or serum markers of bone formation and resorption. The number of tartrate-resistant acid phosphatase-positive multinuclear cells in the metaphysis of the tibia did not change significantly with treatment. The responsiveness of the pituitary to a provocative i.v. dose of ipamorelin or GHRH showed that the plasma GH response was marginally reduced (P<0.03) after ipamorelin, but unchanged after GHRH. The pituitary GH content was unchanged by ipamorelin treatment. Whether ipamorelin or other GH secretagogues may have a place in the treatment of children with growth retardation requires demonstration in future clinical studies., (Copyright 1999 Harcourt Publishers Ltd.)

In a randomized cross-over study in five healthy males we compared 75-min constant i.v. infusion of saline, low-dose recombinant human (rh) insulin-like growth factor-I (rhIGF-I; 1.5 microg/kg/h) and high-dose rhIGF-I (9.0 microg/kg/h). Serum samples were analysed for ultrafiltered free IGF-I (fIGF-I), total IGF-I (tIGF-I), tIGF-II and IGF-binding protein-1 (IGFBP-1) and -3. Free and total IGF-I were unchanged during saline infusion. Low-dose rhIGF-I caused a small increment in fIGF-I [+41%, from 0.64 +/- 0.19 (mean +/- SEM) to 0.90 +/- 0.25 microg/l;P< 0.05] and tIGF-I (+9%, from 220 +/- 31 to 239 +/- 33 microg/l;P< 0.05). High-dose rhIGF-I increased tIGF-I by 40% (from 227 +/- 36 to 329 +/- 31 microg/l;P< 0.05), and fIGF-I by 11.5 times (from 0.56 +/- 0.20 to 6.46 +/- 1.39 microg/l;P< 0.05). The pharmacokinetic profile of fIGF-I was calculated after high-dose IGF-I only. The disappearance of fIGF-I followed first order kinetics with an apparent half-life of 14.4 +/- 1.0 [11.2-17.1 (range)] min. The clearance was estimated to 52 +/- 20 (16-128) ml/min/kg and the volume of distribution to 1102 +/- 464 (388-2899) ml/kg. In the three experiments, there were no differences in IGFBP-1, and tIGF-II and IGFBP-3 remained unchanged. In conclusion, fIGF-I remained within the physiological range after low-dose rhIGF-I, whereas high-dose rhIGF-I resulted in supraphysiological concentrations. Since the half-life estimates for each subject were remarkably similar, this parameter most likely does not explain the observed variation in clearance and volume of distribution of fIGF-I. Instead, differences in the circulating and cellular IGF-I binding capacity may be of importance., (Copyright 1999 Harcourt Publishers Ltd.)

Glucocorticoids usually inhibit growth despite a paradoxical increase in total IGF-I. To investigate the effect of methylprednisolone on free IGF-I, rats were treated with for 3 days (0, 1, 2, 4, and 6 mg/kg per day). A dose-dependent decrease in ultrafiltrated serum free IGF-I was observed, being lowest after 6 mg/kg (P < 0.001 all groups vs controls). Total IGF-I was increased in the groups receiving 2 mg/kg (P < 0.05). Weight change in the 24 h prior to blood sampling was positively correlated with free IGF-I (R = 0.46, P = 0.0002), but not with total IGF-I. Immunoassayable IGFBP-1 was decreased in rats given 4 mg/kg (P = 0.001), whereas there was no change in IGFBP-3 or acid-labile subunit. We propose that in rats the glucocorticoid-induced weight loss may in part be due to suppression of circulating free IGF-I.

The high affinity growth hormone binding protein (GHBP) in human serum derives from the extracellular domain of the GH receptor. It is well known that fat mass correlates positively to GHBP levels, but it is uncertain whether GH secretory status influences GHBP levels. Since body composition is known to change during GH substitution in adult GHD patients, we determined the relation between GHBP and body composition during GH substitution in GHD adults. Twenty-five GHD adults aged 45.0 +/- 1.8 years, were examined before and after 12 months of placebo-controlled GH substitution (2 IU/m2) in a parallel design. A group of 27 healthy age- and gender-matched normal-weight adults provided reference data. The participants underwent anthropometric measurements [body mass index (BMI), waist/hip ratio (W/H)], computer-tomography (CT-scan) of femoral and abdominal regions, dual-energy X-ray absorptiometry (DEXA-scan), and bioimpedance (BIA), as well as blood sampling. At baseline, the GHBP levels were increased compared to controls (1.63 +/- 0.14 nmol/l vs 1.12 +/- 0.1 nmol/l, P = 0.01). During 12 months of GH substitution, GHBP levels decreased to the levels of the control subjects. GHBP correlated positively to indices of adiposity in GHD patients at baseline: intra-abdominal fat (r = 0.54, P = 0.005), subcutaneous abdominal fat (r = 0.59, P < 0.002), body fat (BIA) (r= 0.41, P= 0.044), BMI (r= 0.58, P = 0.002), and total body fat (DEXA scan) (r= 0.61, P < 0.001). After 12 months of GH substitution, different estimates of body fat were significantly decreased in the GH treated group, but the positive relationship between GHBP and these estimates of body fat was maintained. In multiple linear regression analyses, fasting insulin levels were also a significant determinant of GHBP levels. We conclude that GHBP levels are increased in GHD patients and decrease to normal levels during 12 months of GH substitution. Furthermore, GHBP is predominantly correlated to indices of adiposity also in GHD patients.

Renal and glomerular growth is inherent in early human and experimental diabetes frequently followed by later increase in urinary albumin excretion (UAE). Treatment with angiotensin converting enzyme (ACE) inhibitors has proven effective in delaying progression of human and experimental diabetic renal changes, and so has somatostatin analog treatment in experimental diabetes. The aim of the present study was to investigate three weeks of octreotide and captopril treatment alone or in combination following three months of untreated experimental diabetes, and compare the effects to those of insulin treatment. Diabetes induced significant increases in renal and glomerular growth and urinary albumin excretion. Octreotide and captopril alone and in combination reduced renal but not glomerular size, and the combined administration reduced UAE. None of these schedules affected blood glucose levels. Insulin treatment inducing euglycemia significantly reduced renal and glomerular size and UAE. In conclusion, insulin treatment with normalization of the diabetic metabolic derangement nearly normalizes renal and glomerular growth and UAE after three months of untreated diabetes. The combined treatment of octreotide and captopril was also followed by a significant decrease in renal growth and reduction in UAE compared to placebo treatment without affecting the metabolic control of the diabetic animals.

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.

The aim was to investigate the effect of lanreotide (Angiopeptin) on urea synthesis. Lanreotide is a somatostatin analogue used in therapy trials of certain cancers. Cancer patients are often protein catabolic, thus the effect of lanreotide on whole body protein metabolism is of importance. We investigated the effect of lanreotide by measuring urea nitrogen synthesis rate (UNSR) and blood alpha-amino nitrogen levels before, during and after a 30 min iv infusion of 25 g of an electrolyte-free amino acid solution. 6 healthy male subjects were studied following, i) placebo (saline), ii) lanreotide 5 mug/kg, and iii) lanreotide 80 mug/kg. Lanreotide decreased urea nitrogen synthesis rate (mmol/h) during amino acid infusion significantly compared to saline, independent of dose of lanreotide (max +/- SE of urea nitrogen synthesis rate measurements in each study: 117 +/- 8 mmol/h (saline), 85 +/- 10 mmol/h (high dose) and 85 +/- 12 mmol/h (low dose)). This occurred in spite of significantly higher plasma alpha-amino nitrogen following lanreotide (peak +/- SE of alpha-amino nitrogen level in each study: 3.7 +/- 0.1 mmol/l placebo versus 4.8 +/- 0.2 mmol/l low dose and 4.7 +/- 0.4 mmol/l high dose (p < 0.01). We conclude that a single dose of lanreotide decreases whole body urea nitrogen synthesis rate thereby conserving body protein. The results indicate that long term lanreotide therapy may not lead to further protein catabolism in cancer patients.

Patients with microvascular angina (syndrome X) may be insulin resistant. We designed a study to establish whether this is the case. 11 patients with microvascular angina were compared with 9 matched subjects with noncardiac chest pain. Patients and controls were evaluated by coronary sinus catheterisation, and by isotopic measurement of glucose turnover, indirect calorimetry, and forearm technique during a 3 h baseline period after overnight fast and during a 2 h hyperinsulinaemic euglycaemic clamp. Pace-induced increase in coronary sinus blood flow was less in patients than in controls, whereas forearm blood flow did not differ between groups. Baseline measures of glucose metabolism were normal. During the clamp, glucose production and lipolysis were equally suppressed in both groups. Mean (SE) total insulin-induced glucose uptake was significantly impaired in patients compared with controls (3.9 [0.7] vs 6.4 [0.7] mg/kg per min; p < 0.01), and insulin-stimulated glucose uptake in the forearm was significantly reduced in patients (0.88 [0.10] vs 1.6 [0.30] mmol/L; p < 0.001). Reduced oxidative and nonoxidative metabolism accounted for the defect in overall glucose uptake in patients. No correlation between changes in coronary sinus blood flow and total body glucose uptake was seen. We found that microvascular angina was associated with substantial insulin resistance. Whether this relation is causal or coincidental is as yet unsettled.

Initial renal hypertrophy in experimental diabetes is prevented by administration of a long-acting somatostatin analogue octreotide (SMS). To investigate the long-term effects of SMS on renal hypertrophy and urinary albumin excretion (UAE), streptozotocin-diabetic and non-diabetic rats were treated with two daily subcutaneous injections of SMS (100 micrograms x 2) for six months. Untreated diabetic and non-diabetic animals were used as reference groups. No differences were seen between the two diabetic groups in respect to body weight, food intake, blood glucose levels, urinary glucose output, hemoglobin A1C(HbA1C), fructosamine, serum growth hormone (rGH) or creatinine clearance, but kidney weight (896 +/- 36 vs. 1000 +/- 24 mg, P less than 0.02), UAE (417 +/- 131 vs. 1098 +/- 187 micrograms/24 hr, P less than 0.02), kidney insulin-like growth factor I (IGF-I) (167 +/- 16 vs. 239 +/- 17 ng/g, P less than 0.01) and serum IGF-I (301 +/- 26 vs. 407 +/- 17 micrograms/liter, P less than 0.01) were all reduced in the SMS-treated diabetic animals when compared to the untreated diabetic group. In non-diabetic rats SMS reduced body weight (274 +/- 3 vs. 293 +/- 5 g, P less than 0.01), kidney weight (695 +/- 9 vs. 764 +/- 17 mg, P less than 0.01), UAE (83 +/- 29 vs. 364 +/- 114 micrograms/24 hr, P less than 0.02), kidney IGF-I (202 +/- 12 vs. 280 +/- 12 ng/g, P less than 0.01), serum IGF-I (428 +/- 21 vs. 601 +/- 54 micrograms/liter, P less than 0.01) and serum rGH (67 +/- 6 vs. 126 +/- 27 micrograms/liter, P less than 0.05) when compared to untreated controls. When kidney weights were expressed in relation to body weight no difference was found between SMS-treated and untreated controls, while the difference between SMS-treated and untreated diabetic animals was still present (P less than 0.01). In conclusion, chronic administration of SMS has abating effects on diabetic renal hypertrophy and UAE, and thus indicates that SMS may reduce development of diabetic kidney lesions in experimental diabetes. The long-term suppressive effects of SMS on renal enlargement and UAE may in part be mediated through reduction in circulating and kidney IGF-I levels.

Management of glucose homeostasis in newly kidney transplanted insulin-dependent diabetic patients is difficult. To examine whether continuous subcutaneous insulin infusion (CSII) could reverse this problem, six consecutive kidney-transplanted Type I diabetic patients either proceeded with conventional insulin therapy (CIT) or were changed to CSII beginning on the third postoperative day. After a mean of 13 days, the insulin administration mode was changed from CIT to CSII (n = 3) or from CSII to CIT (n = 3), and continued for a further 15 days. Mean blood glucose calculated on the basis of four daily measurements (8.00, 12.00, 17.00, 22.00 h) during the study periods was significantly lower during CSII (8.0 +/- 0.4 mmol/l, mean +/- SEM) than on CIT (11.0 +/- 0.6 mmol/l; p less than 0.005). Moreover, the variability of blood glucose expressed as the M-value was lower during the pump treatment compared to CIT (p less than 0.001), while the number of blood glucose values below 3.0 mmol/l was similar (3.8 vs. 4.4%). Diurnal metabolic and hormonal profiles were twice determined on each regimen with 2 hourly sampling. Glycemic control was again found to be improved during CSII therapy as compared to CIT (p less than 0.01 or 0.05 less than p less than 0.10). Moreover, insulin pump treatment resulted in a significant reduction of two major intermediary metabolites, lactate and glycerol (p less than 0.05 and p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Juvenile diabetic patients were studied 60-72 hours after insulin withdrawal when moderate ketoacidosis had developed. Somatostatin infusion for 4 hours in five patients resulted in almost complete suppression of plasma pancreatic glucagon and growth hormone, a fall in plasma-cyclic-adenosine-monophosphate (A.M.P.) concentrations, and a large fall in plasma-glucose concentration. After infusion plasma concentrations of these substances rose again. Blood-ketone-bodies, plasma-free-fatty-acids (F.F.A.), and plasma glycerol concentrations, however, did not decrease appreciably with somatostatin administration. In three patients 2 to 3 h somatostatin infusions were twice superimposed upon a continuous 9-5 h insulin infusion (1 unit/h). An insulin effect was noticeable within 30 minutes, with pronounced falls in the concentrations of plasma glucose, pancreatic glucagon, F.F.A., and blood-ketone-bodies. There was no significant change in these patterns when somatostatin was administered or withdrawn. These results do not indicate that somatostatin infusion would be useful in the treatment of manifest diabetic ketoacidosis.

Excess production of growth hormone (GH) in poorly controlled diabetes is believed to be a causal factor in the development of diabetic angiopathy, the mechanism(s) of which is unknown. The present study was undertaken to determine whether exogenous growth hormone would specifically change some quantities and functional parameters known to often be abnormal in long-standing diabetes and thought to result from the development of vascular lesions in general. The authors studied capillary resistance, factor VIII coagulant antigen (F VIII:Ag), von Willebrand factor (vWf:Ag), fibronectin, fibrinogen, and tissue-type plasminogen activator (t-PA) before, during, and after 1 week's subcutaneous GH administration (6 IU per day divided into two doses). Capillary resistance decreased insignificantly, but returned to higher levels (p less than 0.05) 1 week after withdrawal. F VIII:Ag, vWf:Ag, fibronectin, and fibrinogen all increased significantly during GH treatment. Except for F VIII:Ag, these quantities returned to pre-medication levels 7 days after termination of GH administration. The present results may contribute to the clarification of the role of GH hypersecretion in diabetic microangiopathy and macroangiopathy.

In a previous study we have shown that the growth retarding effect of selenium in infant rats occurs concomitantly with severely reduced growth hormone responses and serum somatomedin C. Furthermore, normal growth may be restored by administration of exogenous growth hormone administration. In the present study we examined the alterations after withdrawal of selenite administration in growth rate, serum growth hormone after GRF 40 injection and serum somatomedin C. Thirty-six rats were divided into 3 groups; i.e. controls, rats on continuous selenite treatment from days 21 to 63 of age and a group where selenium was withdrawn on day 42. The first 2 groups grew linearly during the experimental period, the second at a very significantly lower rate. In the third group after cessation of exposure a brief growth spurt occurred followed by a growth rate significantly different from that of the other 2 groups. The reduced GH response to GRF 40 stimulation was normalized 3 weeks after withdrawal, whereas serum somatomedin C remained at the same low level as in those rats on continuous selenite administration. There were other signs of liver lesion at day 42, i.e. elevated ALAT and reduced serum albumin, changes which became insignificant in all 3 groups at the end of the experiment. These results demonstrate that whereas stimulated growth hormone secretion was reestablished 3 weeks after termination of selenium exposure, severely reduced liver somatomedin C production persisted. An improvement in growth rate was also noted, but normal growth rate was not reached 3 weeks after discontinuation of the selenite treatment.