Biomedical subjects

H Orskov

Publications and source records attributed to H Orskov.

At least 109 records · Page 6Linked to original sources

PubMed1994

Augmented effect of short-term pulsatile versus continuous insulin delivery on lipid metabolism but similar effect on whole-body glucose metabolism in obese subjects.

The present study was designed to examine the effect of pulsatile versus continuous insulin delivery on glucose and lipid metabolism in insulin-resistant subjects. Six obese women (body mass index, 40.0 +/- 2.8 kg/m2) underwent a euglycemic glucose clamp (plasma glucose, 90 mg/dL) twice. In random order, insulin was infused intravenously for 375 minutes either at a constant rate (0.4 mU/kg/min) or in a pulsatile manner (2.4 mU/kg/min for 2 minutes followed by an off interval of 10 minutes). Endogenous insulin release was suppressed by infusion of somatostatin (250 micrograms/h). Mean circulating insulin concentrations were similar during the two protocols (pulsatile v continuous infusion, 60 +/- 10 v 56 +/- 9 mU/L), but pulsatile infusion was accompanied by oscillations with an amplitude of 120 mU/L. After 6 hours of pulsatile versus continuous insulin, isotopically determined total glucose disposal (3-3H-glucose) and hepatic glucose production (HGP) were comparable (pulsatile v continuous, 2.80 +/- 0.56 v 2.82 +/- 0.51 and 0.37 +/- 0.14 v 0.32 +/- 0.17 mg/kg/min). However, the rate of glucose oxidation (indirect calorimetry) was augmented (P < .05), whereas lipid oxidation tended to be diminished (.10 > P > .05) following pulsatile infusion. In addition, blood glycerol was more suppressed with pulsatile (31 +/- 9 nmol/L) than with continuous infusion (36 +/- 10 nmol/L, P < .05), whereas blood lactate, alanine, and 3-hydroxybutyrate were similar in the two infusion protocols.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1994

Effect of lanreotide, a somatostatin analogue, on urea synthesis in normal man.

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.

Journal Article↗

PubMed1994

Growth hormone administration stimulates energy expenditure and extrathyroidal conversion of thyroxine to triiodothyronine in a dose-dependent manner and suppresses circadian thyrotrophin levels: studies in GH-deficient adults.

OBJECTIVE: The impact of exogenous GH on thyroid function remains controversial although most data add support to a stimulation of peripheral T4 to T3 conversion. For further elucidation we evaluated iodothyronine and circadian TSH levels in GH-deficient patients as part of a GH dose-response study. PATIENTS: Eight GH-deficient adults, who received stable T4 substitution due to central hypothyroidism; two patients, who were euthyroid without T4 supplementation were studied separately. DESIGN: All patients were initially studied after at least 4 weeks without GH followed by 3 consecutive 4-week periods in fixed order during which they received daily doses of 1, 2 and 4 IU of GH/m2 body surface area. The patients were hospitalized for 24 hours at the end of each period. MEASUREMENTS: Circulating total and free concentrations of T4 and T3, total rT3 and TSH were measured once at the end of each study period. Circadian TSH levels were recorded during the period without GH and during GH treatment with 2 IU GH. RESULTS: Highly significant GH dose-dependent increases in total and free T3 and a reduction in rT3 were observed. The T3/T4 ratio also increased with increasing GH dosages (P < 0.001). In seven patients subnormal T3 levels were recorded in the period off GH, despite T4 levels well within the normal range. Resting energy expenditure also increased and correlated with free T3 levels (r = 0.47, P < 0.05). The circadian TSH levels exhibited a significant nocturnal increase during the period without GH, whereas GH therapy significantly suppressed the TSH levels and blunted the circadian rhythm (mean TSH levels (mU/l) 0.546 +/- 0.246 (no GH) vs 0.066 +/- 0.031 (2 IU GH) (P < 0.05)). The two euthyroid non-T4 substituted patients exhibited qualitatively similar changes in all parameters. CONCLUSIONS: GH administration stimulated peripheral T4 to T3 conversion in a dose-dependent manner. Serum T3 levels were subnormal despite T4 substitution when the patients were off GH but normalized with GH therapy. Energy expenditure increased with GH and correlated with free T3 levels. GH caused a significant blunting of serum TSH. These findings suggest that GH plays a distinct role in the physiological regulation of thyroid function in general, and of peripheral T4 metabolism in particular.

Adult↗

PubMed1994

Somatostatin-stimulated insulin-like growth factor binding protein-1 release is abolished by hyperinsulinemia.

It was demonstrated recently that administration of lanreotide and octreotide, two somatostatin octapeptide analogs, increased circulating insulin-like growth factor binding protein 1 (IGFBP-1) levels. The present study demonstrates that native somatostatin 14 shares this ability and that the increase in abolished by concomitant hyperinsulinemia within the physiological range. Five fasting healthy volunteers underwent a hyperinsulinemic as well as a normo-insulinemic (i.e. basal insulinemic) euglycemic clamp lasting 8 h (serum insulin levels remained constant, about 570 vs. 16 pmol/L). Immediately before the clamps, a somatostatin infusion (500 micrograms/h) was started and continued throughout. During normo-insulinemia, IGFBP-1 levels increased slowly from 6.3 +/- 6.2 to 36.1 +/- 14.8 micrograms/L (P < 0.05) reaching maximum after 7 h constant somatostatin infusion, whereas hyperinsulinemia induced a significant decrease from basal levels (from 4.7 +/- 5.4 to 1.1 +/- 1.5 micrograms/L) after 8 h (mean +/- SD, n = 5). These results may indicate hitherto unnoticed interactions of somatostatin and insulin on IGFBP-1 release with possible impact on IGF-I action at the cellular level.

Adult↗

PubMed1994

Dose-dependent stimulation of insulin-like growth factor-binding protein-1 by lanreotide, a somatostatin analog.

It was recently reported that octreotide, besides its many, almost obligatory, inhibitory actions, stimulates the release of insulin-like growth factor-binding protein-1. The present study sought to exclude the possibility that the inescapable preceding somatostatin analog-induced reduction in serum insulin participated in the observed effect. We, therefore, administered sc two clinically relevant doses (5 and 80 micrograms/kg) of lanreotide, another somatostatin octapeptide analog, which induced identical 60% initial suppressions of serum insulin. In spite of this, clear dose-dependent increases in insulin-like growth factor-binding protein-1 were observed, starting between 1-2 h after administration of lanreotide, and levels were still elevated several-fold 5 h after administration of 80 micrograms/kg lanreotide. In addition, we found that infusion of amino acids had no discernible effect on binding protein-1 release. The changes found in immunoreactive binding protein-1 were confirmed employing Western ligand blotting. The data indicate that the lanreotide-induced increase in binding protein-1 levels in serum is not due to the changes in circulating insulin. The magnitude and duration of the increase raise the possibility that the stimulation may have clinically relevant implications in somatostatin analog treatment.

Adult↗

PubMed1994

Cardiac triiodothyronine nuclear receptor binding capacities in amiodarone-treated, hypo- and hyperthyroid rats.

Parameters that are assumed to be under direct control by thyroid hormonal state were evaluated in amiodarone-treated, hypo- and hyperthyroid rats. Special attention was paid to evaluating similarities between hypothyroid and amiodarone-treated rats, with special focus on myocardial nuclear triiodothyronine (T3) receptor binding characteristics. Rats were rendered hypothyroid by adding KClO4 to the drinking water for 6 weeks (N = 14). Hyperthyroidism was induced by adding 0.003% L-thyroxine to the drinking water for 6 weeks (N = 14). Fourteen rats were treated orally for 6 weeks with amiodarone, whereas 14 rats served as untreated controls. Equilibrium binding characteristics for T3 nuclear receptors were determined by means of a simple and rapid method with excellent reproducibility and sensitivity. Body temperature and heart rate were lowered in hypothyroid and amiodarone-treated rats. Maximum binding capacities of beta-adrenergic receptors were reduced by 39% and 14% (p < 0.05) in hypothyroid and amiodarone-treated rats, respectively, and increased by 28% (p < 0.05) in hyperthyroid rats. Maximum binding capacities for voltage-operated Ca2+ channels were increased by 35% and 16% in hypothyroid and amiodarone-treated rats (p < 0.05), respectively, and decreased by 24% in hyperthyroid rats (p < 0.05). Maximum binding capacities for T3 receptors (expressed per unit of DNA) were reduced by 39% and 32% in hypothyroid and amiodarone-treated rats (p < 0.05), respectively, and increased by 63% in hyperthyroid rats (p < 0.05). In hypothyroid and amiodarone-treated rats, myocardial T3 content was extremely reduced (less than 0.05 nmol/kg and 0.06 +/- 0.08 nmol/kg, respectively, compared with control levels of 1.55 +/- 0.46 nmol/kg). In vitro competition studies of amiodarone and its desethyl analogue revealed that both drugs are potentially capable of displacing T3 from its nuclear receptor at concentrations close to what are considered therapeutic drug levels. Myocardial nuclear T3 receptor maximum binding capacities decreased to a similar degree in hypothyroid and amiodarone-treated rats and increased in hyperthyroid rats. Several other similarities between hypothyroid and amiodarone-treated rats suggest that amiodarone may act by inducing a state of thyroid hormonal resistance.

Amiodarone↗

PubMed1994

Lanreotide, a somatostatin analogue, reduces insulin-like growth factor I accumulation in proliferating aortic tissue in rabbits in vivo. A preliminary study.

Coronary artery restenosis following percutaneous transluminal angioplasty occurs with a very high incidence. Major efforts have been aimed at revealing the mechanisms and at developing therapies that might prevent or delay the myointimal proliferation. Most clinical trials have been unsuccessful. Endothelial denudation was induced in 30 rabbits using balloon catheterization of iliac arteries and aorta. Immunoreactive insulin-like growth factor I (IGF-I) was measured in arterial tissue samples obtained 1, 2 and 4 days postoperatively using a double extraction procedure to remove IGF-I binding proteins. Half of the animals were treated with subcutaneous injections of lanreotide, 10 micrograms/kg twice daily, and the other half served as controls. In the latter group, arterial IGF-I was unaltered from baseline at day 1 and increased by 300 and 400% at days 2 and 4. No increase was observed in the rabbits treated with lanreotide. The results indicate that initial local accumulation of IGF-I may be one of the mechanisms involved in myointimal proliferation after experimental arterial injury. The reduction of local IGF-I accumulation by lanreotide may be involved in the previously observed reduction in myointimal proliferation.

Animals↗

PubMed1994

Effect of growth hormone on steroidogenesis, insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 production and DNA synthesis in cultured human luteinized granulosa cells.

Numerous clinical and experimental observations have suggested that GH is important in ovarian function. We have investigated the effect of GH alone and GH in combination with FSH on the secretion of oestradiol, progesterone, insulin-like growth factor-I (IGF-I) and IGF-binding protein-1 (IGFBP-1) and on [3H]thymidine incorporation in cultured human luteinized granulosa cells. Granulosa cells from patients undergoing treatment for in vitro fertilization were isolated and cultured for 2 days in culture medium with 10% serum. After this preincubation, the medium was removed and the cells were incubated with GH (1, 10 and 100 micrograms/l) with or without FSH in serum-free medium and in the presence of [3H]methylthymidine (2 microCi/ml). GH alone resulted in a significant dose-dependent increase of oestradiol (P < 0.05) and in IGFBP-1 (P < 0.002) in the medium. The release of IGF-I was undetectable and there was no increase in [3H]thymidine incorporation with GH alone. Neither GH nor FSH alone stimulated granulosa cell proliferation or progesterone release, while the combination induced increases (P < 0.001) in both. The stimulatory effect of GH on steroidogenesis, IGFBP-1 production and granulosa cell proliferation supports a putative role for GH in the regulation of ovarian function.

Carrier Proteins↗

PubMed1993

[Long-term treatment with octreotide of patients with acromegaly].

We bring our experiences with and results of octreotide treatment for 0.5 to seven years in 26 highly selected acromegalic patients, i.e. they had almost all been operated upon before or were for other reasons not first-choice neurosurgical candidates. Sixteen patients responded immediately to octreotide and achieved good control of symptoms and average serum growth hormone levels below 5 micrograms/l. Five additional patients responded adequately to octreotide after a renewed neurosurgical attempt, and two other patients achieved satisfactory control after successful neurosurgery. Thus we had to resort to radiation therapy in three out of these 26 patients. We should like to emphasize the fact that acromegalic patients, who initially do not respond adequately to octreotide therapy, may often do so after a renewed partial adenomectomy. Octreotide therapy has in our hands been practically without side effects, apart from gastrointestinal symptoms during the initial days of treatment. All 26 patients had an ultrasound-scan of the gallbladder and biliary tracts before and during long-term octreotide administration, and with the exception of one patient with gallbladder sediment, in whom no pretreatment scanning had been performed, we had no development of biliary tract abnormalities in these up to 65 year old patients. This may be due to composition and timing of meal intake in relation to that of octreotide. Fecal fat excretion, D-vitamin metabolites in serum and prothrombin time were similar in octreotide-treated and untreated acromegalic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acromegaly↗

PubMed1993

Insulin resistance in microvascular angina (syndrome X)

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.

Alanine↗

PubMed1993

Assessment of proinsulin's effects on intermediary metabolism using the forearm technique in normal man.

We have compared the effects of human proinsulin and insulin on forearm metabolism. Seven normal, non-obese subjects were infused with 386 pmol/kg per hour of proinsulin and 180 pmol/kg per hour of insulin using the euglycaemic clamp technique. Glucose appearance and utilization rates were quantified using a primed continuous infusion of [6',6'-2H2]glucose. Mean blood glucose was 4.1 +/- 0.1 and 4.1 +/- 0.2 mmol/l during proinsulin and insulin infusions respectively. Basal insulin concentrations increased from 0.02 +/- 0.01 to 0.25 +/- 0.03 nmol/l. The proinsulin infusion was chosen to give steady-state levels approximately 20-fold higher on a molar basis than those of insulin, based on previous findings that proinsulin has only 5% the biological potency of insulin. Basal proinsulin concentrations increased from 0.003 to 5.4 +/- 0.3 nmol/l. Hepatic glucose production was suppressed similarly during the last hour of each hormone infusion: 0.07 +/- 0.16 (proinsulin, P), and 0.01 +/- 0.13 (insulin, I) mg/kg per minute. Glucose disposal, however, was significantly increased during the final hour of the insulin infusion: 4.7 +/- 0.4 (I) and 3.4 +/- 0.2 (P) mg/kg per minute (P = 0.025). Net forearm glucose uptake (FGU) increased by a greater amount during insulin compared with proinsulin infusion: 1.44 +/- 0.02 (I) and 0.71 +/- 0.01 (P) mumol/100 ml forearm per minute (P < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1993

Peripheral and hepatic insulin sensitivity in non-insulin-dependent diabetes mellitus: effect of nonesterified fatty acids.

Plasma nonesterified fatty acid (NEFA) levels are increased in the insulin-stimulated state in non-insulin-dependent diabetes mellitus (NIDDM) and may contribute to the decrease in peripheral and hepatic insulin sensitivity. To test this hypothesis and to avoid the confounding effect of obesity, we examined the effect of decreasing plasma NEFA levels on peripheral and total glucose metabolism in eight non-obese, NIDDM patients. Each received 250 mg Acipimox (a nicotinic acid analogue) or placebo at 0 and 120 minutes on separate occasions. [6,6-2H2]-glucose (0 to 300 minutes) and insulin (120 to 300 minutes) were infused in each study, and isoglycemia was maintained. Plasma NEFA levels (140 +/- 30 v 600 +/- 70 mumol/L [SEM]; P < .001) and forearm NEFA uptake measured with [1-14C]-palmitate (+93 +/- 21 v +313 +/- 42 nmol x 100 mL forearm-1; P < .001) were decreased with acipimox during the basal period (90 to 120 minutes), with no change in forearm glucose uptake (+334 +/- 80 and +330 +/- 60 nmol x 100 mL forearm-1 x min-1) and hepatic glucose output ([HGO] 13.6 +/- 0.9 and 13.4 +/- 0.7 mumol.kg-1 x min-1). Serum insulin (256 +/- 12 and 266 +/- 18 pmol/L) and plasma glucose (9.5 +/- 0.6 and 9.4 +/- 0.5 mmol/L) levels were comparable during the clamp period (270 to 300 minutes).(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes Mellitus, Type 2↗

PubMed1993

The effects of subcutaneous human proinsulin on the production of 64/65 split proinsulin, glucose turnover and intermediary metabolism in non-insulin-dependent diabetic man.

We have compared the effects of subcutaneously injected human proinsulin, insulin zinc suspension and inactive diluent (control) on glucose turnover, intermediary carbohydrate and lipid metabolism in non-insulin-dependent diabetic man. Six weight-matched (24.8 +/- 1.6 kg M-2) non-insulin-dependent diabetic subjects underwent 3 separate, randomized, 10 h isoglycemic clamps. Glucose turnover was measured using a primed continuous infusion of [6'6'2H2] glucose. Each subject received 0.35 U/kg of hormone or control made up to isovolumetric amounts. The mean blood glucose level of 7.3 +/- 0.8 mmol/l was similar at the start of each isoglycemic clamp. Incremental area under the curve proinsulin levels (1195 +/- 146 nmol/l) were about 21-fold higher, on a molar basis, than insulin (62.4 +/- 10 nmol/l). Des 64/65 split proinsulin increased in a parallel manner to intact proinsulin (r = 0.99, P < 0.0001) and comprised approximately 13% of the intact proinsulin concentration. Hepatic glucose production was suppressed similarly following proinsulin and insulin zinc injection. However, both proinsulin and insulin zinc had a significantly greater effect on suppression of hepatic glucose production compared to control (P = 0.01, P = 0.009, respectively). Metabolic clearance rate of glucose fell significantly during the control studies compared to insulin zinc or proinsulin injections (P < 0.05). Blood lactate, pyruvate and alanine concentrations were similar following control or hormone injections. However blood glycerol, 3-hydroxybutyrate and plasma-non-esterified fatty acids were suppressed significantly by proinsulin and insulin zinc compared to control injections. The conclusions were: (1) In overnight fasted hyperglycemic non-insulin-dependent subjects s.c. injections of proinsulin and insulin zinc can produce similar effects on glucose turnover, intermediary lipid and carbohydrate metabolism. (2) Similar carbohydrate intermediary metabolism profiles can be obtained following insulin zinc, proinsulin or control injections. (3) However lipolysis and ketogenesis were significantly suppressed by both hormones compared to control. (4) Subcutaneous proinsulin injection resulted in approximately 13% conversion to des 64/65 split proinsulin.

Alanine↗

PubMed1993

Octreotide treatment does not improve impaired glucose uptake in cirrhosis.

Forearm glucose uptake during a hyperglycaemic (10 mmol/l) glucose clamp was diminished to 33% of the normal value (p = 0.012) in six cirrhotic patients compared with matched control subjects. Fasting insulin concentrations were significantly elevated in the cirrhotic patients confirming insulin resistance which may have been induced by chronic hyperinsulinaemia. The cirrhotic patients received one week of treatment with 50 micrograms octreotide subcutaneously three times daily which reduced pre-dose fasting insulin levels from 26.2 +/- 7.9 to 18.1 +/- 6.2 mU/l p < 0.005, and post dose levels to 7.0 +/- 3.5 mU/l p < 0.005. However when the glucose clamp was repeated 20 hours after the last dose of octreotide no change was detected in clamp glucose requirements, forearm glucose uptake, or stimulated insulin secretion. It was concluded that one week of lowering insulin levels does not reverse the insulin resistance of cirrhosis.

Adult↗

PubMed1993

Growth hormone dose regimens in adult GH deficiency: effects on biochemical growth markers and metabolic parameters.

OBJECTIVE: We examined the effects of different doses of GH on insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), body composition, energy expenditure, and various metabolites in GH deficient adults, in order to approach a metabolically appropriate GH dosage in young GH deficient adults. DESIGN: Ten GH deficient patients (age 21-43) were studied after 4 weeks without GH followed by three consecutive 4-week periods, where the patients received in a fixed order GH 1, 2 and 4 IU/m2 s.c. per day. At the end of each period the patients were hospitalized for a 24-hour examination. RESULTS: Mean 24-hour levels of GH (mIU/l) were 2.7 +/- 0.3 (0 GH), 7.2 +/- 0.9 (1), 10.8 +/- 1.5 (2) and 18.9 +/- 2.7 (4 IU/m2) (mean +/- SEM) (P < 0.01). Likewise, IGF-I levels increased dose dependently from 61 +/- 21 to 206 +/- 65, 260 +/- 70 and 468 +/- 171 micrograms/l (P < 0.05); serum IGF-I in an age and sex matched control group was 248 +/- 25 micrograms/l. Corresponding serum IGFBP-3 levels also increased from 1860 +/- 239 to 3261 +/- 379, 3762 +/- 434 and 4384 +/- 652 micrograms/l (P = 0.01) respectively. Significant increases in diurnal serum insulin levels after 4 IU/m2 were recorded, whereas plasma glucose levels remained unchanged. Lipid intermediates increased dose independently during GH administration. GH caused a significant increase in resting energy expenditure, whereas the respiratory exchange ratio was unaltered. Fat mass was increased without GH therapy and decreased during the study. Four patients made complaints during 4 IU/m2 GH administration, probably related to GH induced fluid retention. CONCLUSION: Based primarily on IGF-I and IGFBP-3 levels our data suggest that a GH replacement dose in young GH deficient adults in the order of 1-2 IU/m2 per day is adequate. This is a relatively low dose as compared to dose regimens in children and adolescents.

Adult↗

PubMed1993

The role of plasma non-esterified fatty acids during exercise in type 2 diabetes mellitus.

Elevated fasting plasma non-esterified fatty acid (NEFA) levels have been reported in Type 2 diabetes. We examined whether such changes persist during low-grade exercise and influence carbohydrate metabolism. Eight Type 2 diabetic patients with moderate glycaemic control and eight healthy controls received the anti-lipolytic agent, acipimox, or placebo on separate occasions before exercising for 45 min at 35% pre-determined VO2max. Fasting plasma NEFA levels were similar (0.40 +/- 0.06 (SEM) and 0.45 +/- 0.05 mmol l-1; healthy and Type 2 diabetic subjects) following placebo, and increased to comparable levels with exercise (0.73 +/- 0.07 and 0.73 +/- 0.10 mmol l-1). Acipimox lowered basal NEFA levels (0.14 +/- 0.03 and 0.28 +/- 0.04 mmol l-1; both p < 0.05 vs placebo), and prevented the rise with exercise. Blood glucose (p < 0.001) and serum insulin (p < 0.01) levels were higher in the Type 2 diabetic patients (vs controls) for both treatments. Whole body lipid oxidation increased from baseline to a comparable degree with exercise following placebo (3.2 +/- 0.3 and 2.8 +/- 0.3 mg kg-1 min-1; healthy and Type 2 diabetic subjects, both p < 0.02). Although less marked, the same was also observed following acipimox (2.0 +/- 0.4 and 2.1 +/- 0.5 mg kg-1 min-1; both p < 0.05). Carbohydrate oxidation increased with exercise in both subject groups, but with no significant difference between the treatments. Thus, the metabolic response to low-grade exercise was normal in Type 2 diabetic patients with moderate glycaemic control, but occurred against a background of hyperinsulinaemia.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxybutyric Acid↗

PubMed1993

Luminal and basolateral uptake and receptor binding of IGF-I in rabbit renal proximal tubules.

The aim of the present study was to quantify and compare the luminal and basolateral binding and uptake of 125I-labeled insulin-like growth factor I (IGF-I) by means of 1) isolated, perfused, proximal tubules combined with electron microscope autoradiography and 2) luminal and basolateral membrane vesicles from rabbit proximal tubules. 125I-IGF-I was added to isolated perfused proximal tubules for 30 min in concentrations of 1.6-3.9 micrograms/l to either the perfusate or the bath. The luminal and basolateral uptake in 30 min averaged 447 and 410 fg/mm, respectively. About 20% of the luminally absorbed IGF-I was digested. Addition of excess unlabeled IGF-I (10(-7) M) to the bath produced complete inhibition of the basolateral binding/uptake, whereas no inhibition of the luminal uptake was seen. Electron microscope autoradiography showed that IGF-I after luminal endocytic uptake to a large extent was transported into lysosomes. After basolateral exposure the major portion of the grains was found over the basolateral cell membrane; however, a significant amount was located over endocytic vacuoles and lysosomes in both apical and basal parts of the cells. In both luminal and basolateral membrane vesicles, single-class, high-affinity binding sites for IGF-I were found with dissociation constants of 6.3 and 5.7 nM, respectively. Specific binding capacities averaged 2.7 and 25.7 pmol IGF-I/mg protein in luminal and basolateral vesicles. The biochemical data suggest an asymmetric distribution of specific IGF-I receptors in the luminal and basolateral membranes, with a greater abundance of receptors in the latter. The extensive basolateral endocytic binding/uptake of IGF-I compared with that of the luminal in isolated perfused tubules differs considerably from the processing of other peptide hormones.

Animals↗

PubMed1993

Marked effects of sustained low growth hormone (GH) levels on day-to-day fuel metabolism: studies in GH-deficient patients and healthy untreated subjects.

The metabolic effects of circadian GH levels in the very low physiological range are unknown. Therefore, we studied 1) GH-deficient patients on receiving GH replacement therapy in whom the last GH injection was replaced with a constant iv infusion starting at 24 h of either GH (35 micrograms/h) or saline (SAL), and 2) an untreated healthy control group. Glucose turnover, indirect calorimetry, and forearm exchange of metabolites were investigated the following day in the basal state (8-11 h) and during a euglycemic (11-13 H) and a hypoglycemic (13-14 h) glucose clamp. During infusion, steady state GH levels increased by 1.9 micrograms/L. Basal and insulin-stimulated energy expenditures (EE) were lower in the patients during SAL than during GH infusion, and the basal respiratory exchange ratio was also lower during GH treatment. Protein EE was elevated during SAL compared to GH infusion (P < 0.05). During the clamp, forearm glucose uptake decreased in the GH study compared to that in the SAL study ((P < 0.05). The patients in the SAL study were more sensitive to insulin during the clamp in terms of suppression of endogenous glucose production (EGP; P < 0.05) and infusion rate of glucose necessary to maintain euglycemia (M value; P < 0.01). Lipid oxidation, in particular in the basal state, was decreased during SAL compared to GH infusion (P < 0.01). The SAL-treated compared with the control group was characterized by decreased basal and insulin-stimulated EE (P < 0.01), increased protein EE (P < 0.01), and hypersensitivity to insulin in terms of suppression of EGP (P < 0.05) and M value (P < 0.01). During the hypoglycemic clamp, the patients in the SAL study were hypersensitive to the hypoglycemic actions of insulin in terms of increased M-value and suppression of EGP, and lipolysis was impaired, as judged by the inhibition of net forearm uptake of FFA. In conclusion, very low GH levels exert powerful actions on day-to-day metabolism, resulting in protein and glucose sparing at the expense of lipids.

Adult↗