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Steen B Pedersen, Jens D Børglum, Kim Brixen and Bjørn Richelsen

Pedersen SB, Borglum JD, Brixen K, Richelsen B. Relationship between sex hormones, body composition and metabolic risk parameters in premenopausal women. Eur J Endocrinol 1995;133: 200–6. ISSN 0804–4643

The metabolic complications associated with obesity are dependent upon the degree of obesity and the distribution of adipose tissue. In order to evaluate the associations between sex hormone status, metabolic risk parameters, obesity and distribution of adipose tissue, 25 premenopausal women with a wide range of body mass index (19.3–48.1 kg/m2 were studied. Body composition was determined by dual-energy x-ray absorptiometry scan and anthropometric measurements; in addition, lipid and sex hormone status were determined and an oral glucose tolerance test was performed. We found that sex hormone-binding globulin was correlated negatively with total fat mass (r = –0.77, p < 0.001) and especially with abdominal localization of adipose tissue (r = –0.85, p < 0.001). Free testosterone was correlated positively with total fat mass (r = 0.40, p < 0.05) and with abdominal fat accumulation (r = 0.64, p < 0.001). Free estrogen was correlated negatively with total amount of adipose tissue (r = –0.40, p < 0.05) but not with the distribution of adipose tissue, Finally, total fatness, abdominal localization of adipose tissue and free testosterone were all associated with elevated metabolic risk factors. However, multiple regression analysis revealed that only abdominal localization of adipose tissue was independently associated with a higher risk profile, whereas the effects of sex hormones or total fatness disappeared when abdominal localization of adipose tissue was included in the analysis. In conclusion, these findings in premenopausal women indicate that the connection between sex hormones and metabolic risk factors might be indirect, probably operating through alterations in the amount of adipose tissue in the abdominal region.

SB Pedersen, University Clinic of Endocrinology and Internal Medicine, Aarthus, Amtssygehus, Tage Hansensgade, DK-8000 Aarhus C, Denmark

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Jens F. Bak, Ole Schmitz, Søren S. Sørensen, Jens Frøkjær, Torben Kjær and Oluf Pedersen


To examine subcellular mechanisms behind the pathogenesis of peripheral insulin resistance in chronic uremic patients, insulin receptor function and glycogen synthase activity were studied in biopsies of skeletal muscle obtained during renal transplant surgery in 9 non-diabetic uremic patients. The results were compared with values obtained in an age- and sex-matched group of subjects with normal renal function, undergoing surgery for urological or gynecological diseases. The recovery of solubilized, wheat germ agglutinin-purified insulin receptors from skeletal muscle was increased among the uremic patients: 49.3 ± 6.1 vs 31.4 ± 2.8 fmol/100 mg muscle in healthy controls (p < 0.03). Basal as well as insulin-stimulated kinase activities of the insulin receptors, expressed as phosphorylation of the synthetic peptide poly(Glu-Tyr(4:1)) were similar. In addition, the maximal activity of the glycogen synthase was enhanced in uremic muscle: 26.6 ± 2.8 vs 19.5 ± 1.8 nmol · (mg protein)−1 · min−1 (p < 0.05), whereas the half-maximal activation constant for glucose-6-phosphate was identical in the two groups. Likewise, the muscle glycogen concentrations were similar in the uremic patients and the normal controls. In conclusion, our data suggest that neither impaired insulin receptor function nor a reduced maximal glycogen synthase activity of skeletal muscle are involved in the pathogenesis of the insulin resistance of patients with chronic renal failure.

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Anders Juul, Søren A Pedersen, Steen Sørensen, Kjeld Winkler, Jens OL Jørgensen, Jens S Christiansen and Niels E Skakkebæk

Juul A, Pedersen SA, Sørensen S, Winkler K, Jørgensen JOL, Christiansen JS, Skakkebæk NE. Growth hormone (GH) treatment increases serum insulin-like growth factor binding protein- bone isoenzyme alkaline phosphatase and forearm bone mineral content in young adults with GH deficiency of childhood onset. Eur J Endocrinol 1994;131:41–9. ISSN 0804–4643

Recent studies have demonstrated that growth hormone (GH)-deficient adults have a markedly decreased bone mineral content compared to healthy adults. However, there are conflicting results regarding the effects of GH treatment on bone mineral content in GH-deficient adults. Therefore, we evaluated the effect of GH treatment on a marker of bone formation (bone alkaline phosphatase), hepatic excretory function and distal forearm bone mineral content in GH-deficient adults. Growth hormone was administered subcutaneously in 21 adults (13 males and 8 females) with GH deficiency of childhood onset for 4 months in a double-blind, placebo-controlled GH trial, while 13 of the patients then received further GH for an additional 14 months. Serum insulin-like growth factor I (IGF-I) increased significantly from 100 to 279 μg/l and IGF binding protein-3 (IGFBP-3) from 1930 to 3355 μg/l after 4 months of GH treatment (p < 0.0001). In addition, the molar ratio between IGF-I and IGFBP-3 increased significantly from 0.22 to 0.33 after GH treatment (p < 0.0001), Bone alkaline phosphatase increased significantly from 38.6 to 92.9 U/l during GH therapy in male patients (p < 0.0001), whereas liver-derived alkaline phosphatase was unaltered by GH. In the females, the increase in bone alkaline phosphatase did not reach statistical significance (19.1 vs 40.0 U/l, p = 0.06). The GH-induced increase in bone alkaline phosphatase correlated significantly with the increase in serum IGFBP-3 (r = 0.46, p = 0.04) but not with the increase in serum IGF-I (p = 0.16). Liver function as assessed by the galactose elimination capacity was within the normal range for healthy adults and did not change after GH treatment. Bone mineral content increased significantly between 7 and 14 months of GH treatment (mean increase in bone mineral content Z score = 0.24 sd/ 7 months), but remained low even after 14 months of GH treatment (Z score = –2.2 ± 0.24 (mean ± sem)). We conclude that GH administration increases serum levels of bone-derived alkaline phosphatase in male patients and has a potentially beneficial impact on bone mineral content in young adults with GH deficiency of childhood onset.

Anders Juul, Department of Growth and Reproduction, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark

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Jens OL Jørgensen, Sten B Pedersen, Jens Børglum, Jan Frystyk, Ken KY Ho, Jens S Christiansen, Hans Ørskov, Werner F Blum and Bjørn Richelsen

Jørgensen JOL, Pedersen SB, Borglum J, Frystyk J, Ho KKY, Christiansen JS, Ørskov H, Blum WF, Richelsen B. Serum concentrations of insulin-like growth factors (IGFs), IGF binding proteins 1 and 3 and growth hormone binding protein in obese women and the effects of growth hormone administration: a double-blind, placebo-controlled study. Eur J Endocrinol 1995;133:65–70. ISSN 0804–4643

Obesity is associated with suppressed growth hormone (GH) concentrations but relatively little is known about insulin-like growth factors(IGFs) and binding proteins for GH and IGFs (GHBP and IGFBPs) and the modulatory effect of GH administration. In a double-blind, crossover design we studied the impact of 5 weeks of placebo or GH administration (0.03 mg·kg−1 body wt·day−1) in nine obese women (mean± sem; age 30.4 ± 2.4 years; body mass index 37.0 ± 2.8kg/m2) on IGF-I, IGF-II, IGFBP-1 and -3 and GHBP. Serum IGF-I (μg/l) levels were subnormal and increased significantly following GH (117 ± 16 (placebo) vs 434 ± 33 (GH) vs 198 ± 15 (control (p < 0.01)). By contrast, serum IGF-II (μg/l) levels were in the normal range and remained unchanged (608 ± 20 (placebo) vs 647 ± 40 (GH) (NS)). Serum IGFBP-3 was in the normal range and increased significantly during GH treatment, although relatively less than IGF-I, such that the molar ratio between IGF-I and IGFBP-3 increased with GH treatment, whereas the ratio between IGF-I + IGF-II and IGFBP-3 remained unchanged. Serum IGFBP-1 was low in the placebo situation but became further and almost completely suppressed during GH treatment. During a 2-h hyperinsulinemic, euglycemic glucose clamp, IGFBP-1 decreased in the placebo study and remained suppressed during GH. Serum GHBP (nmol/l) levels were elevated substantially compared to non-obese controls (p < 0.001) and did not change during GH treatment (2.37 ± 0.36 (placebo) vs 2.21 ± 0.25 (GH) vs 0.80 ± 0.19 (control)). In conclusion. obese subjects have low total IGF-I levels but may exhibit relatively increased free IGF-I levels due to the suppression of IGFBP-1. This presumed elevation in free IGF-1 in obesity may explain the normal levels of IGFBP-3 and IGF-II, which contrasts with classic GH deficiency. Furthermore, obese subjects are responsive to exogenous GH in terms of total IGF-I generation and normalization of the ratio between IGF-I and IGFBP-3. Finally, obesity is associated with marked elevations in GHBP levels that were unaffected by 5 weeks of GH administration.

Jens OL Jørgensen, Medical Department M, Aarhus Kommunehospital, DK-8000 C, Aarhus, Denmark

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Jens O. L. Jørgensen, Søren A. Pedersen, Leif Thuesen, Jørgen Jørgensen, Jens Møller, Jørn Müller, Niels E. Skakkebæk and Jens S. Christiansen


Growth hormone treatment in GH-deficient adults has proved beneficial in recent short-term trials, but long-term results have not yet been reported. Thirteen GH-deficient adults (4 females, 9 males; mean (sem) age 26.4 (1.7) years), who had completed 4 months of GH therapy in a double-blind placebo-controlled cross-over study were followed, for further 16.1 (0.8) months of uninterrupted GH therapy in an open design. A significant mean increase of 1.3 cm in linear height was recorded, whereas body mass index remained unchanged. Mean muscle volume of the thigh, estimated by computerised tomography, increased significantly compared with that of the initial placebo period (p=0.01), and a slight decrease was recorded in adipose tissue volume of the thigh (p=0.10) and subscapular skinfold thickness (p=0.10). Still, the muscle to fat ratio of the thigh was significantly lower compared with that of normal subjects (72.6/27.4 vs 77.9/22.1) (p<0.01). The mean isometric strength of the quadriceps muscles increased significantly during long-term GH therapy (p<0.01), but remained lower compared with that of normal subjects (1.66 (0.10) vs 2.13 (0.11) Nm/kg body weight). Exercise capacity performed on a bicycle ergometer increased significantly after long-term therapy (p<0.05), but still did not reach the values seen in normal subjects (22.5 (3.4) vs 37.4 (4.2) watt · min · kg−1· No adverse reactions were recorded during long-term therapy and hemoglobin A1c remained unchanged. These data suggest that long-term GH replacement therapy in GH-deficient adults has beneficial effects on several physiological features which are subnormal in these patients.

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Per H Andersen, Bjørn Richelsen, Jens Bak, Ole Schmitz, Niels S Sørensen, Rodolphe Lavielle and Oluf Pedersen

In a short-term (eight days) double-blind crossover study involving 10 obese patients, the effects of dexfenfluramine on glucose and lipid metabolism were examined. The protocol comprised whole body in vivo measurements (hyperinsulinemic euglycemic clamp in combination with indirect calorimetry) and in vitro studies of isolated adipocytes (lipolysis and glucose transport). All study participants were weight stable during the study period (103.1±3.2, placebo vs 103.3±3.1 kg, dexfenfluramine, NS). The following parameters were significantly reduced after dexfenfluramine treatment: fasting levels of plasma glucose (6.2±0.2 vs 5.7±0.2 mmol/l, p<0.01), serum insulin (168.0±14.5 vs 138.9±7.9 pmol/l, p<0.05), serum C-peptide (0.68±0.03 vs 0.58±0.02 nmol/l, p<0.05) and total serum cholesterol (6.07±0.41 vs 5.48±0.38 mmol/l, p< 0.01). In the basal state glucose oxidation rate was significantly reduced by 36% (p<0.001), whereas non-oxidative glucose disposal was significantly increased by 41% (p<0.01), following dexfenfluramine treatment. Insulin-stimulated (2 mU·kg−1·min−1) glucose disposal rate tended to be increased (18%, p=0.10) after dexfenfluramine. In conclusion, dexfenfluramine possesses beneficial regulatory effects on glucose and lipid metabolism in non-diabetic obese patients, independently of weight loss.

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Henning Beck-Nielsen, Oluf Pedersen, Jens Peder Bagger and Niels Schwartz Sørensen


Using [125I]insulin at 172 pmol/l (1 ng/ml) the binding of insulin to mononuclear leucocytes isolated from peripheral blood was studied.

Our present study comprised 21 healthy subjects (22–33 years old, 90–110% of ideal weight) and a comparable group of 22 obese subjects (20–37 years old, minimum 150% of ideal weight). A significant difference in insulin binding was found between the two groups, the mean specific insulin binding fraction in normals being 1.92 ± 0.58 (s) × 10−2 and that for the obese 1.19 ± 0.41 (s) × 10−2 (P < 0.01).

No correlation was found between body weight and the number of insulin receptors in the obese subjects. However, the number of insulin receptors was negatively correlated to fat cell size (P < 0.05). Insulin receptors in subjects were also negatively correlated to fasting plasma insulin (P < 0.05).

Insulin receptors were studied in 11 obese subjects before and after 10 days of fasting. A significant increase in the number of insulin receptors was observed with a simultaneous decrease in plasma insulin to normal values.

The results indicate that obesity complicated by hyperinsulinism is associated with a decrease in the number of insulin receptors compared with the normal. This finding may in part explain the decreased insulin sensitivity of the hyperinsulinaemic obese.

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Oluf Pedersen, Bjørn Richelsen, Jens Bak, Jon Arnfred, Jørgen Weeke and Ole Schmitz

Abstract. Insulin action on glucose utilization was characterized in adipocytes from 10 thyrotoxic patients, 6 hypothyroid patients and 10 age- and sex-matched control subjects. In thyrotoxic patients insulin binding at low insulin concentrations was reduced (P < 0.05) and accompanied by impaired insulin sensitivity of glucose transport (P < 0.02), glucose oxidation (P < 0.05) and lipogenesis (P < 0.05). Glucose transport and glucose oxidation rates also exhibited depressed maximal insulin responsiveness (P < 0.05). In hypothyroid patients insulin binding was reduced, too, (P < 0.05) and associated with impaired sensitivity to insulin of glucose transport (P < 0.05). Both glucose transport and lipogenesis rates showed decreased maximal insulin responsiveness (P < 0.05). In conclusion: In man, both hyper- and hypothyroidism are characterized by insulin resistance of adipocyte glucose utilization localized to insulin binding as well as to insulin-stimulated glucose transport and metabolism.

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Jan H. Kristiansen, Jens Brøchner-Mortensen, Kaj O. Pedersen, Søren Jensen and Torben Glud


Nine patients with primary hyperparathyroidism were studied to investigate the renal tubular reabsorption of calcium and sodium. Fasting serum and urine samples were analysed, and the glomerular filtration rate and the renal plasma clearance of lithium were determined simultaneously. Comparison was made with 9 ageand sex-matched normocalcemic controls. In the proximal tubule, there was a significantly higher absolute reabsorption of calcium in patients than in controls, whereas the fractional reabsorption rate of calcium did not differ between the two groups. In the distal tubule, the absolute calcium reabsorption rate was significantly higher in the patients, whereas the fractional reabsorption rate of calcium was significantly lower than in controls. In the patient group there was a significantly positive linear correlation between the increased tubular capacity for calsium reabsorption and the absolute proximal calcium reabsorption rate, but not between the increased capacity and the absolute distal calcium reabsorption rate. No significant differences were found in the renal tubular handling of sodium between patients and controls. Our results suggest that the increased capacity for tubular calcium reabsorption in primary hyperparathyroidism mainly is localized in the proximal tubule, and that the renal tubular handling of calcium and sodium in this disease differs from that in familial hypocalciuric hypercalcemia.

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Monika J Bak, Nicolai Wewer Albrechtsen, Jens Pedersen, Bolette Hartmann, Mikkel Christensen, Tina Vilsbøll, Filip K Knop, Carolyn F Deacon, Lars O Dragsted and Jens J Holst


To determine the specificity and sensitivity of assays carried out using commercially available kits for glucagon and/or oxyntomodulin measurements.


Ten different assay kits used for the measurement of either glucagon or oxyntomodulin concentrations were obtained. Solutions of synthetic glucagon (proglucagon (PG) residues 33–61), oxyntomodulin (PG residues 33–69) and glicentin (PG residues 1–69) were prepared and peptide concentrations were verified by quantitative amino acid analysis and a processing-independent in-house RIA. Peptides were added to the matrix (assay buffer) supplied with the kits (concentration range: 1.25–300 pmol/l) and to human plasma and recoveries were determined. Assays yielding meaningful results were analysed for precision and sensitivity by repeated analysis and ability to discriminate low concentrations.

Results and conclusion

Three assays were specific for glucagon (carried out using the Millipore (Billerica, MA, USA), Bio-Rad (Sundbyberg, Sweden), and ALPCO (Salem, NH, USA) and Yanaihara Institute (Shizuoka, Japan) kits), but none was specific for oxyntomodulin. The assay carried out using the Phoenix (Burlingame, CA, USA) glucagon kit measured the concentrations of all three peptides (total glucagon) equally. Sensitivity and precision were generally poor; the assay carried out using the Millipore RIA kit performed best with a sensitivity around 10 pmol/l. Assays carried out using the BlueGene (Shanghai, China), USCN LIFE (Wuhan, China) (oxyntomodulin and glucagon), MyBioSource (San Diego, CA, USA) and Phoenix oxyntomodulin kits yielded inconsistent results.