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Birgit Nyholm, Sanne Fisker, Sten Lund, Niels Møller and Ole Schmitz

Abstract

Objective: To explore a possible association between serum concentration of leptin, insulin sensitivity and non-insulin-dependent diabetes mellitus (NIDDM).

Design: Forty first-degree relatives of NIDDM patients and 35 control subjects matched for age, gender and body mass index underwent a hyperinsulinaemic (insulin infusion rate 0·6 mU/kg per min) euglycaemic clamp combined with indirect calorimetry. Serum leptin was measured in fasting blood samples obtained before the clamp.

Results: All subjects had a normal oral glucose tolerance test. Insulin-stimulated glucose uptake (M) was decreased in the relatives compared with the control subjects (4·58 ± 0·27 versus 606 ± 0·25 mg/kg per min, P < 0·001). Conversely, serum leptin was increased in the relatives (9·6·/÷ 1·1 versus 6·1·/÷ 1·2 ng/ml (geometric mean·/÷ antilog s.e.m.). P < 0·05). A positive correlation was observed between circulating levels of leptin and percentage body fat (P < 0·001) and inverse correlations were found between leptin, M (P < 0·01), maximal aerobic capacity (VO2 max) (P < 0·01), and energy expenditure (P ≤ 0·01) in both groups. In multiple linear regression analysis, percentage body fat, gender and M significantly determined the level of leptin (r 2 = 0·71, P < 0·001) whereas family history of NIDDM and VO2 max did not.

Conclusion: Serum leptin is increased in insulin-resistant offspring of NIDDM patients. The association between leptin, anthropometric measures and insulin sensitivity is, however, comparable with that of a control group. The increased concentrations of serum leptin in the relatives appear to be associated with the insulin resistance, but not with a family history of NIDDM.

European Journal of Endocrinology 136 173–179

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Stig Engkjær Christensen, Otto Lunde Jørgensen, Niels Møller and Hans Ørskov

Abstract. The effects of increases in body temperature on growth hormone (GH)-release were studied in 10 young normal males in the fasting state as well as postprandially.

The temperature increase of one degree centigrade was attained by external heating using thermostatically controlled water blankets covered by heat-reflecting aluminium foil. The increase in plasma GH after heating was partially suppressed in the non-fasting state reaching a mean of 7.9 ± 3.5 (sem), ng/ml, range 1.0–36 ng/ml. In contrast all subjects exhibited higher increases, mean 18.3 ± 4.0 ng/ml, range 7–44 ng/ml, in response to heating when fasting.

The results were compared in the same subjects to the plasma GH-responses obtained during exercise (450 kpm/min for 40 min) inducing a similar increase in body temperature of about one degree centrigrade. Nevertheless the response in plasma GH (8.4 ± 3.3 ng/ml, range 0.4–34 ng/ml) was smaller than obtained by the heat test despite a rate of temperature increase on exercise which was about twice as high. Furthermore, the same exercise performed in a cold room under circumstances which precluded any major rises in core temperature resulted in complete inhibition of GH-release. The results indicate that exercise per se does not stimulate GH-secretion, indeed it may inhibit the response expected to be evoked by the exercise-induced rise in temperature.

Evidence is also presented that it is core and not cutaneous temperature which modulated GH release.

The procedure used for inducing the rise in temperature and plasma GH may be used as a simple, acceptable and safe clinical test for GH-insufficiency.

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Stig Engkjær Christensen, Otto Jørgensen, Jan Møller, Niels Møller and Hans Ørskov

Abstract. Ten young healthy normal-weight males were studied in four test situations designed to elucidate the relative role of body temperature increase vs that of exercise per se for pituitary hormone release. Tympanic temperature was recorded continuously during the tests. Elevation of body temperature at rest induced by external heating resulted in parallel changes in serum prolactin (Prl), also found when temperature spontaneously returned towards normal. In contrast, temperature elevation of the same magnitude through exercise (450 kpm/min for 40 min) induced no change in Prl secretion. It is concluded that increase in core temperature is a stimulus of Prl secretion and suggested that exercise apparently inhibits the stimulatory effect.

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Ermina Bach, Andreas B Møller, Jens O L Jørgensen, Mikkel H Vendelbo, Niels Jessen, Steen B Pedersen, Thomas S Nielsen and Niels Møller

Objective

Acute and chronic inflammatory and metabolic responses are generated by lipopolysaccharide (LPS) during acute illness and in the pathogenesis of the metabolic syndrome, type 2 diabetes and cardiovascular disease, but whether these responses depend on intact pituitary release of hormones are not clearly identified. We compared the metabolic effects of LPS in hypopituitary patients (HPs) (in the absence of growth hormone (GH) and ACTH responses) and healthy control subjects (CTR) (with normal pituitary hormone responses).

Design

Single-blind randomized.

Methods

We compared the effects of LPS on glucose, protein and lipid metabolism in eight HP and eight matched CTR twice during 4-h basal and 2-h hyperinsulinemic–euglycemic clamp conditions with muscle and fat biopsies in each period during infusion with saline or LPS.

Results

LPS increased cortisol and GH levels in CTR but not in HP. Also, it increased whole-body palmitate fluxes (3-fold) and decreased palmitate-specific activity (SA) 40–50% in CTR, but not in HP. G(0)/G(1) Switch Gene 2 (G0S2 – an inhibitor of lipolysis) adipose tissue (AT) mRNA was decreased in CTR. Although LPS increased phenylalanine fluxes significantly more in CTR, there was no difference in glucose metabolism between groups and intramyocellular insulin signaling was unaltered in both groups.

Conclusions

LPS increased indices of lipolysis and amino acid/protein fluxes significantly more in CTR compared with HP and decreased adipocyte G0S2 mRNA only in CTR. Thus, in humans intact pituitary function and appropriate cortisol and GH release are crucial components of the metabolic response to LPS.

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Jens OL Jorgensen, Werner F Blum, Nanette Horn, Niels Møller, Jens Møller, Michael B Ranke and Jens S Christiansen

To evaluate the short-term effects of growth hormone (GH), insulin and different levels of glycemia on insulin-like growth factors (IGF) I and II and IGF binding proteins (IGFBP) 1, 2 and 3, we studied six GH-deficient adolescents during a night and the following day in the postabsorptive (basal) state followed by sequential euglycemic (5 mmol/l) and hypoglycemic (3 mmol/l) glucose clamps concomitant with an intravenous infusion (starting at 24.00 h) of GH (35 μg/h) or saline. Current GH therapy was withdrawn 24 h prior to each study. Nocturnal levels of IGF-I, IGF-II, IGFBP-2 and IGFBP-3 remained stable during both studies. Nocturnal serum IGFBP-1 increased and correlated inversely with insulin in both studies. Regression analysis revealed a significant inverse correlation between mean nocturnal IGFBP-2 and IGFBP-3 levels. During the daytime, serum IGF-I declined slowly during saline infusion, whereas serum IGF-II remained stable in both studies. Serum IGFBP-1 displayed a gradual significant decline during the basal state and the euglycemic and hypoglycemic clamps seemed to be unaffected by GH levels. By contrast, serum IGFBP-2 remained stable during the same period in both the GH and the saline study. Serum IGFBP-3 declined insignificantly during the daytime in the saline study. In conclusion: a strong inverse correlation between IGFBP-1 and insulin is confirmed; serum IGFBP-2 exhibits a constant circadian pattern, which seems independent of both ambient glucose and insulin levels and short-term GH deprivation but, on the other hand, shows a strong inverse correlation with IGFBP-3 levels; it is possible that IGFBP-2 levels are regulated by IGFBP-3 or IGFBP-3 binding site availability.

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Jens Fuglsang, Puk Sandager, Jan Frystyk, Niels Møller, Allan Flyvbjerg and Per Ovesen

Objective

To determine the levels of adiponectin and its subforms before and immediately after delivery to estimate the effect of cessating advanced pregnancy on circulating adiponectin levels.

Design and methods

In a cohort of 37 women with uncomplicated singleton pregnancies and 6 women with twin pregnancies, serum adiponectin was measured before caesarean section (CS) in the fasting state, and 24 and 48 h after CS.

Results

Serum adiponectin levels declined within 24 h of delivery from median 8.34 mg/l (range 5.57–20.47) to 6.81 mg/l (4.16–17.39) after 24 h and 6.84 mg/l (3.83–17.42) after 48 h. This corresponded to a relative decrease to 83±6 and 81±7% of pregnant values after 24 and 48 h respectively (P<0.001, ANOVA). In twin pregnancies, maternal adiponectin levels displayed a decrease that was the same as that displayed by them after birth (P<0.001).

High-molecular weight adiponectin constituted 50±8% (range 34–68%) of total adiponectin. Absolute changes in adiponectin levels after delivery were most pronounced in this subfraction. The percentage medium-molecular weight adiponectin decreased slightly, but significantly (from 37±6 to 35±5%, P<0.001), and a similar statistically significant rise was observed in the low-molecular weight fraction (from 13±2 to 15±3%; P<0.001) within 48 h of delivery.

Conclusions

Decreases in adiponectin levels occur shortly after delivery, and adiponectin subforms initiate the changes towards the non-pregnant state.

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Jens Fuglsang, Puk Sandager, Niels Møller, Sanne Fisker, Hans Ørskov and Per Ovesen

Objective: During pregnancy, placental growth hormone (PGH) is secreted into the maternal circulation, replacing pituitary GH. It is controversial whether PGH levels decline during vaginal birth. After placental expulsion, PGH is eliminated from the maternal blood. GH binding protein (GHBP) and body mass index (BMI) influence GH kinetics, but their impact on PGH kinetics is unknown. The present study was undertaken to define the kinetics of PGH during vaginal delivery and Caesarian section and to relate these kinetics to GHBP and BMI.

Design: A short term, prospective cohort study.

Methods: Twelve women had repeated blood samples drawn during vaginal delivery. From 26 women undergoing planned Caesarian delivery (CS) repeated blood samples were withdrawn before, during and after the CS, allowing PGH half-life determination.

Results: During vaginal delivery, median PGH values did not change before expulsion of the placenta, although individual fluctuations were seen. Clearance of PGH from the maternal circulation was best described by a two-compartment model. The initial half-life of serum PGH was (mean ± s.d.) 5.8 ± 2.4 min, and the late half-life was (median) 87.0 min (range: 25.1–679.6 min). The late half-life was correlated to the pre-gestational BMI (r = 0.39, P = 0.047), but not to the serum GHBP concentration.

Conclusions: Serum PGH did not decrease significantly during vaginal delivery. Elimination of PGH fitted a two-compartment model, with an estimated initial half-life of 5.8 min. The late phase serum half-life of PGH was related to BMI, suggesting a role for maternal fat mass in PGH metabolism.

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Jens Otto L. Jørgensen, Werner F. Blum, Niels Møller, Michael B. Ranke and Jens S. Christiansen

Abstract.

Knowledge of the circadian patterns of serum IGF-I I and the large molecular weight IGF binding protein, IGFBP-3 might, apart from its physiological relevance, be of clinical interest, inasmuch as measurements of these parameters are being introduced into the evaluation of GH deficiency. We therefore evaluated the 24-h (08.00-08.00 h) patterns of serum IGF-II and IGFBP-3 in 8 GH-deficient patients who were studied during three periods when receiving 1. GH (2 IU) at 20.00 h; 2. GH (2 IU) at 08.00 h and 3. no GH. For comparison, 10 age- and sex-matched untreated healthy subjects were studied once under similar conditions. The serum IGF-II levels of the patients were relatively stable over the 24-h periods, yielding mean levels which were significantly lower during no GH: 553±78 (evening GH), 554±54 (morning GH), and 429±65 μg/l (no GH). The mean IGF-II level in the normal subjects was 635±29 μg/l, which was significantly higher than in either patient study. Similarly, stable 24-h levels of IGFBP-3 were recorded in all studies. The mean IGFBP-3 level of the patients was significantly lower when they received no GH, and the mean level in the healthy subjects was higher than in any of the patient studies: 1853±301 (no GH), 2755 ± 317 (evening GH), 2904±269 (morning GH), and 3856±186 μg/l (healthy subjects). However, minute but significant changes over time, characterised by slight decrements at night, were observed for both parameters in several of the studies. Nevertheless, since both IGF-II and IGFBP-3 display rather stable 24-h levels in the individual, it is concluded that measurements of these parameters in evaluation of growth retardation can be based on a single daytime sample.

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Poul F Vestergaard, Mikkel H Vendelbo, Steen B Pedersen, Anders Juul, Steffen Ringgard, Niels Møller, Niels Jessen and Jens O L Jørgensen

Objective

The mechanisms underlying the impact of age and gender on the GH–IGF1 axis remain unclear. We tested the hypothesis that age and gender have impacts on GH signaling in human subjects in vivo.

Design

A total of 20 healthy non-obese adults (‘young group’ <30 years (5F/5M) and ‘old group’ >60 years (5F/5M)) were studied after: i) an i.v. GH bolus (0.5 mg) and ii) saline.

Methods

Muscle and fat biopsies were obtained after 30 and 120 min. Total and phosphorylated STAT5B proteins, gene expression of IGF1, SOCS1, SOCS2, SOCS3 and CISH, body composition, VO2max, and muscle strength were measured.

Results

In the GH-unstimulated state, women displayed significantly elevated levels of CISH mRNA in muscle (P=0.002) and fat (P=0.05) and reduced levels of IGF1 mRNA in fat. Phosphorylated STAT5B (pSTAT5b) was maximally increased in all subjects 30 min after GH exposure and more pronounced in women when compared with men (P=0.01). IGF1, SOCS1, SOCS2, SOCS3, and CISH mRNA expression increased significantly in muscle after 120 min in all subjects with no impact of age and gender. GH-induced pSTAT5b correlated inversely with lean body mass (LBM; r=−0.56, P=0.01) and positively with the CISH mRNA response (r=0.533, P=0.05).

Conclusion

i) GH signaling in muscle and fat after a single GH bolus in healthy human subjects is age independent, ii) we hypothesize that constitutive overexpression of CISH may contribute to the relative GH resistance in women, and iii) experimental studies on the impact of sex steroid administration and physical training on GH signaling in human subjects in vivo are required.

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Mikkel H Vendelbo, Britt Christensen, Solbritt B Grønbæk, Morten Høgild, Michael Madsen, Steen B Pedersen, Jens O L Jørgensen, Niels Jessen and Niels Møller

Objective

Fasting and exercise stimulates, whereas glucose suppresses GH secretion, but it is uncertain how these conditions impact GH signaling in peripheral tissues. To test the original ‘feast and famine hypothesis’ by Rabinowitz and Zierler, according to which the metabolic effects of GH are predominant during fasting, we specifically hypothesized that fasting and exercise act in synergy to increase STAT-5b target gene expression.

Design and methods

Eight healthy men were studied on two occasions in relation to a 1 h exercise bout: i) with a concomitant i.v. glucose infusion (‘feast’) and ii) after a 36 h fast (‘famine’). Muscle and fat biopsy specimens were obtained before, immediately after, and 30 min after exercise.

Results

GH increased during exercise on both examination days and this effect was amplified by fasting, and free fatty acid (FFA) levels increased after fasting. STAT-5b phosphorylation increased similarly following exercise on both occasions. In adipose tissue, suppressors of cytokine signaling 1 (SOCS1) and SOCS2 were increased after exercise on the fasting day and both fasting and exercise increased cytokine inducible SH2-containing protein (CISH). In muscle, SOCS2 and CISH mRNA were persistently increased after fasting. Muscle SOCS1, SOCS3, and CISH mRNA expression increased, whereas SOCS2 decreased after exercise on both examination days.

Conclusions

This study demonstrates that fasting and exercise act in tandem to amplify STAT-5b target gene expression (SOCS and CISH) in adipose and muscle tissue in accordance with the ‘feast and famine hypothesis’; the adipose tissue signaling responses, which hitherto have not been scrutinized, may play a particular role in promoting FFA mobilization.