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Mikkel Andreassen, Jan Frystyk, Jens Faber and Lars Østergaard Kristensen

Introduction

The GH/IGF1 axis may modulate inflammatory processes. However, the relationship seems complicated as both pro- and anti-inflammatory effects have been demonstrated.

Methods/design

Twelve healthy volunteers (mean age 36, range 27–49 years) were treated in random order with increasing doses of GH for 3 weeks (first week 0.01 mg/kg per day, second week 0.02 mg/kg per day, and third week 0.03 mg/kg per day) or a GH receptor antagonist (pegvisomant; first week 10 mg/day and last two weeks 15 mg/day), separated by 8 weeks of washout. Circulating levels of the pro-inflammatory cytokines tumor necrosis factor α (TNFα (TNFA)), interleukin 6 (IL6), and IL1β (IL1B) and the acute phase proteins (APPs) C-reactive protein (CRP), haptoglobin, orosomucoid, YKL40 (CHI3L1), and fibrinogen were measured.

Results

During GH treatment, IGF1 (median 131 (Inter-quartile range (IQR) 112–166) vs 390 (322–524) μg/l, P=0.002) increased together with TNFα (0.87 (0.74–1.48) vs 1.27 (0.80–1.69) ng/l, P=0.003), IL6 (1.00 (0.83–1.55) vs 1.35 (0.80–4.28) ng/l, P=0.045), and fibrinogen (9.2 (8.8–9.6) vs 11.1 (9.4–12.4) μM, P=0.002). By contrast, orosomucoid decreased (18.0 (15.5–24.3) vs 15.0 (15.0–17.0) μM, P=0.018). CRP, YKL40, and haptoglobin were unchanged. During pegvisomant treatment, IGF1 decreased (139 (117–171) vs 91 (78–114) ng/ml, P=0.005). Orosomucoid (21.0 (16.3–23.8) vs 22.0 (17.0–29.3) μM, P=0.036) and CRP (1.00 (0.62–1.77) vs 1.43 (0.71–3.29) mg/l, P=0.074) increased without an increase in pro-inflammatory cytokines.

Conclusions

GH/IGF1 action appears to modulate the initial stage of the inflammatory response as well as downstream processes elucidated by levels of APPs. The data suggest a complicated relationship not allowing any simple conclusions as to whether GH/IGF1 actions have mainly pro- or anti-inflammatory effects in vivo.

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Ana Pokrajac, Jan Frystyk, Allan Flyvbjerg and Peter J Trainer

Background

Somatostatin analogues are frequently used for medical treatment of acromegaly. The rationale for their use is based on the inhibition of pituitary GH secretion; however, there is in vitro evidence that octreotide also acts to inhibit hepatic IGF1 generation.

Aim & design

We studied the pituitary-independent effects of octreotide on IGF1 generation in 11 severely GH-deficient (GHD) humans (age 38, range 23–52; seven males; body mass index 24.7±3 kg/m2; peak-stimulated GH <3 μg/l; 3±1 pituitary hormone deficiencies) on a stable dose of GH replacement (0.4±0.1 mg) for at least 6 months. Patients were studied before and after 50 μg of s.c. octreotide three times a day for 7 days.

Results

At study entry, all patients had total IGF1 within age- and gender-related reference range (SDS 0.4±1.0). Octreotide treatment resulted in a significant decrease in total IGF1 (by 18%, 208±89 vs 173±62 μg/l, P=0.04), free IGF1 (by 13%, 0.83±0.36 vs 0.70±0.33 μg/l, P=0.01) and IGFBP3 (6%, 4475±745 vs 4209±912 μg/l, P=0.02). Octreotide suppressed fasting insulin from 8.1±3.4 to 6.3±4.1 mU/l (P=0.01) and was associated with an increase in fasting glucose from 5.2±0.9 to 5.8±0.9 mmol/l (P<0.01). IGFBP1 increased by 84% from 42±26 to 95±52 μg/l (P=0.04).

Conclusion

Our study demonstrates that octreotide induces a significant decrease in IGF1 in severely GHD adults on a fixed dose of GH replacement. This is the evidence for a non-pituitary action of octreotide on the GH/IGF1 axis, most likely by antagonising the action of GH on hepatic IGF1 generation and indirectly, by suppressing insulin secretion.

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Kurt Højlund, Henning Beck-Nielsen, Allan Flyvbjerg and Jan Frystyk

Objective

Low levels of adiponectin, IGF-binding protein 1 (IGFBP1) and IGFBP2 and high levels of leptin correlate with several indices of insulin resistance and risk of type 2 diabetes. However, in insulin receptoropathies, plasma adiponectin is paradoxically increased despite severe insulin resistance, whereas the IGF axis is sparsely described. Here, we aimed to characterise the multimeric distribution of adiponectin and the IGF axis in humans with a heterozygous INSR mutation (Arg1174Gln).

Methods

Blood samples obtained from six Arg1174Gln carriers and ten lean, healthy controls before and after a euglycaemic–hyperinsulinaemic clamp were examined for plasma adiponectin multimers, leptin, total IGF1, IGF2, free IGF1, IGFBP1 and IGFBP2.

Results

Despite tenfold elevated fasting insulin and marked insulin resistance in Arg1174Gln carriers, the levels of total adiponectin, leptin, IGFBP1 and IGFBP2 were similar to those observed in controls, while total IGF1, IGF2 and free IGF1 levels were increased. The relative fraction of high-molecular weight adiponectin was increased, whereas both the absolute concentration and the fraction of low-molecular weight adiponectin were decreased in Arg1174Gln carriers. Interestingly, exogenous insulin failed to suppress total adiponectin in Arg1174Gln carriers, but reduced IGFBP1 and increased IGFBP2 as in controls.

Conclusion

The normal levels of adiponectin, IGFBP1 and IGFBP2 in the face of highly elevated insulin levels suggest an impaired ability of insulin to suppress markers of common insulin resistance in carriers of a dominant-negative INSR mutation. However, together with the adaptive increases in IGF1 and IGF2 and a potentially improved distribution of adiponectin multimers, these changes may contribute to rescue insulin action in insulin receptor-deficient individuals.

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Ulrick Espelund, Søren Cold, Jan Frystyk, Hans Ørskov and Allan Flyvbjerg

Objective

Epidemiological studies imply an association between circulating IGF1 and breast cancer, whereas the role of IGF2, which also acts on the IGF1 receptor, is less settled. This study investigates the association between IGF2 and breast cancer in patients with localized disease.

Design

The participants were women with well-characterized, early stage, localized breast cancer (n=43) and matched healthy women (n=38), from whom fasting serum levels of IGF-related peptides were measured.

Results

In patients, mean free IGF2 was increased (+57%, P<0.001), in spite of reduced total IGF2 levels (−12%, P=0.003) when compared with controls. Similar changes were seen in free IGF1 (+28%, P=0.004) and total IGF1 (−16% P=NS). Pro-IGF2 and IGF-binding protein 1 (IGFBP1) were unchanged. IGFBP2 was reduced by 22% in the patients (P=0.004). The patients showed reduced IGFBP3 protease activity and accordingly increased levels of intact IGFBP3, whereas total IGFBP3 was unchanged.

Conclusion

Women with localized, early-stage breast cancer show elevated circulating free IGF1 and IGF2, reduced total IGF2 and alterations in IGFBPs. The changes observed despite minimal cancer disease suggest a role for the circulating IGF system in the progression of breast cancer in women.

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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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Kristine Z Rubeck, Michael Madsen, Caroline Marie Andreasen, Sanne Fisker, Jan Frystyk and Jens Otto L Jørgensen

Context

Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial.

Objective

To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA).

Design and methods

Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)).

Results

Total and bioactive IGF1 (μg/l) levels were similar (total: 185±10 (SA) versus 171±8 (surgery) (P=0.28); bioactive: 1.9±0.2 vs 1.9±0.1 (P=0.70)). Suppression of total and free GH (μg/l) during OGTT was blunted in the SA group (total GHnadir: 0.59±0.08 (SA) versus 0.34±0.06 (surgery) (P=0.01); free GHnadir: 0.43±0.06 vs 0.19±0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02).

Conclusions

i) Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

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Ulrick Espelund, Jens Meldgaard Bruun, Bjørn Richelsen, Allan Flyvbjerg and Jan Frystyk

Background: In normal subjects up to 10% of circulating insulin-like growth factor II (IGF-II) consists of pro-IGF-II. However, its regulation and biological impact remains unknown. In obese subjects, serum free and total IGF-II are increased, and we therefore investigated the impact of obesity and diet on serum pro-IGF-II.

Design: Non-diabetic, obese subjects (n = 34) with a body mass index (BMI) of 38.9 ± 0.5 kg/m2 were subjected to 8 weeks with very low calorie diet (800 kcal/day) followed by 12 weeks with a weight-stabilizing diet. Fasting serum was collected before the study, and after 8 and 20 weeks. Pro-IGF-II was determined after acid-gel chromatography using a novel, highly specific in-house assay, free and total IGFs were measured after ultrafiltration and acid-ethanol extraction, respectively, and IGF-binding proteins (IGFBPs) were measured with specific immunoassays.

Results: Diet reduced BMI and fasting levels of insulin and glucose (P < 0.001). Serum pro-IGF-II was markedly reduced in obese subjects as compared with matched normal-weight controls (means and 95% confidence intervals: 93 μg/l (82–104 μg/l) versus 171 μg/l (152–192 μg/l), respectively; P < 0.001), and levels remained unchanged after the weight loss. In contrast, during the study period total and free IGF-II decreased (P < 0.05), whereas total IGF-I, IGFBP-1 and IGFBP-2 increased (P < 0.001). Serum free IGF-I remained unaltered. Cross-sectional and longitudinal correlation analyses showed that pro-IGF-II was closer and more consistently associated with IGF-I than IGF-II.

Conclusion: This study demonstrates that pro-IGF-II is reduced in obesity, in contrast to mature IGF-II. This indicates a hitherto unrecognized link between nutrition and pro-IGF-II. In addition, our data indicate that pro-IGF-II is regulated independently of mature IGF-II.

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Zhulin Ma, Jens Sandahl Christiansen, Torben Laursen, Torsten Lauritzen and Jan Frystyk

Objective

Insulin regulates the GH–IGF1 axis. Insulin analogs differ from human insulin in receptor affinity and possibly liver accessibility. Therefore, we compared the GH–IGF1 axis response with human NPH insulin, insulin detemir, and insulin glargine in patients with type 1 diabetes (T1D).

Methods

A total of 17 patients (seven were women) with T1D (age of 42 (24–63) years (mean and range), BMI of 24.7 (19.5–28.3) kg/m2, HbA1c of 7.2 (6.3–8.0) % (55 (45–64) mmol/mol), T1D duration of 26 (8–45) years) were studied using a randomized, three-period crossover design. Patients received s.c. injections of equal, individual doses of NPH, detemir, and glargine at 1800 h. Plasma glucose, serum total IGF1, bioactive IGF, IGF-binding protein (IGFBPs), and GH were measured hourly for 14 h post-injection.

Results

When compared with the area under the curve (AUC) following NPH and glargine, detemir resulted in the lowest 6–14 h AUC (mean and range) of IGFBP1 (1518 (1280–1800)) vs 1621 (1367–1922) vs 1020 (860–1210) μg/l×h) and GH (17.1 (14.1–20.6) vs 15.4 (12.7–18.6) vs 10.2 (8.5–12.3) μg/l×h), but in the highest AUC of bioactive IGF (3.8 (3.5–4.2) vs 3.7 (3.4–4.0) vs 4.4 (4.1–4.8) μg/l×h) (all P<0.01). These differences were unrelated to plasma glucose. By contrast, profiles of total IGF1, IGFBP2, and IGFBP3 were comparable.

Conclusions

Independent of plasma glucose, a single dose of detemir caused larger suppression in serum IGFBP1 than NPH and glargine, whereas bioactive IGF was higher, thereby explaining the lower GH levels. Thus, detemir appears to be more liver specific than NPH insulin and glargine.

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Dorte Glintborg, Marianne Andersen, Claus Hagen, Jan Frystyk, Veronica Hulstrøm, Allan Flyvbjerg and Anne Pernille Hermann

Objective: Polycystic ovary syndrome (PCOS) patients are abdominally obese and are at increased risk of developing the metabolic syndrome. Low adiponectin and ghrelin levels in PCOS patients could be caused by insulin resistance as well as high testosterone levels.

Design: Adiponectin and ghrelin levels were evaluated in 51 hirsute PCOS patients referred to the outpatient clinic of an academic, tertiary care medical centre and in 63 weight-matched female controls. Relationships between adiponectin, ghrelin, leptin, body composition, testosterone and insulin were examined.

Methods: Measurements of body composition including waist-hip-ratio (WHR), body mass index (BMI) and whole body dual-energy X-ray absorptiometry scan measures of body fat mass. Measurements of fasting levels of adiponectin, ghrelin, leptin, androgen status, oestradiol, lipid variables and insulin during follicular phase.

Results: Adiponectin levels were significantly decreased in obese PCOS patients compared with weight-matched controls (geometric mean (−2 to 2 s.d.) 5.3 (2.5–11.1) vs 7.3 (3.0–17.4) mg/l, P<0.05). Mean ghrelin was significantly lower in hirsute PCOS patients than in controls (0.6 (0.3 to 1.4) vs 0.8 (0.4 to 1.7) μg/l, P<0.001) and this remained significant after subdividing subjects according to waist circumference and BMI. During multiple regression analysis, testosterone correlated positively with adiponectin and negatively with ghrelin independent of BMI, WHR and total fat mass.

Conclusion: Obese hirsute PCOS patients demonstrated significantly lower adiponectin levels than weight-matched controls suggesting a very high risk for the metabolic syndrome. Furthermore, ghrelin levels were decreased in hirsute PCOS patients and showed a significant, negative correlation with testosterone independent of body composition.

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Jian-Wen Chen, Michael F Nielsen, Andrea Caumo, Hendrik Vilstrup, Jens Sandahl Christiansen and Jan Frystyk

Objective: Liver cirrhosis is characterized by reduced circulating IGF-I and this has been linked to an adverse clinical outcome. Therefore, we investigated the dynamic changes in circulating total, free, and bioactive IGF-I, IGF-binding protein (IGFBP)-1, IGFBP-2, and IGFBP-1-bound IGF-I (binary complex) during an oral glucose tolerance test (OGTT) in patients with liver cirrhosis.

Methods: Seven Caucasian males with liver cirrhosis and seven healthy males matched for age (54.4 ± 3.2 vs 54.6 ± 4.4 years) and body mass index (25.3 ± 1.2 vs 25.9 ± 1.3 kg/m2) were studied. Blood samples were drawn at 0, 30, 60, 90, 120, 150, and 180 min for determination of serum total and free IGF-I, IGFBP-1, IGFBP-2, and binary complex, while bioactive IGF-I was measured at 0, 30, 60, 120, and 180 min.

Results: In comparison with healthy subjects, baseline levels of total (47%), free (36%), and bioactive IGF-I (51%) were lower, while IGFBP-1 (268%) was higher (P < 0.05), IGFBP-2 (172%) tended to be higher (P > 0.05), and the binary complex unchanged (~100%) in cirrhotic patients. Serum total and free IGF-I, and IGFBP-2 remained unchanged in both study groups during the OGTT. Bioactive IGF-I decreased by 29% from baseline to 60 min in cirrhotic patients and remained low at the end of the OGTT (P < 0.05). A similar tendency was observed in healthy controls (P = 0.052). Concomitantly, IGFBP-1, binary complex, and IGFBP-1 saturation index decreased significantly in both groups. The disappearance of the binary complex was about twofold faster than that of IGFBP-1 (P < 0.05).

Conclusion: Despite unchanged concentrations of total and free IGF-I, bioactive IGF-I declined significantly after an oral glucose load in patients with liver cirrhosis and the same tendency was observed in healthy subjects. We speculate that the reduction in bioactive IGF-I may be related to the higher levels of free IGFBP-1 and the faster disappearance of IGFBP-1-bound IGF-I.