| 1. |
- Christiansen, J. S., et al.
(author)
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Growth Hormone Research Society perspective on the development of long-acting growth hormone preparations
- 2016
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In: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 174:6
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Journal article (peer-reviewed)abstract
- Objective: The Growth Hormone (GH) Research Society (GRS) convened a workshop to address important issues regarding trial design, efficacy, and safety of long-acting growth hormone preparations (LAGH). Participants: A closed meeting of 55 international scientists with expertise in GH, including pediatric and adult endocrinologists, basic scientists, regulatory scientists, and participants from the pharmaceutical industry. Evidence: Current literature was reviewed for gaps in knowledge. Expert opinion was used to suggest studies required to address potential safety and efficacy issues. Consensus process: Following plenary presentations summarizing the literature, breakout groups discussed questions framed by the planning committee. Attendees reconvened after each breakout session to share group reports. A writing team compiled the breakout session reports into a draft document that was discussed and revised in an open forum on the concluding day. This was edited further and then circulated to attendees from academic institutions for review after the meeting. Participants from pharmaceutical companies did not participate in the planning, writing, or in the discussions and text revision on the final day of the workshop. Scientists from industry and regulatory agencies reviewed the manuscript to identify any factual errors. Conclusions: LAGH compounds may represent an advance over daily GH injections because of increased convenience and differing phamacodynamic properties, providing the potential for improved adherence and outcomes. Better methods to assess adherence must be developed and validated. Long-term surveillance registries that include assessment of efficacy, cost-benefit, disease burden, quality of life, and safety are essential for understanding the impact of sustained exposure to LAGH preparations.
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| 2. |
- Johannsson, Gudmundur, 1960, et al.
(author)
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Growth Hormone Research Society perspective on biomarkers of GH action in children and adults
- 2018
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In: Endocrine Connections. - : Bioscientifica. - 2049-3614. ; 7:3
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Journal article (peer-reviewed)abstract
- Objective: The Growth Hormone Research Society (GRS) convened a Workshop in 2017 to evaluate clinical endpoints, surrogate endpoints and biomarkers during GH treatment of children and adults and in patients with acromegaly. Participants: GRS invited 34 international experts including clinicians, basic scientists, a regulatory scientist and physicians from the pharmaceutical industry. Evidence: Current literature was reviewed and expert opinion was utilized to establish the state of the art and identify current gaps and unmet needs. Consensus process: Following plenary presentations, breakout groups discussed questions framed by the planning committee. The attendees re-convened after each breakout session to share the group reports. A writing team compiled the breakout session reports into a document that was subsequently discussed and revised by participants. This was edited further and circulated for final review after the meeting. Participants from pharmaceutical companies were not part of the writing process. Conclusions: The clinical endpoint in paediatric GH treatment is adult height with height velocity as a surrogate endpoint. Increased life expectancy is the ideal but unfeasible clinical endpoint of GH treatment in adult GH-deficient patients (GHDA) and in patients with acromegaly. The pragmatic clinical endpoints in GHDA include normalization of body composition and quality of life, whereas symptom relief and reversal of comorbidities are used in acromegaly. Serum IGF-I is widely used as a biomarker, even though it correlates weakly with clinical endpoints in GH treatment, whereas in acromegaly, normalization of IGF-I may be related to improvement in mortality. There is an unmet need for novel biomarkers that capture the pleiotropic actions of GH in relation to GH treatment and in patients with acromegaly.
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| 3. |
- Chen, Weena J Y, et al.
(author)
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Association of plasma osteoprotegerin and adiponectin with arterial function, cardiac function and metabolism in asymptomatic type 2 diabetic men
- 2011
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In: Cardiovascular Diabetology. - : Springer Science and Business Media LLC. - 1475-2840. ; 10, s. 67-
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Journal article (peer-reviewed)abstract
- BACKGROUND:Osteoprotegerin (OPG), a soluble member of the tumor necrosis factor receptor superfamily, is linked to cardiovascular disease. Negative associations exist between circulating OPG and cardiac function. The adipocytokine adiponectin (ADPN) is downregulated in type 2 diabetes mellitus (T2DM) and coronary artery disease and shows an inverse correlation with insulin sensitivity and cardiovascular disease risk. We assessed the relationship of plasma OPG and ADPN and arterial function, cardiac function and myocardial glucose metabolism in T2DM.METHODS:We included 78 asymptomatic men with uncomplicated, well-controlled T2DM, without inducible ischemia, assessed by dobutamine-stress echocardiography, and 14 age-matched controls. Cardiac function was measured by magnetic resonance imaging, myocardial glucose metabolism (MMRglu) by 18F-2-fluoro-2-deoxy-D-glucose positron emission tomography. OPG and ADPN levels were measured in plasma.RESULTS:T2DM patients vs. controls showed lower aortic distensibility, left ventricular (LV) volumes, impaired LV diastolic function and MMRglu (all P < 0.05). In T2DM men vs. controls, OPG levels were higher (P = 0.02), whereas ADPN concentrations were decreased (P = 0.04). OPG correlated inversely with aortic distensibility, LV volumes and E/A ratio (diastolic function), and positively with LV mass/volume ratio (all P < 0.05). Regression analyses showed the associations with aortic distensibility and LV mass/volume ratio to be independent of age-, blood pressure- and glycated hemoglobin (HbA1c). However, the associations with LV volumes and E/A ratio were dependent of these parameters. ADPN correlated positively with MMRglu (P < 0.05), which, in multiple regression analysis, was dependent of whole-body insulin sensitivity, HbA1c and waist.CONCLUSIONS:OPG was inversely associated with aortic distensibility, LV volumes and LV diastolic function, while ADPN was positively associated with MMRglu. These findings indicate that in asymptomatic men with uncomplicated T2DM, OPG and ADPN may be markers of underlying mechanisms linking the diabetic state to cardiac abnormalities.TRIAL REGISTRATION:Current Controlled Trials ISRCTN53177482.
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| 9. |
- Brismar, K, et al.
(author)
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Adiponectin, IGFBP-1 and -2 are independent predictors in forecasting prediabetes and type 2 diabetes
- 2023
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In: Frontiers in endocrinology. - : Frontiers Media SA. - 1664-2392. ; 13, s. 1092307-
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Journal article (peer-reviewed)abstract
- Adiponectin and insulin-like growth factor (IGF) binding proteins IGFBP-1 and IGFBP-2 are biomarkers of insulin sensitivity. IGFBP-1 reflects insulin sensitivity in the liver, adiponectin in adipose tissue and IGFBP-2 in both tissues. Here, we study the power of the biomarkers adiponectin, IGFBP-1, IGFBP-2, and also included IGF-I and IGF-II, in predicting prediabetes and type 2 diabetes (T2D) in men and women with normal oral glucose tolerance (NGT).DesignSubjects with NGT (35-56 years) recruited during 1992-1998 were re-investigated 8-10 years later. In a nested case control study, subjects progressing to prediabetes (133 women, 164 men) or to T2D (55 women, 98 men) were compared with age and sex matched NGT controls (200 women and 277 men).MethodsThe evaluation included questionnaires, health status, anthropometry, biochemistry and oral glucose tolerance test.ResultsAfter adjustment, the lowest quartile of adiponectin, IGFBP-1 and IGFBP-2 associated independently with future abnormal glucose tolerance (AGT) in both genders in multivariate analyses. High IGFs predicted weakly AGT in women. In women, low IGFBP-2 was the strongest predictor for prediabetes (OR:7.5), and low adiponectin for T2D (OR:29.4). In men, low IGFBP-1 was the strongest predictor for both prediabetes (OR:13.4) and T2D (OR:14.9). When adiponectin, IGFBP-1 and IGFBP-2 were combined, the ROC-AUC reached 0.87 for women and 0.79 for men, higher than for BMI alone.ConclusionDifferences were observed comparing adipocyte- and hepatocyte-derived biomarkers in forecasting AGT in NGT subjects. In women the strongest predictor for T2D was adiponectin and in men IGFBP-1, and for prediabetes IGFBP-2 in women and IGFBP-1 in men.
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| 10. |
- Friedrich, Nele, et al.
(author)
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Age and sex specific reference intervals across life-span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I/IGFBP-3 ratio measured by new automated chemiluminescence assays.
- 2014
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In: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 99:5
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Journal article (peer-reviewed)abstract
- Context: Measurement of IGFBP-3 can aid the diagnosis of growth hormone related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I/IGFBP-3 ratio are associated with clinical endpoints like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. Objectives: Establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I/IGFBP-3 ratio by newly developed automated immunoassays. Setting: Multicentre study with samples from 11 cohorts from the USA, Canada and Europe Participants: 14,970 subjects healthy subjects covering all ages from birth to senescence. Main outcome measures: Concentrations of IGFBP-3 and the IGF-I/IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays. Results: Both the concentration of IGFBP-3 and the IGF-I/IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I/IGFBP-3 ratio occurs already around the age of 15, with a slightly earlier and higher peak in females. Beyond the age of 60, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I/IGFBP-3 ratio remain significantly higher in males. Conclusions: We present an extensive set of assay specific, age and sex-adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I/IGFBP-3 ratio and demonstrate distinct sex specific differences across lifespan.
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| 14. |
- Hedman, Christina A, et al.
(author)
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Intraperitoneal insulin delivery to patients with type 1 diabetes results in higher serum IGF-I bioactivity than continuous subcutaneous insulin infusion
- 2014
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In: Clinical Endocrinology. - : Wiley-Blackwell. - 0300-0664 .- 1365-2265. ; 81:1, s. 58-62
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Journal article (peer-reviewed)abstract
- ObjectiveType 1 diabetes (T1D) is associated with low IGF-I and altered levels of IGF-binding proteins (IGFBPs) in plasma. This may be of importance for insulin sensitivity and the risk of developing diabetic complications. We hypothesized that IGF-I bioactivity is affected by the route of insulin administration and that continuous intraperitoneal insulin infusion (CIPII) has a more pronounced effect than continuous subcutaneous insulin infusion (CSII).Design and methodsWe compared 10 patients with T1D on CIPII with 20 age- and sex-matched patients on CSII. Blood sampling was carried out 7–9 am after an overnight fast. All patients were C-peptide negative. IGF-I bioactivity was measured in vitro using a specific IGF-I kinase receptor activation (KIRA) assay. IGF-I was also measured by immunoassay together with IGF-II, IGFBP-1 and IGFBP-2.ResultsWhen compared with subcutaneous insulin, intraperitoneal insulin resulted in (CIPII vs CSII) higher IGF-I bioactivity (1·83 ± 0·76 vs 1·16 ± 0·24 μg/l; P = 0·02), IGF-I (120 ± 35 vs 81 ± 19 μg/l; P = 0·01) and IGF-II (1050 ± 136 vs 879 ± 110 μg/l; P = 0·02). By contrast, log-transformed IGFBP-1 was reduced (P = 0·013), whereas log-transformed IGFBP-2 was not different (P = 0·12). There was a positive correlation between IGF bioactivity and IGF-I (r = 0·69; P < 0·001) and an inverse correlation between IGF-I bioactivity and log10 IGFBP-1 (r = −0·68, P < 0·001).ConclusionThe in vitro IGF-I bioactivity was higher in patients treated with CIPII compared with CSII supporting the theory that the route of insulin administration is of importance for the activity of the IGF system. Intraperitoneal insulin administration may therefore be beneficial by correcting the alterations of the IGF system in T1D.
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- Hoybye, C, et al.
(author)
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Serum adiponectin levels in adults with Prader-Willi syndrome are independent of anthropometrical parameters and do not change with GH treatment
- 2004
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In: European journal of endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 151:4, s. 457-461
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Obesity and growth hormone (GH) deficiency are common in Prader-Willi syndrome (PWS) and these patients are at risk of metabolic diseases in adult life and of reduced life span. Low adiponectin values are associated with obesity and the metabolic syndrome. We therefore found it of interest to measure adiponectin levels in PWS. PATIENTS AND METHODS: 17 adults, nine men and eight women, 17 to 32 years of age, with a mean body mass index (BMI) of 35+/-3.2 kg/m2 participated. All had clinical PWS. They were randomized to treatment with placebo or GH (Genotropin) for six months, and subsequently all received GH for 12 months. At baseline, serum total adiponectin levels in the PWS patients were compared with 25 lean and 34 obese controls. Body composition and various metabolic parameters, including adiponectin, were studied every six months in the PWS group. RESULTS: Serum adiponectin levels in PWS subjects were significantly lower (P<0.001) compared with lean and significantly higher (P<0.001) compared with obese controls. In PWS patients, no correlation was found between adiponectin and anthropometrical parameters or measures of insulin sensitivity (e.g. fasting insulin and insulin sensitivity as estimated by the homeostasis model assessment), or between adiponectin and IGF binding protein-1 or IGF-I. Adiponectin did not change during GH intervention. CONCLUSION: In this study of adults with PWS serum total adiponectin levels were higher than in controls with simple obesity and were independent of anthropometrical parameters. In accordance with this the metabolic syndrome is not necessarily present in all PWS patients. Correction of GH deficiency had no effect on serum adiponectin levels.
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| 20. |
- Khalili, Payam, et al.
(author)
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Total adiponectin does not predict cardiovascular events in middle-aged men in a prospective, long-term follow-up study
- 2010
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In: Diabetes & Metabolism. - : Elsevier BV. - 1262-3636 .- 1878-1780. ; 36:2, s. 137-143
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Journal article (peer-reviewed)abstract
- Aim. Plasma total adiponectin is a marker of insulin resistance, but its role in predicting cardiovascular events is unclear. We aimed to investigate the role of adiponectin as a predictor of cardiovascular risk in middle-aged men, and to describe the association between adiponectin and glucose metabolism. Methods. In this population-based prospective study of middle-aged men (n=3885), total adiponectin was analyzed. All individuals had undergone an oral glucose tolerance test (OGTTs), and the mean follow-up duration was 27 years. Regression analyses were carried out for indices of glucose metabolism in relation to quintiles (Q1-Q5) of total aliponectin levels. After stratification for smoking or not, the association between total adiponectin and the first incidence of fatal or non-fatal cardiovascular disease (CVD) was analyzed, using Cox's proportional-hazards regression model.Results. In a separate multiple-regression analysis and after adjusting for possible confounders, the relationship between adiponectin levels and markers of glucose metabolism were found to be significant (P<0.05). However, adiponectin did not independently predict the risk of stroke, coronary events, or a combination of these two outcomes.Conclusion. Levels of total plasma adiponectin are not useful for predicting long-term cardiovascular events in middle-aged men, but are strongly associated with glucose metabolism and markers of insulin resistance. (c) 2010 Elsevier Masson SAS. All rights reserved.
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