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JA Janssen and SW Lamberts

The incidence of peripheral, cerebro- and cardiovascular disease (CVD) in patients with type 2 diabetes mellitus is approximately twice as high as in the non-diabetic population. Conventional cardiovascular risk factors such as plasma lipids, lipoproteins and hypertension only partially explain this excessive risk of developing atherosclerosis and CVD. Meta-analysis of studies performed in non-diabetic populations indicates that the risk of CVD increases continuously with glucose levels above 4.2 mmol/l. The glucose hypothesis suggests that treatment which normalizes glucose levels prevents or delays the long-term complications of diabetes mellitus. However, the outcome of the UK Prospective Diabetes Study demonstrates that glucose control does not completely prevent CVD.In healthy subjects, serum IGF-I levels peak in early adulthood, after which they gradually decrease with increasing age. Several observations suggest that there is a premature and progressive age-related decline in serum IGF-I bioactivity in type 2 diabetics, which eventually results in a (relative) IGF-I deficiency. In type 2 diabetics, close relationships have been demonstrated between glycaemic control and serum IGF-I levels, with worse control being associated with lower IGF-I levels. Several studies (in non-diabetics) suggest that lowered circulating IGF-I levels account for a poor outcome of CVD. We previously observed in a population-based study that a genetically determined lowered IGF-I expression increases the risk of myocardial infarction with type 2 diabetes.This genetic approach overcomes the problem that cross-sectional studies cannot distinguish whether changes in IGF-I levels are a cause or a consequence of a disease. IGF-I is an important metabolic regulatory hormone. In addition, IGF-I suppresses myocardial apoptosis and improves myocardial function in various models of experimental cardiomyopathy. Compared with other growth factors, the 'survival' effect of IGF-I on myocardium seems rather unique.Therefore, we hypothesize that the premature and progressive decline in serum IGF-I bioactivity in ageing patients with type 2 diabetics is an important pathophysiological abnormality. It contributes not only to elevated glucose and lipid levels, but also to the progression and the poor outcome of CVD. If this hypothesis is proven to be right, treatment with IGF-I as an adjunct to insulin offers great potential and might not only improve metabolic control but also reduce the incidence and prevalence of CVD in type 2 diabetes patients. However, there is as yet no experimental evidence that long-term (replacement) treatment with IGF-I prevents, delays or reduces CVD in type 2 diabetes patients. Clinical trials are necessary to prove that long-term IGF-I treatment, preferably in the form of a better-tolerated IGF-I/IGF-binding protein-3 complex, improves the overall cardiovascular risk in type 2 diabetes.

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JA Romijn, JW Smit and SW Lamberts

Hormonal substitution therapy has been extremely successful, with respect to morbidity and mortality, in the treatment of the major syndromes of endocrine insufficiency. However, many patients treated for endocrine insufficiencies still suffer from more or less vague complaints and a decreased quality of life. It is likely that these complaints are, at least in part, caused by intrinsic imperfections of hormone replacement strategies in mimicking normal hormone secretion. Unfortunately, these complaints are often difficult to assess by clinicometric or biochemical tests, because the effects of hormones in general, and thus of hormone replacement strategies in particular, are difficult to quantify at the tIssue level. Therefore, in clinical practice we rely mostly on plasma variables - 'plasma endocrinology' - which are a poor reflection of hormone action at the tIssue level. Appreciation of these intrinsic shortcomings of endocrine therapy is of utmost importance to prevent incorrect labelling of the complaints of many endocrine patients and to achieve further improvement in endocrine replacement strategies.

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SW Lamberts, JA Romijn and WM Wiersinga

In recent years the future position of clinical endocrinology has been extensively discussed by Western European endocrine societies. Clinical endocrinology seems to suffer from being too intellectual, generating too little income, and lacking too few spectacular interventions. In this manuscript we describe 'the endocrine patient' of the past, the present, and the future. Complete therapeutic breakthroughs resulting in 'cure' are compared with 'halfway technologies' which help in creating the (life-long) chronic endocrine patient. The potential use of molecular diagnostics in optimalizing hormone replacement therapy is discussed. Clinical endocrinology is at risk of developing into a subspecialty where life-style drugs created for new diseases or conditions are offered, but also actively pursued by otherwise healthy individuals (e.g. in normal short stature, regulation of appetite, body composition, sexuality, reproduction and aging). The potential opportunities and risks for clinical endocrinology in creating 'the endocrine patient' of the future are discussed.

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SW Lamberts, AJ van der Lely and LJ Hofland

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EG Lichtenauer-Kaligis, PM van Hagen, SW Lamberts and LJ Hofland

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EG Lichtenauer-Kaligis, VA Dalm, SP Oomen, DM Mooij, PM van Hagen, SW Lamberts and LJ Hofland

BACKGROUND: Somatostatin (SS)-binding sites have been demonstrated in human lymphoid tissues and peripheral blood cells. However, not much is known with respect to the SS receptor subtype (sst) expression pattern and the expression of SS itself in the immune system. OBJECTIVE: The aim of this study was to evaluate the mRNA expression of the five known sst (sst(1-5)) in peripheral blood mononuclear cell (sub)populations. Moreover, the expression of the mRNAs encoding SS and the SS-like peptide cortistatin (CST) in immune cell subsets was studied. METHODS: RT-PCR and quantitative PCR were performed to evaluate sst, SS and CST mRNA expression in cells in the basal or activated state. Fluorescence-activated cell sorter (FACS) analysis using fluorescent SS was performed to visualize sst protein on cell membranes. RESULTS: B- and T-lymphocytes selectively expressed sst(3) mRNA. sst(3) expression in B-lymphocytes was significantly lower compared with T-lymphocytes. Unstimulated, freshly isolated monocytes did not express any sst mRNA. Upon activation, monocytes selectively expressed sst(2) mRNA, whereas T-lymphocyte activation upregulated sst(3) expression. sst(2) mRNA expression on monocytes was confirmed by FACS analysis. B- and T-lymphocytes did not express SS mRNA, while both cell types expressed CST mRNA. CST mRNA expression was downregulated following T-lymphocyte activation. CONCLUSION: We demonstrate for the first time unequivocally that human peripheral blood B- and T-lymphocytes selectively express sst(3), whereas monocytes do not express sst. However, upon activation, monocytes are induced to express sst(2A). No expression of SS mRNA was detected in any cell type, whereas all cell types expressed CST mRNA. The differential expression of sst and CST mRNA in lymphocytes and monocytes suggests a functional significance for the CST-sst interaction in immune cells, but further studies should be performed to evaluate the significance of sst and CST in these cells.

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I Rietveld, JA Janssen, A Hofman, HA Pols, CM van Duijn and SW Lamberts

OBJECTIVE: Recent studies have demonstrated an association between a 192 bp polymorphism of the IGF-I gene and total IGF-I serum levels, birth weight, body height and the risk of developing diabetes and cardiovascular diseases later on in life. This IGF-I gene polymorphism in the promoter region of the IGF-I gene may directly influence the expression of IGF-I. In the present study we evaluated the role of this polymorphism in the age-related decline in serum IGF-I levels. SUBJECTS AND METHODS: All subjects were participants of the Rotterdam Study, a population-based cohort study of diseases in the elderly. We studied a total group of 346 subjects, who comprised two subgroups: a randomly selected population-based sample of 196 subjects, and a group of 150 subjects selected on IGF-I genotype. In the total group of 346 individuals the relationship between this 192 bp polymorphism and the age-related decline in circulating total IGF-I levels was studied. RESULTS: Homozygous carriers of the 192 bp allele demonstrated significant decline in serum IGF-I with age (r=-0.29, P=0.002). This decline is similar to that seen in the general population. An age-related decline in serum total IGF-I was not observed in heterozygotes (r=-0.06, P=0.48) and non-carriers (r = -0.12, P=0.32). Interestingly, the relationship between age and serum IGF-binding protein-3 levels showed the same pattern. CONCLUSION: We observed only in homozygous carriers of the 192 bp alleles of the IGF-I gene an age-related decline in circulating total IGF-I levels, but not in heterozygotes and non-carriers of the 192 bp allele. We hypothesize that this IGF-I gene polymorphism directly or indirectly influences GH-mediated regulation of IGF-I secretion.

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JA Janssen, H Burger, RP Stolk, DE Grobbee, FH de Jong, SW Lamberts and HA Pols

OBJECTIVE: Little is known about the association between free IGF-I levels and bone mineral density (BMD). DESIGN: A cross-sectional study of 218 healthy subjects (103 men, 115 women, age 55-80 years) was carried out. METHODS: Fasting serum free IGF-I, total IGF-I, estradiol and sex hormone-binding globulin (SHBG) levels were measured. The ratio of estradiol to SHBG was used as an index of free estradiol. BMD measurements were performed by dual-energy X-ray absorptiometry of the lumbar spine and the proximal femur. RESULTS: In multivariate analyses with BMD of the lumbar spine as the dependent variable and serum free IGF-I, age, body mass index (BMI) and the free estradiol index as independent variables, the free IGF-I was positively related to the BMD of the lumbar spine in men (P = 0.02) but not in women. When the same analyses for the lumbar BMD were performed with total serum IGF-I the association was also only statistically significant in men (P = 0.05). In multivariate analyses with the trochanter BMD as the dependent variable and serum free IGF-I, total IGF-I, age, BMI and the free estradiol index as independent variables, the associations between (free and total) IGF-I and the trochanter BMD in men was of borderline significance. CONCLUSIONS: In elderly men free and total IGF-I were positively related to lumbar BMD, while (free and total) IGF-I was borderline positively related to trochanter BMD. As these relationships were not observed in elderly women, we suggest a weak gender-specific anabolic effect of IGF-I on BMD on trabecular bone.

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AW van den Beld, WF Blum, HA Pols, DE Grobbee and SW Lamberts

BACKGROUND: In a cross-sectional study in 403 healthy, independently living elderly men (mean age 78 years), we determined which are the main physiological determinants of functional ability in the elderly, and which components of the somatotropic system contribute to the maintenance of functional ability. METHODS: Functional ability was assessed by the number of problems in activities of daily living and by a measure of physical performance. Other physical characteristics included leg extensor strength, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass. Serum insulin-like growth factor (IGF)-I and its binding proteins (IGFBP) -1, -2 and -3 concentrations were all measured by RIA. RESULTS: Muscle strength was related to a lower degree of disability. Further, it was positively related to physical performance and bone mineral density (all P<0.001). Fat mass influenced activities of daily living and physical performance negatively and bone mineral density positively (all P<0.001). Serum concentrations of IGF-I and IGFBP-3 were not related to any of the physical characteristics. High serum IGFBP-2 concentrations were related to a higher degree of disability (P<0.001), a lower physical performance (P=0.006), muscle strength (P=0.002), bone mineral density of proximal femur (P=0.007), lean mass and fat mass (both P<0.001). Serum insulin and IGFBP-1 concentrations were independently, positively related to lean mass (P=0.003) and fat mass (P<0.001). CONCLUSIONS: In independently living elderly men, functional ability appears to be determined by muscle strength (positive) and fat mass (negative). Low serum IGFBP-2 concentrations are a powerful indicator for overall good physical functional status, probably inversely reflecting the integrated sum of nutrition and the biological effects of growth hormone, IGF-I and insulin.

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D Ferone, PM van Hagen, R Pivonello, A Colao, SW Lamberts and LJ Hofland