Glucocorticoids and Sarcoidosis: A Longitudinal Study on the Effects on Cortical and Trabecular Bone.

BACKGROUND: Glucocorticoid induced osteoporosis is a well-known side effect of glucocorticoid treatment. In sarcoidosis the impact on bone by glucocorticoid treatment is complex due to hormonal disturbances of calcium and vitamin-D, which by itself may cause bone loss. In this study we aimed to investigate the longitudinal impact of glucocorticoids on cortical and trabecular bone in patients with mild, recently diagnosed sarcoidosis. METHODS: Ten patients (8 females; mean age 44 (±13)) were studied during one year of glucocorticoid treatment. The assessment of mainly cortical to purely trabecular bone was made by dual X-ray absorptiometry (DXA) of the spine and hip, quantitative ultrasound of the calcaneus, and magnetic resonance relaxometry of the spine and calcaneus. Bone and hormonal measurements were performed at baseline, after 3, 6, and 12 months, and baseline, 3 weeks and 3 months, respectively. RESULTS: DXA of the spine, decreased from baseline at 6 months (P=0.01). R2' of the calcaneus decreased with time (B: -3.6;P=0.03). In the females (n=8) there was a significant decrease in DXA of the spine when comparing 3 months and 6 months (P=0.03), and 3 months and 12 months (P=0.02) and a decrease in R2'of the calcaneus from baseline to 12 months (P=0.01). There was no change in hormonal levels. CONCLUSION: Treatment of initial mild sarcoidosis with dose tapered glucocorticoid therapy only mildly affects the final trabecular and cortical bone and hormone levels. Dose tapering is an important part in glucocorticoid therapy, likely contributing to the mild effects on bone observed in this study.

Markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the anti-oxidant coenzyme Q10 on inflammatory activity.

Major long-term complications in patients with diabetes are related to oxidative stress, caused by the hyperglycaemia characteristic for diabetes mellitus. The anti-oxidant coenzyme Q10 (CoQ10) has therefore been proposed as a beneficial supplement to diabetes treatment. Apart from its anti-oxidative function, CoQ10 appears to modulate immune functions by largely unknown mechanisms. The aim of this study was therefore to investigate the effect of CoQ10 on antimicrobial peptides and natural killer (NK) cells, both innate immune components implicated in the pathogenesis of diabetes and diabetes-associated long-term complications such as cardiovascular disease. We determined serum levels of antimicrobial peptides and the phenotype of NK cells isolated from peripheral blood of patients with type 1 (T1DM) or type 2 diabetes mellitus (T2DM) and from healthy controls. In addition, the same parameters were determined in diabetic patients after a 12-week period of CoQ10 supplementation. Two antimicrobial peptides, the human cathelicidin antimicrobial peptide (CAMP) and the human beta defensin 1 (hBD1), were reduced in serum from patients with T1DM. This defect was not reversible by CoQ10 supplementation. In contrast, CoQ10 reduced the levels of circulating hBD2 in these patients and induced changes in subset distribution and activation markers in peripheral NK cells. The results of the present study open up novel approaches in the prevention of long-term complications associated to T1DM, although further investigations are needed.

Clinical outcomes after 24 months of insulin therapy in patients with type 2 diabetes in five countries: results from the TREAT study.

OBJECTIVE: To assess factors associated with insulin regimens at initiation, changes in treatment and metabolic control over 2 years of insulin therapy in patients with type 2 diabetes in five countries. RESEARCH DESIGN AND METHODS: TREAT was a prospective, 24 month, observational study in patients with type 2 diabetes initiating insulin in clinical practice. Patient characteristics were collected at baseline and metabolic outcomes at 3, 6, 12, 18 and 24 months after initiation. RESULTS: A total of 985 patients were enrolled, 886 assessed at baseline and 734 (82.8%) at 24 months. Baseline characteristics varied between countries: 52.8% of patients were men; mean age was 60.4 years; body mass index, 29.7 kg/m²; time since diagnosis, 10.1 years; HbA1c, 9.6%. Less than 25% of patients met ADA/IDF targets for blood pressure/LDL cholesterol. Overall, 50.1% of patients were initiated on long/intermediate insulin, 39.3% on mixture and 7.8% on basal-bolus; distribution varied between countries. Patients on long/intermediate were more likely to have lower baseline HbA1c and be intensified to other regimens (19.4%). No oral antidiabetic medication was used for 16.4% initiating on long/intermediate, 47.4% on mixture and 62.3% with basal-bolus. Overall, mean HbA1c decreased from 9.6% to 7.6%, with little difference between regimens at endpoint. The percentage of patients with hypoglycaemia was highest at 6 months and with basal-bolus. LIMITATIONS: Sites were not selected at random. Drop-out of patients prior to 24 months may have introduced a bias that favoured responders. CONCLUSIONS: Mean baseline HbA1c was high, indicating delayed initiation of insulin treatment. Blood pressure and lipids were suboptimally controlled. Insulin regimens varied between countries, changed little and resulted in similar HbA1c levels after 24 months.

Effects of lifestyle on plasma levels of the IGF system and the antioxidants coenzyme Q10 and vitamin E in Kenyan rural and urban populations.

OBJECTIVE: Overnight fasting blood plasma insulin-like growth factor-I (IGF-I), insulin-like growth factor binding protein-1 (IGFBP-1), coenzyme Q10, (CoQ) vitamin E and plasma lipids were compared between a semi-nomadic Samburu population and relatively urbanized cohorts from Nairobi, Kenya. RESEARCH DESIGN AND METHODS: 143 middle aged subjects without known diabetes were included. IGF-I and IGFBP-1 were analyzed by RIA, and CoQ and vitamin E by HPLC. Plasma lipid levels were analyzed by standard laboratory methods routinely used in the clinics. RESULTS: The age adjusted IGF-I serum levels were low in the Samburu male and female populations, ranging from 0 to -4 IGFSD-score (SDS), and a minor part of the investigated population reaching as low as -5 and -7 SDS. The Nairobi cohorts showed significantly higher values reaching from -2.5 to +1 SDS (P<0.0001). The nomadic Samburu population showed fasting IGFBP-1 values ranging from 30-100 µg/l, while that of the urbanized Nairobi cohorts was considerably lower (25-60 µg/l) (P<0.0001). CoQ concentrations of the Nairobi cohorts were 1.5-2.0 nmol/ml similar to the levels found in several European countries. The Samburu population on the other hand showed extremely high CoQ values ranging from 2 to 9 nmol/ml (P<0.0001). Vitamin E levels of the Nairobi group were low (5-20 nmol/ml), but the Samburu population had even lower levels ranging from 3 to 15 nmol/ml (P<0.0001). Plasma lipid levels such as cholesterol, triglycerides, LDL/HDL, ApoB/ApoA ratios as well as BMI and weight were significantly higher in the Nairobi population (P<0.0001). CONCLUSIONS: Low IGF-I and high IGFBP-1 levels of the Samburu cohorts indicate malnutrition. High lipid levels of the Nairobi cohorts indicate that these groups have several risk factors for cardiovascular diseases and diabetes type2.

A common variant in the FTO locus is associated with waist-hip ratio in Indian adolescents.

BACKGROUND: Common variants in the FTO locus, and near MC4R locus, have been shown to have a robust association with obesity in children and adults among various ethnic groups. Associations with obesity traits among Indian adolescents have not been determined. OBJECTIVE: To study the association of rs9939609 (FTO) and rs17782313 (MC4R) to obesity related anthropometric traits in Indian adolescents. METHODS: Subjects for the current study were recruited from a cross-sectional cohort of 1,230 adolescents (age mean ± SD: 17.1 ± 1.9 years) from South India. RESULTS: The variant at the FTO locus was found to be associated with waist-hip ratio (WHR) but not with overall obesity in this population. No significant association was observed for obesity-traits and Mc4R variant rs17782313. CONCLUSION: The common variant of FTO (rs9939609) is associated with body fat distribution during early growth in Indian adolescents and may predispose to obesity and metabolic consequences in adulthood.

Sitagliptin improves beta-cell function in patients with acute coronary syndromes and newly diagnosed glucose abnormalities--the BEGAMI study.

BACKGROUND: Newly detected impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) are common in patients with acute coronary syndrome (ACS; i.e. unstable angina/myocardial infarction) and related to disturbed beta-cell function. The aim of this study is to test the hypothesis that treatment with a dipeptidyl peptidase-4 inhibitor initiated soon after a coronary event improves beta-cell function. METHODS: Acute coronary syndrome ACS patients with IGT or T2DM (n = 71), screened by oral glucose tolerance test (OGTT) 4-23 days (median 6 days) after hospital admission, were randomly assigned to sitagliptin 100 mg (n = 34) or placebo (n = 37) and treated for a duration of 12 weeks. All patients received lifestyle advice but no glucose-lowering agents other than the study drug. The study end-point was beta-cell function assessed using the insulinogenic index (IGI = ΔInsulin30 /ΔGlucose30 ), derived from an OGTT, and acute insulin response to glucose (AIRg) assessed by a frequently sampled intravenous glucose tolerance test. RESULTS: The IGI and AIRg did not differ at baseline between the sitagliptin and placebo groups (69.9 vs. 66.4 pmol mmol(-1) and 1394 vs. 1106 pmol L(-1) min(-1) respectively). After 12 weeks, the IGI was 85.0 in the sitagliptin and 58.1 pmol/mmol in the placebo group (P = 0.013) and AIRg was 1909 and 1043 pmol L(-1) min(-1) (P < 0.0001) in the sitagliptin and placebo groups respectively. Fasting glucose at baseline was 6.1 mmol L(-1) in sitagliptin-treated patients and 6.0 mmol L(-1) in those who received placebo compared with 5.8 and 5.9 mmol L(-1) respectively, after 12 weeks of treatment. Post load glucose metabolism improved in significantly more sitagliptin-treated patients compared with the placebo group (P = 0.003). Sitagliptin was well tolerated. CONCLUSION: Sitagliptin improved beta-cell function and glucose perturbations in patients with ACS and newly diagnosed glucose disturbances.

Genetic and functional analyses of MRAS and HNF1A genes in diabetes and diabetic nephropathy.

Evidence has recently indicated that the MRAS and HNF1A genetic polymorphisms are associated with coronary artery disease. The MRAS and HNF1A genes are located on chromosomes 3q and 12q within the regions where associations with diabetes and diabetic nephropathy occur. We thus performed genetic and functional analyses of these two genes to evaluate their impacts on diabetes and diabetic nephropathy. MRAS and HNF1A genetic polymorphisms were genotyped in 1399 Czech subjects including non-diabetic controls (339), type 1 (243) and type 2 (817) diabetic patients with and without diabetic nephropathy using TaqMan allelic discrimination. Gene expression levels in the kidneys of diabetic Goto-Kakizaki and Wistar rats were detected with real-time RT-PCR. Despite no significance in genetic analysis of diabetic subjects, SNP rs2259816 in the HNF1A gene tended to associate with diabetic nephropathy in type 1 diabetic patients. The hnf1a gene expression was significantly decreased in kidney tissues of Goto-Kakizaki rats compared to Wistar and insulin-treated Goto-Kakizaki rats. There was neither significant association in the MRAS genetic polymorphism with diabetic nephropathy nor variation of mras gene expression in the kidneys of Goto-Kakizaki and Wistar rats. Data from the present study have not proved any significant association of the MRAS and HNF1A genetic polymorphisms with diabetes and diabetic nephropathy in a cohort of Czech population. However, the functional analysis and the trend in genetic analysis suggest that the HNF1A gene may have primary genetic impact on the development of diabetic nephropathy.

Acute hypoxia induces apoptosis of pancreatic ß-cell by activation of the unfolded protein response and upregulation of CHOP.

The success of pancreatic ß-cells transplantation to treat type 1 diabetes has been hindered by massive ß-cell dysfunction and loss of ß-cells that follows the procedure. Hypoxia-mediated cell death has been considered one of the main difficulties that must be overcome for transplantation to be regarded as a reliable therapy. Here we have investigated the mechanisms underlying ß-cell death in response to hypoxia (1% O(2)). Our studies show that mouse insulinoma cell line 6 (Min6) cells undergo apoptosis with caspase-3 activation occurring as early as 2 h following exposure to hypoxia. Hypoxia induces endoplasmic reticulum stress in Min6 cells leading to activation of the three branches of the unfolded protein response pathway. In response to hypoxia the pro-apoptotic transcription factor C/EBP homologous protein (CHOP) is upregulated. The important role of CHOP in the apoptotic process was highlighted by the rescue of Min6 cells from hypoxia-mediated apoptosis observed in CHOP-knockdown cells. Culturing isolated pancreatic mouse islets at normoxia showed intracellular hypoxia with accumulation of hypoxia-inducible factor-1α and upregulation of CHOP, the latter one occurring as early as 4 h after isolation. Finally, we observed that pancreatic islets of type 2 db/db diabetic mice were more hypoxic than their counterpart in normoglycemic animals. This finding indicates that hypoxia-mediated apoptosis may occur in type 2 diabetes.

Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance.

AIMS/HYPOTHESIS: Vitamin D deficiency may increase the risk of type 2 diabetes. We therefore investigated whether serum concentrations of 25-hydroxyvitamin D [25(OH)D] would predict the development of prediabetes (impaired fasting glucose, impaired glucose tolerance or the two combined) and type 2 diabetes, either on their own or when combined with serum concentrations of IGF-1 or IGF-binding protein-1 (IGFBP-1), which may interact with 25(OH)D. METHODS: At baseline, participants aged 35-56 years without known type 2 diabetes were examined using OGTTs, 25(OH)D and IGF peptide measurements, and anthropometric and lifestyle data. Participants who had prediabetes or type 2 diabetes at follow-up 8-10 years later were selected as cases; these were then age- and sex-matched to controls with normal glucose tolerance (NGT) at both baseline and follow-up, giving a total of 980 women and 1,398 men. RESULTS: Men but not women in the highest quartile of 25(OH)D level had a decreased OR for developing type 2 diabetes after adjustment for confounders (OR 0.52, 95% CI 0.30, 0.90), an effect accounted for by individuals with prediabetes, but not with NGT, at baseline. In both sexes, progression from prediabetes to type 2 diabetes was reduced by about 25% per 10 nmol/l increase in 25(OH)D. A high IGFBP-1 value was a better predictor of a reduced risk of type 2 diabetes than high 25(OH)D for both sexes, whereas high IGF-1 concentrations predicted a decreased risk only in men. CONCLUSIONS/INTERPRETATION: High serum 25(OH)D concentrations predict a reduced risk of type 2 diabetes in individuals with prediabetes, but not NGT. There were no significant interactions between 25(OH)D and IGFBP-1 or IGF-1 in terms of risk of diabetes. Our data suggest that vitamin D supplementation should be evaluated for the prevention of type 2 diabetes in prediabetic individuals.

Coenzyme Q10 prevents GDP-sensitive mitochondrial uncoupling, glomerular hyperfiltration and proteinuria in kidneys from db/db mice as a model of type 2 diabetes.

AIMS/HYPOTHESIS: Increased oxygen consumption results in kidney tissue hypoxia, which is proposed to contribute to the development of diabetic nephropathy. Oxidative stress causes increased oxygen consumption in type 1 diabetic kidneys, partly mediated by uncoupling protein-2 (UCP-2)-induced mitochondrial uncoupling. The present study investigates the role of UCP-2 and oxidative stress in mitochondrial oxygen consumption and kidney function in db/db mice as a model of type 2 diabetes. METHODS: Mitochondrial oxygen consumption, glomerular filtration rate and proteinuria were investigated in db/db mice and corresponding controls with and without coenzyme Q10 (CoQ10) treatment. RESULTS: Untreated db/db mice displayed mitochondrial uncoupling, manifested as glutamate-stimulated oxygen consumption (2.7 ± 0.1 vs 0.2 ± 0.1 pmol O(2) s(-1) [mg protein](-1)), glomerular hyperfiltration (502 ± 26 vs 385 ± 3 µl/min), increased proteinuria (21 ± 2 vs 14 ± 1, µg/24 h), mitochondrial fragmentation (fragmentation score 2.4 ± 0.3 vs 0.7 ± 0.1) and size (1.6 ± 0.1 vs 1 ± 0.0 µm) compared with untreated controls. All alterations were prevented or reduced by CoQ10 treatment. Mitochondrial uncoupling was partly inhibited by the UCP inhibitor GDP (-1.1 ± 0.1 pmol O(2) s(-1) [mg protein](-1)). UCP-2 protein levels were similar in untreated control and db/db mice (67 ± 9 vs 67 ± 4 optical density; OD) but were reduced in CoQ10 treated groups (43 ± 2 and 38 ± 7 OD). CONCLUSIONS/INTERPRETATION: db/db mice displayed oxidative stress-mediated activation of UCP-2, which resulted in mitochondrial uncoupling and increased oxygen consumption. CoQ10 prevented altered mitochondrial function and morphology, glomerular hyperfiltration and proteinuria in db/db mice, highlighting the role of mitochondria in the pathogenesis of diabetic nephropathy and the benefits of preventing increased oxidative stress.

The endothelin receptor antagonist bosentan improves peripheral endothelial function in patients with type 2 diabetes mellitus and microalbuminuria: a randomised trial.

AIMS/HYPOTHESIS: Endothelial dysfunction is important in the development of vascular complications in diabetes. Patients with type 2 diabetes have increased production of the vasoconstrictor and pro-inflammatory peptide, endothelin-1. Short-term intra-arterial administration of endothelin antagonists improves endothelium-dependent vasodilatation in patients with type 2 diabetes. We tested the hypothesis that oral administration of the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria. METHODS: This placebo-controlled and double-blind study was performed on 46 patients with type 2 diabetes and microalbuminuria (urine albumin/creatinine ratio >3 mg/mmol) at a medical university department. Patients were randomised to bosentan, 125 mg two times per day (n = 28), or placebo (n = 28) for 4 weeks. The computer-generated randomisation code was kept in sealed envelopes. Patients and people doing examinations or assessing outcomes were blinded. The primary endpoint was change in microvascular endothelium-dependent vasodilatation, based on change in digital reactive hyperaemia index. The secondary endpoint was change in brachial artery flow-mediated vasodilatation. RESULTS: Reactive hyperaemia index increased from 1.73 ± 0.43 (mean ± SD) at baseline to 2.08 ± 0.59 at follow-up (p < 0.05) in the bosentan group (n = 22), but did not change in the placebo group (1.84 ± 0.49 to 1.87 ± 0.47; n = 24). The change in reactive hyperaemia index from baseline was greater in the bosentan group than in the placebo group (p < 0.05). Nitroglycerine-induced digital hyperaemia was not affected. Brachial artery flow-mediated vasodilatation and blood pressure did not change during treatment. CONCLUSIONS/INTERPRETATION: Oral treatment of 4 weeks duration with the dual endothelin receptor antagonist, bosentan, improves peripheral endothelial function in patients with type 2 diabetes and microalbuminuria.

Treatment with low-dose prednisolone is associated with altered body composition but no difference in bone mineral density in rheumatoid arthritis patients: a controlled cross-sectional study.

OBJECTIVES: To determine whether low-dose prednisolone affects body composition and bone mineral density (BMD) in patients with rheumatoid arthritis (RA), also considering inflammation and physical disability. METHODS: This cross-sectional study included 100 patients (50 women) with RA with a median (IQR) disease duration of 8 (4-15) years. Fifty patients had been treated with prednisolone (5-7.5 mg) for at least 2 years (the P-group) and 50 patients matched for gender and age had not (the NoP-group). Body composition and BMD were assessed by dual-energy X-ray absorptiometry (DXA). Disease activity (28-joint Disease Activity Score, DAS28) and physical disability (Health Assessment Questionnaire, HAQ) were assessed. RESULTS: The total patient group had increased fat mass (FM) and a high trunk:peripheral fat ratio, of which 38% had a fat free mass index (FFMI, kg/m²) below the 10th percentile of a reference population. The P-group had significantly higher FM but similar lean body mass (LBM) and BMD compared with the NoP-group. In multivariate analyses, treatment with prednisolone and a higher HAQ score were significantly and independently associated with higher FM but not with LBM. Higher C-reactive protein (CRP) was independently associated with lower LBM. Higher HAQ score and low weight were significantly and independently associated with lower BMD at femoral neck and lumbar spine. CONCLUSIONS: RA patients treated with low-dose prednisolone had significantly higher FM than patients without prednisolone, an effect that was independent of current inflammation. However, there was no association between prednisolone treatment and muscle mass or BMD. Thus, the net effect of prednisolone on body composition and bone is different in inflammatory diseases such as RA.

Phototherapy with ultraviolet radiation: a study of hormone parameters and psychological effects.

BACKGROUND AND OBJECTIVES: Patients report well-being as they are treated with phototherapy. We investigated hormone parameters and psychological well-being after phototherapy in a placebo-controlled study. METHODS: A total of 77 patients with dermatological conditions and 22 healthy volunteers were divided into four groups. The patients received phototherapy either on the whole body or only on hands and/or feet. The volunteers were given either whole-body phototherapy or placebo light. Serum or plasma samples were analysed for cortisol, calcium, magnesium, phosphate, TSH, T(4), T(3) and 25-hydroxyvitamin D, and urine samples for cortisol. Patients and volunteers answered a questionnaire before and 6 weeks after phototherapy/placebo light. Psychiatric ratings were performed according to the Comprehensive Psychopathological Self-rating Scale for Affective Syndromes, a self-report version of which has been transformed to correspond to the Montgomery-Asberg Depression Rating Scale (MADRS). RESULTS: In the patients who received whole-body irradiation, we observed a significant improvement in both MADRS score and cognitive-symptom score after the completion of phototherapy. We also observed a significantly higher level of 25-hydroxyvitamin D after phototherapy, but no difference in the other hormone parameters. CONCLUSION: Whole-body phototherapy of patients with dermatological conditions results in improved well-being and significantly higher levels of 25-hydroxyvitamin D in serum.

Low levels of insulin-like growth-factor-binding protein-1 (IGFBP-1) are prospectively associated with the incidence of type 2 diabetes and impaired glucose tolerance (IGT): the Söderåkra Cardiovascular Risk Factor Study.

AIM: To explore the association between baseline levels of insulin-like growth-factor-binding protein-1 (IGFBP-1), a marker of insulin sensitivity, and the development of type 2 diabetes or impaired glucose tolerance (IGT) in a specifically defined middle-aged population. METHODS: This cross-sectional population-based screening study was conducted in 1989-1990 and included baseline data for 664 non-diabetic subjects aged 40-59 years. Clinical data were collected and blood samples analyzed for blood glucose, serum lipids and insulin. Blood specimens were frozen at baseline and later analyzed for IGF-I, IGFBP-1 and C-reactive protein (CRP). At the follow-up in 2006, the incidence of type 2 diabetes and IGT was reported based on primary-care medical records. RESULTS: During the 17-year observation period, 42 subjects (6.3%) developed type 2 diabetes/IGT. Those in the lowest quintile of IGFBP-1 (< or =24 microg/L) at baseline had a diabetes incidence of 12.6% while, in the highest quintile of IGFBP-1 (> or =59 microg/L), the incidence was 1.5%. Cox's proportional-hazards model regression analyses were used to determine the incidence of type 2 diabetes/IGT, corrected for age and gender, in relation to IGFBP-1, CRP and waist circumference. Subjects in the lowest IGFBP-1 quintile showed an independently increased risk of type 2 diabetes/IGT [hazards ratio (HR): 3.54; 95% CI 1.18-10.6; P=0.024]. For CRP and waist circumference, the corresponding figures were HR: 6.81; 95% CI 2.50-18.6; P<0.001 and HR: 3.33; 95% CI 1.47-7.6; P=0.004, respectively. CONCLUSION: Low levels of IGFBP-1 predicted the long-term development of type 2 diabetes or IGT in a middle-aged population. The association was independent of CRP and abdominal obesity.

Cachexia in rheumatoid arthritis is associated with inflammatory activity, physical disability, and low bioavailable insulin-like growth factor.

OBJECTIVES: To examine the impact of inflammation, insulin-like growth factor (IGF-1) and its regulating binding protein (IGFBP-1) on lean body mass (LBM) in patients with rheumatoid arthritis (RA). METHODS: In 60 inpatients (50 women), inflammatory activity was measured by Disease Activity Score 28 (DAS28), C-reactive protein (CRP), and interleukin (IL)-6, and physical disability by the Health Assessment Questionnaire (HAQ). LBM was assessed by dual-energy X-ray absorptiometry (DXA) and fat free mass index (FFMI; kg/m(2)) and fat mass index (FMI; kg/m(2)) were calculated. RESULTS: Median age was 65 years and disease duration 13 years. Fifty per cent of the patients had FFMI below the 10th percentile of a reference population and 45% had FMI above the 90th percentile, corresponding to the condition known as rheumatoid cachexia (loss of muscle mass in the presence of stable or increased FM). DAS28, CRP, and IL-6 correlated negatively with LBM (p = 0.001, 0.001, and 0.018, respectively), as did HAQ (p = 0.001). Mean (confidence interval) IGF-1 was in the normal range, at 130 (116-143) microg/L. IGFBP-1 levels were elevated in patients (median 58 microg/L in women and 59 microg/L in men) compared with a normal population (33 microg/L in women and 24 microg/L in men). The ratio IGF-1/IGFBP-1, which reflects bioavailable IGF-1, was low (2.0 microg/L) and was positively correlated with LBM (p = 0.015). In multiple regression analysis, 42% of the LBM variance was explained by IGF-1/IGFBP-1, HAQ score, and DAS28. CONCLUSION: A large proportion of RA inpatients, mainly women, had rheumatoid cachexia. The muscle wasting was explained by inflammatory activity and physical disability as well as low bioavailable IGF-1.

Insulin-like growth factor-binding protein-1 in the prediction and development of type 2 diabetes in middle-aged Swedish men.

AIMS/HYPOTHESIS: Insulin-like growth factor-binding protein-1 (IGFBP-1) production in the liver is inhibited by insulin, and low circulating levels are associated with the metabolic syndrome. The aim of this study was to evaluate the predictive role and change in IGFBP-1 concentrations during development of abnormal glucose regulation. METHODS: IGFBP-1 levels were determined at baseline and at 10 years in an incident case-control prospective study of Swedish white men aged 35-56 years. Individuals with normal glucose tolerance at baseline who developed abnormal glucose tolerance during a 10 year period (n = 355) according to WHO criteria were pair-matched to controls for age and family history of diabetes. RESULTS: Fasting IGFBP-1 concentrations were lower in individuals who later developed abnormal glucose regulation and correlated inversely with fasting proinsulin values (r = -0.48; p < 0.0001), and both were significant predictors. Individuals in the highest quartile at baseline for an algorithm incorporating fasting IGFBP-1, blood glucose, proinsulin and waist and height had a 40-fold increased risk of developing type 2 diabetes compared with the lowest quartile (95% CI 7.7-214). IGFBP-1 increased 32% (95% CI 17-49%) during the 10 years in those developing diabetes and was increased in relation to insulin levels, suggesting the emergence of hepatic insulin resistance. Moreover, elevated IGFBP-1 levels at follow-up were associated with higher 2 h glucose values during an OGTT. CONCLUSIONS/INTERPRETATION: Low IGFBP-1 predicts the development of abnormal glucose regulation and, as an inhibitor of the insulin-like actions of insulin-like growth factors, elevated levels of IGFBP-1 after the development of diabetes may also play a pathophysiological role.

Desmopressin increases IGF-binding protein-1 in humans.

CONTEXT: IGF binding protein-1 (IGFBP-1) is essential for IGF-I bioavailability. High levels of IGFBP-1 are encountered in critically ill patients and are a good predictor marker in acute myocardial infarction. The mechanisms responsible for the elevated IGFBP-1 levels in these conditions are still unclear. Interestingly, high levels of vasopressin have been reported in the above-mentioned conditions. OBJECTIVE: To study the effect of vasopressin on IGFBP-1 in humans. DESIGN: Placebo-controlled cross-over study in patients with central diabetes insipidus (CDI) in whom potential interference from endogenous vasopressin secretion is minimized. After a 3-day desmopressin washout period, each patient received i.v. saline on day 1 and desmopressin (3 mug) on day 2. Blood samples were taken after administration, every 2 h during the whole night, starting at 2000 h. PATIENTS AND SETTING: Fourteen inpatients with CDI in an endocrinology department of a university hospital. RESULTS: Serum IGFBP-1 increased within 4 h after 1-desamino-8-d-arginine vasopressin (DDAVP) by 375+/-73%, compared with a spontaneous fasting increase by 252+/-46% following placebo administration (P<0.05). No changes were registered in the levels of either classically regulators of IGFBP-1 (insulin, glucagon, and cortisol) or of IGF-I and glucose. The decrease in plasma osmolarity induced by DDAVP did not precede the increase in IGFBP-1. CONCLUSIONS: DDAVP increases serum levels of IGFBP-1. Further investigation is essential to unravel the clinical potential of this interaction in conditions associated with high IGFBP-1 levels.

Pathophysiology and treatment of patients with type 2 diabetes exhibiting failure to oral drugs.

It is generally accepted that a poor glycaemic control increases the risk for development of vascular complications in diabetic patients. This advocates for early introduction of insulin treatment in patients with type 2 diabetes exhibiting a secondary failure to oral treatment. This strategy is facilitated by introduction of long-acting insulin glargine and biphasic insulin aspart 70/30. The introduction of Glucagon-like peptide-1 (GLP-1) mimetics and dipeptidyl peptidase 4 (DPP-4) inhibitors in treatment of type 2 diabetes will however, to a large extent, influence therapeutic policy. Thus we suggest that DPP-4 inhibitors or long-acting GLP-1 mimetics will be used as either first-line therapy or as an early addition to metformin. The already generated results in animal and clinical studies suggest that these two classes of antidiabetic drugs may in addition to improving glycaemic control protect islet beta-cell mass and thereby postpone development of a secondary failure. When patients treated with metformin, sulfonylurea (SU), tiazolidinediones or a combination of these drugs fail, the GLP-1 mimectics may be preferred to insulin treatment. First, the risk of hypoglycaemia is less if not combined with SU. Secondly, the body weight is usually decreased while insulin treatment increases weight. Patients not responding to GLP-1 mimetics or experiencing significant side effects will be treated with insulin. Irrespective of the policy used for the drug treatment of type 2 diabetes, exercise and proper diet will remain important for optimization of metabolic control.