Kidney biopsy in patients with diabetes mellitus.

BACKGROUND: The clinical consequences of the results obtained by kidney biopsy in patients with diabetes mellitus Type 1 or Type 2 have been controversial. Our study was conducted to assess clinical symptoms and histological diagnoses in patients with diabetes mellitus Type 1 and Type 2 undergoing kidney biopsy. DESIGN, SETTING AND PATIENTS: Observational study. The study included data from 567 consecutive renal biopsies of patients with diabetes mellitus Type 1 or 2 and chronic kidney disease (CKD) examined by standard histopathological procedures. The main outcome measures were incidence of diabetic nephropathy (DN) and glomerulonephritis (GN), predictors for the presence of both DN or GN. RESULTS: Approximately 70% of patients with diabetes mellitus Type 1 or 2 and evidence for CKD had DN. Glomerular diseases present in approximately 30% of patients with diabetes were predominantly immune complex GN and secondary focal glomerulosclerosis, followed by IgA-GN, which was associated with microhematuria (p = 0.01) and hypertension (p = 0.04). Only a minority had membranous GN, which was associated with nephrotic syndrome (p = 0.004). Progressive CKD predicted the presence of GN in diabetes mellitus Type 2 (r = -0.98; p = 0.02). CONCLUSION: GN is not uncommon in patients with diabetes and evidence for CKD. Kidney biopsy should therefore be considered in patients with diabetes and progressive CKD.

Angiotensin inhibition stimulates PPARgamma and the release of visfatin.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) exhibit beneficial antidiabetic effects in patients with type 2 diabetes independent of their blood pressure-lowering effects. Some antidiabetic properties of ARB and ACE-I might by exerted by activation of peroxisome proliferator-activated receptor gamma (PPARgamma). However, it is not clear whether this action is drug specific. MATERIALS AND METHODS: The binding affinity of telmisartan, valsartan, lisinopril, rosiglitazone and angiotensin II to PPARgamma was assessed in a cell-free assay system. PPARgamma signalling was studied in isolated skeletal muscle cells using Western blot analysis of phosphorylated protein kinase B (pAKT) and phosphorylated insulin like growth factor-1 receptor (pILGF-1R). Further, the ability of the drugs under study to stimulate the release of the adipocytokine visfatin was investigated in isolated human adipocytes, skeletal muscle cells, and umbilical vein endothelial cells (HUVEC). RESULTS: The binding affinity to PPARgamma was highest for telmisartan with a half-maximal effective concentration of 463 nM, followed by lisinopril (2.9 microM) and valsartan (6.2 microM). In skeletal muscle cells phosphorylation of ILGF-1R was 2-fold increased after incubation with telmisartan or valsartan and 1.7-fold with lisinopril. pAKT expression was enhanced after incubation with telmisartan, valsartan and with lisinopril. The release of visfatin from adipocytes was 1.6-fold increased after treatment with lisinopril and about 2.0-fold increased with telmisartan and valsartan. Similar results were obtained in skeletal muscle cells and HUVEC. CONCLUSIONS: Our data confirm agonism of telmisartan, valsartan and lisinopril on PPARgamma. Pharmacokinetic differences may explain different potencies of PPARgamma stimulation by drugs acting on the renin-angiotensin system in clinical settings.

Detecting prostate cancer by intracellular macrophage prostate-specific antigen (PSA): a more specific and sensitive marker than conventional serum total PSA.

BACKGROUND: Serum prostate-specific antigen (PSA) is a standard method and a widely used marker for prostate cancer, but it has a poor specificity for early detection. Herein we demonstrate that intracellular macrophage PSA (imPSA) enables screening and differentiation between benign and malignant prostate disease. MATERIALS AND METHODS: The efficacy of intracellular macrophage PSA in circulating and tissue macrophages was therefore investigated in a double-centre study of 38 prostate cancer patients and 36 healthy controls by fluorescent-activated cell sorting analysis and immunohistology. RESULTS: Both methods uncovered the existence of PSA-positive macrophages specific for patients with prostate cancer. In addition, we demonstrate the superiority of our new test over standard serum total PSA in a blinded double-centre trial. ImPSA had a marked higher sensitivity and specificity than serum total PSA (imPSA: sensitivity 92%, specificity 92%, positive predictive value 92%; serum total PSA: sensitivity 79.5%, specificity 87.5%, positive predictive value 26.8%). CONCLUSION: In this study, we demonstrate that imPSA is a new prostate cancer screening method that is highly sensitive and more specific than standard PSA testing.

Postprandial intradialytic dysglycaemia and diabetes in maintenance haemodialysis patients.

BACKGROUND: Although the risk of developing dysglycaemia has been investigated in different communities this incidence is poorly studied in patients on maintenance haemodialysis (MHD). MATERIALS AND METHODS: In a multicentre observational cohort study the occurrence of dysglycaemia was assessed in 239 primary normoglycaemic end stage renal disease (ERSD) patients on MHD. Dysglycaemia (fasting blood glucose > 110 mg dL(-1), > 140 mg dL(-1) 2 h after food intake) or diabetes (fasting blood glucose > 126 mg dL(-1) or > 200 mg dL(-1) at any time) were defined according to WHO criteria and cases were compared with age matched controls within the cohort. RESULTS: Dysglycaemia was found in 82 primary normoglycaemic ESRD patients (34%) within 31 months after initiation of MHD. In 31 of these patients type 2 diabetes was diagnosed. When compared with matched control MHD patients differences in body mass index (BMI), HbA1c and postprandial blood glucose were detectable (P < 0.05). Increments in 0.1% of HbA1c were related with 11% higher odds for dysglycaemia (P = 0.002). In a subgroup of 36 primary normoglycaemic MHD patients who developed dysglycaemia event-free survival was 64%, 53%, 31%, 17% and 11% after 1, 2, 3, 4 and 5 years of haemodialysis treatment. CONCLUSION: Onset of dysglycaemia or diabetes is frequent in ESRD patients after onset of chronic haemodialysis. Routine measurement of blood glucose before and after haemodialysis should be implemented as a standard of care during MHD.

Effect of rosiglitazone on visfatin and retinol-binding protein-4 plasma concentrations in HIV-positive patients.

Thiazolidinediones (TZD) may improve insulin resistance in patients with diabetes and HIV. The novel adipocytokines visfatin and retinol-binding protein-4 (RBP-4) have been proposed to influence the development of impaired glucose tolerance. The impact of TZD on these cytokines is yet unknown. In this randomized, double-blind, placebo-controlled parallel group study, 37 lean HIV-positive subjects aged 19-50 years were treated with 8 mg/day rosiglitazone (n=20) or placebo (n=17) for 6 months. Insulin sensitivity was estimated from the homeostasis model assessment (HOMA) index. Fasting visfatin, RBP-4, leptin, and adiponectin plasma concentrations were analyzed by immunoassays. Rosiglitazone had no effect on impaired insulin sensitivity, but increased median plasma visfatin from 6.2 ng/ml (95% CI: 5.9; 6.5) to 13.7 ng/ml (12.6; 19.1) (P<0.001) and adiponectin from 3.2 ng/ml (2.2; 4.0) to 4.0 ng/ml (3.3; 8.5; P<0.001). RBP-4 was lowered from 21.0 ng/ml (19.6; 23.1) to 16.3 ng/ml (15.2; 17.0; P<0.001), and leptin concentrations were unchanged. Adipocytokine concentrations were stable in subjects receiving placebo, where a deterioration in insulin sensitivity was detectable (P<0.05). Changes in visfatin and RBP-4 were correlated in subjects receiving rosiglitazone (r=-0.64, P<0.01) but not placebo (r=0.12, P=0.15). TZD treatment affects circulating adipocytokine concentrations in subjects with HIV. Reductions in RBP-4 and increases in visfatin may contribute to the pharmacodynamic action of TZD on glucose homeostasis. Quantification of adipocytokines might be useful to assess TZD treatment effectiveness in insulin-resistant subjects with HIV.

Postprandial blood glucose level in maintenance hemodialysis patients predicts post-transplant-diabetes-mellitus.

Post-transplant-diabetes-mellitus (PTDM) is a frequent complication after kidney transplantation. One-hundred-and-seven patients with kidney transplantation were screened for the occurrence of PTDM. Of these, full data sets from 49 subjects were available with documented glucose concentrations during maintenance hemodialysis (MHD) and regular clinical follow-up of 7-34 months. For assessment of glucose metabolism the response to a standard meal during MHD was used in normoglycemic patients based on fasting blood glucose. Abnormal postprandial blood glucose concentration was defined as >140 mg/dl 2 h after food intake.Twelve end stage renal disease patients had abnormal postprandial blood glucose on MHD. All 12 subjects but also four MHD patients with normal postprandial and fasting blood glucose values developed PTDM. Multivariate Cox-regression analysis revealed that abnormal postprandial blood glucose is a strong predictor for PTDM (Hazard ratio: 42.3 (IQR: 7.9-227.2); p<0.001). Fasting blood glucose (94 vs. 100 mg/dl) was not different between MHD patients who did (n=16) or did not (n=33) develop PTDM.This study suggests that measurement of postprandial blood glucose during MHD identifies patients who develop PTDM after kidney transplantation. It should be used for screening of patients at risk.

Alcohol acutely increases vascular reactivity together with insulin sensitivity in type 2 diabetic men.

Moderate alcohol consumption is associated with increased insulin sensitivity and reduced cardiovascular risk. We hypothesized that this relates to a direct effect of alcohol and therefore investigated whether acute alcohol intake altered insulin sensitivity or endothelial function in patients with type 2 diabetes. In an open-label two period design, the effect of a single oral dose of 40 g of alcohol (168 ml 40% vodka) on an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and on endothelium-dependent (flow mediated, FMD) or endothelium-independent (glyceroltrinitrate (GTN)-induced) vasodilation of the brachial artery measured by ultrasound was studied. Experiments were carried out in twelve male patients with type 2 diabetes mellitus (64+/-6 years, body mass index 28.4+/-5.7 kg/m (2)). Baseline insulin sensitivity index (S (I)) was 1.10+/-0.34 min (-1).microU (-1).ml, baseline FMD was +4.1+/-3.0%, and GTN-induced vasodilation +7.4+/-2.3% from resting brachial artery diameter. Acute alcohol intake increased alcohol plasma levels to 0.33+/-0.04 per thousand, S (I) to 1.86+/-0.45 min (-1).microU (-1).ml (p<0.05), and FMD to +8.2+/-2.8% (p<0.05), while GTN-induced dilation remained unchanged. No relationship was detectable between the observed changes. We conclude that alcohol intake acutely increases endothelium-dependent brachial artery vasodilation in patients with type 2 diabetes together with insulin sensitivity. This acute effect might explain some beneficial effects of low alcohol consumption in epidemiological observations.

Plasma adipocyte and epidermal fatty acid binding protein is reduced after weight loss in obesity.

AIM: Plasma adipocyte fatty acid binding protein (A-FABP) and epidermal fatty acid binding protein (E-FABP) concentrations have been linked to obesity and the metabolic syndrome. In this study, we investigated whether plasma A-FABP and E-FABP concentrations are altered by weight loss in obese patients. METHODS: In a prospective study, fasting plasma A-FABP and E-FABP concentrations were measured before and 6 months after gastric banding in 33 morbidly obese patients, with a body mass index (BMI) of 46 +/- 5 kg/m(2). Eleven healthy subjects with a BMI < 25 kg/m(2) served as controls. RESULTS: A-FABP and E-FABP plasma concentrations were higher in obese subjects (36.7 +/- 6.7 and 3.7 +/- 0.7 ng/ml, respectively) than in controls (18.1 +/- 0.6 and 2.6 +/- 0.5, respectively, p < 0.01). Gastric banding reduced BMI to 40 +/- 5 kg/m(2), A-FABP to 32.6 +/- 5.4 ng/ml and E-FABP to 1.9 +/- 0.7 ng/ml (all p < 0.05) after 6 months. Insulin sensitivity as estimated by the Homeostasis Model Assessment insulin resistance index was unchanged. A-FABP concentrations were significantly associated with BMI before and 6 months after surgery (p < 0.05, r = 0.42 and r = 0.37 respectively). CONCLUSIONS: Elevated plasma A-FABP and E-FABP concentrations in morbidly obese subjects are reduced after gastric banding-induced weight loss. This suggests that FABP may be associated with improvement of metabolic conditions over time.

The release of the adipocytokine visfatin is regulated by glucose and insulin.

AIMS/HYPOTHESIS: The novel insulin-mimetic adipocytokine visfatin has been linked to the metabolic syndrome, but its regulation has not been characterised to date. Since insulin-mimetic actions of visfatin may be part of the feedback regulation of glucose homeostasis, we hypothesised that visfatin concentrations are influenced by glucose or insulin blood levels in humans. SUBJECTS, MATERIALS AND METHODS: In this randomised, double-blind, placebo-controlled crossover study, nine healthy male subjects (age 26+/-6 years) attended three different study days. On each day, systemic glucose concentrations of 5.0, 8.3 and 11.1 mmol/l were attained by stepwise increases in i.v. infusions of glucose, representing fasting and postprandial conditions. Visfatin plasma concentrations were studied during concomitant exogenous hyperinsulinaemia, inhibition of endogenous insulin production by somatostatin infusion, and placebo time control. Additionally, human adipocytes were cultured to study visfatin release and mRNA expression in vitro. RESULTS: Glucose concentrations of 8.3 and 11.1 mmol/l increased circulating visfatin from baseline concentrations of 0.5+/-0.0 ng/ml to 0.9+/-0.1 and 2.1+/-0.3 ng/ml, respectively (p<0.01). Glucose-induced elevation of visfatin was prevented by co-infusion of insulin or somatostatin (p<0.05). Cultured subcutaneous and visceral adipocytes released an equivalent amount of visfatin upon glucose-concentration- and time-dependent stimulation. Visfatin secretion involved the phosphatidylinositol 3-kinase (PI3-kinase) and protein kinase B (AKT) pathways. The mRNA expression pattern of visfatin was consistent with this altered protein release. CONCLUSIONS/INTERPRETATION: Circulating visfatin concentrations are increased by hyperglycaemia. This effect is suppressed by exogenous hyperinsulinaemia or somatostatin infusion. Glucose signalling for visfatin release in adipocytes involves the PI3-kinase/AKT pathway.

C-reactive protein is expressed and secreted by peripheral blood mononuclear cells.

C-reactive protein (CRP) protects against bacterial pathogens and is a predictor of cardiovascular events. CRP is produced by vascular and organ-specific cells but the generation of CRP from peripheral blood mononuclear cells (PBMC) is poorly established. In a randomized, double-blind, placebo-controlled, two-way cross-over trial six healthy volunteers received a bolus infusion of 20 IU/kg Escherichia coli endotoxin [lipopolysaccharide (LPS)] or placebo. Intracellular CRP protein and CRP secretion of peripheral blood mononuclear cells (PBMC) was measured at baseline and 6 h after LPS by flow cytometry and enzyme-linked immubosorbent assay (ELISA), respectively. CRP mRNA expression was determined by real-time polymerase chain reaction (PCR). Regulation of the expression pathway was assessed using specific inhibitors in vitro. Small amounts of CRP protein and mRNA were detectable in PBMC, which were up-regulated between two- and eightfold by endotoxaemia in vivo. Augmented expression and release of CRP by LPS was consistent in PBMC cell culture experiments. LPS, interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-alpha increased and IL-10 reduced CRP expression in PBMC. Toll-like receptor (TLR)-4, nuclear factor (NF)-kappaB and protein kinase C (PKC) activation were identified as intracellular signal transduction pathways of LPS-induced CRP expression. Constitutive CRP expression and release in PBMC is enhanced by inflammatory stimuli in vivo and in vitro. LPS might induce CRP generation via activation of TLR-4, NF-kappaB and PKC.