Gábor Winkler

Tumor necrosis factor system in insulin resistance in gestational diabetes

OBJECTIVE The aim of the study was to investigate the pathophysiological role of the tumor necrosis factor (TNF) system in insulin resistance in patients with gestational diabetes (GDM) and during the course of normal pregnancy. PATIENTS AND METHODS Thirty women with GDM (16-39 gestational weeks), 35 healthy pregnant women (15 first, nine second and 11 third trimester) and 25 healthy age-matched non-pregnant women were studied. Serum TNF-alpha, and its soluble receptors 1 and 2 (sTNFR-1 and -2) were measured. RESULTS In non-diabetic pregnant women in the third trimester all measures were significantly higher (P<0.05 or less) than in the first trimester and in non-pregnant women (BMI 27.6 +/- 4.1 (+/- S.D.), 24.1 +/- 2.6, 22.4 +/- 2.4 kg/m(2)), serum TNF-alpha (4.6 +/- 0.6, 4.1 +/- 0.4, 4.1 +/- 0.4 ng/l), sTNFR-1 (2.7 +/- 0.9, 2.0 +/- 0.5, 2.0 +/- 0.1 microg/l), sTNFR-2 (5.6 +/- 2.6, 4.6 +/- 2.1, 3.3 +/- 0.2 microg/l), C-peptide (3.1 +/- 1.7, 1.1 +/- 0.7, 1.1 +/- 0.8 microg/l), and C-peptide:blood glucose ratio (0.6 +/- 0.2, 0.2 +/- 0.1, 0.2 +/- 0.1 microg/mmol). In GDM these measures were even higher than in any subgroup of healthy pregnant women (BMI) (33.4 +/- 6.4 kg/m(2), TNF-alpha) (6.3 +/- 0.6 microg/l), sTNFR-1 (3.0 +/- 0.5 microg/l), sTNFR-2 (10.0 +/- 6.9 microg/l, C-peptide 6.0 +/- 2.7 microg/l, C-peptide:blood glucose ratio: 1.2 +/- 0.5 microg/mmol, P<0.01). Significant (P<0.01) positive linear correlations were found in gestational diabetic and non-diabetic women between serum TNF-alpha, C-peptide levels, and BMI. In gestational diabetic women, in multivariate analysis studying the dependency of C-peptide only BMI remained significant (r(2)=0.67, P=0.01). CONCLUSIONS Our observation emphasizes the obesity-related component of insulin resistance driven by adipocytokines, such as TNF-alpha and its receptors during the course of normal pregnancy and GDM.

Elevated serum TNF-α level as a link between endothelial dysfunction and insulin resistance in normotensive obese patients

Aims The aim of the study was to analyse the role of tumour necrosis factor‐alpha (TNF‐α) in insulin resistance and endothelial dysfunction in patients with different types of obesity.

Elevated serum tumor necrosis factor-alpha concentrations and bioactivity in Type 2 diabetics and patients with android type obesity

The role of tumor necrosis factor-alpha in insulin resistance has been studied in 59 patients with Type 2 diabetes, 28 with android type obesity and 35 healthy lean controls. Immunoreactive concentrations and bioactivity of serum tumor necrosis factor-alpha have repeatedly been determined in 8 weeks intervals for 12 months, five times per patients, by using ELISA and L929 cell cytotoxicity bioassay. Significantly higher immunoreactive tumor necrosis factor-alpha concentrations and bioactivity have been found in both, the Type 2 diabetic and obese groups as compared to the healthy persons. Tumor necrosis factor-alpha concentrations and bioactivity have showed a significant positive linear correlation with the elevated basal serum C-peptide levels and body mass indexes in both groups of patients. According to these data the cytokine might play a role in insulin resistance in obesity as well in Type 2 diabetes.

Oestrogen and vitamin D receptor (VDR) genotypes and the expression of ErbB-2 and EGF receptor in human rectal cancers

Oestrogen/oestrogen receptor (ER) and vitamin D/vitamin D receptor (VDR) systems have been implicated in the pathogenesis of colorectal cancers. The expression of erbB-2 and epidermal growth factor receptor (EGFR) in colorectal cancers has been suggested to have diagnostic and prognostic significance. In our study, XbaI and PvuII polymorphisms of the ER gene and the BsmI polymorphism of the VDR gene were studied in 56 Caucasian patients with rectal cancer. The relationship between the ER and VDR genotypes and the expression of oncogenes was also investigated. The presence of the x allele of ER gene significantly correlated with the overexpression of the erbB-2 and EGFR oncogenes. Significantly increased erbB-2 expression was observed in patients with the VDR B allele. The XXbb allelic combination of the ER/VDR genes was associated with a significantly lower erbB-2 expression, whereas in the other genotypes significantly higher oncogene expression was seen. Our data raise the possibility that ER/VDR gene polymorphisms accompanied by variable oncogene expression might influence the pathogenetic processes of colorectal cancers.

Influence of leptin and the TNF system on insulin resistance in pregnancy and their effect on anthropometric parameters of newborns

Background.  We studied the contribution of the tumor necrosis factor system and leptin to insulin resistance during the course of normal pregnancy.

Calcium-sensing receptor A986S polymorphism in human rectal cancer

Abstract.Background and aims: In vivo and in vitro experiments show the protective role of calcium ions (Ca2+) against colorectal cancer. The calcium-sensing receptor (CaSR) detects extracellular Ca2+ concentration. An association between the CaSR A986S polymorphism and serum calcium in healthy adults has been reported. Subjects with AA genotype had lower serum concentrations of Ca2+ than other genotypes. The expression of erbB-2, epidermal growth factor receptor (EGFR), p53, and ras in colorectal cancer has been suggested to have diagnostic and prognostic significance. Patients and methods: We investigated the relationship between the CaSR A986S polymorphism and the expression of erbB-2, EGFR, p53, and ras as well as the UICC stage in 56 patients with rectal cancer. Results: The occurrence of the genotype AA was not different in cancer patients and in 112 controls. In the presence of the coexpression of major oncogenes, patients with genotype AA were in significantly higher UICC stages than in the case of AS genotype. During the follow-up period AA genotype showed a tendency for poor prognosis. Conclusions: Our observation raises the possibility that genetic alterations of CaSR influence the pathogenesis of rectal cancer.

Resveratrol and Oxidative Stress in Diabetes Mellitus

Oxidative stress plays a key role in the pathogenesis of diabetes mellitus, contributing not only to the development, but also to the progression of diabetes and its related complications. Both immunosuppressive and antioxidant effects of resveratrol in attenuating the increased oxidative stress due to responses of β-cells to leukocyte activation have been implicated in the prevention of type 1 diabetes mellitus. Resveratrol affords advantageous effects by decreasing the oxidative injury and the recruitment of the nutritive precapillary arterioles in the context of disease states associated with insulin resistance, such as metabolic syndrome, pre-diabetes, and type 2 diabetes mellitus. The antioxidant properties of resveratrol could result from its direct effects by acting as a free radical scavenger, as well as its ability to indirectly activate antioxidant enzymes, and other mechanisms. These indirect effects could be conferred either via increased expression/activation/translocation of sirtuin 1, nuclear factor erythroid 2-related factor 2, superoxide dismutase, catalase, heme oxygenase-1, and glyoxalase or the suppression of inducible nitric oxide synthase and p47phox translocation/expression with the resultant inhibition of nicotinamide adenine dinucleotide (phosphate) oxidase. In addition to reducing oxidative stress, resveratrol could also improve the carbohydrate metabolism by promoting similar beneficial metabolic processes to those found in caloric restriction via the activation of sirtuin 1, as well as by increasing the level of glucagon-like peptide 1, by exerting an estrogen-like effect, or by stimulating the peroxisome proliferator-activated receptor-γ activity. In our preliminary human study we examined the effects of resveratrol in type 2 diabetic patients. In agreement with animal studies, we found that resveratrol treatment markedly decreased the insulin resistance and blood glucose levels, whereas we could not detect increases in insulin secretion. We also found that the onset of the postprandial glucose peak was manifested after a longer lag time in the postprandial period with resveratrol treatment, while there were no changes in amylin, glucagon-like peptide 1, and gastric inhibitory polypeptide levels; hormones that prolong gastric emptying. Additionally, we found decreased urinary excretion rates of ortho-tyrosine with resveratrol treatment, indicating a lowered degree of the hydroxyl free radical production in these patients. These findings support the notion that resveratrol decreases oxidative stress through its broad direct and indirect antioxidant effects, and this could be a promising approach for the prevention and treatment of diabetes mellitus. Further studies are undoubtedly warranted to better comprehend the effects of resveratrol in humans, since there is very limited data from human observations.

Cost-effectiveness of a risk-based secondary screening programme of type 2 diabetes.

The objective of this study was to develop a long‐term economic model for type 2 diabetes to describe the entire spectrum of the disease over a wide range of healthcare programmes. The model evaluates a public health, risk‐based screening programme in a country specific setting.

Intimal-Medial Thickness of the Carotid Artery in NIDDM Patients

and bilateral pulmonary infiltrates on CXR examination. The authors propose that in the absence of the common causes of noncardiogenic pulmonary edema, such as sepsis, drug intoxication, burns, pancreatitis, uremia, near drowning, embolism, or shock, the rapid administration of crystalloids and altered capillary permeability may have been the contributing mechanisms (8-10). Carroll and Matz (11) reported nine patients with type 1 diabetes who developed adult respiratory distress syndrome. All were found to have metabolic acidosis, acetone in the blood, and noncardiogenic pulmonary edema. Several mechanisms have been proposed to explain such presentations. One mechanism involves altered vascular permeability in the diabetic state. Yamashita et al. (12) found enhanced endothelial cell permeability to albumin and fluorescein-labeled dextran when cultured with high concentrations of glucose (400 mg/dl). This enhancement in permeability was temperature dependent. Wardle (13) suggests hyperglycemia induced enhancement in the production of diacylglycerol and then protein kinase C, generation of free radicals, formation of sorbitol, and the loss of surface heparin sulfates. McNally et al. (14) measured contractile responses of resistance arteries from diabetic and nondiabetic patients. The endothelial cells from diabetic patients appeared to have defective excitation-contraction coupling mechanisms involving the acetylcholine receptor. This may lead to increased blood flow and subsequent microangiopathy due to a rise in capillary pressure, eventually resulting in enhanced vascular permeability Theoretically, such mechanisms may apply to the pulmonary circulation. Noncardiogenic pulmonary edema should be considered in acute dyspnea associated with diabetic ketoacidosis.