Radivoj Kocic

Susceptibility to oxidative stress, insulin resistance, and insulin secretory response in the development of diabetes from obesity.

BACKGROUND/AIM [corrected] Oxidative stress plays a critical role in the pathogenesis of various diseases. Recent reports indicate that obesity may induce systemic oxidative stress. The aim of the study was to potentiate oxidative stress as a factor which may aggravate peripheral insulin sensitivity and insulinsecretory response in obesity in this way to potentiate development of diabetes. The aim of the study was also to establish whether insulin-secretory response after glucagonstimulated insulin secretion is susceptible to prooxidant/antioxidant homeostasis status, as well as to determine the extent of these changes. METHODS A mathematical model of glucose/insulin interactions and C-peptide was used to indicate the degree of insulin resistance and to assess their possible relationship with altered antioxidant/prooxidant homeostasis. The study included 24 obese healthy and 16 obese newly diagnozed non-insulin dependent diabetic patients (NIDDM) as well as 20 control healthy subjects, matched in age. RESULTS Total plasma antioxidative capacity, erythrocyte and plasma reduced glutathione level were significantly decreased in obese diabetic patients, but also in obese healthy subjects, compared to the values in controls. The plasma lipid peroxidation products and protein carbonyl groups were significantly higher in obese diabetics, more than in obese healthy subjects, compared to the control healthy subjects. The increase of erythrocyte lipid peroxidation at basal state was shown to be more pronounced in obese daibetics, but the apparent difference was obtained in both the obese healthy subjects and obese diabetics, compared to the control values, after exposing of erythrocytes to oxidative stress induced by H2O2. Positive correlation was found between the malondialdehyde (MDA) level and index of insulin sensitivity (FIRI). CONCLUSION Increased oxidative stress together with the decreased antioxidative defence seems to contribute to decreased insulin sensitivity and impaired insulin secretory response in obese diabetics, and may be hypothesized to favour the development of diabetes during obesity.

Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.

Subclinical hypothyroidism: association with cardiovascular risk factors and components of metabolic syndrome

The aim of this cross-sectional study was to evaluate the cardiovascular risk in patients with subclinical hypothyroidism (SH) and metabolic syndrome (MetS) components. The study included 60 patients with SH and a control group of 60 healthy volunteers, gender and age matched, with normal thyroid-stimulating hormone (TSH) and free thyroxin (FT4) concentration. The following measurements were made in all participants: TSH, FT4, thyroid peroxidase antibodies, anti-thyroglobulin antibodies, body mass index (BMI), waist circumference, blood pressure, fasting plasma glucose, total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), TC/HDL cholesterol and LDL/HDL cholesterol ratio, basal insulin level and homeostatic model assessment insulin resistance (HOMA-IR) index. MetS was diagnosed according to the National Cholesterol Education Program Adult Treatment Panel III criteria. The results showed that the following indices were statistically significantly higher in the SH group: BMI (p < 0.05), diastolic blood pressure (p < 0.001), TC (p < 0.05), TG (p < 0.05) and basal insulin level (p < 0.05). Although MetS parameters were present in a higher per cent in the SH group, there was a significantly higher number of patients with hypertension and decreased HDL cholesterol (p < 0.05). More frequently, MetS was diagnosed in SH patients (46.67%) than in the control group (33.33%), although the difference was not statistically significant. These results indicated that the traditional cardiovascular risk factors were more frequently present in SH patients as compared to euthyroid participants. Our results did not confirm significantly higher presence of MetS in SH patients in comparison with euthyroid respondents.

ANTIOXIDANTS MODULATE ADENOSINE METABOLISM IN RAT MESANGIAL CELLS CULTURED UNDER HIGH GLUCOSE CONDITIONS

Glomerular mesangial cells play a major role in glomerular hemodynamics, considered also as antigen-presenting cells participating in immune response. Mesangial dysfunction and proliferation are typical lesions of diabetic glomerulopathy. Adenosine, a local hormone, produced by mesangial cells is a metabolic regulator of renal blood flow, capable of decreasing glomerular filtration rate (GFR), exerting immunosuppressive, antiproliferative and anti-inflammatory properties. Since it was well established that antioxidants confer protection against increased oxidative stress that occurs in diabetes, the effect of captopril, reduced glutathione and melatonin on adenosine metabolism was investigated. Glomerular mesangial cells obtained from collagenase treated glomeruli, isolated from renal cortex of Sprague-Dowley rats, were grown under high glucose conditions (30 mmol/L) as a model of diabetic microenvironment. The activity of adenosine metabolizing enzymes: 5′-nucleotidease (5′-NU) responsible for its production and adenosine deaminase (ADA)—responsible for its degradation were investigated. Hyperglycemic conditions led to decreased adenosine production via 5′-NU and decreased removal via ADA. Captopril, given in therapeutic concentration induced enzyme activities in normoglycemic conditions and restored hyperglycemia—induced decrease. In order to investigate if the presence of SH groups may be responsible for this improvement, the cells were exposed to reduced glutathione, and it exerted almost equal effect, given in physiological and higher concentrations. Melatonin increased 5′-NU activity only in physiological glucose conditions. Presented results confirm potential renoprotective effect of SH-group containing antioxidant supplementation during diabetes in restoring adenosine metabolism.

Possible impact of plasma RNase activity on immune dysfunction in juvenile diabetes mellitus

Aim:  The ribonuclease (RNase) family represents important enzymes used widely in biomedical and biotechnological applications, as well as for diagnostic and therapeutic purposes. This study was undertaken to test the possibility that plasma alkaline RNase (free or inhibitory bound) determination may be useful in studying the dysregulation of nucleic acid and oligonucleotide metabolism as a possible pathogenetic mechanism in development of immune dysfunction in juvenile diabetes mellitus.

Protective effect of interferon-? on the DNA- and RNA-degrading pathway in anti-Fas-antibody induced apoptosis

Aim:  Fas membrane‐associated polypeptide antigen is a receptor molecule responsible for apoptosis‐mediated signals. In animal models of acute viral hepatitis, apoptosis of hepatocytes is mediated by Fas‐death receptors; therefore, the aim of this study was to evaluate the effect of interferon (IFN)‐α on apoptotic markers and nuclease activity against different coding and non‐coding single and double stranded RNAs during Fas‐induced liver apoptosis.

Circulating Ribonucleic Acids and Metabolic Stress Parameters May Reflect Progression of Autoimmune or Inflammatory Conditions in Juvenile Type 1 Diabetes

The sensing of ribonucleic acids (RNAs) by the monocyte/macrophage system occurs through the TLR7/8 Toll-like receptor family, the retinoic acidi–nducible protein I (RIG-I), and the melanoma differentiation–associated protein-5 (MDA-5). The aim of the present study was to evaluate the effect of circulating RNAs, isolated from juvenile type 1 diabetic patients and healthy control children, on the inflammatory, apoptotic, and antiviral response in human peripheral blood mononuclear cells (PBMCs) isolated from a healthy donor. Obtained effects were compared to the effects of metabolic stress parameters (hyperglycemia, oxidative and nitrosative stress). Forty-eight patients with juvenile type 1 diabetes and control children were included in the study. By performing the chromatographic analysis of circulating RNAs, the peak at the retention time 0.645 min for diabetic and control RNA samples was identified. To determine whether circulating RNAs have an agonistic or antagonistic effect on the signaling pathways involved in inflammatory, apoptotic, and antiviral cascade, their effect on TLR8, RIG-I, MDA-5, MyD88, NF-κB, IRF-3, phosphoIRF-3, IRF-7, RIP, and p38 was evaluated. A significantly lower level was achieved by cultivating PBMCs with circulating RNAs isolated from type 1 diabetic children, compared to the intact PBMCs, in relation to TLR-8, MDA-5, NF-κB, phospho IRF-3, and RIP, while it was higher for Bax. All the metabolic stress conditions up-regulated NF-κB, Bcl-2, and Bax. The NF-κB, determination seems to be the most sensitive parameter that may reflect disease processes associated with the progression of autoimmune or inflammatory conditions, while the IRF3/phosphoIRF3 ratio may suggest an insufficient antiviral response.

Optimal surgical treatment for bilateral multinodular goitre

Objective:  In the present study, we compared subtotal thyroidectomy (STT) with total thyroidectomy (TT) in the management of bilateral multinodular goitre.

Circulating nucleic acids in type 1 diabetes may modulate the thymocyte turnover rate

The autoimmunity of type 1 diabetes is associated with T-cell hyperactivity. Current study was designed to examine the effect of circulating ribonucleic acids (RNAs), isolated from type 1 diabetic patients on proliferative, apoptotic and inflammatory potential of rat thymocytes. Rat thymocytes were assayed for proliferating nuclear cell antigen (PCNA), Bcl-2, Bax and NF-κB level, using the flow cytometric and fluorometric assays. Cells were allocated into groups, treated with RNAs purified from plasma of juvenile diabetics, adult type 1 diabetic patients, control healthy children, healthy adult persons, nucleic acids and polynucleotide standards (RNA, polyC, PolyA, PolyIC, and CpG). The upregulation of PCNA and Bcl-2 protein and downregulation of Bax protein and NF-κB was shown when the thymocytes where incubated with RNA purified from plasma of juvenile type 1 diabetic patients. The dysregulation of inflammatory cascade and central tolerance may be a defect in autoimmune diseases related to innate immunity leading to corresponding alteration in adaptive immune response.

Continuous subcutaneous insulin infusion vs. multiple daily injections

BackgroundIntensive insulin therapy should be proposed for most type 1 diabetic patients. It can be achieved by a continuous subcutaneous insulin infusion (CSII) or by multiple daily injections (MDI). Debate remains regarding the optimal delivery of such therapy.AimTo compare the efficacy of glycemic control, hypoglycemia frequency, dose of insulin and weight in the type 1 diabetic patients, after switching from MDI to CSII.MethodsIn this retrospective study we analyzed HbA1c, profiles of blood glucose, weight, dose of insulin and hypoglycemia, 6 months before and 6 months after the initiation of CSII, in 18 patients with type 1 diabetes mellitus.ResultsBlood glucose control is considerably improved during CSII, as measured by HbA1c and mean blood glucose concentrations. Fasting blood glucose, postprandial glucose and also of glycemic variability were significantly lower. The total insulin doses during the CSII period were significantly lower. There was a small non significant increase in weight during CSII. There was a significant decrease in a number of mild hypoglycemic events, a small non significant decrease of asymptomatic hypoglycemia and a small non significant increase of nocturnal hypoglycemia.ConclusionsCSII provides significant improvement of blood glucose control with lower risk for hypoglycemia.