Abdullah Olgun

EFFECT OF TESTOSTERONE ON INSULIN SENSITIVITY IN MEN WITH IDIOPATHIC HYPOGONADOTROPIC HYPOGONADISM

OBJECTIVE To assess the presence of insulin resistance (IR) among a homogeneous cohort of male patients with idiopathic hypogonadotropic hypogonadism (IHH) and to investigate the effects of testosterone therapy on IR in this specific group. METHODS Twenty-four male patients with untreated IHH and 20 age-, sex-, and weight-matched eugonadal healthy control subjects were recruited for the study. Plasma glucose, plasma insulin, total and free testosterone, follicle-stimulating hormone, luteinizing hormone, estradiol, and sex hormone-binding globulin levels were measured in fasting blood samples, and biochemical and hormonal analyses were performed for all study participants. IR was calculated by the homeostasis model assessment of insulin resistance (HOMA-IR) formula and the quantitative insulin sensitivity check index (QUICKI). Body mass index was calculated by weighing and measuring the heights of all study participants at the beginning of the investigation. Body fat mass and body lean mass were calculated as percentages of body weight by bioelectrical impedance analysis of body composition. Sustanon 250 (a combination of 4 testosterones) was administered intramuscularly once every 3 weeks for 6 months to male patients with IHH after a basal anthropometric, biochemical, and hormonal evaluation. The response to therapy was monitored by regular clinical examinations and serum testosterone measurements. After 6 months of testosterone treatment, the entire anthropometric, biochemical, and hormonal evaluation was repeated 14 days after the last injection of testosterone. RESULTS Before treatment, male patients with IHH had higher fasting plasma glucose concentrations, higher fasting plasma insulin levels, a higher HOMA-IR score, and a lower QUICKI when compared with the control group. After testosterone treatment in the patient group, the HOMA-IR score decreased dramatically to the level in the control group. The high body fat mass of the male patients with IHH was reduced significantly after testosterone treatment, concomitant with significant increases in body mass index and body lean mass. CONCLUSION Insulin sensitivity improves and body fat mass decreases with long-term testosterone replacement therapy.

MEFV mutations in familial Mediterranean fever: association of M694V homozygosity with arthritis

ObjectiveFamilial Mediterranean fever (FMF) is an autosomal recessive recurrent polyserositis with a higher prevalence in some ethnic groups, including Turks. Mutations in the FMF gene (MEFV) were found associated with FMF. The aim of this study was to analyze MEFV gene mutations in FMF patients to gain insight into the mutation phenotype correlation.ObjectivesWe analyzed the most frequent mutations (M680I, M694V, V726A, and E148Q) in a group of young male Turkish FMF patients using an amplification refractory mutation system and a commercial kit.ResultsM694V mutation was detected in 80% of the patients. After making a strict diagnostic discrimination between arthralgia and arthritis, arthritis was present in 71% of homozygous and 29.4% of heterozygous patients for M694V mutation. Other mutations were not found to correlate with specific symptoms or findings.ConclusionThe homozygosity of M694V mutation in the MEFV gene is associated with arthritis in FMF patients.

Potential effects of zinc on information processing in boys with attention deficit hyperactivity disorder.

PURPOSE The aims of the present study were to investigate the relationship between plasma zinc levels and amplitudes and latencies of P1, N2, and P3 in parietal and frontal areas in children with ADHD, and to compare these zinc levels and event-related potentials (ERPs) indices with controls. METHODS 28 boys with ADHD were divided into two groups according to plasma zinc levels: low zinc group (N=13, zinc level <80 microg/dL) and zinc non-deficient group (N=15, zinc level >or=80 microg/dL). ERP indices from parietal and frontal brain regions were recorded in children with ADHD and in 24 normal boys by using an auditory oddball paradigm. Plasma zinc levels were measured by an atomic absorption spectrophotometer. RESULTS The plasma zinc levels were significantly lower in both ADHD groups (means are 65.8 microg/dL in low zinc group and 89.5 microg/dL in zinc non-deficient group) than controls (mean: 107.8 microg/dL; both p values <0.017). In ADHD compared to controls, the amplitudes of P3 in frontal and parietal regions were significantly lower, and the latency of P3 in parietal region was significantly longer (all p values <0.017). In low zinc ADHD group compared to zinc non-deficient ADHD group, the latencies of N2 in frontal and parietal region were significantly shorter (all p values <0.017). In addition, there was a medium but significant positive correlation between plasma zinc levels and amplitude and latency of frontal N2 wave in ADHD. CONCLUSIONS These results can suggest that plasma zinc levels might have an effect on information processing in ADHD children, and lower zinc levels seem to affect N2 wave. Since N2 wave changes may reflect a different inhibition process, further studies are warranted to investigate the effect of zinc on inhibitory process in children with ADHD, and in low zinc and non-deficient ADHD groups.

Chitotriosidase Levels in Healthy Elderly Subjects

Abstract:  Chitotriosidase (CHIT) belongs to the family of glycosylhydrolases and is highly homologous to chitinases from lower organisms. The enzyme CHIT is of interest for clinical reasons, because it is selectively expressed in chronically activated tissue macrophages. In most ethnic groups, ∼6% of all individuals are homozygous for CHIT deficiency. Pathological tissue macrophages in several disease conditions massively express CHIT. A shared feature of such cells in the different conditions is the accumulation of lipid material in the lysosomal apparatus. Serum CHIT activity is significantly increased in individuals suffering from atherosclerosis disease and is related to the severity of the atherosclerotic lesion, suggesting a possible role as atherosclerotic extent marker. Our objective is to determine the levels of serum CHIT activity in healthy elderly subjects. Healthy 90 (between 65–94 years old) elderly people and 69 (between 20–44 years old) young people were chosen. Serum CHIT enzymatic activity was determined with the flurometric enzyme activity assay using artificial 4‐MU substrate. We found CHIT activity 270 ± 21 (nmol/mL/h) (values are mean ± SD) in elderly people and 136 ± 17 in young people. There are statistical differences between elderly and young subjects.

Oxidative phosphorylation enzyme complexes in caloric restriction.

Free radicals, generated especially by electron leakage from mitochondrial electron transport chain (ETC), are accepted as one of the possible causes of aging. Long-term caloric restriction (CR) is known to increase the species specific average and maximum life spans. Thus it provides a means for investigating mechanisms of aging. There is evidence suggesting a decrease in the free radical production with CR. In this study, Blue-Native PAGE (BN-PAGE) technique was used to investigate the effect of CR on the oxidative phosphorylation enzyme complexes. Of the total 30 female Swiss Albino balb/c mice, 15 were used as control and the other 15 as CR group. Alternate day feeding regimen was used in the CR group for 66 weeks beginning at the end of 3rd month. In the control group, 5 (33.3%) mice died, 3 (20%) of them of breast cancer, 2 (13.3%) of unknown causes and no death cases were observed in the CR group during the study. BN-PAGE was performed on the extracts from brain mitochondrial fractions. Complexes II and V were excluded from the study due to some analytical limitations. No difference was found in the levels of complexes I and III between the groups. In the CR group, complex IV level was found increased and the ratio of complex III-IV decreased compared with the control group. Since there is a slight increase (108%) in the level of complex IV in the CR group, our results could suggest possible partial compensation of electron leakage in the upstream complexes in ETC, and the decrease of free radical production with CR.

Mitochondrial DNA-Deficient Models and Aging

Abstract:  Human mitochondrial DNA (mtDNA) encodes 13 subunits of oxidative phosphorylation (OXPHOS) enzyme complexes I, III, IV, and V except complex II. MtDNA is more sensitive to oxidative damage than nuclear DNA. MtDNA defects are involved in many pathologies including aging. Several mtDNA‐deficient cell culture, yeast, and animal models were generated to study the role of mtDNA in many physiological processes. Ethidium bromide (EB), an agent that is known to inhibit mtDNA replication with a negligible effect on nuclear DNA, is generally used to generate mtDNA‐deficient models. The antibiotics chloramphenicol and doxycycline, which were known to inhibit mitochondrial translation, were also used to generate the same phenotype. Cultured mtDNA‐deficient cells need uridine and pyruvate to survive. At the organismal level, uridine can be supplemented, but pyruvate supplementation can cause a worser phenotype because of lactic acidosis. In C. elegans, EB, when used during larval development, increases life span, but decreases, when used after the beginning of adult stage. This should be kept in mind since mitochondria‐related genes are generally detected in genome‐wide screening studies for longevity. We believe that conditional knockout studies need to be carried out for these genes after reaching adulthood. MtDNA mutator mouse did not show an increase of free radical production. Therefore, the downstream phenomena to mtDNA defects are likely ineffective pyrimidine synthesis (dihydroorotate dehydrogenase, DHODH, needs a functional respiratory chain) and excess NADH (decreased NAD pool) in addition to free radicals.

The plasma levels of soluble P-selectin in subjects with prediabetes

Prediabetes has been associated with an increased risk of cardiovascular disease and mortality. Soluble P‐selectin (sP‐selectin) is an index of platelet activation and also a risk factor for future vascular events. sP‐selectin levels were investigated in prediabetic subjects who had no confounding factors such as hypertension, obesity or dyslipidaemia. sP‐selectin, hsCRP levels and HOMA‐IR indexes were measured in 40 prediabetic subjects (n = 24 for IFG and n = 16 for IGT) and age‐, sex‐ and BMI‐matched 40 healthy controls. sP‐selectin levels in prediabetic subjects were not significantly different compared with those in controls (p = 0.12). Prediabetic group had similar hsCRP (p = 0.29), higher HOMA‐IR indexes (p < 0.001) and lower HDL cholesterol levels (p = 0.001) when compared with healthy controls. The power of the study was 0.93 for sP‐selectin, 0.7 for hsCRP and 1.0 for HOMA. Our data suggest that sP‐selectin may not contribute to the prothrombotic state as well as the accelerated atherogenesis associated with prediabetes.

The effect of isoprenoid side chain length of ubiquinone on life span.

The isoprenoid side chain length of ubiquinone (Q) can have an effect on the life span of mammals. The short living mouse and rat have Q(9), while primates have Q(10) as the major form. Ubiquinones (Qs) having longer hydrophobic tail are likely more imbedded in the mitochondrial inner membrane than the ones having shorter tails. In case of short tail length, ubisemiquinone (Q(*-)) produced during electron transport can be more exposed to the aqueous phase on both sides of the membrane, generate more superoxide radical and damage the neighbouring macromolecules. Considering the inefficient subcellular distribution of exogenous Q, production of transgenic animals synthesizing Qs having longer than 10 isoprenoid units (Q(>10)) can increase their life span.

Biological effects of deuteronation: ATP synthase as an example

BackgroundIn nature, deuterium/hydrogen ratio is ~1/6600, therefore one of ~3300 water (H2O) molecules is deuterated (HOD + D2O). In body fluids the ratio of deuterons to protons is ~1/15000 because of the lower ionization constant of heavy water. The probability of deuteronation rather than protonation of Asp 61 on the subunit c of F0 part of ATP synthase is also ~1/15000. The contribution of deuteronation to the pKa of Asp 61 is 0.35.Theory and DiscussionIn mitochondria, the release of a deuteron into the matrix side half-channel of F0 is likely to be slower than that of a proton. As another example, deuteronation may slow down electron transfer in the electron transport chain (ETC) by interfering with proton coupled electron transport reactions (PCET), and increase free radical production through the leakage of temporarily accumulated electrons at the downstream complexes.ConclusionDeuteronation, as exemplified by ATP synthase and the ETC, may interfere with the conformations and functions of many macromolecules and contribute to some pathologies like heavy water toxicity and aging.

Serum chitotriosidase activity: is it a new inflammatory marker in obese children?

Abstract Chitotriosidase (ChT) is an enzyme secreted by activated macrophages and involved in defense against, and in degradation of chitin-containing pathogens, such as fungi, nematodes, and insects. In addition, it plays an important role in the development of atherosclerosis related with systemic low-grade inflammation. To this effect of activity of ChT, we aimed to investigate serum ChT activity in obese subjects and to determine to relation with insulin resistance and high-sensitive C-reactive protein (hsCRP). A total of 73 obese subjects (10.9±2.6 years of age, 44 male patients) and 41 age and gender-matched healthy lean subjects (11.6±2.9 years of age, 18 male patients) were included in this study, between 2007 and 2008. The criterion for diagnosing obesity was defined as the body mass index (BMI) being over 97th percentile of the same gender and age. Fasting serum glucose, insulin, hsCRP and ChT levels were measured. We compared the differences in variables between obese and lean subjects with Student’s t-test compared after ascertaining that the data were normally distributed. All data were expressed as mean±standard deviation. There was statistically significant increase in serum ChT activity of obese subjects, while there was statistically significant difference in serum hsCRP levels when compared to healthy lean subjects (30.0±17.9 and 23.0±17.8, p=0.045; 2.3±3.1 and 0.7±1.2, p=0.001). Obese subjects had significantly higher BMI-SDS, TG and HOMA-IR and lower HDL-C levels when compared with the healthy lean subjects (p<0.05). Correlation analysis showed no significant correlation between serum ChT activity and hsCRP, HOMA-IR and BMI-SDS (p>0.05). Although the data need to be validated by further investigation, the observations made in this study seem to indicate that serum ChT activity may not be a useful marker for monitoring systemic low-grade inflammation and insulin resistance in obese subjects.