РОЛЬ ОСТЕОКАЛЬЦИНУ В РЕГУЛЯЦІЇ СЕКРЕЦІЇ ІНСУЛІНУ ТА ОСТЕОТРОПНИХ ЕФЕКТІВ РІЗНИХ КЛАСІВ ПРОТИДІАБЕТИЧНИХ ПРЕПАРАТІВ (огляд літератури і власні дослідження)

Background. Current data suggest that bone tissue produces hormonally active factors - modulators of metabolic processes throughout the body. The most significant osteoproteins is osteocalcin, the non-collagen structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream during the resorption of bone tissue. Osteocalcin is involved in the regulation of energy balance, insulin secretion, peripheric insulin sensitivity, and adipocyte’s function, while being an important marker of bone remodeling. The aim of this study was to investigate the relationship between osteocalcin levels and metabolic parameters in 97 patients with type 2 diabetes over 50 years of age, in the course of pharmacotherapy using different classes of antidiabetic drugs, namely human insulin, glucagon-like peptide-1 agonists (aGLP), and sodium-glucose co-transporter 2 (SGLT2) inhibitors, depending on presence of obesity. Results. There was found the highest serum osteocalcin level in patients without obese who received a metabolically active therapy with insulin or aGLP-1, comparing to nonobese subjects of SGLT2 inhibitors therapy group. The lowest level of HbA1c and triglycerides observed in non-obese patients on the background of taking aGLP-1. Conclusion. It can be assumed that the factor determining the hypoglycemic efficacy of investigated drugs may be the pathogenesis of type 2 diabetes which depends on the degree of obesity, while the type of antidiabetic therapy has a corrective effect, probably mediated by changes in body weight and fat distribution.Background. Current data suggest that bone tissue produces hormonally active factors - modulators of metabolic processes throughout the body. The most significant osteoproteins is osteocalcin, the non-collagen structural protein of the bone matrix, which is synthesized by osteoblasts and enters the bloodstream during the resorption of bone tissue. Osteocalcin is involved in the regulation of energy balance, insulin secretion, peripheric insulin sensitivity, and adipocyte’s function, while being an important marker of bone remodeling. The aim of this study was to investigate the relationship between osteocalcin levels and metabolic parameters in 97 patients with type 2 diabetes over 50 years of age, in the course of pharmacotherapy using different classes of antidiabetic drugs, namely human insulin, glucagon-like peptide-1 agonists (aGLP), and sodium-glucose co-transporter 2 (SGLT2) inhibitors, depending on presence of obesity. Results. There was found the highest serum osteocalcin level in patients without obese who received a metabolically active therapy with insulin or aGLP-1, comparing to nonobese subjects of SGLT2 inhibitors therapy group. The lowest level of HbA1c and triglycerides observed in non-obese patients on the background of taking aGLP-1. Conclusion. It can be assumed that the factor determining the hypoglycemic efficacy of investigated drugs may be the pathogenesis of type 2 diabetes which depends on the degree of obesity, while the type of antidiabetic therapy has a corrective effect, probably mediated by changes in body weight and fat distribution

ВЗАЄМОЗВ’ЯЗКИ ОСТЕОКАЛЬЦИНУ З ГОРМОНАЛЬНО-МЕТАБОЛІЧНИМИ ПОРУШЕННЯМИ ЧОЛОВІКІВ З ЦУКРОВИМ ДІАБЕТОМ 2 ТИПУ З РІЗНИМ СТУПЕНЕМ ОЖИРІННЯ (огляд літератури і власні дослідження)

The bone hormone osteocalcin is formed by osteoblasts and is partially released into the bloodstream during bone resorption, being a biomarker of bone remodeling. Osteocalcin also plays an important role in the endocrine regulation of metabolic and energy processes in the body and in their coordination. Osteocalcin uses a feedback mechanism to regulate insulin secretion, insulin sensitivity of peripheral tissues, and adipokine levels. In general, the secretion of osteocalcin and insulin are important factors in the formation of hormonal-metabolic phenotype, body composition, determination of regional distribution and metabolic activity of both bone and adipose tissue.The aim of this study was to establish the relationship between osteocalcin concentration and hormonal changes in men with type 2 diabetes with and without obesity on the background of involutive changes. Results. 64 men with type 2 diabetes, older than 50 years, were divided into 2 groups by BMI: 1) non-obese, BMI <30 kg / m2 (n = 31); 2) -obese, BMI ≥ 30 kg / m2 (n = 33). Lower levels of insulin secretion (lower serum C-peptide and insulin levels) were observed in non-obese patients in the absence of a compensatory increase in proinsulin levels. It can be assumed that the increase in the concentration of osteocalcin in group 1 is compensatory, although it does not have a significant effect on blood glucose levels. However, it may have a protective effect on the severity of insulin resistance syndrome and related metabolic disorders. Lower levels of osteocalcin in the obese group were associated with a higher degree of insulin resistance and insulin secretion. There was no significant difference between the two groups in serum proinsulin levels, as well as in androgen supply, which was assessed by the levels of total testosterone, testosteronestradiol-binding globulin, and free testosterone index. Conclusion. Lower levels of osteocalcin may be a marker of an increased risk of adverse metabolic changes in obese patients with type 2 diabetes, followed by complications compared to non-overweight patientsThe bone hormone osteocalcin is formed by osteoblasts and is partially released into the bloodstream during bone resorption, being a biomarker of bone remodeling. Osteocalcin also plays an important role in the endocrine regulation of metabolic and energy processes in the body and in their coordination. Osteocalcin uses a feedback mechanism to regulate insulin secretion, insulin sensitivity of peripheral tissues, and adipokine levels. In general, the secretion of osteocalcin and insulin are important factors in the formation of hormonal-metabolic phenotype, body composition, determination of regional distribution and metabolic activity of both bone and adipose tissue.The aim of this study was to establish the relationship between osteocalcin concentration and hormonal changes in men with type 2 diabetes with and without obesity on the background of involutive changes. Results. 64 men with type 2 diabetes, older than 50 years, were divided into 2 groups by BMI: 1) non-obese, BMI <30 kg / m2 (n = 31); 2) -obese, BMI ≥ 30 kg / m2 (n = 33). Lower levels of insulin secretion (lower serum C-peptide and insulin levels) were observed in non-obese patients in the absence of a compensatory increase in proinsulin levels. It can be assumed that the increase in the concentration of osteocalcin in group 1 is compensatory, although it does not have a significant effect on blood glucose levels. However, it may have a protective effect on the severity of insulin resistance syndrome and related metabolic disorders. Lower levels of osteocalcin in the obese group were associated with a higher degree of insulin resistance and insulin secretion. There was no significant difference between the two groups in serum proinsulin levels, as well as in androgen supply, which was assessed by the levels of total testosterone, testosteronestradiol-binding globulin, and free testosterone index. Conclusion. Lower levels of osteocalcin may be a marker of an increased risk of adverse metabolic changes in obese patients with type 2 diabetes, followed by complications compared to non-overweight patient

Induction of oxidative stress and lipid peroxidation in rats chronically exposed to cypermethrin through dermal application

Present study was undertaken to study the effect of cypermethrin on oxidative stress after chronic dermal application. The insecticide was applied dermally at 50 mg/kg body weight in different groups of Wistar rats of either sex weighing 150~200 g. Significant (p < 0.05) increase in catalase activity was observed after 30 days of exposure. However, the superoxide dismutase activity declined significantly after 60 days of exposure. The activity of glutathione peroxidase and blood glutathione levels declined significantly (p < 0.05) after 30 days of cypermethrin dermal application. However, the activity of glutathione S-transferase increased significantly (p < 0.05) in all groups after 60 days of dermal exposure. Significant increase in lipid peroxidation was observed from 30 days onwards and reached a peak after 120 days of application

Acute Inhibition of Selected Membrane-Proximal Mouse T Cell Receptor Signaling by Mitochondrial Antagonists

T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR) with cognate peptide/major histocompatibility complex (MHC) plus lymphocyte function-associated antigen 1 (LFA-1) with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS) platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour) with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin), resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s). Thus, activation of Akt and PLC-γ1 and entry of extracellular Ca2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption) could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours) on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function

Reduction of Hydrophilic Ubiquinones by the Flavin in Mitochondrial NADH:Ubiquinone Oxidoreductase (Complex I) and Production of Reactive Oxygen Species†

ABSTRACT: NADH:ubiquinone oxidoreductase (complex I) from bovine heart mitochondria is a complicated, energy-transducing, membrane-bound enzyme that contains 45 different subunits, a non-covalently bound flavin mononucleotide, and eight iron-sulfur clusters. The mechanisms of NADH oxidation and intramolecular electron transfer by complex I are gradually being defined, but the mechanism linking ubiquinone reduction to proton translocation remains unknown. Studies of ubiquinone reduction by isolated complex I are problematic because the extremely hydrophobic natural substrate, ubiquinone-10, must be substituted with a relatively hydrophilic analogue (such as ubiquinone-1). Hydrophilic ubiquinones are reduced by an additional, non-energy-transducing pathway (which is insensitive to inhibitors such as rotenone and piericidin A). Here, we show that inhibitor-insensitive ubiquinone reduction occurs by a ping-pong type mechanism, catalyzed by the flavin mononucleotide cofactor in the active site for NADH oxidation. Moreover, semiquinones produced at the flavin site initiate redox cycling reactions with molecular oxygen, producing superoxide radicals and hydrogen peroxide. The ubiquinone reactant is regenerated, so the NADH:Q reaction becomes superstoichiometric. Idebenone, an artificial ubiquinone showing promise in the treatment of Friedreich’s Ataxia, reacts at the flavin site. The factors which determine the balance of reactivity between the two sites of ubiquinone reduction (the energy-transducing site and the flavi

Pastoralism and Emergent Complex Settlement in the Middle Bronze Age, Azerbaijan: Isotopic analyses of mobility strategies in transformation

Objectives. This article explores the scale and seasonal patterns of mobility at the complex settlement site of Qızqala during the Middle Bronze Age (2400–1,500 BCE). By integrating human bone, teeth, and environmental samples this research tests the hypothesis of the persistent importance of community-wide seasonal pastoral transhumance during the early formation of complex settlement systems of the South Caucasus. Methods. This research applies stable oxygen and radiogenic strontium isotope analyses on incremental samples of human tooth enamel, bulk tooth enamel, and bone to resolve mobility patterns. Sequential and bulk sampling techniques elucidate seasonal and residential mobility behaviors. Extensive environmental isotope samples of plant and water were collected through regional survey and establish local and regional isotopic baselines, which are compared to human isotope analysis results. Results. Qızqala individuals exhibit low isotopic variability compared to regional contemporaries. 87Sr/86Sr ratios from human remains indicate seasonal and residential isotopic variability within the baseline ranges of local landscapes. δ18O values display erratic patterns, but correspond to seasonal variability with fluctuations between highland and lowland altitudinal zone baseline values. Conclusions. Results suggest that isotopic analysis of multiple elements and sequential enamel samples offers finer resolution on the complexities of human mobility strategies and elucidate the daily lives of often overlooked mobile populations. Higher resolution of individual mobility reveals shared routine behaviors that underscore the importance of diverse social collaborations in forming complex polities in the South Caucasus

Pancreatic β-Cell Death in Response to Pro-Inflammatory Cytokines Is Distinct from Genuine Apoptosis

A reduction in functional β-cell mass leads to both major forms of diabetes; pro-inflammatory cytokines, such as interleukin-1beta (IL-1β) and gamma-interferon (γ-IFN), activate signaling pathways that direct pancreatic β-cell death and dysfunction. However, the molecular mechanism of β-cell death in this context is not well understood. In this report, we tested the hypothesis that individual cellular death pathways display characteristic phenotypes that allow them to be distinguished by the precise biochemical and metabolic responses that occur during stimulus-specific initiation. Using 832/13 and INS-1E rat insulinoma cells and isolated rat islets, we provide evidence that apoptosis is unlikely to be the primary pathway underlying β-cell death in response to IL-1β+γ-IFN. This conclusion was reached via the experimental results of several different interdisciplinary strategies, which included: 1) tandem mass spectrometry to delineate the metabolic differences between IL-1β+γ-IFN exposure versus apoptotic induction by camptothecin and 2) pharmacological and molecular interference with either NF-κB activity or apoptosome formation. These approaches provided clear distinctions in cell death pathways initiated by pro-inflammatory cytokines and bona fide inducers of apoptosis. Collectively, the results reported herein demonstrate that pancreatic β-cells undergo apoptosis in response to camptothecin or staurosporine, but not pro-inflammatory cytokines

Manganese Superoxide Dismutase: Guardian of the Powerhouse

The mitochondrion is vital for many metabolic pathways in the cell, contributing all or important constituent enzymes for diverse functions such as β-oxidation of fatty acids, the urea cycle, the citric acid cycle, and ATP synthesis. The mitochondrion is also a major site of reactive oxygen species (ROS) production in the cell. Aberrant production of mitochondrial ROS can have dramatic effects on cellular function, in part, due to oxidative modification of key metabolic proteins localized in the mitochondrion. The cell is equipped with myriad antioxidant enzyme systems to combat deleterious ROS production in mitochondria, with the mitochondrial antioxidant enzyme manganese superoxide dismutase (MnSOD) acting as the chief ROS scavenging enzyme in the cell. Factors that affect the expression and/or the activity of MnSOD, resulting in diminished antioxidant capacity of the cell, can have extraordinary consequences on the overall health of the cell by altering mitochondrial metabolic function, leading to the development and progression of numerous diseases. A better understanding of the mechanisms by which MnSOD protects cells from the harmful effects of overproduction of ROS, in particular, the effects of ROS on mitochondrial metabolic enzymes, may contribute to the development of novel treatments for various diseases in which ROS are an important component

Loss Of Opa1 Disturbs Cellular Calcium Homeostasis And Sensitizes For Excitotoxicity

Optic atrophy 1 (OPA1) mutations cause dominant optic atrophy (DOA) with retinal ganglion cell (RGC) and optic nerve degeneration. The mechanism for the selective degeneration of RGCs in DOA remains elusive. To address the mechanism, we reduced OPA1 protein expression in cell lines and RGCs by RNA interference. OPA1 loss results in mitochondrial fragmentation, deficiency in oxidative phosphorylation, decreased ATP levels, decreased mitochondrial Ca 2+ retention capacity, reduced mtDNA copy numbers, and sensitization to apoptotic insults. We demonstrate profound cristae depletion and loss of crista junctions in OPA1 knockdown cells, whereas the remaining crista junctions preserve their normal size. OPA1-depleted cells exhibit decreased agonist-evoked mitochondrial Ca 2+ transients and corresponding reduction of NAD + to NADH, but the impairment in NADH oxidation leads to an overall more reduced mitochondrial NADH pool. Although in our model OPA1 loss in RGCs has no apparent impact on mitochondrial morphology, it decreases buffering of cytosolic Ca 2+ and sensitizes RGCs to excitotoxic injury. Exposure to glutamate triggers delayed calcium deregulation (DCD), often in a reversible manner, indicating partial resistance of RGCs to this injury. However, when OPA1 is depleted, DCD becomes irreversible. Thus, our data show that whereas OPA1 is required for mitochondrial fusion, maintenance of crista morphology and oxidative phosphorylation, loss of OPA1 also results in defective Ca 2+ homeostasis. © 2013 Macmillan Publishers Limited All rights reserved