11 beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle

OBJECTIVE: Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity. \ud RESEARCH DESIGN AND METHODS: Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action. \ud RESULTS: Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer$^{307}$ insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer$^{307}$ IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer$^{307}$ IRS1 decreased and pThr$^{308}$ Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.\ud CONCLUSIONS: Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer$^{307}$ IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer$^{307}$ IRS1, increases pThr$^{308}$ Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action

Analysis of the technology of rolling 5,5 mm-diameter wire rod of cold upsetting steel in the morgan block mill

The commercial technology of rolling 5,5 mm-diameter wire rod in Poland’s most modern rolling line has been examined within the study. The material used for the investigation was the 20MnB4 steel intended for subsequent cold working. From the performed analysis of the investigation results it has been found that the technology of rolling wire rod of cold upsetting steel, which is used currently in the Rolling Mill under examination, allows the production of finished products that can be deformed with a relative reduction of about 33 %. At larger plastic deformations,cracks occur in the material, which disqualifies it from further cold working

11 beta-hydroxysteroid dehydrogenase type 1 regulates glucocorticoid-induced insulin resistance in skeletal muscle

OBJECTIVE: Glucocorticoid excess is characterized by increased adiposity, skeletal myopathy, and insulin resistance, but the precise molecular mechanisms are unknown. Within skeletal muscle, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) converts cortisone (11-dehydrocorticosterone in rodents) to active cortisol (corticosterone in rodents). We aimed to determine the mechanisms underpinning glucocorticoid-induced insulin resistance in skeletal muscle and indentify how 11beta-HSD1 inhibitors improve insulin sensitivity. \ud RESEARCH DESIGN AND METHODS: Rodent and human cell cultures, whole-tissue explants, and animal models were used to determine the impact of glucocorticoids and selective 11beta-HSD1 inhibition upon insulin signaling and action. \ud RESULTS: Dexamethasone decreased insulin-stimulated glucose uptake, decreased IRS1 mRNA and protein expression, and increased inactivating pSer$^{307}$ insulin receptor substrate (IRS)-1. 11beta-HSD1 activity and expression were observed in human and rodent myotubes and muscle explants. Activity was predominantly oxo-reductase, generating active glucocorticoid. A1 (selective 11beta-HSD1 inhibitor) abolished enzyme activity and blocked the increase in pSer$^{307}$ IRS1 and reduction in total IRS1 protein after treatment with 11DHC but not corticosterone. In C57Bl6/J mice, the selective 11beta-HSD1 inhibitor, A2, decreased fasting blood glucose levels and improved insulin sensitivity. In KK mice treated with A2, skeletal muscle pSer$^{307}$ IRS1 decreased and pThr$^{308}$ Akt/PKB increased. In addition, A2 decreased both lipogenic and lipolytic gene expression.\ud CONCLUSIONS: Prereceptor facilitation of glucocorticoid action via 11beta-HSD1 increases pSer$^{307}$ IRS1 and may be crucial in mediating insulin resistance in skeletal muscle. Selective 11beta-HSD1 inhibition decreases pSer$^{307}$ IRS1, increases pThr$^{308}$ Akt/PKB, and decreases lipogenic and lipolytic gene expression that may represent an important mechanism underpinning their insulin-sensitizing action

Determination of characteristics of plasticity of selected medium and high carbon steel grades in hot torsion test

This study presents results of the examinations aimed at determination of rheological properties of selected grades of medium and high-carbon steel grades ( C45 and C72D). The examinations were carried out for the hot torsion test using STD 812 torsion plastometer. The results of experimental studies were approximated with the function used for determination of yield stress depending on strain, strain rate and temperature. The study allowed for development of mathematical models of rheological properties of steel grades studied in the analysed scope of parameters of strain and temperature

Theoretical and experimental analysis of the backward extrusion process with a rotational die of AZ31 alloy

In this work theoretical and experimental analysis of the backward extrusion with a rotary die of the AZ31 alloy has been performed. The modification of the classical extrusion was based on the use of a rotary die. The results of theoretical research have confirmed that the use of the modified backward extrusion causes the appearance of shear stress in deformed material, which could affects the activation of additional mechanisms of deformation. The numerical modelling of the rotating extrusion of AZ31 alloy has been conducted by using the computer program Forge®. The experimental tests were carried out in the conditions of the STD 810 torsion plastometer using newly designed tools

Retrospective harm benefit analysis of pre-clinical animal research for six treatment interventions

The harm benefit analysis (HBA) is the cornerstone of animal research regulation and is considered to be a key ethical safeguard for animals. The HBA involves weighing the anticipated benefits of animal research against its predicted harms to animals but there are doubts about how objective and accountable this process is.i. To explore the harms to animals involved in pre-clinical animal studies and to assess these against the benefits for humans accruing from these studies; ii. To test the feasibility of conducting this type of retrospective HBA.Data on harms were systematically extracted from a sample of pre-clinical animal studies whose clinical relevance had already been investigated by comparing systematic reviews of the animal studies with systematic reviews of human studies for the same interventions (antifibrinolytics for haemorrhage, bisphosphonates for osteoporosis, corticosteroids for brain injury, Tirilazad for stroke, antenatal corticosteroids for neonatal respiratory distress and thrombolytics for stroke). Clinical relevance was also explored in terms of current clinical practice. Harms were categorised for severity using an expert panel. The quality of the research and its impact were considered. Bateson's Cube was used to conduct the HBA.The most common assessment of animal harms by the expert panel was 'severe'. Reported use of analgesia was rare and some animals (including most neonates) endured significant procedures with no, or only light, anaesthesia reported. Some animals suffered iatrogenic harms. Many were kept alive for long periods post-experimentally but only 1% of studies reported post-operative care. A third of studies reported that some animals died prior to endpoints. All the studies were of poor quality. Having weighed the actual harms to animals against the actual clinical benefits accruing from these studies, and taking into account the quality of the research and its impact, less than 7% of the studies were permissible according to Bateson's Cube: only the moderate bisphosphonate studies appeared to minimise harms to animals whilst being associated with benefit for humans.This is the first time the accountability of the HBA has been systematically explored across a range of pre-clinical animal studies. The regulatory systems in place when these studies were conducted failed to safeguard animals from severe suffering or to ensure that only beneficial, scientifically rigorous research was conducted. Our findings indicate a pressing need to: i. review regulations, particularly those that permit animals to suffer severe harms; ii. reform the processes of prospectively assessing pre-clinical animal studies to make them fit for purpose; and iii. systematically evaluate the benefits of pre-clinical animal research to permit a more realistic assessment of its likely future benefits

Analitičko i numeričko utvrđivanje prostiranja temperature na traci hlađenoj zrakom

The paper analyzes the distribution of temperature of 60S2A steel strip cooled in air. Both analytical and numerical methods were applied in investigation. From among the known analytical methods of temperature distribution determination, Tselikov’s [1], and the Fourier’s [2] methods were used. The numerical examination of temperature distribution presented in the paper involved carrying out a computer simulation of strip air cooling. For this purpose, the Forge 2D software [3] was employed, which relies on the finite-element method in performing computations. Comparison of results obtained by analytical methods with numerical computation results and for the real technological process has also been made within the study.U radu se analizira prostiranje temperature u čeličnoj traci 60S2A hlađenoj zrakom. Tijekom istraživanja primjenjivala se i jedna i druga metoda. Između poznatih analitičkih metoda utvrđivanja prostiranja temperature koristile su se Tselikova [1] i Fourierova [2] metoda. Numeričko ispitivanje temperature koje je prikazano u radu uključuje i provođenje kompjuterske simulacije hlađenja trake zrakom. U tu je svrhu primijenjen Forgeov software 2D [3] koji se u računanju oslanja na metodu konačnih elemenata. Unutar studije je također provedena i usporedba rezultata dobivenih analitičkim metodama s numeričkim izračunima