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

Role of the IRS-1 and/or -2 in the pathogenesis of insulin resistance in Dahl salt-sensitive (S) rats

Insulin resistance is a common finding in hypertensive humans and animal models. The Dahl salt-sensitive (S) rat is an ideal model of genetically predetermined insulin resistance and salt-sensitive hypertension. Along the insulin signaling pathway, the insulin receptor substrates 1 and 2 (IRS-1 and -2) are important mediators of insulin signaling. IRS-1 and/or IRS-2 genetic variant(s) and/or enhanced serine phosphorylation correlate with insulin resistance. The present commentary was designed to highlight the significance of IRS-1 and/or -2 in the pathogenesis of insulin resistance. An emphasis will be given to the putative role of IRS-1 and/or -2 genetic variant(s) and serine phosphorylation in precipitating insulin resistance

Medical school faculty discontent: prevalence and predictors of intent to leave academic careers

<p>Abstract</p> <p>Background</p> <p>Medical school faculty are less enthusiastic about their academic careers than ever before. In this study, we measured the prevalence and determinants of intent to leave academic medicine.</p> <p>Methods</p> <p>A 75-question survey was administered to faculty at a School of Medicine. Questions addressed quality of life, faculty responsibilities, support for teaching, clinical work and scholarship, mentoring and participation in governance.</p> <p>Results</p> <p>Of 1,408 eligible faculty members, 532 (38%) participated. Among respondents, 224 (40%; CI95: 0.35, 0.44) reported that their careers were not progressing satisfactorily; 236 (42%; CI95: 0.38, 0.46) were "seriously considering leaving academic medicine in the next five years." Members of clinical departments (OR = 1.71; CI95: 1.01, 2.91) were more likely to consider leaving; members of inter-disciplinary centers were less likely (OR = 0.68; CI95: 0.47, 0.98). The predictors of "serious intent to leave" included: Difficulties balancing work and family (OR = 3.52; CI95: 2.34, 5.30); inability to comment on performance of institutional leaders (OR = 3.08; CI95: 2.07, 4.72); absence of faculty development programs (OR = 3.03; CI95: 2.00, 4.60); lack of recognition of clinical work (OR = 2.73; CI95: 1.60, 4.68) and teaching (OR = 2.47; CI95: 1.59, 3.83) in promotion evaluations; absence of "academic community" (OR = 2.67; CI95: 1.86, 3.83); and failure of chairs to evaluate academic progress regularly (OR = 2.60; CI95: 1.80, 3.74).</p> <p>Conclusion</p> <p>Faculty are a medical school's key resource, but 42 percent are seriously considering leaving. Medical schools should refocus faculty retention efforts on professional development programs, regular performance feedback, balancing career and family, tangible recognition of teaching and clinical service and meaningful faculty participation in institutional governance.</p

Inhibition of MLC Phosphorylation Restricts Replication of Influenza Virus—A Mechanism of Action for Anti-Influenza Agents

Influenza A viruses are a severe threat worldwide, causing large epidemics that kill thousands every year. Prevention of influenza infection is complicated by continuous viral antigenic changes. Newer anti-influenza agents include MEK/ERK and protein kinase C inhibitors; however, the downstream effectors of these pathways have not been determined. In this study, we identified a common mechanism for the inhibitory effects of a significant group of anti-influenza agents. Our studies showed that influenza infection activates a series of signaling pathways that converge to induce myosin light chain (MLC) phosphorylation and remodeling of the actin cytoskeleton. Inhibiting MLC phosphorylation by blocking RhoA/Rho kinase, phospholipase C/protein kinase C, and HRas/Raf/MEK/ERK pathways with the use of genetic or chemical manipulation leads to the inhibition of influenza proliferation. In contrast, the induction of MLC phosphorylation enhances influenza proliferation, as does activation of the HRas/Raf/MEK/ERK signaling pathway. This effect is attenuated by inhibiting MLC phosphorylation. Additionally, in intracellular trafficking studies, we found that the nuclear export of influenza ribonucleoprotein depends on MLC phosphorylation. Our studies provide evidence that modulation of MLC phosphorylation is an underlying mechanism for the inhibitory effects of many anti-influenza compounds

Maternal Plasma 25-Hydroxyvitamin D Concentrations and the Risk for Gestational Diabetes Mellitus

Background: Evidence is accumulating for a role of vitamin D in maintaining normal glucose homeostasis. However, studies that prospectively examined circulating concentrations of 25-hydroxyvitamin D (25-[OH] D) in relation to diabetes risk are limited. Our objective is to determine the association between maternal plasma 25-[OH] D concentrations in early pregnancy and the risk for gestational diabetes mellitus (GDM). Methods: A nested case-control study was conducted among a prospective cohort of 953 pregnant women. Among them, 57 incident GDM cases were ascertained and 114 women who were not diagnosed with GDM were selected as controls. Controls were frequency matched to cases for the estimated season of conception of the index pregnancy. Results: Among women who developed GDM, maternal plasma 25-[OH] D concentrations at an average of 16 weeks of gestation were significantly lower than controls (24.2 vs. 30.1 ng/ml, P<0.001). This difference remained significant (3.62 ng/ml lower on average in GDM cases than controls (P value = 0.018)) after the adjustment for maternal age, race, family history of diabetes, and pre-pregnancy BMI. Approximately 33% of GDM cases, compared with 14% of controls (P<0.001), had maternal plasma 25-[OH] D concentrations consistent with a pre-specified diagnosis of vitamin D deficiency (<20 ng/ml). After adjustment for the aforementioned covariates including BMI, vitamin D deficiency was associated with a 2.66-fold (OR (95% CI): 2.66 (1.01–7.02)) increased GDM risk. Moreover, each 5 ng/ml decrease in 25-[OH] D concentrations was related to a 1.29-fold increase in GDM risk (OR (95% CI): 1.29 (1.05–1.60)). Additional adjustment for season and physical activity did not change findings substantially. Conclusions: Findings from the present study suggest that maternal vitamin D deficiency in early pregnancy is significantly associated with an elevated risk for GDM

Duffy antigen receptor for chemokines mediates chemokine endocytosis through a macropinocytosis-like process in endothelial cells

Background: The Duffy antigen receptor for chemokines (DARC) shows high affinity binding to multiple inflammatory CC and CXC chemokines and is expressed by erythrocytes and endothelial cells. Recent evidence suggests that endothelial DARC facilitates chemokine transcytosis to promote neutrophil recruitment. However, the mechanism of chemokine endocytosis by DARC remains unclear. Methodology/Principal Findings: We investigated the role of several endocytic pathways in DARC-mediated ligand internalization. Here we report that, although DARC co-localizes with caveolin-1 in endothelial cells, caveolin-1 is dispensable for DARC-mediated 125I-CXCL1 endocytosis as knockdown of caveolin-1 failed to inhibit ligand internalization. 125I-CXCL1 endocytosis by DARC was also independent of clathrin and flotillin-1 but required cholesterol and was, in part, inhibited by silencing Dynamin II expression. 125I-CXCL1 endocytosis was inhibited by amiloride, cytochalasin D, and the PKC inhibitor Gö6976 whereas Platelet Derived Growth Factor (PDGF) enhanced ligand internalization through DARC. The majority of DARC-ligand interactions occurred on the endothelial surface, with DARC identified along plasma membrane extensions with the appearance of ruffles, supporting the concept that DARC provides a high affinity scaffolding function for surface retention of chemokines on endothelial cells. Conclusions/Significance: These results show DARC-mediated chemokine endocytosis occurs through a macropinocytosis-like process in endothelial cells and caveolin-1 is dispensable for CXCL1 internalization. © 2011 Zhao et al