IRS1-Independent Defects Define Major Nodes of Insulin Resistance

SummaryInsulin resistance is a common disorder caused by a wide variety of physiological insults, some of which include poor diet, inflammation, anti-inflammatory steroids, hyperinsulinemia, and dyslipidemia. The common link between these diverse insults and insulin resistance is widely considered to involve impaired insulin signaling, particularly at the level of the insulin receptor substrate (IRS). To test this model, we utilized a heterologous system involving the platelet-derived growth factor (PDGF) pathway that recapitulates many aspects of insulin action independently of IRS. We comprehensively analyzed six models of insulin resistance in three experimental systems and consistently observed defects in both insulin and PDGF action despite a range of insult-specific defects within the IRS-Akt nexus. These findings indicate that while insulin resistance is associated with multiple deficiencies, the most deleterious defects and the origin of insulin resistance occur independently of IRS

Grain-size controls on the morphology and internal geometry of river-dominated deltas

Predictions of a delta's morphology, facies, and stratigraphy are typically derived from its relative wave, tide, and river energies, with sediment type playing a lesser role. Here we test the hypothesis that, all other factors being equal, the topset of a relatively noncohesive, sandy delta will have more active distributaries, a less rugose shoreline morphology, less topographic variation in its topset, and less variability in foreset dip directions than a highly cohesive, muddy delta. As a consequence its stratigraphy will have greater clinoform dip magnitudes and clinoform concavity, a greater percentage of channel facies, and less rugose sand bodies than a highly cohesive, muddy delta. Nine self-formed deltas having different sediment grain sizes and critical shear stresses required for re-entrainment of mud are simulated using Deflt3D, a 2D flow and sediment-transport model. Model results indicate that sand-dominated deltas are more fan-shaped while mud-dominated deltas are more birdsfoot in planform, because the sand-dominated deltas have more active distributaries and a smaller variance of topset elevations, and thereby experience a more equitable distribution of sediment to their perimeters. This results in a larger proportion of channel facies in sand-dominated deltas, and more uniformly distributed clinoform dip directions, steeper dips, and greater clinoform concavity. These conclusions are consistent with data collected from the Goose River Delta, a coarse-grained fan delta prograding into Goose Bay, Labrador, Canada. A reinterpretation of the Kf-1 parasequence set of the Cretaceous Last Chance Delta, a unit of the Ferron Sandstone near Emery, Utah, USA uses Ferron grain-size data, clinoform-dip data, clinoform concavity, and variance of dip directions to hindcast the delta's planform. The Kf-1 Last Chance Delta is predicted to have been more like a fan delta in planform than a birdsfoot delta

Oxygen, the Janus gas; its effects on human placental development and function

The accumulation of oxygen in the earth's atmosphere enabled metabolic pathways based on high-energy electron transfers that were capable of sustaining complex multicellular organisms to evolve. This advance came at a price, however, for the high reactivity of oxygen posed a major challenge as biological molecules became susceptible to oxidative damage, resulting in potential loss of function. Many extant physiological systems are therefore adapted, and homeostatically regulated, to supply sufficient oxygen to meet energy demands whilst also protecting cells, and mitochondria in particular, from excessive concentrations that could lead to oxidative damage. The invasive form of implantation displayed by the human conceptus presents particular challenges in this respect. During the first trimester, the conceptus develops in a low oxygen environment that favours organogenesis in the embryo, and cell proliferation and angiogenesis in the placenta. Later in pregnancy, higher oxygen concentrations are required to support the rapid growth of the fetus. This transition, which appears unique to the human placenta, must be negotiated safely for a successful pregnancy. Normally, onset of the maternal placental circulation is a progressive periphery-centre phenomenon, and is associated with extensive villous regression to form the chorion laeve. In cases of miscarriage, onset of the circulation is both precocious and disorganized, and excessive placental oxidative stress and villous regression undoubtedly contribute to loss of the pregnancy. Comparison of experimental and in vivo data indicates that fluctuations in placental oxygen concentration are a more powerful stimulus for the generation of oxidative stress than chronic hypoxia alone. Placental oxidative and endoplasmic reticulum stress appear to play key roles in the pathophysiology of complications of pregnancy, such as intrauterine growth restriction and preeclampsia, through their adverse impacts on placental function and growth. Establishing an inviolable maternal blood supply for the second and third trimesters is therefore one of the most crucial aspects of human placentation

Large meta-analysis of genome-wide association studies identifies five loci for lean body mass

Lean body mass, consisting mostly of skeletal muscle, is important for healthy aging. We performed a genome-wide association study for whole body (20 cohorts of European ancestry with n = 38,292) and appendicular (arms and legs) lean body mass (n = 28,330) measured using dual energy X-ray absorptiometry or bioelectrical impedance analysis, adjusted for sex, age, height, and fat mass. Twenty-one single-nucleotide polymorphisms were significantly associated with lean body mass either genome wide (p < 5 x 10(-8)) or suggestively genome wide (p < 2.3 x 10(-6)). Replication in 63,475 (47,227 of European ancestry) individuals from 33 cohorts for whole body lean body mass and in 45,090 (42,360 of European ancestry) subjects from 25 cohorts for appendicular lean body mass was successful for five single-nucleotide polymorphisms in/ near HSD17B11, VCAN, ADAMTSL3, IRS1, and FTO for total lean body mass and for three single-nucleotide polymorphisms in/ near VCAN, ADAMTSL3, and IRS1 for appendicular lean body mass. Our findings provide new insight into the genetics of lean body mass

Chemistry of interstitial-water samples from ODP Leg 105 sites (Table 1)

More than 100 interstitial-water samples from Sites 645, 646, and 647 were analyzed for major and minor ion chemistry. All sites display increases in calcium and decreases in magnesium with depth. The rate of change for these ions varies from site to site as a result of differences in rates of diffusion and sediment/water chemical reactions related to sediment lithology, physical properties, and redox conditions. The latter condition is reflected by the rate of sulfate reduction at each site. The lowest sulfate concentrations were observed at Site 645, where anomalously large depletions of calcium and magnesium are also recorded just below the sediment/water interface. Other dissolved ions, such as potassium, lithium, and strontium, also display overall anomalous depletions at Site 645. In contrast, concentration gradients of most cations at Sites 646 and 647, where dissolved sulfate is present, are more linear and may be primarily supported by diffusion between layer II basalts below and seawater above. Interstial-water dD and d18O display concomitant decreases with depth at each site. A minor exception occurs at Site 645, where d18O values become more positive in deeper portions of the sequence. This, together with the fact that correlations between dD and d18O vary from site to site, suggests that these isotopes are dissimilarly affected by reactions involving interstitial waters and layer II basalt and/or sediments. Interstitial-water d18O may be more sensitive to low-temperature reactions with basalts and volcaniclastics, which results in an overall depletion. Sediment diagenesis at deeper depths may slightly enrich interstitial-water d18O. The effects of such processes on dD values may be negligible

Investigating a New Project Center: Cuenca, Ecuador

This study, prepared for Worcester Polytechnic - Institute (WPI), details how Cuenca, Ecuador could serve the university as an international center for students to complete their Interactive Qualifying Project (IQP). We used preferences of faculty and students derived from survey results and interviews, guidelines provided by the university, and information about existing centers to identify qualities appropriate for a new IQP project center. Through a literature review and an on-site investigation, we assessed Cuenca's suitability and recommended specific housing, sponsors, and projects

Goat Cart: The Autonomous Golf Cart

The MQP improved on the computer vision and object detection systems, installed a server-controlled throttle, and added safety features and kill switches, for an existing autonomous vehicle based on a 1995 golf cart. Our team upgraded existing power systems to make the cart self-sustaining, even when in motion. The team upgraded wiring gauges and used terminals, shrink wrap, and solder to secure connections between components. All additions were properly mounted for safety and ease of access. This platform is prepared for future teams to develop software, add better control on steering and braking, and use the autonomous vehicle for various user applications

Glucose infusion causes insulin resistance in skeletal muscle of rats without changes in Akt and AS160 phosphorylation

Hyperglycemia is a defining feature of Type 1 and 2 diabetes. Hyperglycemia also causes insulin resistance, and our group (Kraegen EW, Saha AK, Preston E, Wilks D, Hoy AJ, Cooney GJ, Ruderman NB.&nbsp;Am J Physiol Endocrinol Metab Endocrinol Metab&nbsp;290: E471&ndash;E479, 2006) has recently demonstrated that hyperglycemia generated by glucose infusion results in insulin resistance after 5 h but not after 3 h. The aim of this study was to investigate possible mechanism(s) by which glucose infusion causes insulin resistance in skeletal muscle and in particular to examine whether this was associated with changes in insulin signaling. Hyperglycemia (&sim;10 mM) was produced in cannulated male Wistar rats for up to 5 h. The glucose infusion rate required to maintain this hyperglycemia progressively lessened over 5 h (by 25%,&nbsp;P&nbsp;&lt; 0.0001 at 5 h) without any alteration in plasma insulin levels consistent with the development of insulin resistance. Muscle glucose uptake in vivo (44%;&nbsp;P&nbsp;&lt; 0.05) and glycogen synthesis rate (52%;&nbsp;P&nbsp;&lt; 0.001) were reduced after 5 h compared with after 3 h of infusion. Despite these changes, there was no decrease in the phosphorylation state of multiple insulin signaling intermediates [insulin receptor, Akt, AS160 (Akt substrate of 160 kDa), glycogen synthase kinase-3&beta;] over the same time course. In isolated soleus strips taken from control or 1- or 5-h glucose-infused animals, insulin-stimulated 2-deoxyglucose transport was similar, but glycogen synthesis was significantly reduced in the 5-h muscle sample (68% vs. 1-h sample;&nbsp;P&nbsp;&lt; 0.001). These results suggest that the reduced muscle glucose uptake in rats after 5 h of acute hyperglycemia is due more to the metabolic effects of excess glycogen storage than to a defect in insulin signaling or glucose transport