Down-regulation of Insulin Receptor Substrate 1 during Hyperglycemia Induces Vascular Smooth Muscle Cell Dedifferentiation

Diabetes is a major risk factor for the development of atherosclerosis, but the mechanism by which hyperglycemia accelerates lesion development is not well defined. Insulin and insulin-like growth factor I (IGF-I) signal through the scaffold protein insulin receptor substrate 1 (IRS-1). In diabetes, IRS-1 is down-regulated, and cells become resistant to insulin. Under these conditions, the IGF-I receptor signals through an alternate scaffold protein, SHPS-1, resulting in pathophysiologic stimulation of vascular smooth muscle cell (VSMC) migration and proliferation. These studies were undertaken to determine whether IRS-1 is functioning constitutively to maintain VSMCs in their differentiated state and, thereby, inhibit aberrant signaling. Here we show that deletion of IRS-1 expression in VSMCs in non-diabetic mice results in dedifferentiation, SHPS-1 activation, and aberrant signaling and that these changes parallel those that occur in response to hyperglycemia. The mice showed enhanced sensitivity to IGF-I stimulation of VSMC proliferation and a hyperproliferative response to vascular injury. KLF4, a transcription factor that induces VSMC dedifferentiation, was up-regulated in IRS-1−/− mice, and the differentiation inducer myocardin was undetectable. Importantly, these changes were replicated in wild-type mice during hyperglycemia. These findings illuminate a new function of IRS-1: that of maintaining cells in their normal, differentiated state. Because IRS-1 is down-regulated in states of insulin resistance that occur in response to metabolic stresses such as obesity and cytokine stimulation, the findings provide a mechanism for understanding how patients with metabolic stress and/or diabetes are predisposed to developing vascular complications

Welding wire pressure sensor assembly

The present invention relates to a device which is used to monitor the position of a filler wire relative to a base material being welded as the filler wire is added to a welding pool. The device is applicable to automated welding systems wherein nonconsumable electrode arc welding processes are utilized in conjunction with a filler wire which is added to a weld pool created by the electrode arc. The invention senses pressure deviations from a predetermined pressure between the filler wire and the base material, and provides electrical signals responsive to the deviations for actuating control mechanisms in an automatic welding apparatus so as to minimize the pressure deviation and to prevent disengagement of the contact between the filler wire and the base material

Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis★

Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4−/y mice that lacked Irs2 in the CNS (bIrs2−/−·Irs4−/y) or only in LepRb-neurons (Lepr∆Irs2·Irs4−/y). bIrs2−/−·Irs4−/y mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr∆Irs2·Irs4−/y mice were not different from Lepr∆Irs2 mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb

Direct Autocrine Action of Insulin on β-Cells: Does It Make Physiological Sense?

In recent years there has been a growing interest in the possibility of a direct autocrine effect of insulin on the pancreatic β-cell. Indeed, there have been numerous intriguing articles and several eloquent reviews written on the subject (1–3); however, the concept is still controversial. Although many in vitro experiments, a few transgenic mouse studies, and some human investigations would be supportive of the notion, there exist different insights, other studies, and circumstantial evidence that question the concept. Therefore, the idea of autocrine action of insulin remains a conundrum. Here we outline a series of thoughts, insights, and alternative interpretations of the available experimental evidence. We ask, how convincing are these, and what are the confusing issues? We agree that there is a clear contribution of certain downstream elements in the insulin signaling pathway for β-cell function and survival, but the question of whether insulin itself is actually the physiologically relevant ligand that triggers this signal transduction remains unsettled

Genetic Inactivation of Pyruvate Dehydrogenase Kinases Improves Hepatic Insulin Resistance Induced Diabetes

Pyruvate dehydrogenase kinases (PDK1-4) play a critical role in the inhibition of the mitochondrial pyruvate dehydrogenase complex especially when blood glucose levels are low and pyruvate can be conserved for gluconeogenesis. Under diabetic conditions, the Pdk genes, particularly Pdk4, are often induced, and the elevation of the Pdk4 gene expression has been implicated in the increased gluconeogenesis in the liver and the decreased glucose utilization in the peripheral tissues. However, there is no direct evidence yet to show to what extent that the dysregulation of hepatic Pdk genes attributes to hyperglycemia and insulin resistance in vivo. To address this question, we crossed Pdk2 or Pdk4 null mice with a diabetic model that is deficient in hepatic insulin receptor substrates 1 and 2 (Irs1/2). Metabolic analyses reveal that deletion of the Pdk4 gene had better improvement in hyperglycemia and glucose tolerance than knockout of the Pdk2 gene whereas the Pdk2 gene deletion showed better insulin tolerance as compared to the Pdk4 gene inactivation on the Irs1/2 knockout genetic background. To examine the specific hepatic effects of Pdks on diabetes, we also knocked down the Pdk2 or Pdk4 gene using specific shRNAs. The data also indicate that the Pdk4 gene knockdown led to better glucose tolerance than the Pdk2 gene knockdown. In conclusion, our data suggest that hepatic Pdk4 may be critically involved in the pathogenesis of diabetes

Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β?

<p>Abstract</p> <p>Background</p> <p>Male <it>Irs2</it>^-/-mice develop fatal type 2 diabetes at 13-14 weeks. Defects in neuronal proliferation, pituitary development and photoreceptor cell survival manifest in <it>Irs2</it>^-/-mice. We identify retarded renal growth in male and female <it>Irs2</it>^-/-mice, independent of diabetes.</p> <p>Results</p> <p>Kidney size and kidney:body weight ratio were reduced by approximately 20% in <it>Irs2</it>^-/-mice at postnatal day 5 and was maintained in maturity. Reduced glomerular number but similar glomerular density was detected in <it>Irs2</it>^-/-kidney compared to wild-type, suggesting intact global kidney structure. Analysis of insulin signalling revealed renal-specific upregulation of PKBβ/Akt2, hyperphosphorylation of GSK3β and concomitant accumulation of β-catenin in <it>Irs2</it>^-/-kidney. Despite this, no significant upregulation of β-catenin targets was detected. Kidney-specific increases in Yes-associated protein (YAP), a key driver of organ size were also detected in the absence of <it>Irs2</it>. YAP phosphorylation on its inhibitory site Ser127 was also increased, with no change in the levels of YAP-regulated genes, suggesting that overall YAP activity was not increased in <it>Irs2</it>^-/-kidney.</p> <p>Conclusions</p> <p>In summary, deletion of <it>Irs2 </it>causes reduced kidney size early in mouse development. Compensatory mechanisms such as increased β-catenin and YAP levels failed to overcome this developmental defect. These data point to <it>Irs2 </it>as an important novel mediator of kidney size.</p

Changes in brain network activity during working memory tasks: a magnetoencephalography study.

In this study, we elucidate the changes in neural oscillatory processes that are induced by simple working memory tasks. A group of eight subjects took part in modified versions of the N-back and Sternberg working memory paradigms. Magnetoencephalography (MEG) data were recorded, and subsequently processed using beamformer based source imaging methodology. Our study shows statistically significant increases in θ oscillations during both N-back and Sternberg tasks. These oscillations were shown to originate in the medial frontal cortex, and further to scale with memory load. We have also shown that increases in θ oscillations are accompanied by decreases in β and γ band oscillations at the same spatial coordinate. These decreases were most prominent in the 20–40 Hz frequency range, although spectral analysis showed that γ band power decrease extends up to at least 80 Hz. β/γ Power decrease also scales with memory load. Whilst θ increases were predominately observed in the medial frontal cortex, β/γ decreases were associated with other brain areas, including nodes of the default mode network (for the N-back task) and areas associated with language processing (for the Sternberg task). These observations are in agreement with intracranial EEG and fMRI studies. Finally, we have shown an intimate relationship between changes in β/γ band oscillatory power at spatially separate network nodes, implying that activity in these nodes is not reflective of uni-modal task driven changes in spatially separate brain regions, but rather represents correlated network activity. The utility of MEG as a non-invasive means to measure neural oscillatory modulation has been demonstrated and future studies employing this technology have the potential to gain a better understanding of neural oscillatory processes, their relationship to functional and effective connectivity, and their correspondence to BOLD fMRI

Nerve growth factor receptor TrkA, a new receptor in insulin signaling pathway in PC12 cells

Background: TrkA is a transmembrane receptor tyrosine kinase for nerve growth factor. Results: TrkA forms a molecular complex with insulin receptor and IRS-1 to induce Akt and Erk5 phosphorylation. Conclusion: The NGF-TrkA receptor influences insulin signaling. Significance: The TrkA receptor is involved in insulin signaling, and NGF may regulate neuronal glucose uptake as neurons are insulin-insensitive. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc