Inhibition of PTP1B Restores IRS1-Mediated Hepatic Insulin Signaling in IRS2-Deficient Mice

[Objective]: Mice with complete deletion of insulin receptor substrate 2 (IRS2) develop hyperglycaemia, impaired hepatic insulin signaling and elevated gluconeogenesis, whereas mice deficient for protein tyrosine phosphatase (PTP) 1B display an opposing hepatic phenotype characterized by increased sensitivity to insulin. To define the relationship between these two signaling pathways in the regulation of liver metabolism, we used genetic and pharmacological approaches to study the effects of inhibiting PTP1B on hepatic insulin signaling and expression of gluconeogenic enzymes in IRS2−/− deficient mice. [Research design and methods]: We analyzed glucose homeostasis and insulin signaling in liver and isolated hepatocytes from IRS2−/− and IRS2−/−/PTP1B−/−. Additionally, hepatic insulin signaling was assessed in control and IRS2−/− mice treated with resveratrol, an anti-oxidant present in red wine. [Results]: In livers of hyperglycaemic IRS2−/− mice, the expression levels of PTP1B and its association with the insulin receptor (IR) were increased. The absence of PTP1B in the double mutant mice restored hepatic IRS1-mediated phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 signaling. Moreover, resveratrol treatment of hyperglycaemic IRS2−/− mice decreased hepatic PTP1B mRNA and inhibited PTP1B activity, thereby restoring IRS1-mediated PI 3-kinase/Akt/Foxo1 signaling and peripheral insulin sensitivity. [Conclusions]: By regulating the phosphorylation state of IR, PTB1B determines sensitivity to insulin in liver and exerts a unique role in the interplay between IRS1 and IRS2 in the modulation of hepatic insulin action.This work was supported by Ministerio de Ciencia e Innovación Grants (Spain) BFU2008-02420, SAF2009- 08114 (to A.M.V.), BFU2008-04901-C03-03 (to M.R.), BFU2005-00084, and SAF2008-00011 (to D.J.B.) and the Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) (Instituto Salud Carlos III). A.G.-R. holds a postdoctoral contract from CIBERDEM.Peer reviewe

The LSST camera corner raft conceptual design: a front-end for guiding and wavefront sensing

The Large Synoptic Survey Telescope (LSST) is a proposed ground based telescope that will perform a comprehensive astronomical survey by imaging the entire visible sky in a continuous series of short exposures. Four special purpose rafts, mounted at the corners of the LSST science camera, contain wavefront sensors and guide sensors. Wavefront measurements are accomplished using curvature sensing, in which the spatial intensity distribution of stars is measured at equal distances on either side of focus by CCD detectors. The four Corner Rafts also each hold two guide sensors. The guide sensors monitor the locations of bright stars to provide feedback that controls and maintains the tracking of the telescope during an exposure. The baseline sensor for the guider is a Hybrid Visible Silicon hybrid-CMOS detector. We present here a conceptual mechanical and electrical design for the LSST Corner Rafts that meets the requirements imposed by the camera structure, and the precision of both the wavefront reconstruction and the tracking. We find that a single design can accommodate two guide sensors and one split-plane wavefront sensor integrated into the four corner locations in the camera

PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice

The role of protein-tyrosine phosphatase 1B (PTP1B) in diabetes was investigated using an antisense oligonucleotide in ob/ob and db/db mice. PTP1B antisense oligonucleotide treatment normalized plasma glucose levels, postprandial glucose excursion, and HbA(1C). Hyperinsulinemia was also reduced with improved insulin sensitivity. PTP1B protein and mRNA were reduced in liver and fat with no effect in skeletal muscle. Insulin signaling proteins, insulin receptor substrate 2 and phosphatidylinositol 3 (PI3)-kinase regulatory subunit p50α, were increased and PI3-kinase p85α expression was decreased in liver and fat. These changes in protein expression correlated with increased insulin-stimulated protein kinase B phosphorylation. The expression of liver gluconeogenic enzymes, phosphoenolpyruvate carboxykinase, and fructose-1,6-bisphosphatase was also down-regulated. These findings suggest that PTP1B modulates insulin signaling in liver and fat, and that therapeutic modalities targeting PTP1B inhibition may have clinical benefit in type 2 diabetes