Insulin and insulin-like growth factor I (IGF-I) are ubiquitous hormones that regulate growth and metabolism of most mammalian cells, including pancreatic ␤-cells. In addition to being an insulin secretagogue, glucose regulates proliferation and survival of ␤-cells. However, it is unclear whether the latter effects of glucose occur secondary to autocrine activation of insulin signaling proteins by secreted insulin. To examine this possibility we studied the effects of exogenous glucose or insulin in ␤-cell lines completely lacking either insulin receptors (␤IRKO) or insulin receptor substrate 2 (␤IRS2KO). Exogenous addition of either insulin or glucose activated proteins in the insulin signaling pathway in control ␤-cell lines with the effects of insulin peaking earlier than glucose. Insulin stimulation of ␤IRKO and ␤IRS2KO cells led to blunted activation of phosphatidylinositol 3-kinase and Akt kinase, while surprisingly, glucose failed to activate either kinase but phosphorylated extracellular signal-regulated kinase. Control ␤-cells exhibited low expression of IGF-1 receptors compared to compensatory upregulation in ␤IRKO cells. The signaling data support the slow growth and reduced DNA and protein synthesis in ␤IRKO and ␤IRS2KO cells in response to glucose stimulation. Together, these studies provide compelling evidence that the growth and survival effects of glucose on ␤-cells require activation of proteins in the insulin signaling pathway.Pancreatic islet ␤-cell regeneration and function are regulated by multiple stimuli, including nutrients, hormones, and growth factors acting via diverse intracellular signaling pathways (4, 43). Glucose is the primary regulator of insulin secretion and insulin biosynthesis, and its effects on growth and survival have been suggested to occur by activation of insulin receptor substrate 2 (IRS-2), a protein in the insulin/insulinlike growth-factor I (IGF-I) signaling pathway (40,45). Indeed, over the last decade most components in the insulin signaling pathway have been identified in murine and human pancreatic ␤-cells (1, 4, 17, 36), and their cross talk with other signaling pathways in ␤-cells is being systematically unraveled using genetic approaches in mice (reviewed in references 4 and 31). For example, insulin signaling has been reported to regulate many effects in ␤-cells that are also promoted by glucose, such as enhancing insulin gene expression, insulin secretion, proinsulin biosynthesis, and cell cycle progression (25,(28)(29)(30)38). Considering the similar effects of insulin and glucose in ␤-cells that occur by activation of largely similar proteins in the insulin/IGF-I signaling pathway, it is unclear whether the effects of glucose require activation of insulin receptors via secreted insulin.Examination of the independent effects of glucose versus insulin on ␤-cell function in vivo is limited by a lack of suitable mouse models. Further, the difficulty in separating the downstream effects of exogenous glucose from those of exogenous insulin in cultured ␤-cells ...

BACKGROUND Previous studies have demonstrated that angiotensin II (Ang II) acts as a growth-promoting factor directly on cardiac myocytes and that angiotensin-converting enzyme inhibitor induces regression of hypertrophied hearts both in experimental animals and in humans. These results suggest that the renin-angiotensin system (RAS) is involved in the formation of left ventricular hypertrophy (LVH). To elucidate the role of RAS in the progression of cardiac hypertrophy, we evaluated the effect of an Ang II receptor antagonist on LVH in spontaneously hypertensive rats (SHRs) and investigated the molecular mechanisms by which antagonizing Ang II receptors reduces cell hypertrophy of myocytes using the in vitro model of mechanical stretch. METHODS AND RESULTS In the in vivo study, we treated SHRs with the nonpeptide Ang II receptor antagonist TCV-116 (0.1, 1, or 10 mg/kg per day) or hydralazine (10 mg/kg per day). Blood pressure was measured by the tail-cuff method, and wall thickness of left ventricle was serially monitored using M-mode echocardiography. Rats were killed at the age of 13, 17, 21, or 25 weeks, and left ventricular (LV) weight, transverse diameter of cardiomyocytes, relative amount of V3 myosin heavy chain (MHC), and degree of interstitial collagen accumulation were examined. Untreated SHRs progressively developed severe hypertension, but treatment with TCV-116 or hydralazine inhibited the increase in blood pressure. Treatment with TCV-116 reduced LV weight, LV wall thickness, transverse diameter of myocytes, relative amount of V3 MHC, and interstitial fibrosis, whereas treatment with hydralazine slightly prevented an increase in LV wall thickness but did not exert significant reduction in other parameters. In the in vitro study, neonatal rat cardiomyocytes were cultured on deformable silicone dishes and mechanically stretched with or without pretreatment of CV-11974 (an active metabolite of TCV-116), and [3H]phenylalanine incorporation, activity of mitogen-activated protein (MAP) kinase, and c-fos mRNA expression were analyzed. Pretreatment of cultured cardiomyocytes with 10(-7) mol/L CV-11974 inhibited an increase in [3H]phenylalanine incorporation, MAP kinase activity, and c-fos gene expression induced by stretch of cardiomyocytes. CONCLUSIONS The Ang II receptor antagonist TCV-116 induced regression of cardiac hypertrophy and had cardioprotective effects on hypertrophied myocardium in vivo, and antagonizing Ang II receptors inhibited intracellular signaling of stretch-mediated cardiomyocyte hypertrophy in vitro. These results suggest a crucial role of the cardiac RAS in the development of LVH produced by pressure overload.

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From the analysis of the ratio of D peak intensity to G peak intensity in Raman spectroscopy, electron beam irradiation with energies of 100 eV was found to induce damage in single-layer graphene. The damage becomes larger with decreasing electron beam energy. Internal strain in graphene induced by damage under irradiation is further evaluated based on G peak shifts. The dosedependent internal strain was approximately 2.22% cm 2 /mC at 100 eV and 2.65 Â 10 À2 % cm 2 /mC at 500 eV. The strain induced by the irradiation showed strong dependence on electron energy. V C 2013 American Institute of Physics. [http://dx.

Expression of insulin receptor substrates (IRS)-1 and -2 within the mammary gland was found to be high at midlactation and dramatically decreased with mammary involution. This observation supports the hypothesis that these proteins are induced in the mammary gland with lactogenesis and involved in normal milk synthesis. To test this hypothesis, lactation capacity, along with indices of mammary secretory cell glucose metabolism and cell signaling were compared in normal mice and mice carrying targeted mutations in either the Irs1 or Irs2 genes. Mammary IRS-1 and IRS-2 protein levels were increased within 1 day of parturition and reached maximal levels by 5 days post partum. Dams carrying germline mutations of Irs1 or Irs2 displayed reduced lactation capacity as assessed by weight gain of pup litters. The reduction was more dramatic in Irs1 K/K versus Irs2 K/K dams. Maternal body weight was also reduced in Irs1 K/K dams as well as in Irs1 Irs2C/K dams. The loss of IRS-1 had little impact on mammary gland expression of milk protein mRNAs, glucose transport, or on the abundance and subcellular localization of hexokinases I and II. The loss of IRS-1 was associated with a compensatory increase in insulin-induced IRS-2 phosphorylation; however, the loss of IRS-1 did also cause a reduction in insulin-dependent mammary gland-specific activation of Akt phosphorylation. These results support the conclusion that IRS-1 is important for insulin-dependent activation of Akt signaling within the lactating mammary gland, but that loss of this protein has only modest impact on normal milk synthesis, since related signaling proteins such as IRS-2 may act in compensatory fashion.

This paper reports the fabrication and operation of a transmission-type polarization rotator for visible light with a wavelength of 450 nm using indirect-transition-type semiconductor crystalline SiC in which Al atoms were implanted as a p-type dopant. A novel dressed-photon-phonon (DPP)-assisted annealing method was used for fabrication. The fabricated device exhibited a gigantic magnetooptical effect induced by interactions between photons, electrons, phonons, and magnetic fields in a nanometric space, mediated by dressed photons. The optical path length for polarization rotation was as short as the thickness of the p-n junction. It operated with a weak magnetic field on the order of mT, generated by injecting current to a ring-shaped electrode on the device surface. The Verdet constant was as large as 9.51 × 10 4 rad/T.m at a wavelength of 450 nm. SQUID measurements confirmed that the SiC crystal exhibited conspicuous ferromagnetic characteristics as a result of the DPP-assisted annealing. In this device, the dressed photons boosted the magnitude of the magnetooptical effect and stabilized the device operation of the polarization rotator.