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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