Insulin resistance is an important risk factor in the
development of cardiovascular diseases such as hypertension and
atherosclerosis. However, despite its importance, the specific role
of insulin resistance in the etiology of these diseases is poorly understood.
At the same time, ethanol (ETOH) is a potent vasoconstrictor that primarily
induces downregulation of mitogen activated protein kinases (MAPKs) which could
exacerbate insulin resistance and possibly lead to cardiovascular diseases. This
article describes how chronic ETOH exposure interferes with insulin signaling
in hypertensive vascular smooth muscle cells (HVSMCs) which leads to the
alteration of MAPKs, the major signaling molecules. Elevated (50-800 mM)
chronic exposure (24 hr) of HVSMCS to ETOH prior to insulin stimulation
decreased insulin-induced ERK 1/2 (MAPKs) and AKT expression. Similar
experiments were conducted using normotensive cells from rat. These cells
showed reductions in insulin-induced ERK 1/2 phosphorylation as well, but only
at higher concentrations of ETOH (400-800 mM). These alterations in insulin signaling
could provide an alternative molecular mechanism that may increase the risk of
insulin resistance, thus increasing the possibility of cardiovascular diseases.
P. De Meyts, “The Structural Basis of Insulin and Insulin-Like Growth Factor-I Receptor Binding and Negative Cooperativity, and Its Relevance to Mitogenic versus Metabolic Signaling,” Diabetologia, Vol. 37, Suppl. 2, 1994, pp. S135-S148. http://dx.doi.org/10.1007/BF00400837
E. Conti, F. Andreotti, A. Sciahbasi, P. Riccardi, G. Marra, E. Menini, et al., “Markedly Reduced Insulin-Like Growth Factor-1 in the Acute Phase of Myocardial Infarction,” Journal of the American College of Cardiology, Vol. 38, No. 1, 2001, pp. 26-32. http://dx.doi.org/10.1016/S0735-1097(01)01367-5
A. Juul, T. Scheike, M. Davidsen, J. Gyllenborg and T. Jorgenson, “Low Serum Insulin-Like Growth Factor 1 Is Associated with Increased Risk of Ischemic Heart Disease: A Population-Based Case Control Study,” Circulation, Vol. 106, No. 8, 2002, pp. 939-944. http://dx.doi.org/10.1161/01.CIR.0000027563.44593.CC
L. Macho, S. Zorad, Z. Radikova, P. Patterson-Buckedahl and R. Kvetnansky, “Ethanol Consumption Affects Stress Response and Insulin Binding Tissue of Rats Endocrine Regulations,” Endocrine Regulation, Vol. 37, No. 4, 2003, pp. 195-202.
A. Natali, S. Vichi, P. Landi, S. Severi, A. L’Abbate and E. Ferrannini, “Coronary Atherosclerosis in Type II Diabetes: Angiographic Findings and Clinical Outcome,” Diabetologia, Vol. 43, No. 5, 2000, pp. 632-641. http://dx.doi.org/10.1007/s001250051352
J. E. P. Brown, D. Onyango, and S. J. Dunmore, “Resistin Down-Regulates Insulin Receptor Expression, and Modulates Cell Viability in Rodent Pancreatic Beta-Cells,” FEBS Letters, Vol. 581, No. 17, 2007, pp. 3273-3276. http://dx.doi.org/10.1016/j.febslet.2007.06.031
L. He, J. C. Marecki, G. Serrero, F. A. Simmen, M. Ronis and T. Badger, “Dose-Dependent Effects of Alcohol on Insulin Signaling: Partial Explanation for Biphasic Alcohol Impact on Human Health,” Molecular Endocrinology, Vol. 21, No. 21, 2007, pp. 2541-2550. http://dx.doi.org/10.1210/me.2007-0036
T. Limin, X. Hou, J. Liu, X. Zhang, N. Sun, L. Gao, et al., “Chronic Ethanol Consumption Resulting in the Downregulation of Insulin Receptor-Subunit, Insulin Receptor Substrate-1, and Glucose Transporter 4 Expression in Rat Cardiac Muscles,” Alcohol, Vol. 43, 2009, pp. 51-58. http://dx.doi.org/10.1016/j.alcohol.2008.11.001
B. Washington, C. Mtshali, S. Williams, H. Smith, J. D. Li, B. Shaw, et al., “Ethanol-Induced Mitogen Activated Protein Kinase Activity Mediated through Protein Kinase C,” Cell and Molecular Biology, Vol. 49, No. 8, 2003, pp. 1351-1356.
A. L. Johnson, G. D. Goode, C. Mtshali, E. L. Myles and B. Washington, “Protein Kinase C-Alpha/BetaII, Delta, and Zeta/Lambda Involvement in Ethanol-Induced MAPK Expression in Vascular Smooth Muscle Cells,” Cell and Molecular Biology, Vol. 53, No. 4, 2007, pp. 38-44.
H. Wang, S. Doronin and C. C. Malbon, “Insulin Activation of Mitogen-Activated Protein Kinases Erk1,2 Is Amplified via Beta-Adrenergic Receptor Expression and Requires the Integrity of the Tyr350 of the Receptor,” The Journal of Biological Chemistry, Vol. 275, No. 46, 2000, pp. 36086-26093. http://dx.doi.org/10.1074/jbc.M004404200
S. Vasdev, V. Gill and P. Singal, “Beneficial Effect of Low Ethanol Intake on the Cardiovascular System: Possible Biochemical Mechanisms,” Journal of Vascular Health and Risk Management, Vol. 2, No. 3, 2006, pp. 263-276. http://dx.doi.org/10.2147/vhrm.2006.2.3.263
B. Taylor, J. Rehm and G. Gmel, “Moderate Alcohol Consumption and the Gastrointestinal Tract,” Digital Distribution, Vol. 23, No. 3-4, 2005, pp. 170-176.
A. E. Seiler, B. N. Ross and R. Rubin, “Inhibition of Insulin-Like Growth Factor-1 Receptor and IRS Signaling by Ethanol in SH-SY5Y Neuroblastoma Cells,” Journal of Neurochemistry, Vol. 76, No. 2, 2001, pp. 573-581. http://dx.doi.org/10.1046/j.1471-4159.2001.00025.x
D. T. Furuya, R. Binsack and U. F. Machado, “Low Ethanol Consumption Increases Insulin Sensitivity in Wistar Rats,” Brazilian Journal of Medical and Biological Research, Vol. 36, No. 1, 2003, pp. 125-130. http://dx.doi.org/10.1590/S0100-879X2003000100017
L. Hansen, Y. Ikeda, G. Olsen, A. Busch and L. Mosthaf, “Insulin Signaling Is Inhibited by Micromolar Concentrations of H2O2,” The Journal of Biological Chemistry, Vol. 274, No. 35, 1999, pp. 25078-25084. http://dx.doi.org/10.1074/jbc.274.35.25078
E. Motley, K. Eguchi, C. Gardner, A. Hicks, C. Reynolds, G. Frank, et al., “Insulin-Induced Akt Activation Is Inhibited by Angiotensin II in the Vasculature through Protein Kinase C,” Hypertension, Vol. 41, No. 3, 2002, pp. 775-780. http://dx.doi.org/10.1161/01.HYP.0000051891.90321.12
Y. Sasaki, N. Hayashi, T. Ito, H. Fusamoto, T. Kamada and J. R. Wands, “Influence of Ethanol on Insulin Receptor Substrate-1-Mediated Signal Transduction during Rat Liver Regeneration,” Alcoholism Supplements, Vol. 29, No. 1, 1994, pp. 99-106.
