TInvestigations in my laboratory have primarily been involved in examining three often related pathologies: obesity/hypertension/diabetes, with a special focus on the role played by glucose uptake and the glucose transporter. Previous studies by others have determined that there are several isoforms of the glucose transporters (GLUTÕs 1-5). The GLUT 4 glucose transporter plays the predominant role in glucose uptake into fat and muscle. This is an insulin-regulated transporter, and factors and pathologies that affect various aspects of insulin regulation can have a significant role on glucose homeostasis in theses tissues.
Basic science studies on the glucose transporter from my laboratory have included the determinations of molecular size of GLUT 4 glucose transporters, and the molecular mechanism regulation of their translocation from an intracellular storage pool to the plasma membrane (1); the effect of various agents on GLUT 4 translocation from an inner storage pool to the cell surface (2-4); the role played by insulin-mediated signal transduction and tyrosine kinase activity on the potentiation of glucose transport the translocation of GLUT4 glucose transporters (5,6); and the posttranscriptional regulation of the GLUT1 transporterÕs gene expression (7).
Clinical investigations from my laboratory have included studying several aspects of obesity, hypertension and diabetes. Previous investigations by others have examined the interrelationship between these three pathologies. At least one common link is an alteration in glucose uptake, which is usually associated with a state of insulin-resistance. Insulin-resistance has been classically described as in state in which there is a decreased biological effect for a given amount of insulin. Since obesity can produce an insulin resistance, it can be categorized as a pathology. It is this insulin-resistance which may be at least one of the causes for the association between obesity/hypertension/diabetes.
Regarding these three pathologies, my laboratory performed studies on: the effect of diabetes on glucose transport and the translocation of GLUT4 glucose transporters (8); the effect of weight-loss in obese individuals on blood flow and hypertension (9); the role on Ang II and itsÕ effect on the sodium pump in hypertension (10); and the role of the renin-angiotensin system and oxidatative damage in the pathogenesis of hypertension and associated cardio vascular disease (11). Overall, these animal and clinical investigations demonstrated that glucose transport and the associated glucose transporter, plays a very significant role in the maintenance of cell homeostasis, and its dysregulation is most often associated with pathology. It is apparent that at least one of the interconnections between the three obesity, hypertension and diabetes, is the manifestation of an insulin-resistance which has an effect on insulin-potentiated glucose transport.
GLUT1 glucose transporter mRNA contains several stability determinants in its 3'-UTR. These include the AU-rich element (ARE) containing an UAUUUAUA motif which has been identified as necessary and sufficient destabilizing sequence, and the AACCACTC motif which has been shown to augment GLUT1 gene expression.
The above figure is a Map of GLUT1 mRNA. The coding region is represented by orange arrow. The ARE (UAUUUAUA) is nucleotides 2408-2415 within the 3'-UTR. The AACCACTC motif is nucleotides 2183-2203 within the 3'-UTR.
Recent studies focusing on the posttranscriptional regulation of gene expression by these cis-elements in the 3'-UTR of mRNA strand indicated that GLUT1 gene expression may be regulated at the posttranscriptional level through the interaction between these stability elements and RNA-binding proteins (RBPs) (7). The rapid stable complex formation between RBP and these stability determinants serves to protect mRNA from turnover and leads to increased mRNA stability, and may result in increased steady-state mRNA levels.
The figure below, diagrammatically illustrates the role of the posttranscriptional regulation of the GLUT1 glucose transporter mRNA in the regulation of its stability. In this regard, GLUT1 mRNA has an AUUUA motif in its 3ÕUTR which acts as a destabilizing region unless protected by a cytosolic RBP, illustrated below.
Jacobs DB, Berinski C, Spangler RA, and Jung CY: Radiation inactivation target size of rat adipocyte glucose transporters in the plasma membrane and intracellular pools. J Bio Chem 262:8084-87, 1987.
Jacobs DB, Mookerjee BK and Jung CY: Furosemide inhibits glucose transport in isolated rat adipocytes via direct inactivation of carrier proteins. J Clin Invest 74:1679-1685, 1985.
Jacobs DB and Jung CY: Sulfonylurea potentiate insulin-induced recruitment of glucose transport carrier in rat adipocytes. J Bio Chem 260:2593-2596, 1985.
Jacobs DB: Fat Cells: Model system to investigate molecular mechanism(s) of sulfonylurea-potentiated glucose transport. Amer J Med 79:59-66, 1985.
Jacobs DB, Hayes GR, Truglia JA and Lockwood DH: Effect of metformin on insulin receptor tyrosine kinase activity in rat adipocytes. Diabetologia 29:798-801, 1986.
Jacobs DB, Hayes GR and Lockwood DH: Chlorpropamide potentiates insulin action in rat adipocytes in the absence of changes in insulin binding and associated receptor tyrosine kinase activity. Metab Clin Exp 36:548-54, 1987.
Jacobs DB, Arthur M. Mandelin II, Giordano T, Xue I, Malter J S, Snyder AK, and Singh SP: Auuua-specific mRNA binding proteins in astrocytes. Life Science, 58:2083-2089 1996.Jacobs DB, JR Sowers, A Hmeidan, T Niyogi, L Simpson, and PR Standley.
Jacobs DB and Lockwood DH: Effect of a sulfonylurea on glucose transport and translocation of glucose transporters in an animal model of diabetes. Diabetes 38:205-211, 1989.
Effects of weight reduction on cellular cation metabolism and vascular resistance. Hypertension 21:308-314, 1993.
Esma R. Isenovic, David B Jacobs Mamdouh H. Kedees, Yong Meng M., Quan Sha M., Nikola Milivojevic, Kiyoshi Kawakami, Gregory Gick, and James R. Sowers: Ang II Regulation of the Na+ Pump Involves the PI3K and p42/44 MAPK Signaling Pathways in VSMC; In Press, Endocrinology.
Jacobs DB, Blendea MC, Sha, Q, Mc Farlane S, Ogrin C, Bahtyiar G, Stas S, Kumar, P, S, and Sowers J. Abrogation of Oxidative stress improves insulin sensitivity in the Ren2 rat model of tissue AngII overexpression submitted.