Abstract
Insulin controls glucose uptake by translocating GLUT4 and other glucose transporters to the plasma membrane in muscle and adipose tissues by a mechanism that appears to require protein kinase C (PKC)-zeta/lambda operating downstream of phosphatidylinositol 3-kinase. In diabetes mellitus, insulin-stimulated glucose uptake is diminished, but with hyperglycemia, uptake is maintained but by uncertain mechanisms. Presently, we found that glucose acutely activated PKC-zeta/lambda in rat adipocytes and rat skeletal muscle preparations by a mechanism that was independent of phosphatidylinositol 3-kinase but, interestingly, dependent on the apparently sequential activation of the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; components of the extracellular signal-regulated kinase (ERK) pathway, including, GRB2, SOS, RAS, RAF, MEK1 and ERK1/2; and, most interestingly, phospholipase D, thus yielding increases in phosphatidic acid, a known activator of PKC-zeta/lambda. This activation of PKC-zeta/lambda, moreover, appeared to be required for glucose-induced increases in GLUT4 translocation and glucose transport in adipocytes and muscle cells. Our findings suggest the operation of a novel pathway for activating PKC-zeta/lambda and glucose transport.
Highlights
Insulin controls glucose uptake by translocating GLUT4 and other glucose transporters to the plasma membrane in muscle and adipose tissues by a mechanism that appears to require protein kinase C (PKC)-/ operating downstream of phosphatidylinositol 3-kinase
Our findings suggest that glucose does increase GLUT4 translocation/glucose transport in these tissues, apparently by activating PKC-/ through a mechanism that is independent of PI 3-kinase but, interestingly, dependent upon both (a) the PYK2/GRB2/SOS/RAS/RAF/MEK1/extracellular signal-regulated kinase (ERK) pathway, which we have recently reported to be activated by glucose [16], and (b) phospholipase D (PLD), which generates phosphatidic acid (PA), a known direct activator of atypical PKCs [17, 18]
It was interesting to find that glucose rapidly activated PKC-/ in rat adipocytes and apparently in skeletal muscles by a novel mechanism requiring PYK2, GRB2, SOS, RAS, MEK1, ERK1/2, and PLD
Summary
We found that glucose acutely activated PKC-/ in rat adipocytes and rat skeletal muscle preparations by a mechanism that was independent of phosphatidylinositol 3-kinase but, interestingly, dependent on the apparently sequential activation of the dantrolene-sensitive, nonreceptor proline-rich tyrosine kinase-2; components of the extracellular signal-regulated kinase (ERK) pathway, including, GRB2, SOS, RAS, RAF, MEK1 and ERK1/2; and, most interestingly, phospholipase D, yielding increases in phosphatidic acid, a known activator of PKC-/. This activation of PKC-/, appeared to be required for glucose-induced increases in GLUT4 translocation and glucose transport in adipocytes and muscle cells. This novel mechanism for activating PKC-/ and stimulating GLUT4 translocation sharply contrasts with that of insulin, which utilizes PI 3-kinase and PDK-1, rather than PYK2/ERK/ PLD, to activate PKC-/ and stimulate GLUT4 translocation/ glucose transport
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have