Ceramide and glucosamine antagonism of alternate signaling pathways regulating insulin- and osmotic shock-induced glucose transporter 4 translocation.
In addition to insulin, hyperosmolarity induces glucose transporter 4 (GLUT4) translocation in 3T3-L1 adipocytes. However, in contrast to insulin this stimulation is independent of PI3K/Akt. In this study we assessed whether ceramide and/or glucosamine, two known insulin-signaling antagonists, also affected the PI3K/Akt-independent signal. Insulin, but not hyperosmolarity, clearly increased the activities of PI3K and Akt. C2-ceramide did not alter insulin-stimulated PI3K activity, but did decrease the ability of insulin to activate Akt and GLUT4 translocation. Consistent with osmotic shock-mediated GLUT4 translocation being independent of PI3K/Akt, GLUT4 translocation induced by hyperosmolarity was not altered by C2-ceramide. In contrast to the specific C2-ceramide-induced attenuation of insulin-stimulated GLUT4 translocation, overexpression of glutamine:fructose-6-phosphate amidotransferase, the rate-limiting enzyme in the synthesis of UDP-N-acetylglucosamine, and/or pretreatment of cells with glucosamine, a precursor of UDP-N-acetylglucosamine, inhibited both insulin- and hyperosmolarity-stimulated GLUT4 translocation. Glucosamine did not alter any of the known proximal insulin signal transduction events. These data suggest that although the hyperosmolarity-induced signal bypasses the initial insulin signal transduction steps, it is likely to induce GLUT4 translocation through activation of a common convergent signal transduction step, targeted by UDP-N-acetylglucosamine, downstream of and/or in parallel to PI3K/Akt.
Kralik
Steve F
SF
Department of Cellular and Integrative Physiology, Indiana University School of Medicine, Center for Diabetes Research, Indianapolis, IN 46202, USA.
Liu
Ping
P
Leffler
Brian J
BJ
Elmendorf
Jeffrey S
JS
D016475:3T3 Cells; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005944:Glucosamine / Q000494:pharmacology*; D051275:Glucose Transporter Type 4; D006595:Hexosamines / Q000096:biosynthesis; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism*; D009124:Muscle Proteins; D009997:Osmotic Pressure; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014764:Viral Proteins / Q000378:metabolism
D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D006595:Hexosamines; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C064769:N-acetylsphingosine; D011518:Proto-Oncogene Proteins; C495693:Slc2a4 protein, mouse; C072216:TRS1 protein, Human herpesvirus 5; D014764:Viral Proteins; D050721:Proto-Oncogene Proteins c-cbl; D011972:Receptor, Insulin; C119570:CBLC protein, human; D005944:Glucosamine; D013110:Sphingosine