Signaling pathways mediating insulin-stimulated glucose transport.
A major action of insulin is to accelerate the rate of uptake of sugar into muscle and adipose cells following a meal. The biochemical mechanism by which this is accomplished has been a subject of intense experimentation, although elucidation of the pathways has remained elusive. In recent years, numerous signaling molecules and cascades modulated by insulin have been identified, although few have been definitively established as important to the metabolic actions of the hormone. An exception to this is the lipid kinase phosphatidylinositide 3'-kinase, which, under many conditions, appears absolutely required for insulin to stimulate hexose uptake into adipocytes. Akt/PKB, a serine/threonine protein kinase activated by insulin in a phosphatidylinositide 3'-kinase-dependent manner, has been implicated as a critical mediator of insulin's actions on metabolism and cell survival. Nonetheless, Akt/PKB's role in many insulin effects, particularly accelerated glucose transport, remains controversial. Interestingly, soluble analogues of ceramide antagonize both insulin's activation of Akt/PKB as well as its stimulation of glucose transport, consistent with a causal relationship between the two.
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Howard Hughes Medical Institute, Cox Institute, University of Pennsylvania Medical School, Philadelphia, Pennsylvania 19104, USA. birnbaum@hhmi.upenn.edu
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D000818:Animals; D001693:Biological Transport, Active; D002518:Ceramides / Q000009:adverse effects*; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D015398:Signal Transduction; D013379:Substrate Specificity
D002518:Ceramides; D005947:Glucose; D051275:Glucose Transporter Type 4; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C495692:SLC2A4 protein, human; C494918:AKT1 protein, human