It is well recognized that the binding of insulin to its cell membrane receptor and the resulting activation of receptor tyrosine kinase are a prerequisite for the action of insulin on cells. It is completely unknown, however, how phosphorylation of the insulin receptor effects the translocation of glucose transporters into the cell membrane or the activation or inhibition of insulin-sensitive enzymes in the cytoplasm, mitochondria, and nucleus of the cell. To bridge this gap, numerous substances with a potential second messenger role have been investigated, but none of them has completely fulfilled all the conditions for being the insulin mediator. This lack of understanding of the mechanism of action of insulin in cells under normal conditions is the underlying cause of the lack of understanding of the biochemical basis of postreceptor insulin resistance, which is observed in several disease states as well as during recovery from a severe trauma or injury. The proposed project is intended to study a potential biochemical mechanism producing postreceptor insulin resistance and through this work contribute not only to understanding the biochemical basis of postreceptor insulin resistance but also the cellular mechanism of action of insulin in general. The proposed project is an extension of our recent finding that insulin resistance in skeletal muscle and liver is associated with elevated tissue concentrations of 1,2-diacylglycerol and ceramide. The project is intended to test the hypothesis that a long- term elevation of tissue 1,2-diacylglycerol and ceramide produces insulin resistance in the tissue. Studies will be performed in both insulin- sensitive and insulin-resistant tissues in vivo and in vitro to determine the activity of protein kinase C and the state of phosphorylation or dephosphorylation of specific phosphoproteins which may participate in insulin signalling in cells. The investigation will also evaluate the role of protein phosphatases-1 and -2A, which may reverse the actions of protein kinase C, and determine whether ceramide and its degradation product, sphingosine, can produce insulin resistance at concentrations actually measured in insulin resistant tissues in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM022825-13A1
Application #
3271359
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1976-09-15
Project End
1997-03-31
Budget Start
1993-04-01
Budget End
1994-03-31
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Albany Medical College
Department
Type
Schools of Medicine
DUNS #
City
Albany
State
NY
Country
United States
Zip Code
12208
David, T S; Ortiz, P A; Smith, T R et al. (1998) Sphingomyelinase has an insulin-like effect on glucose transporter translocation in adipocytes. Am J Physiol 274:R1446-53
Turinsky, J; Damrau-Abney, A; Loegering, D J (1998) Blood flow and glucose uptake in denervated, insulin-resistant muscles. Am J Physiol 274:R311-7
Smith, T R; Elmendorf, J S; David, T S et al. (1997) Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4. Am J Physiol 272:E1071-9
Turinsky, J; Damrau-Abney, A; Elmendorf, J S et al. (1997) Effect of monensin on 2-deoxyglucose uptake, the insulin receptor and phosphatidylinositol 3-kinase activity in rat muscle. J Endocrinol 154:85-93
Turinsky, J; Nagel, G W; Elmendorf, J S et al. (1996) Sphingomyelinase stimulates 2-deoxyglucose uptake by skeletal muscle. Biochem J 313 ( Pt 1):215-22
Elmendorf, J S; Damrau-Abney, A; Smith, T R et al. (1995) Insulin-stimulated phosphatidylinositol 3-kinase activity and 2-deoxy-D-glucose uptake in rat skeletal muscles. Biochem Biophys Res Commun 208:1147-53
Turinsky, J; O'Sullivan, D M; Bayly, B P (1992) Modulation of prostaglandin E2 synthesis in rat skeletal muscle. Am J Physiol 262:E476-82
Turinsky, J; Nagel, G W (1992) Effect of sphingoid bases on basal and insulin-stimulated 2-deoxyglucose transport in skeletal muscle. Biochem Biophys Res Commun 188:358-64
Turinsky, J; Bayly, B P; O'Sullivan, D M (1991) 1,2-Diacylglycerol and ceramide levels in rat liver and skeletal muscle in vivo. Am J Physiol 261:E620-7
Turinsky, J; Long, C L (1990) Free amino acids in muscle: effect of muscle fiber population and denervation. Am J Physiol 258:E485-91

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