Mechanisms that underlie clinical insulin resistance will only be clarified when we more fully understand how insulin controls metabolic processes, in particular, glucose transport. During the past decade, it has become increasingly clear that bioactive lipids and lipid- regulated signalling factors play important roles in the mechanisms whereby insulin controls glucose transport and other metabolic processes in muscle and adipose tissues. From very recent findings, it also appears that: (a) small G-proteins, Rho and ARF, are involved in the activation of certain insulin-sensitive lipid-signalling pathways; (b) protein kinase C-zeta (PKC-zeta) is rapidly activated by insulin; and (c) both Rho and PKC-zeta may play an important role in glucose transport. The hypothesis that will be tested presently is that glucose transport is regulated, at least in part, by insulin-induced alterations in: (a) phosphatidylinositol (PI) 3-kinase and a functionally inter- related small G-protein, Rho; (b) bioactive lipids, most notably, D3-PO4 derivatives of PI; and (c) downstream protein kinases, including PKC- zeta. We postulate that insulin, through PI 3-kinase, regulates Rho and PKC-zeta and both Rho and PKC-zeta, in turn, are required for, and may actively participate in GLUT4 translocation and glucose transport (see Fig. 1). We also postulate that GTPgammaS can enter this signalling pathway by activating Rho and PI3-kinase.
The specific aims are to: 1. Define the role of PI 3-kinase during insulin-induced activation of Rho. 2. Determine whether Rho is upstream of PKC-zeta in the action of insulin or GTPgammaS. 3. Define the role of PI 3-kinase in insulin-induced activation of PKC-zeta. 4. Examine the roles of PKC-zeta and Rho in insulin-stimulated glucose transport.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Endocrinology Study Section (END)
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Blondel, Olivier
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University of South Florida
Internal Medicine/Medicine
Schools of Medicine
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Sajan, Mini P; Nimal, Sonali; Mastorides, Stephen et al. (2012) Correction of metabolic abnormalities in a rodent model of obesity, metabolic syndrome, and type 2 diabetes mellitus by inhibitors of hepatic protein kinase C-?. Metabolism 61:459-69
Ortmeyer, Heidi K; Sajan, Mini P; Miura, Atsushi et al. (2011) Insulin signaling and insulin sensitizing in muscle and liver of obese monkeys: peroxisome proliferator-activated receptor gamma agonist improves defective activation of atypical protein kinase C. Antioxid Redox Signal 14:207-19
Sajan, M P; Bandyopadhyay, G; Miura, A et al. (2010) AICAR and metformin, but not exercise, increase muscle glucose transport through AMPK-, ERK-, and PDK1-dependent activation of atypical PKC. Am J Physiol Endocrinol Metab 298:E179-92
Farese, Robert V; Sajan, Mini P (2010) Metabolic functions of atypical protein kinase C: ""good"" and ""bad"" as defined by nutritional status. Am J Physiol Endocrinol Metab 298:E385-94
Sajan, M P; Standaert, M L; Rivas, J et al. (2009) Role of atypical protein kinase C in activation of sterol regulatory element binding protein-1c and nuclear factor kappa B (NFkappaB) in liver of rodents used as a model of diabetes, and relationships to hyperlipidaemia and insulin resistance. Diabetologia 52:1197-207
Sajan, Mini P; Standaert, Mary L; Nimal, Sonali et al. (2009) The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity. J Lipid Res 50:1133-45
Temofonte, N; Sajan, M P; Nimal, S et al. (2009) Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1-dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle. Diabetologia 52:60-4
Farese, Robert V; Sajan, Mini P; Yang, Hong et al. (2007) Muscle-specific knockout of PKC-lambda impairs glucose transport and induces metabolic and diabetic syndromes. J Clin Invest 117:2289-301
Casaubon, L; Sajan, M P; Rivas, J et al. (2006) Contrasting insulin dose-dependent defects in activation of atypical protein kinase C and protein kinase B/Akt in muscles of obese diabetic humans. Diabetologia 49:3000-8
Luna, V; Casauban, L; Sajan, M P et al. (2006) Metformin improves atypical protein kinase C activation by insulin and phosphatidylinositol-3,4,5-(PO4)3 in muscle of diabetic subjects. Diabetologia 49:375-82

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