Atypical PKC (aPKC) activation appears to be required for increases in glucose transport, and, most importantly, this activation is defective in obesity and type 2 diabetes. Thus, it is critical to elucidate mechanisms used by insulin, exercise and other agents to activate aPKCs. Although initial findings suggest that IRS-1 is required for insulin activation of aPKCs, thiazolidinediones (TZDs) were reported to activate aPKCs and glucose transport in 3T3/L1 adipocytes via CbI/PI3K, independently of IRS-1/2. Importantly, insulin activates CbI/PI3K to the same extent as TZDs in 3T3/L1 adipocytes, and, while this is small relative to IRS-1/PI3K, initial findings suggest that CbI/PI3K is required for activation of aPKCs and glucose transport by insulin. Accordingly, IRS-1 and Cbl may be co-required for PI3K and aPKC activation in these and other cells. To examine this possibility (a) Cbl mutants will be expressed in 3T3/L1 adipocytes and L6 myocytes to see if pYXXM motifs in Cbl are required for activation of the SH2 domain of p85/PI3K, aPKCs and glucose transport; and (b) mice and brown adipocytes in which IRS-1 or IRS-2 has been knocked out will be used to see if IRS-1/2 are required for activation of aPKCs and glucose transport in muscle and adipocytes. Concerning exercise, we have reported that exercise and AICAR activate aPKCs, AICAR uses ERK and phospholipase D (PLD) to activate aPKCs, and aPKCs are required for AICAR-stimulated glucose transport. To see if aPKCs are required for exercise-stimulated glucose transport, we will use transgenic mice that express kinase-inactive aPKCs or muscle-specific aPKC knockout mice. The see if AICAR uses PYK2 to sequentially activate ERK, PLD, aPKCs and glucose transport, we will use viral-mediated expression of mutant forms of these signaling factors. Finally, the hypothesis that insulin-stimulated glucose transport is dependent on aPKCs will be definitively tested in adipocytes and myocytes derived from embryonic stem cells in which PKC-lambda has been knocked out by recombinant methods.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Physiological Chemistry Study Section (PC)
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Blondel, Olivier
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University of South Florida
Internal Medicine/Medicine
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Sajan, Mini P; Hansen, Barbara C; Higgs, Margaret G et al. (2018) Atypical PKC, PKC?/?, activates ?-secretase and increases A?1-40/42 and phospho-tau in mouse brain and isolated neuronal cells, and may link hyperinsulinemia and other aPKC activators to development of pathological and memory abnormalities in Alzheimer's Neurobiol Aging 61:225-237
Sajan, Mini; Hansen, Barbara; Ivey 3rd, Robert et al. (2016) Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1? and Increases in A?1-40/42 and Phospho-Tau May Abet Alzheimer Development. Diabetes 65:1892-903
Sajan, Mini P; Ivey 3rd, Robert A; Farese, Robert V (2015) BMI-related progression of atypical PKC-dependent aberrations in insulin signaling through IRS-1, Akt, FoxO1 and PGC-1? in livers of obese and type 2 diabetic humans. Metabolism 64:1454-65
Sajan, Mini P; Ivey, Robert A; Lee, Mackenzie C et al. (2015) Hepatic insulin resistance in ob/ob mice involves increases in ceramide, aPKC activity, and selective impairment of Akt-dependent FoxO1 phosphorylation. J Lipid Res 56:70-80
Ivey, Robert A; Sajan, Mini P; Farese, Robert V (2014) Requirements for pseudosubstrate arginine residues during autoinhibition and phosphatidylinositol 3,4,5-(PO?)?-dependent activation of atypical PKC. J Biol Chem 289:25021-30
Farese, Robert V; Lee, Mackenzie C; Sajan, Mini P (2014) Atypical PKC: a target for treating insulin-resistant disorders of obesity, the metabolic syndrome and type 2 diabetes mellitus. Expert Opin Ther Targets 18:1163-75
Farese, Robert V; Lee, Mackenzie C; Sajan, Mini P (2014) Hepatic Atypical Protein Kinase C: An Inherited Survival-Longevity Gene that Now Fuels Insulin-Resistant Syndromes of Obesity, the Metabolic Syndrome and Type 2 Diabetes Mellitus. J Clin Med 3:724-40
Sajan, Mini P; Acevedo-Duncan, Mildred E; Standaert, Mary L et al. (2014) Akt-dependent phosphorylation of hepatic FoxO1 is compartmentalized on a WD40/ProF scaffold and is selectively inhibited by aPKC in early phases of diet-induced obesity. Diabetes 63:2690-701
Sajan, Mini P; Jurzak, Michael J; Samuels, Varman T et al. (2014) Impairment of insulin-stimulated glucose transport and ERK activation by adipocyte-specific knockout of PKC-? produces a phenotype characterized by diminished adiposity and enhanced insulin suppression of hepatic gluconeogenesis. Adipocyte 3:19-29
Sajan, Mini P; Ivey 3rd, Robert A; Lee, Mackenzie et al. (2014) PKC? haploinsufficiency prevents diabetes by a mechanism involving alterations in hepatic enzymes. Mol Endocrinol 28:1097-107

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