Insulin action will be studied in terms of 4 interrelated areas including 1) the isolation, purification to homogeneity and structure determination of several novel mediators of insulin action; 2) the separate high affinity binding and bioactivity domains of the insulin molecule; 3) the mechanism of the enhanced insulin receptor phosphorylation in the presence of the hormone and its possible relationship to mediator formation and 4) studies on the biochemical mechanism(s) of insulin resistance in human cells of diabetic patients.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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University of Virginia
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Pak, Y; Hong, Y; Kim, S et al. (1998) In vivo chiro-inositol metabolism in the rat: a defect in chiro-inositol synthesis from myo-inositol and an increased incorporation of chiro-[3H]inositol into phospholipid in the Goto-Kakizaki (G.K) rat. Mol Cells 8:301-9
Farese, R V; Standaert, M L; Yamada, K et al. (1994) Insulin-induced activation of glycerol-3-phosphate acyltransferase by a chiro-inositol-containing insulin mediator is defective in adipocytes of insulin-resistant, type II diabetic, Goto-Kakizaki rats. Proc Natl Acad Sci U S A 91:11040-4
Romero, G; Larner, J (1993) Insulin mediators and the mechanism of insulin action. Adv Pharmacol 24:21-50
Huang, L C; Fonteles, M C; Houston, D B et al. (1993) Chiroinositol deficiency and insulin resistance. III. Acute glycogenic and hypoglycemic effects of two inositol phosphoglycan insulin mediators in normal and streptozotocin-diabetic rats in vivo. Endocrinology 132:652-7
Pak, Y; Paule, C R; Bao, Y D et al. (1993) Insulin stimulates the biosynthesis of chiro-inositol-containing phospholipids in a rat fibroblast line expressing the human insulin receptor. Proc Natl Acad Sci U S A 90:7759-63
Asplin, I; Galasko, G; Larner, J (1993) chiro-inositol deficiency and insulin resistance: a comparison of the chiro-inositol- and the myo-inositol-containing insulin mediators isolated from urine, hemodialysate, and muscle of control and type II diabetic subjects. Proc Natl Acad Sci U S A 90:5924-8
Pak, Y; Huang, L C; Lilley, K J et al. (1992) In vivo conversion of [3H]myoinositol to [3H]chiroinositol in rat tissues. J Biol Chem 267:16904-10
Pak, Y; Larner, J (1992) Identification and characterization of chiroinositol-containing phospholipids from bovine liver. Biochem Biophys Res Commun 184:1042-7
Lilley, K; Zhang, C; Villar-Palasi, C et al. (1992) Insulin mediator stimulation of pyruvate dehydrogenase phosphatases. Arch Biochem Biophys 296:170-4
Kilgour, E; Larner, J; Romero, G (1992) The generation of inositolglycan mediators from rat liver plasma membranes: the role of guanine nucleotide binding proteins. Biochem Biophys Res Commun 186:1151-7

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