Diabetes mellitus may be caused by a deficiency in either the amount of circulating insulin or the ability of cells to respond to the hormone. The long term objectives of this project are to delineate mechanisms involved in insulin action and insulin resistance. It can be inferred that insulin binding to a receptor on the plasma membrane generates a signal(s) (not yet identified) that is transmitted to the inside of the cell and causes changes in metabolic processes. Insulin resistance can be caused by a defect at a step after receptor binding, as is the case in denervated skeletal muscle.
One aim i s to identify the defect in the denervated muscle responsible for its resistance to the hormone. We have evidence that increased protein phosphorylation is involved, and will try to identify the kinase and/or phosphatase responsible.
Other aims are to determine if motor neurons maintain the ability of muscle to respond to insulin by releasing trophic substances or by promoting muscle activity. More complete understanding of the steps in the pathway of insulin action in normal cells might be necessary to define post-receptor defects. We propose to continue our investigation of the mechanism by which insulin stimulates the dephosphorylation and activation of glycogen synthase (GS). Glucose transport-dependent and -independent pathways exist for insulin-stimulated dephosphorylation of GS in fat cells.
Aims are to find out if these 2 pathways exist in muscle. GS is phosphorylated on several sites and we plan to determine which sites are affected by insulin. Such information is essential for understanding the mechanism of GS activation, and might provide clues concerning the mediators of insulin action. Insulin is known to stimulate the phosphorylation of some proteins. Increased phosphorylation of an appropriate protein might trigger dephosphorylation of others. For example, inhibitor 2 (I-2) is a regulatory protein which, when in a dephosphorylated form, is a potent inhibitor of Type I phosphatase. Phosphorylation of I-2 on an appropriate site results in phosphatase activation. We have evidence that insulin stimulates the phosphorylation of I-2 in fat cells.
An aim i s to determine if the hormonal effect involves sites in I-2 that affect its phosphatase inhibitory activity. Another aim is to determine if the effects of other agents, such as glucagon and adrenergic agonists, on protein phosphorylation could be mediated, in part, through changes in I-2 phosphorylation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK028312-10
Application #
3228734
Study Section
Physiological Chemistry Study Section (PC)
Project Start
1981-04-01
Project End
1992-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Zhang, Chongben; Wendel, Angela A; Keogh, Matthew R et al. (2012) Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Proc Natl Acad Sci U S A 109:1667-72
Péterfy, Miklós; Harris, Thurl E; Fujita, Naoya et al. (2010) Insulin-stimulated interaction with 14-3-3 promotes cytoplasmic localization of lipin-1 in adipocytes. J Biol Chem 285:3857-64
Liu, Guang-Hui; Qu, Jing; Carmack, Anne E et al. (2010) Lipin proteins form homo- and hetero-oligomers. Biochem J 432:65-76
Blancquaert, Sara; Wang, Lifu; Paternot, Sabine et al. (2010) cAMP-dependent activation of mammalian target of rapamycin (mTOR) in thyroid cells. Implication in mitogenesis and activation of CDK4. Mol Endocrinol 24:1453-68
Kim, Hyun Bae; Kumar, Anil; Wang, Lifu et al. (2010) Lipin 1 represses NFATc4 transcriptional activity in adipocytes to inhibit secretion of inflammatory factors. Mol Cell Biol 30:3126-39
Kumar, Anil; Lawrence Jr, John C; Jung, Dae Young et al. (2010) Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism. Diabetes 59:1397-406
Gropler, Matthew C; Harris, Thurl E; Hall, Angela M et al. (2009) Lipin 2 is a liver-enriched phosphatidate phosphohydrolase enzyme that is dynamically regulated by fasting and obesity in mice. J Biol Chem 284:6763-72
Wang, Lifu; Lawrence Jr, John C; Sturgill, Thomas W et al. (2009) Mammalian target of rapamycin complex 1 (mTORC1) activity is associated with phosphorylation of raptor by mTOR. J Biol Chem 284:14693-7
Chen, Zhouji; Gropler, Matthew C; Norris, Jin et al. (2008) Alterations in hepatic metabolism in fld mice reveal a role for lipin 1 in regulating VLDL-triacylglyceride secretion. Arterioscler Thromb Vasc Biol 28:1738-44
Wang, Lifu; Harris, Thurl E; Lawrence Jr, John C (2008) Regulation of proline-rich Akt substrate of 40 kDa (PRAS40) function by mammalian target of rapamycin complex 1 (mTORC1)-mediated phosphorylation. J Biol Chem 283:15619-27

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