The overall objectives of this project are to clarify the molecular mechanisms by which inducible nitric oxide synthase (iNOS) mediates insulin resistance. The previous studies revealed that: (1) iNOS inhibition significantly ameliorates whole-body insulin resistance, and improves depressed expression of insulin receptor substrate (IRS)-1 and IRS-2, and IRSs-mediated insulin signaling in obese, diabetic (ob/ob) mice; (2) S-nitrosylation reversibly inactivates Akt/PKB; and that (3) S-nitrosylated Akt/PKB was increased in diabetic mice. Chronic inflammation and cellular stress signaling have been implicated in obesity-induced insulin resistance. However, its origin and potential cross-talks between the stress signaling pathways remain elusive. The preliminary experiments showed that: (1) gene disruption of S-nitrosoglutathione reductase (GSNOR), a negative regulator of protein S-nitrosylation, caused insulin resistance and aggravated high-fat diet-induced diabetes in mice; (2) activation of endoplasmic reticulum (ER) stress, NF- kappaB and c-Jun N-terminal kinase (JNK/SAPK) was attenuated by iNOS inhibitor in the liver of ob/ob mice; and (3) alleviation of ER stress by overexpression of an ER chaperone blocked iNOS-induced decrease in IRS-2 expression in cultured hepatocytes. Based on the previous studies and convincing preliminary data, the following hypotheses will be tested: that protein S-nitrosylation plays an important role in insulin resistance; and that iNOS contributes to the development of insulin resistance not only as a downstream effector of inflammation, but also as an enhancer of stress signaling pathways.
Aim 1 will determine a role of GSNOR in insulin resistance in GSNOR knockout mice and liver-specific GSNOR transgenic mice. ? Aim 2 will determine whether increased iNOS expression in liver is sufficient to induce insulin resistance in mice.
Aim 3 will clarify a role of iNOS in activation of ER stress, IKK-NF-kappaB and JNK/SAPK pathways in ob/ob mice.
Aim 4 will clarify a role of ER stress in iNOS-mediated insulin resistance. The proposed studies will provide novel, significant insights to understand the pathogenesis of insulin resistance in an integrated manner. Insulin resistance, attenuated responsiveness to insulin, is a major causative factor for diabetes, and a risk factor for ischemic heart disease. This project will provide new information to establish novel strategies to prevent and/or treat insulin resistance and obesity-related diabetes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK058127-04A1
Application #
7197692
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Blondel, Olivier
Project Start
2002-07-01
Project End
2010-08-31
Budget Start
2006-09-15
Budget End
2007-08-31
Support Year
4
Fiscal Year
2006
Total Cost
$329,080
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Tamura, Yoshiaki; Chiba, Yuko; Tanioka, Toshihiro et al. (2011) NO donor induces Nec-1-inhibitable, but RIP1-independent, necrotic cell death in pancreatic ýý-cells. FEBS Lett 585:3058-64
Kida, Kotaro; Yamada, Marina; Tokuda, Kentaro et al. (2011) Inhaled hydrogen sulfide prevents neurodegeneration and movement disorder in a mouse model of Parkinson's disease. Antioxid Redox Signal 15:343-52
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