This project has focused on discovering the molecular and biochemical mechanisms responsible for insulin resistance in human skeletal muscle in vivo. Our findings led us to focus on abnormalities in insulin signaling, specifically those involving IRS-1, and especially those defects that arise subsequent to lipid oversupply and inflammation. In the most recent funding period, we have discovered a number of novel phosphorylation sites in IRS-1 and showed how at least one of these sites functions to modulate IRS-1 action. In experiments designed to assess how lipid oversupply alters gene expression and insulin action in skeletal muscle, we discovered through a global gene expression analysis that lipid oversupply produces an inflammatory response in healthy skeletal muscle that results in increased synthesis of extracellular matrix proteins, MMPs, TIMPs, and connective tissue growth factor (CTGF), a mediator of TGF-p action. Preliminary results indicate that activation of the NF-KB pathway accompanied this response. This finding opens a new bridge between inflammation and muscle insulin resistance. Moreover, the inflammatory changes associated with insulin resistance are likely to be related to changes in IRS-1 serine/threonine phosphorylation, connecting these findings with the IRS-1 project. To mechanistically define the role of lipid- induced proinflammatory changes and to connect these changes with IRS-1 serine/threonine phosphorylation, we propose: 1) To develop a more complete serine/threonine phosphorylation map for IRS-1 and apply this map to characterize these sites in vitro and in vivo in humans in Aims 2-4. 2) To determine the time course of lipid-induced inflammatory events in skeletal muscle and circulating factors and connect these events with IRS-1 serine/threonine phosphorylation. 3) To use a local, femoral artery infusion of Liposyn to determine to what extent the lipid-induced inflammatory response and insulin resistance in skeletal muscle requires the influence of exogenous circulating factors. 4) To determine the extent to which the inflammatory response to lipids is present in naturally occurring insulin resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047936-15
Application #
8019519
Study Section
Special Emphasis Panel (ZRG1-CIDO-K (01))
Program Officer
Laughlin, Maren R
Project Start
1994-09-30
Project End
2012-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
15
Fiscal Year
2011
Total Cost
$515,144
Indirect Cost
Name
Arizona State University-Tempe Campus
Department
Other Basic Sciences
Type
Schools of Arts and Sciences
DUNS #
943360412
City
Tempe
State
AZ
Country
United States
Zip Code
85287
Luo, Moulun; Mengos, April E; Mandarino, Lawrence J et al. (2016) Association of liprin β-1 with kank proteins in melanoma. Exp Dermatol 25:321-3
Xie, Xitao; Yi, Zhengping; Sinha, Sandeep et al. (2016) Proteomics analyses of subcutaneous adipocytes reveal novel abnormalities in human insulin resistance. Obesity (Silver Spring) 24:1506-14
McLean, Carrie S; Mielke, Clinton; Cordova, Jeanine M et al. (2015) Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity. PLoS One 10:e0127089
DeMenna, Jacob; Puppala, Sobha; Chittoor, Geetha et al. (2014) Association of common genetic variants with diabetes and metabolic syndrome related traits in the Arizona Insulin Resistance registry: a focus on Mexican American families in the Southwest. Hum Hered 78:47-58
Miranda, Danielle N; Coletta, Dawn K; Mandarino, Lawrence J et al. (2014) Increases in insulin sensitivity among obese youth are associated with gene expression changes in whole blood. Obesity (Silver Spring) 22:1337-44
Boyle, Kristen E; Hwang, Hyonson; Janssen, Rachel C et al. (2014) Gestational diabetes is characterized by reduced mitochondrial protein expression and altered calcium signaling proteins in skeletal muscle. PLoS One 9:e106872
Mielke, Clinton J; Mandarino, Lawrence J; Dinu, Valentin (2014) AMASS: a database for investigating protein structures. Bioinformatics 30:1595-600
Mielke, Clinton; Lefort, Natalie; McLean, Carrie G et al. (2014) Adenine nucleotide translocase is acetylated in vivo in human muscle: Modeling predicts a decreased ADP affinity and altered control of oxidative phosphorylation. Biochemistry 53:3817-29
Beeman, Scott C; Mandarino, Lawrence J; Georges, Joseph F et al. (2013) Cationized ferritin as a magnetic resonance imaging probe to detect microstructural changes in a rat model of non-alcoholic steatohepatitis. Magn Reson Med 70:1728-38
Chakkera, Harini A; Mandarino, Lawrence J (2013) Calcineurin inhibition and new-onset diabetes mellitus after transplantation. Transplantation 95:647-52

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