Insulin resistance in skeletal muscle contributes to the metabolic derangements in obesity and Type II (non-insulin dependent) diabetes mellitus (NIDDM). Although major advances have been made in understand the mechanisms by which insulin signals its effects in muscle, much less is known regarding how abnormalities in insulin signaling contribute to insulin resistance in this tissue. We have shown that although insulin stimulated insulin receptor tyrosine phosphorylation is considerably reduced in muscle biopsies from patients with NIDDM, with consequent decreased in IRS-1 and PI 3-kinases signaling, insulin normally activates the MAP kinases cascade in these very insulin resistant patients. The overall goal of this proposal is to further characterize insulin resistance with respect to the PI 3-kinase pathway in obese and NIDDM patients and to begin to discern the mechanisms responsible for the discordance in insulin resistance with respect to the PI 3-kinase pathway in obese and NIDDM patients and to begin to discern the mechanisms responsible for the discordance insulin signaling to the PI 3-kinase and MAP kinase pathways. Specifically, we propose 1) To determine the nature of the abnormalities in insulin signaling in muscle from patients with Type II diabetes. We will test the hypothesis a) that the maximal response is reduced and the time course is altered, and we will continue to explore the mechanisms underlying our observation that insulin resistance is restricted to PI 3-kinase and does not affect the MAP kinase pathway, 2) that IRS-2 signaling is regulated differently than IRS-1 in muscle of diabetics, and 3) that the IGF-I receptor or IGF-1/insulin hybrid receptor are activated by insulin, and could potentially contribute to signaling to the MAP kinase pathway. We also propose 2) to more closely examine the mechanisms involved in the decrease in insulin stimulation or insulin receptor tyrosine phosphorylation in muscle from Type II diabetics. We will test the hypothesis that a) insulin receptor tyrosine kinase (IRTK) activity is not as reduced as insulin receptor autophosphorylation, especially toward exogenous substrates, b) increased serine phosphorylation of the receptor inhibits tyrosine phosphorylation in diabetics, and 3) that the inhibitory protein Grb-IR association with the insulin receptor is greater in diabetics than in control.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Metabolism Study Section (MET)
Program Officer
Laughlin, Maren R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center San Antonio
Internal Medicine/Medicine
Schools of Medicine
San Antonio
United States
Zip Code
Luo, Moulun; Mengos, April E; Ma, Wuqiong et al. (2017) Characterization of the novel protein KIAA0564 (Von Willebrand Domain-containing Protein 8). Biochem Biophys Res Commun 487:545-551
Shaibi, Gabriel; Singh, Davinder; De Filippis, Eleanna et al. (2016) The Sangre Por Salud Biobank: Facilitating Genetic Research in an Underrepresented Latino Community. Public Health Genomics 19:229-38
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
Luo, Moulun; Mengos, April E; Mandarino, Lawrence J et al. (2016) Association of liprin ?-1 with kank proteins in melanoma. Exp Dermatol 25:321-3
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
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
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
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
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
Mielke, Clinton J; Mandarino, Lawrence J; Dinu, Valentin (2014) AMASS: a database for investigating protein structures. Bioinformatics 30:1595-600

Showing the most recent 10 out of 66 publications