Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality among the U.S. population. Therefore, new and better ways to prevent and treat T2DM are urgently needed. Insulin resistance is one of the earliest and most significant abnormalities in the pathogenesis of T2DM. However, the molecular basis for the insulin resistance of T2DM is not fully understood. Toll-like receptor (TLR) 4 is a cell surface receptor that generates immune responses by activating a cascade of pro-inflammatory events. TLR4 is expressed on insulin-target (myocytes, hepatocytes, adipocytes) and inflammatory (monocytes/macrophages) cells. This receptor is activated by bacteria-derived lipopolysaccharide (LPS) and by saturated free fatty acids (FFA). Studies from various groups, including ours, have shown that TLR4 expression is elevated in muscle and inflammatory cells from insulin resistant subjects. Several studies also have demonstrated that the plasma concentration of two TLR4 ligands, FFA and LPS, is increased in obese and T2DM subjects. Moreover, emerging evidence from cell culture and animal studies suggest that TLR4 and downstream pathways [MAPKs and nuclear factor (NF)?B] could play an important role in the pathogenesis of insulin resistance and T2DM. Despite the considerable body of data linking TLR4 with insulin resistance, it is not known whether TLR4 is directly involved in the pathogenesis of insulin resistance in obese and T2DM human subjects. In this study, we will utilize a specific TLR4 inhibitor in vivo with the goals to (i) determine the role that TLR4 signalng plays in the pathogenesis of insulin resistance and T2DM in humans;and (ii) elucidate the mechanism/s by which TLR4 mediates insulin resistance in human subjects. We propose two Aims to test the following hypotheses: (1) Pharmacologic inhibition of TLR4 with E5564 will prevent lipid-induced insulin resistance in lean normal glucose-tolerant subjects;and (2) Pharmacologic inhibition of TLR4 with E5564 will reduce inflammation and improve glucose metabolism in insulin resistant (obese nondiabetic and obese T2DM) subjects. The results from this study will advance our understanding about the pathophysiology of insulin resistance in human subjects, and, if positive, will validate TLR4 as a viable target for T2DM prevention and treatment.

Public Health Relevance

The causes of type 2 diabetes are not fully understood. In this study we will test whether blocking a molecule called TLR4 with a pharmacologic agent can improve glucose (sugar) metabolism in obese and type 2 diabetic subjects. Our findings could help design new ways to prevent and treat type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK080157-06
Application #
8776615
Study Section
Special Emphasis Panel (ZRG1-EMNR-R (02))
Program Officer
Abraham, Kristin M
Project Start
2008-01-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$379,598
Indirect Cost
$99,598
Name
University of Texas Health Science Center
Department
Biology
Type
Schools of Medicine
DUNS #
800772162
City
San Antonio
State
TX
Country
United States
Zip Code
78229
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Ghosh, Sangeeta; Lertwattanarak, Raweewan; Garduño, Jose de Jesus et al. (2015) Elevated muscle TLR4 expression and metabolic endotoxemia in human aging. J Gerontol A Biol Sci Med Sci 70:232-46
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Hussey, Sophie E; Liang, Hanyu; Costford, Sheila R et al. (2013) TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipid-induced inflammation and insulin resistance in muscle cells. Biosci Rep 33:37-47
Liang, Hanyu; Hussey, Sophie E; Sanchez-Avila, Alicia et al. (2013) Effect of lipopolysaccharide on inflammation and insulin action in human muscle. PLoS One 8:e63983
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Zhang, Jingjing; Zhang, Ning; Liu, Meilian et al. (2012) Disruption of growth factor receptor-binding protein 10 in the pancreas enhances ýý-cell proliferation and protects mice from streptozotocin-induced ýý-cell apoptosis. Diabetes 61:3189-98
Jensen, Jørgen; Tantiwong, Puntip; Stuenæs, Jorid T et al. (2012) Effect of acute exercise on glycogen synthase in muscle from obese and diabetic subjects. Am J Physiol Endocrinol Metab 303:E82-9

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