Obesity associated Type 2 diabetes (T2D) is a major global cause of morbidity and mortality, and yet current therapies are inadequate. The onset of T2D is often preceded by a condition known as insulin resistance in which tissues become increasingly insensitive to the natural hormone, necessitating the need for more insulin secretion by the pancreas. If this compensatory increase does not occur, blood glucose concentrations rise and T2D occurs. Multiple factors contribute to insulin resistance, but inflammation of visceral adipose tissue (VAT) resulting in chronic release of pro-inflammatory cytokines is known to be a major factor. We recently showed that the adaptive immune system plays a fundamental role in regulating this process. Oligoclonal IFN-? producing (Th1) CD4+ T cells in VAT overcome the anti-inflammatory effects of Th2 and Treg cells, and activate M1 macrophages. B-2 cells contribute to the development of insulin resistance by overcoming the anti-inflammatory effects of B-1 cells through their activation of VAT Th1 cells and secretion of pathogenic IgG autoantibodies. Studies of obese non-diabetic humans have revealed that the proportion of Th1 T cells in VAT is highly correlated with body mass index and that insulin resistance is linked to a specific autoantibody signature. These findings strongly support our central hypothesis that the development of insulin resistance in obesity has a significant autoimmune component involving cooperative effects of both B cells and T cells. In this project, we propose to more clearly define the mechanisms contributing to adaptive immune regulation of insulin resistance. We will pursue this objective through the following specific aims: 1) Identiy the mechanisms by which B-1 and B-2 cell subsets exert their opposing effects on insulin resistance in DIO mice. 2) Identify immunologic targets that worsen or protect against obesity related insulin resistance in DIO mice. 3) Assess the clinical significance of the autoantibody signature associated with insulin resistance in obese human subjects. The results of these experiments promise to yield new diagnostic and therapeutic modalities to manage this important disease.

Public Health Relevance

Type 2 diabetes is an extremely common yet poorly understood disease that occurs more frequently in obese persons. We have discovered that fatty tissues in obese people are invaded by white blood cells, called T cells and B cells, that help cause diabetes. In this project we will analyze how this occurs, with the goal of developing new means to predict who will develop diabetes and novel ways to prevent and treat it.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Abraham, Kristin M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
Schools of Medicine
United States
Zip Code
McLaughlin, Tracey; Ackerman, Shelley E; Shen, Lei et al. (2017) Role of innate and adaptive immunity in obesity-associated metabolic disease. J Clin Invest 127:5-13
Pham, T D; Chng, M H Y; Roskin, K M et al. (2017) High-fat diet induces systemic B-cell repertoire changes associated with insulin resistance. Mucosal Immunol 10:1468-1479
Ghazarian, Magar; Revelo, Xavier S; Nøhr, Mark K et al. (2017) Type I Interferon Responses Drive Intrahepatic T cells to Promote Metabolic Syndrome. Sci Immunol 2:
Shen, Lei; Zhang, Hong; Caimol, Maria et al. (2015) Invariant natural killer T cells in lupus patients promote IgG and IgG autoantibody production. Eur J Immunol 45:612-23
Spitzer, Matthew H; Gherardini, Pier Federico; Fragiadakis, Gabriela K et al. (2015) IMMUNOLOGY. An interactive reference framework for modeling a dynamic immune system. Science 349:1259425
Shen, Lei; Chng, Melissa Hui Yen; Alonso, Michael N et al. (2015) B-1a lymphocytes attenuate insulin resistance. Diabetes 64:593-603
Chng, Melissa Hui Yen; Alonso, Michael N; Barnes, Sarah E et al. (2015) Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance. Mediators Inflamm 2015:593075
Alonso, Michael N; Gregorio, Josh G; Davidson, Matthew G et al. (2014) Depletion of inflammatory dendritic cells with anti-CD209 conjugated to saporin toxin. Immunol Res 58:374-7
McLaughlin, Tracey; Liu, Li-Fen; Lamendola, Cindy et al. (2014) T-cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb Vasc Biol 34:2637-43
Winer, Daniel A; Winer, Shawn; Chng, Melissa H Y et al. (2014) B Lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell Mol Life Sci 71:1033-43

Showing the most recent 10 out of 12 publications