Basic Science Newsbrief

March 2011

Immune Cells at the Interface of Obesity and Insulin Resistance

Madhumita Jagannathan-Bogdan and Barb Nikolajczyk


Type 2 Diabetes (T2D) has become one of the fastest growing epidemics in the United States and is associated with an increased risk for a number of serious, sometimes life-threatening complications such as cardiovascular disease, kidney disease and blindness. Due to this rapid T2D increase in the population, diabetes-related healthcare costs are skyrocketing. Present treatments for T2D are expensive with detrimental side effects and long-term efficacy only in some individuals. Understanding the pathophysiology of T2D is essential to developing more effective treatments.


 T2D is a chronic inflammatory disease characterized by elevated serum levels of pro-inflammatory cytokines such as IL-1β, TNF-α and IL-8. Chronic inflammation in T2D is thought to begin as an inflammatory response to necrosis of expanding adipose tissue resulting from over-nutrition. As adipose tissue expands, monocytes migrate into the adipose tissue and differentiate into cytokine-producing macrophages, which in turn promote cytokine production from adipocytes (i.e., adipokines).  A cytokine-driven feed-forward loop between monocytes/macrophages and adipocytes produces an inflammatory milieu, which promotes insulin resistance, a hallmark of T2D. Recent work indicates that T cells may precede monocyte infiltration into adipose tissue. CD8+ T cells, one of the two major T cell subsets, migrate into adipose tissue and produce chemotactic cytokines that recruit monocytes. CD4+ T cells, the second major subset, also infiltrate the adipose tissue and produce inflammatory cytokines. Importantly, a pro-inflammatory cytokine, IL-17, is produced at elevated levels by CD4+ T cells (Th17 cells) from T2D patients. These T cells require monocyte cross talk for elevated IL-17 production, revealing an indirect mechanism for monocyte-mediated inflammation in T2D. Another T cell subset, regulatory T cells (Tregs) is important for inflammation regulation in adipose tissue. Tregs are decreased in circulation and in adipose tissue from obese/T2D patients, and in adipose tissue of mouse models of T2D, potentially contributing to uncontrolled inflammation. Taken together, elucidating the mechanisms behind T cell induced inflammation in T2D have opened new doors for novel T2D treatments focused on immunomodulation.


 Only a subset of obese individuals exhibit chronic inflammatory responses that perpetuate metabolic imbalance and T2D, and whether immunological changes will allow clinicians to discern patients who will become insulin resistant is an important outstanding question in immunometabolism research. However, focus on human inflammatory T cells has yielded some insight into this clinically critical question. Our detailed analysis of IL-17-secreting Th17 cells showed that although stimulated T cells from both obese/non-diabetic and obese/T2D patients activate the IL-17 gene to similar levels, T cells from obese T2D donors have significantly elevated IL-17 protein production compared to T cells from obese/non-diabetic donors. Elevated IL-17 production, despite structurally similar Th17 promoters, brings up the intriguing possibility that loss of specific layers of mRNA regulation in the immune system promotes the transition from insulin sensitivity to insulin resistance and T2D. The positive correlation between Th17 cells and body mass index (BMI) in T2D but not in obese/non-diabetic subjects further supports this possibility. Th17 cells may also play unappreciated indirect roles in the transition from euglycemic obesity to insulin resistance due to the plieotropic functions of IL-17. For example, IL-17 induces production of IL-8, is a strong chemoattractant that likely perpetuates further infiltration of immune cells into the adipose tissue. Future studies to definitely identify roles of inflammatory T cells (and other immune cells) have high potential to assist clinicians in preventing the transition from obese/insulin sensitive to obese/T2D. Significantly, Th17 cells have also been strongly implicated in other non-metabolic inflammatory diseases such as colitis and multiple sclerosis, indicating that treatments aimed at regulating these cells may have broad clinical applicability.


 The study of immunometabolism will provide insights into several critical unanswered questions in metabolic imbalance: 1) Does obesity lead to inflammation or do both occur simultaneously? 2) How does inflammation promote insulin resistance? 2) If obesity leads to inflammation, and then inflammation leads to insulin resistance/T2D, what is the threshold of inflammation that must be reached to transiently or permanently achieve insulin resistance in an obese individual? 3) Why do only a subset of obese individuals eventually become diabetic? Answers to these and other immunology-related questions will guide fundamentally new treatments to the Endocrinologists's limited arsenal to combat the epidemic of obesity and T2D.

Interested in highlighting your research in the TOS Basic Sciences newsbrief?  Send ideas to the Editors, Dr. Gerald Denis ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ) or Dr. Barbara Nikolajczyk ( This e-mail address is being protected from spambots. You need JavaScript enabled to view it ), for consideration.

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