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Targeting Neutrophils and Leukotrienes to Treat Type 2 Diabetes


Obesity is accompanied by local and systemic changes related to chronic inflammation, which may promote insulin resistance, cell failure and type 2 diabetes (T2D). Many experimental approaches and types of studies implicate inflammation in these conditions, but the ones likely to be most useful and important for patients with T2D have either high translational potential or clear avenues to clinical studies. We previously showed that NF-?B is activated in obesity and appears to promote pathologies associated with diabetes. We further showed that salicylates target NF-?B and lower glucose in obese rodents. We translated this anti-inflammatory approach to patients with T2D, first with small pilot trials and then larger TINSAL-T2D Phase 2 and 3 clinical trials. This application provides a new and exciting alternative approach to targeting inflammation in T2D that is entirely distinct from any previous attempt. In mice we found that neutrophils are rapidly upregulated in adipose tissue (AT) during the induction of obesity, and that six distinct methods for reducing neutrophil number and/or recruitment may provide consistent improvements in insulin resistance and glucose intolerance. The six distinct approaches include 1) Antibody depletion of neutrophils using a highly selective monoclonal antibody, 2) Genetic ablation of the enzyme leukotriene A4 hydrolase (Lta4h), which catalyzes production of the neutrophil chemoattractant, LTB4, 3) Genetic ablation of the high affinity LTB4 receptor, BLT1, and treatment of mice either with 4) Zileuton, a 5-lipoxygenase (5-LO) inhibitor approved for treating patients with asthma, 5) Bestatin, an LTA4H inhibitor, and 6) CP105696, a BLT1 receptor antagonist developed to treat arthritis and asthma. Preliminary results further show that these six distinct approaches all improve insulin resistance and glucose intolerance in parallel with diminishing neutrophil number and/or neutrophil recruitment to AT. However the six approaches do not selectively target AT, but their effects are systemic, potentially affecting all tissues and cell types. We therefore delineate which tissues are affected by the six interventions and which is responsible for the metabolic improvements. We initially focus on liver and lung, as these are established sites of neutrophil recruitment and involvement in host defense and tissue injury. However these tissues are also different, as liver steatosis accompanies obesity and contributes to T2D. By contrast, lung is neither thought to contribute to T2D nor accumulate lipid. We also develop a series of new mouse models to selectively block production of the neutrophil chemoattractant LTB4 in AT, liver and myeloid lineages. These approaches simultaneously identify sites for neutrophil recruitment leading to metabolic dysregulation and methods for reversal to provide metabolic improvements. Proposed studies provide a clear rationale and direct avenue for translating this new approach to patients with T2D.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.