Targeting Neutrophils and Leukotrienes to Treat Type 2 Diabetes

描述（由申请人提供）：肥胖伴随着与慢性炎症相关的局部和全身改变，可能促进胰岛素抵抗、β细胞衰竭和2型糖尿病（T2D）。许多实验方法和研究类型都涉及这些情况下的炎症，但那些可能对T2D患者最有用和最重要的方法要么具有很高的转化潜力，要么具有明确的临床研究途径。我们之前的研究表明，NF-κB在肥胖中被激活，似乎促进了与糖尿病相关的病理。我们进一步发现水杨酸盐在肥胖啮齿动物中靶向NF-κB和降低葡萄糖。我们将这种抗炎方法应用于T2D患者，首先是小规模的试点试验，然后是更大规模的TINSAL-T2D二期和三期临床试验。该应用程序提供了一种新的、令人兴奋的替代方法来靶向T2D炎症，这与以往的任何尝试都完全不同。在小鼠中，我们发现脂肪组织（AT）中的中性粒细胞在诱导肥胖过程中迅速上调，并且六种不同的减少中性粒细胞数量和/或募集的方法可能会持续改善胰岛素抵抗和葡萄糖耐受不良。这六种不同的方法包括：1)使用高选择性单克隆抗体消耗中性粒细胞；2)基因消融白三烯A4水解酶（Lta4h），它催化中性粒细胞化学引诱剂LTB4的产生；3)基因消融高亲和力LTB4受体BLT1，并使用4)Zileuton（一种被批准用于治疗哮喘患者的5-脂氧合酶（5- lo）抑制剂，5）Bestatin（一种Lta4h抑制剂）和6)CP105696治疗小鼠。一种用于治疗关节炎和哮喘的BLT1受体拮抗剂。初步结果进一步表明，这六种不同的方法都可以改善胰岛素抵抗和葡萄糖耐受不良，同时减少中性粒细胞数量和/或中性粒细胞募集到AT。然而，这六种方法不是选择性地靶向AT，但它们的作用是全身性的，可能影响所有组织和

DESCRIPTION (provided by applicant): Obesity is accompanied by local and systemic changes related to chronic inflammation, which may promote insulin resistance, β 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-κB is activated in obesity and appears to promote pathologies associated with diabetes. We further showed that salicylates target NF-κB 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.