Targeting Neutrophils and Leukotrienes to Treat Type 2 Diabetes

描述（由申请人提供）：肥胖伴随与慢性炎症相关的局部和全身变化，可能促进胰岛素抵抗、β细胞衰竭和2型糖尿病（T2 D）。许多实验方法和研究类型涉及这些疾病中的炎症，但对T2 D患者可能最有用和最重要的方法具有高转化潜力或明确的临床研究途径。我们以前的研究表明NF-κB在肥胖症中被激活，并似乎促进了与糖尿病相关的病理。我们进一步表明，水杨酸靶向NF-κB和降低肥胖啮齿动物的葡萄糖。我们将这种抗炎方法应用于T2 D患者，首先进行小型试点试验，然后进行更大规模的TINSAL-T2 D 2期和3期临床试验。该应用提供了一种新的和令人兴奋的替代方法来靶向T2 D中的炎症，这与以前的任何尝试完全不同。在小鼠中，我们发现在诱导肥胖期间，中性粒细胞在脂肪组织（AT）中迅速上调，并且用于减少中性粒细胞数量和/或募集的六种不同方法可以提供胰岛素抵抗和葡萄糖耐受不良的一致改善。这六种不同的方法包括：1）使用高选择性单克隆抗体去除中性粒细胞的抗体，2）催化中性粒细胞化学引诱物LTB 4产生的酶白三烯A4水解酶（Lta 4 h）的遗传消融，3）高亲和力LTB 4受体BLT 1的遗传消融，以及用4）齐留通，一种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LTA 4 H抑制剂，和6）CP 105696，一种开发用于治疗关节炎和哮喘的BLT 1受体拮抗剂。初步结果进一步表明，这六种不同的方法都改善了胰岛素抵抗和葡萄糖耐受不良，同时减少了中性粒细胞数量和/或中性粒细胞募集到AT。然而，这六种方法并不选择性地靶向AT，但它们的作用是全身性的，可能影响所有组织， 细胞类型。因此，我们描述了哪些组织受到六种干预措施的影响，哪些组织负责代谢改善。我们首先关注肝脏和肺，因为这些是中性粒细胞募集和参与宿主防御和组织损伤的既定场所。然而，这些组织也是不同的，因为肝脏脂肪变性伴随肥胖并导致T2 D。相比之下，肺被认为既不会导致T2 D，也不会积累脂质。我们还开发了一系列新的小鼠模型，以选择性地阻断AT、肝脏和骨髓谱系中嗜中性粒细胞趋化因子LTB 4的产生。这些方法同时鉴定导致代谢失调的中性粒细胞募集位点和逆转以提供代谢改善的方法。拟议的研究为将这种新方法转化为T2 D患者提供了明确的理论基础和直接途径。

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.