Targeting galectin-3 to overcome insulin resistance in type 2 diabetes

靶向 Galectin-3 克服 2 型糖尿病的胰岛素抵抗

• 批准号: 10007279
• 负责人: HAFIZ AHMED
• 金额: $ 30万
• 依托单位: GLYCOMANTRA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2022-05-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10007279
• 关键词: Adipocytes; Adult; Affinity; Agreement; American; Animal Model; Binding; Biological Markers; Blood; Body Weight; Cause of Death; Cells; Clinical Trials; Data; Diabetes Mellitus; Diet; Disease; Dose; Engineering; Fat-Restricted Diet; Fatty acid glycerol esters; Female; Frequencies; Future; Galactose Binding Lectin; Galectin 3; Gene Proteins; Genetic; Glucose Intolerance; Goals; Heart Diseases; Hepatocyte; High Fat Diet; Hormones; Immune; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Investigational Drugs; Licensing; Ligands; Link; Liver; Malignant Neoplasms; Measures; Mediating; Metabolic syndrome; Modeling; Mus; Muscle; Muscle Cells; Names; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Outcome Study; Pancreas; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase I Clinical Trials; Play; Prediabetes syndrome; Production; Publications; Publishing; Receptor Activation; Receptor Signaling; Research; Resolution; Role; Signal Transduction; Source; Technology; Testing; Therapeutic; Time; Toxic effect; United States; base; cell bank; experimental study; glucose tolerance; glucose uptake; immunoregulation; impaired glucose tolerance; improved; indexing; insulin sensitivity; insulin signaling; insulin tolerance; loss of function; macrophage; male; mouse model; novel; phase 1 study; primary endpoint; restoration

Project Summary/Abstract Obesity-associated insulin resistance is a hallmark of type 2 diabetes (T2D) and plays a central role in metabolic syndrome. Numerous studies suggest a firm connection between obesity-induced inflammation and insulin resistance mediated by macrophages and other immune cells. A recent elegant study by Olefsky and his team [Cell publication PMID: 27814523 ] shows that galectin-3 (Gal3), a beta-galactoside-binding lectin, is a macrophage-derived instigator of “insulin resistance and impaired glucose tolerance”, associated with obesity- induced T2D. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. The study shows that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These fundamental observations elucidate a novel role of Gal3 that promotes obesity-mediated inflammation (macrophage-derived Gal3) and insulin resistance and suggest that specific inhibition of Gal3 may represent a promising therapeutic strategy to restore insulin sensitivity. Our scientific premise is that we have developed a very potent Gal3 antagonist, named TFD100, from a natural dietary source [PNAS publication, PMID 23479624]. TFD100 specifically targets Gal3 with picomolar affinity – the affinity is so high (10-100-fold more) to counteract Gal3’s natural affinity to its intrinsic ligands such as IR. In our preliminary studies, Gal3 inhibited IR activation of the engineered CHO/IR/IRS-1 cells, which was reversed by TFD100. Our research team has extensive expertise in a relevant mouse model of T2D – a high fat diet (HFD)-induced model in C57BL/6 (B6) . We demonstrated increased expression of Gal3 in liver of HFD fed mice compared to that of low fat diet (LFD) fed mice. Gal3 is also high in obese mice. Moreover, Gal3 levels in sera of T2D patients are found significantly linked with indices of insulin resistance. Based on the preliminary data we hypothesize that that specific inhibition of Gal3 with TFD100 will interfere with Gal3-IR interactions on myocytes, adipocytes and hepatocytes and thereby restore insulin sensitivity. We will test this hypothesis in the following specific aim: Investigate the therapeutic utility of TFD100 for treating T2D in a relevant mouse model. First we will determine TFD100’s ability to impede Gal3-mediated cellular insulin resistance. Various cells such as adipocytes, myocytes, hepatocytes, and engineered CHO/IR/IRS-1 cells will be treated with TFD100 and determine its effect on IR activation, signaling, and glucose uptake. Next, we will determine TFD100’s ability to treat HFD-induced obesity, insulin resistance, and T2D in both male and female mice. After drug (TFD100) treatment, glucose and insulin tolerance (primary endpoint) will be measured. For other endpoints, resolution of inflammation and restoration of insulin signaling will be measured by the frequency of pro-inflammatory biomarkers (gene and protein) in blood, liver, muscle and fat. This also includes determination of changes in pro-inflammatory immune cell frequencies such as polarization of macrophages. This study, for the first time, will explore the therapeutic utility of a very potent natural compound that outcompetes Gal3’s intrinsic interaction with the IR to reverse insulin resistance.

项目总结/摘要 肥胖相关的胰岛素抵抗是2型糖尿病（T2 D）的标志，并在糖尿病发病中起着核心作用。 代谢综合征大量研究表明，肥胖引起的炎症与 巨噬细胞和其他免疫细胞介导的胰岛素抵抗。Olefsky最近的一项优雅的研究， 他的团队[Cell publication PMID：27814523 ]表明，半乳糖凝集素-3（Gal 3），一种β-半乳糖苷结合凝集素，是一种 巨噬细胞衍生的“胰岛素抵抗和糖耐量受损”的煽动者，与肥胖相关- 诱发T2 D。向小鼠施用Gal 3引起胰岛素抗性和葡萄糖耐受不良，而 通过遗传或药理学功能丧失抑制Gal 3，可改善肥胖患者的胰岛素敏感性 小鼠研究表明，Gal 3可直接与胰岛素受体（IR）结合并抑制下游IR 发信号。这些基本的观察阐明了Gal 3的一个新的作用，即促进肥胖介导的 炎症（巨噬细胞来源Gal 3）和胰岛素抗性，并提示Gal 3的特异性抑制 可能代表了恢复胰岛素敏感性的有希望的治疗策略。我们的科学前提是 已经从天然膳食来源中开发了一种非常有效的Gal 3拮抗剂，命名为TFD 100 [PNAS 出版物，PMID 23479624]。TFD 100以皮摩尔亲和力特异性靶向Gal 3-亲和力如此之高 （10-100倍），以抵消Gal 3对其固有配体如IR的天然亲和力。 在研究中，Gal 3抑制工程化CHO/IR/IRS-1细胞的IR活化，这被TFD 100逆转。我们 研究团队在T2 D的相关小鼠模型方面具有广泛的专业知识-高脂肪饮食（HFD）诱导 型号为C57 BL/6（B6）。我们证明了与对照组相比，HFD喂养小鼠肝脏中Gal 3的表达增加。 低脂肪饮食（LFD）喂养的小鼠。Gal 3在肥胖小鼠中也很高。此外，T2 D患者血清中的Gal 3水平 发现患者与胰岛素抵抗指数显著相关。根据初步数据， 假设用TFD 100特异性抑制Gal 3将干扰Gal 3-IR相互作用， 肌细胞、脂肪细胞和肝细胞，从而恢复胰岛素敏感性。我们将测试这个 以下特定目的的假设：研究TFD 100治疗T2 D的治疗效用， 相关小鼠模型。首先，我们将确定TFD 100阻碍Gal 3介导的细胞胰岛素分泌的能力。 阻力各种细胞如脂肪细胞、肌细胞、肝细胞和工程化的CHO/IR/IRS-1细胞将 用TFD 100处理，并确定其对IR活化、信号传导和葡萄糖摄取的影响。接下来我们就 确定TFD 100治疗男性和女性HFD诱导的肥胖、胰岛素抵抗和T2 D的能力 小鼠药物（TFD 100）治疗后，将测量葡萄糖和胰岛素耐受性（主要终点）。为 其他终点，炎症的消退和胰岛素信号传导的恢复将通过 血液、肝脏、肌肉和脂肪中促炎生物标志物（基因和蛋白质）的频率。这也包括 确定促炎免疫细胞频率的变化，例如巨噬细胞的极化。 这项研究将首次探索一种非常有效的天然化合物的治疗效用， 竞争胜过Gal 3与IR的内在相互作用以逆转胰岛素抗性。