Coupling novel non-invasive imaging methods and new gene therapies to detect and treat type 2 diabetes

正常运作的脂肪组织对人类健康至关重要。脂肪营养不良综合征最明显地说明了这一点，在这种综合征中，无法适当地发育或维持脂肪组织往往会导致严重的代谢性疾病，包括脂肪肝和糖尿病。肥胖者也会遭受相对脂肪不足的痛苦，因为他们的脂肪细胞变得过于饱满，因此无法适当地储存更多的营养。与脂肪营养不良症一样，脂质随后溢出到其他组织，特别是肝脏，导致胰岛素抵抗和糖尿病。因此，支持肥胖和脂肪营养不良的负面代谢后果的机制明显重叠。脂肪营养不良是一种毁灭性的疾病，报道不足。目前唯一有效的治疗方法是瘦素，这种激素通常由脂肪组织分泌，在脂肪营养不良患者中减少或消失。瘦素可以抑制饥饿，但对患者的肝脏也有好处，可以减少脂肪肝，改善他们的糖尿病。瘦素对一部分患有脂肪肝和糖尿病的超重个体也有有益的影响。然而，瘦素治疗需要每天痛苦的注射，而且高昂的费用意味着患者很少使用它。脂肪营养不良患者，以及肥胖和糖尿病患者，也可能有低水平的另一种由脂肪分泌的荷尔蒙，称为脂联素。脂联素通过多种机制改善胰岛素敏感性。然而，脂联素替代治疗脂肪营养不良的效果还没有得到检验。在这个项目中，我们将利用我们最近开发的用腺相关病毒(AAV)驱动的蛋白质表达作为脂肪营养不良的临床前模型的基因治疗能力。我们将使用AAV递送瘦素和/或脂联素，以恢复这些激素的水平。然后我们将研究这些治疗如何影响胰岛素敏感性和其他代谢健康指标，特别是脂肪肝。作为这项工作的一部分，我们将应用一种名为快速场周期成像(FFC成像)的新型、尖端非侵入性成像方法来比较肥胖和脂肪营养不良中的脂肪肝疾病。我们还将在我们的脂肪营养不良的临床前模型中确定AAV基因治疗如何影响脂肪肝疾病。人类对脂肪组织和纤维化的初步研究表明，FFC技术具有出色的能力，能够区分不同类型的脂肪组织，并检测非酒精性脂肪性肝病的不同阶段的纤维化。这种方法将使我们能够评估治疗效果，并有助于在未来的研究中转化为人类研究。总的来说，该项目结合了对罕见和常见疾病的代谢健康的研究，以及对新的潜在基因治疗方法的临床前分析，以及尖端的医学物理方法。这将使我们能够定义新的方法来理解、诊断和治疗脂肪肝，脂肪肝是支持2型糖尿病发展的代谢性疾病的标志性特征。

Appropriately functioning adipose tissue is essential for human health. This is most dramatically illustrated by lipodystrophy syndromes, in which the inability to develop or maintain adipose tissue properly often leads to severe metabolic disease including fatty liver and diabetes. Obese individuals also suffer relative adipose insufficiency because their adipocytes become overfilled and so unable to store further nutrients appropriately. As in lipodystrophy, lipids then spill over into other tissues, especially the liver, causing insulin resistance and diabetes. Thus, the mechanisms underpinning the negative metabolic consequences of obesity and lipodystrophy overlap significantly. Lipodystrophy is a devastating and under-reported condition. The only currently effective therapy is the hormone leptin, normally secreted by adipose tissue and reduced or absent in lipodystrophy patients. Leptin acts to suppress hunger but also has beneficial effects in the liver of patients, reducing fatty liver and improving their diabetes. Leptin may also have beneficial effects in a subset of overweight individuals with fatty liver and diabetes. However, leptin treatment requires painful daily injections and the high cost means it is rarely available to patients. Lipodystrophy patients, and obese, diabetic individuals, can also have low levels of another hormone secreted by adipose called adiponectin. Adiponectin improves insulin sensitivity via multiple mechanisms. However, the effects of adiponectin replacement in lipodystrophy have not been examined.In this project we will exploit our recently developed ability to use adeno-associated virus (AAV) driven expression of proteins as gene therapy in a pre-clinical model of lipodystrophy. We will use AAV to deliver leptin and/or adiponectin to restore levels of these hormones. We will then examine how these treatments affect insulin sensitivity and other metabolic health measures, in particular fatty liver disease. As part of this work we will apply a novel, cutting-edge non-invasive imaging method called Fast Field-Cycling imaging (FFC imaging) to compare fatty liver disease in obesity and lipodystrophy. We will also define how fatty liver disease is affected by AAV gene therapy in our preclinical model of lipodystrophy. FFC techniques have shown excellent capabilities from human pilot studies on the characterisation of fatty tissues and fibrosis, being able to differentiate different types of adipose tissue and to detect the different stages of fibrosis in non-alcoholic fatty liver disease. This method will allow us to assess treatment effects and to facilitate translation to human studies in future studies.Overall this project combines the study of metabolic health in rare and common disease with preclinical analysis of new potential gene therapy approaches as well as cutting edge medical physics methods. Together this will allow us to define new ways to understand, diagnose and treat fatty liver, a signature feature of metabolic disease that underpins the development of type 2 diabetes.