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

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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.