Studies on the mechanisms of glucolipotoxicity in human beta cells in the context of type 2 diabetes mellitus

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Diabetes mellitus is one of the most prevalent diseases worldwide with a rapidly increasing incidence. More than 90% of patients suffer from type 2 diabetes. Obesity is of particular importance in the pathogenesis, a consequence of Western style diet with an excess of carbohydrate and high-fat food constituents. Subsequent insulin resistance results in dysfunction and stepwise loss of insulin-secreting beta cells through gradual deterioration of glucose tolerance, thereby causing hyperglycaemia and increased plasma free fatty acid levels. These phenomena are also known as glucotoxicity and lipotoxicity. Reactive oxygen species (superoxide radicals, hydrogen peroxide, hydroxyl radicals) mediate this toxicity, which arise in the metabolism of fatty acids and glucose. The term glucolipotoxicity combines both phenomena and is in the focus of this project. Despite the great scientific interest, the underlying mechanisms are not fully understood. For this purpose, in the planned project, the analysis of the structure-toxicity relationships of fatty acids in combination with increased glucose concentrations is the main conceptual tool to be used, which has proven to be particularly helpful in the elucidation of the underlying pathomechanisms. The studies will be performed on human EndoC-βH1 beta cells and in primary islets of patients with and without type 2 diabetes. This focus has been chosen to create optimal conditions for translation to the patient. Three main goals have been defined for this project. 1) Comparative genome analyses after fatty acid and glucose exposure are to be carried out. 2) Verification of interesting target genes using RT-qPCR with special attention to the interactions between glucotoxicity and lipotoxicity. 3) In a final step, genetically modified human EndoC-βH1 beta cells are to be generated to gain a deeper insight in the in-depth mechanistic understanding. For this purpose the importance of the various subcellular organelles (mitochondria, peroxisomes, endoplasmic reticulum) for glucolipotoxicity will be elucidated using a broad range of methods with regard to the formation of mediators, in particular toxic reactive oxygen species. The intention of these planned studies is to advance the understanding of the molecular mechanisms underlying glucolipotoxicity to the extent that a complete picture of the mechanisms of toxicity and their signaling pathways can be presented. This should open up perspectives for the establishment of new interventional measures. These may be preventative lifestyle measures, specifically with respect to a healthy diet, but also new pharmaco-therapeutic approaches aiming at an improvement of the impaired glucose tolerance in the type 2 diabetic metabolic state by restoring normal beta cell function.