Investigation of phenotypes associated with genetic variants of metabolic interest

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Disturbances in the communication network between key organ systems including skeletal muscle, adipose tissue and liver and their hormonal signals are associated with the development of insulin resistance and diabetes. Detailed phenotyping is of high relevance for the better understanding of metabolic perturbances in subphenotypes of diabetes in order to individualize therapy and to improve risk assessment for the development of diabetes-related complications.The main focus of the research fellowship is the determination of specific gene variants such as rare and functionally significant mutations within the diabetes subphenotypes, which would facilitate precision medicine and in turn stratified prevention and subsequently the treatment of diabetes. Furthermore, humans with rare extreme metabolic phenotypes such as severe insulin resistance syndromes will be studied to discover new genetic disorders and add to the knowledge of genotype-phenotype correlation.By applying specialised techniques of metabolic phenotyping in carriers of distinct genetic variants of patients with diabetes, metabolic anomalies, which can remain unrecognised in population-based analyses, can be unmasked. To this end, distinct independent but related approaches will be applied at the Institute of Metabolic Science, University of Cambridge, each of which will exploit the power of rare human genetic variants with major functional metabolic impact. To explore the perturbances of insulin resistance, dyslipidemia, fatty liver disease and type 2 diabetes, rare mutations will be studied, which are associated with metabolic phenotypes, abnormal fat distribution, loss-of-function mutations and patients with extreme metabolic phenotypes related to insulin resistance. Revealing genetic information and studying rare mutations in metabolic extensively phenotyped patients will allow to optimize the quality of metabolic control in diabetes in the first years of the disease which are of importance to adjust therapy in particular of high-risk patients from early on. Exploring the genetic relevance and its application to extensive metabolic phenotyping will deepen the knowledge and understanding of diabetes and its related comorbidities and complications and enable a more effective diagnosis as well as individualized, risk-adapted treatment of patients with diabetes.