Investigation of phenotypes associated with genetic variants of metabolic interest

包括骨骼肌、脂肪组织和肝脏在内的关键器官系统及其激素信号之间的通信网络的干扰与胰岛素抵抗和糖尿病的发展有关。详细的表型分析对于更好地了解糖尿病亚表型中的代谢紊乱具有重要意义，以便个性化治疗和改善糖尿病相关并发症发展的风险评估。研究奖学金的主要重点是确定特定的基因变异，如糖尿病亚表型中罕见的和功能重要的突变，这将促进精确医疗，进而分层预防和随后的糖尿病治疗。此外，还将对具有罕见极端代谢表型（如严重胰岛素抵抗综合征）的人类进行研究，以发现新的遗传疾病，并增加基因型-表型相关性的知识。通过对糖尿病患者的不同遗传变异携带者应用专门的代谢表型分析技术，可以发现在基于人群的分析中无法识别的代谢异常。为此，剑桥大学代谢科学研究所将采用不同的独立但相关的方法，每种方法都将利用具有主要功能代谢影响的罕见人类遗传变异的力量。为了探索胰岛素抵抗、血脂异常、脂肪肝和2型糖尿病的紊乱，将研究与代谢表型、脂肪分布异常、功能丧失突变和具有与胰岛素抵抗相关的极端代谢表型的患者相关的罕见突变。揭示遗传信息和研究代谢广泛表型患者中的罕见突变将允许在疾病的最初几年优化糖尿病的代谢控制质量，这对于调整治疗，特别是高血糖患者的治疗具有重要意义。探索遗传相关性及其在广泛代谢表型中的应用将加深对糖尿病及其相关合并症的认识和理解和并发症，并使糖尿病患者的更有效的诊断以及个性化的，适应风险的治疗成为可能。

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.