Defining human hepatic insulin resistance
The deposition of fat in liver cells (hepatic steatosis) is often accompanied with hepatic insulin resistance. However, it remains unclear if the accumulation of intracellular triglyceride merely causes insulin resistance, or whether the association between these two variables is due to a common underlying molecular pathophysiology and/or non-canonical feedback mechanisms.
Within the liver, insulin normally acts through cell-surface receptors to suppress gluconeogenesis and glycogenolysis, and to promote lipogenesis and glycogen synthesis (Farese RV et al, 2012). We have previously demonstrated that humans defined as insulin resistant (based on fasting systemic circulating insulin concentrations) have higher hepatic de novo lipogenesis than individuals defined as insulin sensitive (Pramfalk et al, 2016). Hepatic insulin resistance typically refers to the impaired ability of insulin to suppress hepatic glucose production and is usually not due to reduced levels of insulin (Farese RV et al, 2012); in obesity systemic levels of circulating insulin are typically high (McQuaid et al, 2011). It remains unclear how to best define hepatic insulin resistance in both in vivo and in vitro cellular models. Therefore, studies will be undertaken to understand and specifically define molecular phenotypes of hepatic insulin resistance, along with the best markers to characterise hepatic insulin resistance. This will be achieved by using an integrated environment and multiple platforms, including in vitro cellular studies, mass spectrometry, single-cell sequencing, single-cell CRISPR, computational modelling of pathways, and clinical translation.
Work on in vitro cellular models, including human primary hepatocytes and cell-lines in cell culture systems, along with the development of spheroid models of hepatocytes. Use of metabolic tracers to track carbohydrate and fat metabolism. A range of aspects of human liver metabolism, cell biology, CRISPR screens, single-cell genomics, mass spectrometry work.
As well as the specific training detailed above, students will have access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford. Students are also able to attend the Methods and Techniques course run by the MRC Weatherall Institute of Molecular Medicine. This course runs through the year, ensuring that students have the opportunity to build a broad-based understanding of differing research techniques.
Generic skills training is offered through the Medical Sciences Division's Skills Training Programme. This programme offers a comprehensive range of courses covering many important areas of researcher development: knowledge and intellectual abilities, personal effectiveness, research governance and organisation, and engagement, influence and impact. Students are actively encouraged to take advantage of the training opportunities available to them.
The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to support the careers of female students and staff.
|1||Farese RV et al, The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab. 2012;15:570-3|
|2||Pramfalk et al. Fasting plasma insulin concentrations are associated with changes in hepatic fatty acid synthesis and partitioning prior to changes in liver fat content in healthy adults. Diabetes. 2016;65:1858-1867|
|3||McQuaid SE et al. Down-regulation of adipose tissue fatty acid trafficking in obesity as a driver for ectopic fat deposition. Diabetes 2011;60:47-55|