Novel non-invasive assessment of de novo lipogenesis and its mechanistic role in human insulin resistance

Background
Worldwide obesity has nearly tripled since 1975 and the World Health Organisation estimates 39% of the adult population are now overweight. Obesity can lead to diabetes and other metabolic disorders such as heart and fatty liver disease. This process can be gradual, quietly occurring over a number of years by a state of insulin resistance, where cells in muscle and liver don't respond well to the hormone insulin and blood sugars rise. Therefore it is imperative that we better understand the mechanisms of insulin resistance in order to be able to intervene at an earlier stage in the development of these diseases, where metabolic changes may still be reversible.

Insulin resistance is closely associated with an accumulation of fat stored in the liver and skeletal muscle. There is growing evidence to suggest a process called de novo lipogenesis (DNL), where fat is generated from excess sugars, is involved in the development of insulin resistance. There are no non-invasive ways to measure the storage of fat from DNL, and taking a biopsy sample from the liver carries substantial risk. Therefore investigations into the storage of DNL-generated fats has been significantly limited.

Aim
To develop a non-invasive method to measure the storage of DNL-generated fats, and to use this to safely examine the relevance of this fat storage in human insulin resistance.

Approach
Magnetic Resonance Spectroscopy (MRS) is a completely non-invasive technique that uses an MRI scanner to generate biochemical information from inside the body. This can tell us about the composition of the tissue and, for example, can measure how much fat it contains. However, normal methods can not distinguish DNL-generated fat from other fat, and so here I plan to design and validate a new special MRS method that will be able to do this. Using both insulin resistant patients and healthy individuals, we shall utilise this new method to investigate the role of DNL-stored fats in the mechanisms of insulin resistance.

Importance
Non-invasive methods to measure the storage of DNL-generated fats will safely enable the investigation of the relevance of stored DNL-fats in human insulin resistance. Understanding such mechanisms is key to preventing a number of metabolic diseases including diabetes, heart and fatty liver disease.

Background
Insulin resistance links obesity to type 2 diabetes and accounts for almost all of the associated comorbidities such as non-alcoholic fatty liver and cardiovascular disease. Insulin resistance is closely associated with an accumulation of lipid stored ectopically in liver and skeletal muscle. Emerging evidence suggests de novo lipogenesis (DNL), the generation of lipid from non-lipid sources, is involved in the pathogenesis of insulin resistance. There are no non-invasive ways to measure the storage of DNL-derived lipid. Existing methods require a biopsy sample which is a procedure associated with substantial risk, and this has significantly limited its investigation.

Aim
To develop a non-invasive method to measure the storage of DNL-derived lipids, and to use this to safely examine the relevance of this lipid storage in human insulin resistance.

Approach
Magnetic Resonance Spectroscopy (MRS) is a completely non-invasive technique that can provide biochemical information from within tissues in vivo. I plan to devise and validate a novel MRS method that will safely and completely non-invasively measure the incorporation of DNL-derived lipid into stored lipid pools. Using unique cohort insulin resistant patients and matched controls, we shall utilise this new method to investigate the role of DNL-stored lipids in the mechanisms of insulin resistance.

Importance
Understanding the pathogenesis of insulin resistance will provide new therapeutic targets for early intervention in a number of diseases linked to the metabolic syndrome, when mechanisms may still be reversible. The novel methodology developed also has the potential to provide a non-invasive biomarker for early detection and/or monitoring response to therapy.