Resolution of type II diabetes following RNY gastric bypass surgery: can gene expression profiling reveal the underlying dynamic mechanisms?

With recent increases in the number of people with obesity, the number of people with diabetes is also rapidly increasing, both in the UK and worldwide. Although we know that the obese are at greater risk of becoming diabetic, how and why this happens is poorly understood. We also do not understand why some extremely obese individuals do not become diabetic.
It is now becoming common for severe obesity to be treated by some form of weight-loss surgery. Surprisingly, in addition to the expected weight loss, some types of surgery can sometimes also 'cure' diabetes - even before there has been any weight loss. This provides an opportunity to investigate the causes of diabetes (apart from obesity), and possibly to identify new ways of treating or curing it.
We will take blood and tissue samples from patients who are having weight-loss surgery, both before surgery and at various times afterwards. From these samples, we will determine which genes are switched on or off following the surgery, and by comparing patients whose diabetes was or was not cured by the surgery with those who have never had diabetes, we will try to find genes that are important in diabetes. We will then try to understand how these diabetes-related genes are controlled, by finding genetic differences between patients that help to explain whether the genes were turned on or off by a lot or just a little. To check that our results are not due to chance, we will look for similar results in additional groups of weight-loss surgery patients.
The results of this research may help to identify patients who will benefit most from weight-loss surgery. It may also provide new ideas about how to develop drugs that can treat or cure diabetes.

The rising prevalence of type 2 diabetes (T2D) represents a major challenge for healthcare provision worldwide. Bariatric surgery is the most effective treatment for morbid obesity and certain operations, such as the Roux-en-Y (RNY) gastric bypass, also have dramatic effects on T2D, including complete long-term remission of the condition in some 40% of patients prior to significant weight loss. Investigation of such T2D remission has the potential to highlight possible biomarkers for stratification of patients likely to show greatest benefit from such approaches, to shed new light on the underlying mechanisms of diabetes risk and protection in morbid obesity, and to identify possible new drug targets for treatment of diabetes.
We will conduct RNAseq on 3 peripheral blood samples (taken immediately before surgery, 2 days after surgery, 6 months after surgery) from each of 3 groups of 50 patients undergoing RNY: non-diaebetic; diabetics who show resolution immediately following surgery; and non-resolving diabetics. The resulting dataset will be examined for differences between those with and without T2D at baseline, and differences between those T2D subjects who experienced resolution of their diabetes and those who did not. This will yield a set of transcripts putatively associated with protection from/risk of diabetes in the context of morbid obesity and another set putatively discriminating between those whose T2D does or does not resolve. These findings will be replicated in a larger set of RNY patients (2,800 total) using droplet digital PCR. We will then carry-out whole-genome genotyping and conduct eQTL analysis of transcripts of interest and seek associations of EQTL loci with diabetes resolution and, in large-scale population cohorts, with quantitative traits relevant to T2D.

The outputs of this research will have a number of key direct impacts.

We will use transcriptomics to elucidate pathophysiological mechanisms in type 2 diabetes in the context of morbid obesity, using sequential samples taken after RNY gastric bypass surgery to investigate the early and late markers of diabetes resolution after surgery. The identification of transcripts that act as markers of diabetes and of its resolution has the potential to enable prediction in advance of surgery who will experience full remission and who will not respond so well to this increasingly used therapeutic modality - often described as "metabolic surgery". In addition to shedding new light on the underlying cellular mechanisms, this information could have immediate clinical utility, and could form the focus of future clinical trials work aimed at validation of such transcripts as useful biomarkers. It is expected that there would be overlap between biomarkers for outcomes of RNY surgery and GLP-1 R agonist response, and this could also be of clinical utility.

eQTL analysis will identify genetic determinants of the level of expression of key transcripts (including those discussed above as potential biomarkers). Where such genetic markers show association with treatment response and/or quantitative traits related to diabetes, these may also have potential for patient stratification.

Treatment of T2D represents a major cost to the NHS, so that any effective biomarkers for patient stratification for potential response to a particular therapeutic modality could have major financial and organisational benefits. The proposed research may have commercially exploitable results, for instance if novel potential targets for anti-diabetic drugs are found. Imperial College has a wealth of experience in managing IP issues. Additionally, more effective targeting of new or existing treatments could lead to significant improvements in well-being, quality of life and ability of T2D patients to contribute to the economy.