Do gut hormones mediate the beneficial effects of Roux-en-Y bypass surgery?

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Obesity and diabetes are very common diseases which often go together. Over 1 in 4 people in the UK are obese. Together, these diseases afflict 300 million people and cause an estimated 3 million premature deaths a year. Surgery to reduce weight and especially the "Roux-en-Y gastric bypass" (RYGB) is known to reduce weight and to cure diabetes. Unfortunately surgery can never be the answer to the global problem of obesity and diabetes as it is very expensive, and can cause serious complications. We need a new, cheaper and adjustable treatment for obesity and diabetes that has the benefits of RYGB but without the side effects.

Gut hormones are hormones that the bowels make in response to eating. These hormones control our appetite and our metabolism (i.e. the method in which our body uses and stores food). The gut hormones glucagon-like peptide-1 (GLP-1), oxyntomodulin (OXM) and peptide YY (PYY) are much increased in level after RYGB. We believe that this increase in GLP-1, OXM and PYY holds the key to our goal to make a new treatment for obesity and diabetes. If we can prove that by artificially increasing GLP-1, OXM and PYY levels we can help obese diabetic patients to lose weight and to improve their blood sugar levels, this would be a breakthrough in treatment.

In this project, we aim to study obese, diabetic patients undergoing the RYGB surgery to see what changes occur in their gut hormone levels, in their metabolism, in their body weight and in their appetite for food. We will compare this to patients who will wear a 'pump' for 28 days. This pump will painlessly deliver a small amount of GLP-1, OXM and PYY via a soft plastic needle under the skin to raise their gut hormone levels. We will see if these pump patients have similar changes to the RYGB group. We will also test out a group of patients to see if similar changes occur when these patients are given a strict low-calorie diet. In this way we hope to understand whether we can make GLP-1, OXM and PYY into a new and better treatment for obesity and diabetes.

Technical Summary

Obesity and the consequential type 2 diabetes (T2D) is the biggest pandemic the world has ever seen, afflicting 300 million people and causing an estimated 3 million premature deaths a year (WHO 2008). This is a considerable problem for public health and for therapeutics. The modern Roux-en-Y gastric bypass surgical procedure (RYGB) is highly effective in treating obesity and T2D: typically there is ~33% loss of body weight, producing complete remission of diabetes in about half the patients. Long term health and life expectation is dramatically increased. RYGB, however, is expensive, somewhat dangerous and is variable in effect. It is not desired by the majority of patients, nor is it practicable to treat the very large numbers of patients who might require it.

The challenge, therefore, is to demonstrate how RYGB works. This is the first step to identifying whether this could be translated into a practical, safe and titratable medical therapy for obesity and diabetes.

The remission of T2D and weight loss after RYGB has been attributed to a number of possible mechanisms, for example restriction of the stomach, interference with postprandial neural signals, delayed absorption of bile salts, delayed absorption of nutriments causing a change in breakdown of nutriments in the colon and / or an alteration of the gut microbiome. The evidence for each of these being the main cause of remission of diabetes is relatively weak. Outstandingly the likeliest mechanism proposed has been the elevation of gut hormones and enhancement thereby of the entero-insular axis.

Our previous work has shown gut hormones induce satiety, can enhance insulin release, and delay food absorption. They are elevated after RYGB. Evidence in animals suggests they might be the key mechanism producing the weight loss and improved carbohydrate tolerance in RYGB. We will establish in man whether this hypothesis is correct.

Planned Impact

The ultimate beneficiaries of our research project will be patients with obesity and diabetes. As obesity is highly prevalent in the UK (25% of the population and rising) and worldwide, our research will clearly have a massive impact outwith the academic community. The following sections will discuss how we plan to maximize the impact of our research.

Application pathways
At the end of the project, we expect to have developed a proof-of-concept that GOP infusion is able to benefit patients with obesity and diabetes. This discovery could be exploited in two main ways:
1. Direct treatment with GLP-1, oxyntomodulin and PYY infusion pumps of patients with obesity and diabetes who are considered presently unsafe for surgery because of their extreme weight and/or uncontrolled diabetes. This would be envisaged as a 'bridge' towards eventual RYGB and similar surgery.
2. To spur the development and clinical use of analogues of GLP-1, oxyntomodulin and PYY as combination treatments for obesity and diabetes. Analogues of these gut hormones are currently in active development by our laboratory, other academic groups and the pharmaceutical industry, and the positive findings from our project would be expected to be directly and rapidly translatable to clinical practice.

The plan for application will be actively discussed and managed between the project team and the MRC.

Communications and engagement
Please see Communications Plan Section.

Resources requested
No extra resources for these impact activities are requested.

Publications

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Choudhury SM (2016) Gastrointestinal hormones and their role in obesity. in Current opinion in endocrinology, diabetes, and obesity

 
Description Collaboration with Jens Holst and Nicolai Wewer Albrechtsen 
Organisation University of Copenhagen
Country Denmark 
Sector Academic/University 
PI Contribution We have supplied samples from our gut hormone and clinical studies.
Collaborator Contribution Have assayed for oxyntomodulin and glucagon using specific assays
Impact Publications: Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass. Tharakan G, Behary P, Wewer Albrechtsen NJ, Chahal H, Kenkre J, Miras AD, Ahmed AR, Holst JJ, Bloom SR, Tan T. Eur J Endocrinol. 2017 Dec;177(6):455-464. doi: 10.1530/EJE-17-0446. Epub 2017 Aug 30. The Effect of a Subcutaneous Infusion of GLP-1, OXM, and PYY on Energy Intake and Expenditure in Obese Volunteers. Tan T, Behary P, Tharakan G, Minnion J, Al-Najim W, Albrechtsen NJW, Holst JJ, Bloom SR. J Clin Endocrinol Metab. 2017 Jul 1;102(7):2364-2372. doi: 10.1210/jc.2017-00469.
Start Year 2017
 
Title Combination gut hormones via subcutaneous infusion 
Description Combination of GLP-1, oxyntomodulin and peptide YY via subcutaneous pump. Proof of principle obtained (funded by MRC Experimental Medicine Challenge Grant). 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact Demonstrated that the GOP infusion is capable of reducing weight and ameliorating glucoswe 
 
Description BBC Horizon 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave interview to BBC Horizon Programme
Year(s) Of Engagement Activity 2016
 
Description BBC filming, July 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact BBC filming
Year(s) Of Engagement Activity 2018
 
Description Bayliss-Starling Lecture 2014 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact talk has been published in special themed issue of J Physiol

talk was well received
Year(s) Of Engagement Activity 2014
 
Description Front page article in the Telegraph 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Front page article in the Telegraph Newspaper on 4th May 2019. Headline was: "The monthly hormone jab hailed as 'most exciting' weight-loss treatment ever"
Year(s) Of Engagement Activity 2018
URL https://www.telegraph.co.uk/science/2018/05/04/hormone-jab-mimics-gastric-band-hailed-exciting-obesi...
 
Description ITV The Tonight Programme 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Gave interview to ITV's 'The Tonight Programme' discussing current research.
Year(s) Of Engagement Activity 2015
URL http://www.itv.com/news/2015-10-21/xxl-britain-tonight/
 
Description Interview for BBC Horizon Documentary "Why Are We Getting So Fat?" 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I was interviewed regarding my research in the GOP infusion. This was broadcast in the UK and I also understand in Australia.
Year(s) Of Engagement Activity 2016
URL http://www.bbc.co.uk/programmes/b07fys2y
 
Description Interview for BBC Persian World Service 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed for BBC Persian World Service programme.
Year(s) Of Engagement Activity 2015
 
Description Interview of BBC Documentary "The Truth About Obesity" 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Interviewed for BBC Documentary "The Truth About Obesity". Not yet broadcast.
Year(s) Of Engagement Activity 2018
 
Description Metabolic effects of kisspeptin 1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Policymakers/politicians
Results and Impact Talk-Metabolic effects of kisspeptin
1st European Congress of Reproductive Endocrinology (EUCRE) Conference, Prato Italy, March 2018
Year(s) Of Engagement Activity 2018
 
Description Multidisciplinary Endocrine Symposium 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Postgraduate students
Results and Impact Annual Imperial Centre for Endocrinology Symposium
Day of presentations and talks.
Talk given: Obesity Surgery vs Medical Treatment: Who Gets What and what is to come?
Year(s) Of Engagement Activity 2018
URL http://www.imperialendo.com/thirteenm
 
Description Pharmaceutical Innovation "Treatment landscape for diabetes and obesity" for Financial Investors 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Industry/Business
Results and Impact A day of lectures and meetings organised by Goldman Sachs to better understand on-going innovation in drug development and how the treatment landscapes could evolve.
Spoke on the following:
Is obesity a disease? Thus, is it insurance reimbursable?
Why is the uptake of current oral anti-obesity agents so poor?
Why isn't bypass surgery not more popular?
Year(s) Of Engagement Activity 2018
 
Description Plenary Lecture, Japan Endocrine Society 2019 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Gave the Plenary Lecture at the Japan Endocrine Society entitled "Gut Hormones and the Brain". This disseminated the research so that a wide range of professionals could benefit.
Year(s) Of Engagement Activity 2019
 
Description Plenary Lecture: Kisspeptin / neurokinin B Pathways: Regulating Emotion and Treatment of Menopausal Symptoms American Endocrine Society meeting, Chicago April 2018 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk-Plenary Lecture: Kisspeptin / neurokinin B Pathways: Regulating Emotion and Treatment of Menopausal Symptoms
American Endocrine Society meeting, Chicago April 2018
Year(s) Of Engagement Activity 2018
 
Description The future of clinical academic training at Tony Gordon's conference in Great Hall, King's College London 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact The future of clinical academic training at Tony Gordon's conference in Great Hall, King's College London-Feb 2018
Year(s) Of Engagement Activity 2018
 
Description The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research, Moller Centre Cambridge, Nov 2016 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact The importance of academic medicine and supporting academic clinical careers Pathway to Independence - developing future clinical academic leaders in cancer research
Moller Centre Cambridge, Nov 2016
Year(s) Of Engagement Activity 2016
 
Description Translating Novel Hormones into New Therapies for Reproductive Disorders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact Talk/Seminar Translating Novel Hormones into New Therapies for Reproductive Disorders
Year(s) Of Engagement Activity 2019