Title: Hepatic glucagon sensitivity before and after bariatric surgery: use of a plasma biomarker to predict resolution of metabolic-associated liver disease
Funder: The Academy of Medical Sciences

Abstract: Hepatic steatosis, the first stage of non-alcoholic fatty liver disease (NAFLD), is highly prevalent and associated with tremendous morbidity and mortality. Bariatric surgery leads to resolution in most but not all patients. There are no pharmaceutical treatments. Glucagon powerfully decreases hepatic fat content, but patients with obesity and NAFLD exhibit hepatic glucagon resistance. I have recently shown that glucagon sensitivity improves following sleeve gastrectomy (SG) in mice with diet-induced obesity, alongside reduction in hepatic steatosis. Furthermore, in a homogenous cohort of mice, pre-operative glucagon resistance was inversely correlated to post-operative liver fat. These findings lead me to hypothesise that improvements in hepatic glucagon sensitivity drive steatosis resolution following bariatric surgery. Aims of this study: 1/ Confirm that hepatic glucagon sensitivity improves following bariatric surgery in patients with hepatic steatosis. 2/ Test whether pre-operative biomarkers of hepatic glucagon resistance predict resolution of hepatic steatosis in patients undergoing bariatric surgery. I will conduct a clinical trial of patients with obesity and hepatic steatosis undergoing bariatric surgery under NICE guidelines. Glucagon sensitivity and hepatic steatosis will be assessed at one month prior to surgery and at two and six months post-operatively using plasma biomarkers, magnetic resonance spectroscopy and alanine turnover. The results of this project will provide rationale for the development of glucagon agonists/ sensitisers for NAFLD and could underpin development of a simple pre-operative test to assist patient selection for bariatric surgery.

Lay abstract: One in four adults worldwide have too much fat stored in the liver. This prevents it from working properly. It can lead to liver failure and death in severe cases. Unfortunately, there are no specific drugs to treat fatty liver. Weight-loss surgery causes improvement in most patients, but like all surgery it has risks. Glucagon is a natural hormone in the blood. Glucagon reduces the amount of fat stored in the liver, but unfortunately it is less effective in patients with fatty liver. In a study of mice with fatty livers, I found that weight-loss surgery not only reduced liver fat but also made mice respond better to glucagon. Interestingly, mice that showed the least response to glucagon before surgery had the greatest improvement in liver fat. These findings lead me to hypothesise that better glucagon action may be an important cause of the improvements in liver fat seen after weight-loss surgery. The aims of my study are twofold. Firstly, to confirm that patients with fatty liver become more responsive to glucagon after weight-loss surgery. Secondly, to determine whether a blood test to measure glucagon responsiveness can predict which patients will have the best outcome from surgery. I will ask patients with fatty liver who are on the waiting list for weight-loss surgery to have a specialized scan and blood tests. Results from this study could underpin development of an exciting new test to help patients with fatty liver decide if weight-loss surgery is the right option for them.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL