GLP-1 and Gut-Brain Communication Research for Obesity and Diabetes

Scientists at the Cedars-Sinai Diabetes and Obesity Research Institute (DORI) are examining the gut hormone glucagon-like peptide-1 (GLP-1), as well as the gut-liver-brain interaction to better understand Type 2 diabetes and obesity, and how the two diseases are linked.

There is an intricate communication system between the gut, brain, liver, pancreas, muscle tissue and fat — the organs involved in blood sugar and body weight regulation. The gut is an endocrine organ with more than 30 hormones. One of these hormones, GLP-1 has an important role in blood sugar control, through the pancreas and insulin secretion, and in weight control, by inducing satiety in the brain. There are likely other functions of GLP-1 that have yet to be discovered.

Currently, there are three research projects that have evolved from data discovered from previous investigations of GLP-1 and its communication with other organs. These studies are focused on understanding glucose regulation and brain activity and elucidating mechanisms affected during metabolic surgery to inspire new treatments for obesity and Type 2 diabetes.

GLP-1 research includes studying diabetes medications that are based on this hormone and are currently on the market. Not only do they improve diabetes but they also produce weight loss. Determining how GLP-1 drugs prescribed for diabetes are causing weight loss may lead to targeted obesity medications.

Comparing brain responses between lean and obese patients using imaging has shown that gut-brain communications differ in the two populations. Understanding why and how these differences occur may illuminate causes for obesity and potential treatments.

DORI researchers also are delving into how bariatric surgery changes gut-brain communication, a change that has led to successful weight loss and diabetes resolution in a majority of patients. Determining what causes the blood sugar control improvement may help scientists find noninvasive alternatives to surgery that will produce the same positive results for weight loss and Type 2 diabetes.

Current DORI research focused on gut-brain-liver communication includes:

  • Validating whether liraglutide has actions on the liver: effects on glucose phosphorylation.
    • Examine medication currently prescribed for Type 2 diabetes (liraglutide) that might act by controlling liver enzyme glucokinase (GCK).
    • Investigate the acute and chronic effects of liraglutide on GCK using an intravenous glucose tolerance test and mathematical modeling.
    • Assess GCK activity in people with Type 2 diabetes.
    • Determine how to better employ current therapeutic options and develop new strategies for preventing and treating diabetes.
  • Evaluating brain activation by gut hormones in patients with Type 2 diabetes and obesity using functional magnetic resonance imaging (FMRI).
    • Examine the brain responses in lean compared with obese and diabetic participants.
    • Introduce various meal/beverage compositions and measure gut-brain communication using FMRI.
    • Observe how the brain responds in lean versus obese and diabetic people to understand the brain’s role in controlling glucose.
    • Determine changes that occur in brain receptors of obese and diabetic participants to develop treatments that would aid in treating and preventing diabetes.
  • Investigating changes in gut hormones and gut-brain communication after gastric bypass surgery.
    • Examine the mechanism of Type 2 diabetes remission that occurs after gastric bypass surgery.
    • Investigate the activation by gut signals of brain centers involved in glucose regulation in Type 2 diabetic, obese patients before and after gastric bypass surgery.
    • Identify what mechanisms change the hormone signaling in gastric bypass surgery.
    • Determine whether therapeutic targets can be created as a noninvasive treatment to mimic actions of gastric bypass surgery in resolution of diabetes and obesity.

Studies of gut-brain communications and GLP-1 are integral to understanding the mechanism of Type 2 diabetes and obesity. This knowledge will lead to better use of current therapeutic options in addition to developing new treatments. Cedars-Sinai research scientists are seeking the least invasive medical interventions, including more reasonable lifestyle approaches that can induce lasting success to help curtail the obesity and diabetes epidemics.

Previous research