The GLP-1 Debate

Glucagon-like peptide-1, GLP-1, is the most studied gut hormone. It promotes weight loss, increases satiety and stimulates insulin secretion while blocking glucagon release. Gastric bypass surgery and gastric sleeve procedure result in significant post-prandial increase in GLP-1. As a result, GLP-1 has been strongly suspected as a key mediator in metabolic surgery especially when it comes to the immediate post-operative diabetes resolution. Several studies in human and animal models have attempted to elucidate the role of GLP-1 in diabetes resolution and remission following bariatric surgery. One of the most interesting experiments were conducted in human gastric bypass subjects. A feeding tube was placed in the gastric remnant and a meal challenge test was conducted. One meal given through the oral route on one day and the same meal given through the feeding tube route on the second day. The difference in insulin, GLP-1 and glucose response was striking; gastric bypass changes the interaction between ingested meal and gastrointestinal system resulting in GLP-1 rise and lower post-prandial glucose levels. Researchers, however, have not been able to firmly establish a cause effect relationship between GLP-1 rise and the metabolic effects of bariatric surgery.

Jorgensen et al demonstrated in diabetic patients who underwent gastric bypass surgery that GLP-1 is essential to insulin function improvement and blood glucose normalization after surgery. The authors blocked the GLP-1 receptor using a high dose of Exendin 9-39 infusion and found that all the postoperative improvements of gastric bypass surgery were abolished by GLP-1 antagonist. Their study was published in Diabetes journal in 2013. It clearly demonstrated a cause effect relationship between GLP-1 and diabetes resolution. Other groups have also blocked the GLP-1 receptor in both human and animal models but found persistent improvement in post-prandial blood glucose level following metabolic surgery. Similarly, animal models with GLP-1 gene knockout show the same degree of diabetes resolution and weight loss following gastric bypass surgery as controls.

There is no doubt that multiple neuro-endocrine pathways between the gut and other organs like the brain, liver and pancreas are involved in mediating the metabolic effects of bariatric surgery. GLP-1 represents one of these pathways. Blocking GLP-1 receptors or using GLP-1 agonists by themselves is unlikely to duplicate the complex metabolic effects of gastric sleeve or gastric bypass surgery. However, GLP-1 is an important marker of gut changes following metabolic surgery. Lap band, gastric balloon, gastric plication, endoscopic sleeve gastroplasty and other purely restrictive procedures have not been found to be associated with any GLP-1 changes. Therefore, it is safe to assume that GLP-1 is a central metabolic marker and novel weight loss procedures that do not alter GLP-1 secretion are less likely to be associated with significant metabolic changes leading to durable weight loss and diabetes resolution or improvement.

A weight loss procedure that does not alter blood Ghrelin level nor increase gastric emptying and post-prandial GLP-1 levels is unlikely to result in durable and significant weight loss. Should we be early adopters of new bariatric treatments that rely on purely restrictive mechanisms of action? The answer is clearly NO. Instead, we ought to investigate and better understand bariatric surgery mechanism of action and accordingly develop endoscopic procedures. It is no longer accepted to develop a weight loss procedure based on mechanical restriction and expect weight loss surgeons to adopt it.