GLP-1 enhances insulin secretion after bariatric surgery

By Will Boggs MD

NEW YORK (Reuters Health) - 12/2/2019

Glucagon-like peptide 1 (GLP-1) plays a major role in driving enhanced insulin secretion following bariatric surgery, researchers from the U.K. report.

"GLP-1 from the gut is so important in controlling blood glucose in people after bariatric-like surgical operations, whilst having little effect on weight loss," said Dr. Fiona M. Gribble from Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, in Cambridge.

"This is very important in our group of gastric-cancer patients who have had their stomachs removed and who face a lifetime of dealing with postprandial symptoms," she told Reuters Health by email.

Postprandial concentrations of GLP-1, peptide YY and insulin are elevated after bariatric surgery, but the importance of GLP-1 in post-bariatric physiology has remained unclear.

Dr. Gribble and colleagues explored the importance of GLP-1 in post-bariatric physiology and the mechanisms underlying elevated postprandial GLP-1 secretion using lean human and mouse models to reduce the confounding effects of metabolic changes due to loss of body weight and adiposity.

Blockage of GLP-1 receptors post-gastrectomy in lean humans (using exendin-9) enhanced glucose concentrations, reduced insulin secretion rates and increased hunger scores after an oral glucose-tolerance test, suggesting an important role of GLP-1 in driving hyperinsulinemia and suppressing hunger in these patients.

Gastrectomy, however, had no effect on the intestinal enteroendocrine (EEC) peptidome or transcriptome in mice or humans, the researchers report in Cell Reports, online February 5.

In mice, intestinal nutrient flow to the distal gut increased after surgery, and this increase correlated with plasma GLP-1 levels.

"The results presented here suggest that the following sequence of events occurs after bariatric and gastrectomy procedures, with substantial impacts on metabolism," the researchers note. "The anatomic rearrangements and altered nutrient flow and digestion do not alter EEC properties, but increased nutrient transit to the distal gut results in enhanced exposure of distal EECs to ingested stimuli and consequent elevations of GLP-1 and peptide YY secretion. GLP-1, despite having some effect on hunger, is not required for early post-operative weight loss, but it is a strong driver of insulin secretion, acting in synergy with high glucose peaks resulting from rapid glucose absorption."

"Surgery to the gut can have major effects on whole body metabolism, particularly if it alters intestinal anatomy, motility, or gastric emptying," Dr. Gribble said. "If digestion and absorption are shifted after surgery to a different region of the small intestine, this can have profound effects on gut hormone secretion, in turn targeting a variety of pathways, including appetite and insulin secretion."

"There is a lot of interest in industry in developing drugs that mimic the surgical outcomes of bariatric surgery for the future treatment of type 2 diabetes and obesity," she said. "It seems that just mimicking the high GLP-1 levels is not enough, because injectable GLP-1 mimetics have been around for a number of years, and whilst being highly effective treatments for type 2 diabetes and obesity, they are nowhere near as good as bariatric surgery."

"The prevailing opinion is that the major benefits of bariatric surgery arise from a combination of physiological changes, including increased GLP-1, peptide YY, and oxyntomodulin," Dr. Gribble said. "There are a number of clinical trials at the moment testing the effects of synthetic peptides designed to target 2 or 3 different gut hormone receptors (e.g. GLP-1 with GIP; GLP-1 with glucagon), in the hope that they will have better clinical outcomes that the current GLP-1 mimetics."

SOURCE: Cell Rep 2019

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