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GLP-1 and colon cancer

Study links GLP-1 to increased risk of colon cancer

The paper now raises the possibility that GLP-1 is an intestinal growth factor

Previous studies have indicated that bariatric surgery could result in an increased risk of developing colon cancer and now researchers from Mount Sinai Hospital in Toronto, Canada, think they may know why. They believe that as much of the stomach and small intestine is bypassed, the food that is consumed is not completely broken down when it reaches the large intestine, or colon. That in turn appears to stimulate overproduction of a gut hormone that may spur the growth of polyps in the colon that have a propensity to become malignant.

In the paper, GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7 published in the journal Cell Metabolism, the researcher explain that the gut hormone such as glucagon-like peptide-2 (GLP-2) is also a gut growth factor, which stimulates cell division in the intestines. Using genetic tools to dissect how the molecule affects cells in the intestine, they demonstrated that increasing the activity of glucagon-like peptide-1 (GLP-1) or eliminating its action by deleting the GLP-1 receptor, can increase or decrease the incidence of intestinal tumours in mice.

"For many years, people focused on GLP-1 as a beta cell growth factor, and some investigators raised questions about the possibility of pancreatic cancer," said senior author, Dr Daniel Drucker an endocrinologist at Mount Sinai Hospital's Lunenfeld-Tanenbaum Research Institute and a Professor of Medicine at the University of Toronto. “We don't have any evidence that that's the case; however, our paper now raises the possibility that GLP-1 is an intestinal growth factor. No previous studies to date have linked long-term use of GLP-1-based drugs with increased rates of cancer; however, we think patients with a previous history, or increased risk, of colon cancer may not be ideally suited for these therapies."

Based on the mouse data, Drucker is also raising questions about the long-term safety of new investigational drugs in clinical development for diabetes and other metabolic diseases, which elevate GLP-1, GLP-2, and bile acids. For example, drugs targeting the glucagon receptor may potentially lead to increased circulating levels of GLP-1, GLP-2, and bile acids, depending on the dose and duration of treatment.

Daniel Ducker

In studies in laboratory mice, a research team led by Drucker found the digestive hormone GLP-1 was "a pretty potent growth factor" for the intestine in the animals, as well as a catalyst for intestinal tumours in other lab mice specially bred to study colorectal cancer.

"If we gave the mice more GLP-1, they got more tumours," said Drucker. "If we took away the GLP-1 receptor from those mice, genetically, they got fewer tumours. So this gets us pretty convinced that we're onto something."

The concern about colon cancer made headlines in 2013 when a Swedish-UK study of more than 77,000 obese patients showed that those who had undergone bariatric surgery had a 60 per cent increased risk of developing the malignancy compared with the general population.

Published in the Annals of Surgery, the researchers reported that people who had the surgery more than tenyears before the study's conclusion, the number of cancer cases was 200 per cent higher than what was expected for the population as a whole; obese subjects who had not had the operation had a 26 per cent higher risk of colon cancer than the general population, but that figure remained stable over time.

"So if you say under what conditions might a human find themselves with increased levels of GLP-1 and the risk for intestinal tumour formation, probably the best delineated situation is the condition of bariatric surgery," he said, explaining that patients have elevated levels of GLP-1, other digestive hormones and bile acids, which are all known to stimulate intestinal growth.

Calling bariatric surgery the best available treatment for obesity and Type 2 diabetes, Drucker said eligible patients shouldn't shy away from the operation but should ensure they have regular screening for colon cancer afterward.

"We're pretty conservative about not overstating the potential clinical relevance of our studies done in mice, but mouse data always generate a hypothesis, and my hypothesis would be that if you have increased levels of gut-growth molecules, I would consider following up with regular colonoscopies for the appropriate patients," he added.

While the research needs to be replicated by other researchers and confirmed in humans, he said patients should discuss the potential link between increased GLP-1 and colon cancer with their doctors.

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