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Newly discovered actions for gut hormone GLP-1 has implications for bariatric surgery and immune disorders

March 03, 2015

In two papers published online today in the journals Cell Metabolism and Diabetes, Dr. Daniel Drucker’s research team at Mount Sinai Hospital’s Lunenfeld-Tanenbaum Research has uncovered new actions of a gut hormone which is typically targeted by drug therapies in the treatment of type 2 diabetes and obesity.  The hormone, called glucagon-like peptide-1 (GLP-1), stimulates insulin production, improves glucose control and helps reduce body weight.  
 
In these two new studies, Dr. Drucker’s team has discovered that GLP-1 has other actions in the body. His team found that GLP-1 stimulates growth of the small and large bowel, which has potential implications for the risk of colon cancer in patients who may be at risk. The researchers also found a new link between GLP-1 and the body’s immune response, which may be helpful for treating disorders impacted by the body’s immune system, such as liver disease, certain cardiovascular diseases, and diabetes.
 
Stimulation of intestinal growth
 
In a paper published online in the journal Cell Metabolism today, researchers led by Dr. Jacqueline Koehler, a research associate in the Drucker lab, identified a new gut-growth promoting role for GLP-1, demonstrating that increasing the activity of GLP-1, or eliminating its action by inactivating the receptor protein for GLP-1, can increase or decrease the incidence of intestinal tumors. In animal models that are prone to cancer, increased levels of GLP-1 were associated with a greater risk for promoting tumour growth.
 
This new information may be relevant for patients who undergo gastric bypass as a treatment option for obesity. While bariatric surgeries have been linked to a decreased risk in many types of cancers, it appears that colon cancer is the only outlier, and the new study published today from scientists at the Lunenfeld-Tanenbaum Research Institute may provide an explanation for this this association.
 
After a gastric bypass, there are increased levels of gut hormones, including GLP-2, GLP-1 as well as bile acids. Gut hormones and bile acids also act as gut growth factors, promoting increased cell proliferation in the intestine.  In the paper, the team of researchers recommends regular colonoscopies for patients who may be at risk for colon cancer who have had, or plan to pursue, surgery for obesity.
 
“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 of, or increased risk of colon cancer may not be ideally suited for therapy with GLP-1 receptor agonists,” says Dr. Drucker.
The paper in Cell Metabolism is titled: “GLP-1R Agonists Promote Normal and Neoplastic Intestinal Growth through Mechanisms Requiring Fgf7”. The authors are: Jacqueline A. Koehler, Laurie L. Baggio, Patricia L. Brubaker, and Daniel J. Drucker.
 
 
New link between GLP-1 and the gut microbiome
In another paper publishing online in Diabetes (an official journal of the American Diabetes Association) today, Dr. Drucker’s research team has uncovered a new role for GLP-1 in the gut. Researchers led by Bernardo Yusta and Laurie Baggio from Dr. Drucker’s lab described a unique connection between GLP-1 and immune cells within the gut, which influence the body’s response to foreign pathogens.
The paper shows that GLP-1 helps to regulate a subset of immune cells, called intestinal intraepithelial lymphocytes, by activating specific proteins on these cells and controlling the intestinal immune response, which helps to fight foreign invaders in the body. The team noticed that mice that lack the receptor protein for GLP-1 developed abnormal gut microbial flora and showed increased inflammation of the gut, highlighting the importance of communication between GLP-1 and the gut’s immune cells.
The findings are significant because the development of many diseases, such as liver disease, diabetes, atherosclerosis, blood vessel disease, and obesity, can be modified in part by inflammation originating from the gut.
 
“This study revealed a new and unexpected function of GLP-1 action in the gut immune system, with implications for the use of drug therapies that target this hormone in the treatment of disorders that are impacted by the immune system,” says Dr. Drucker.
 
His team is now looking at how much effect GLP-1 has on the immune system when the body is in a normal, healthy state to understand how to best treat the body’s abnormal immune response when things go awry.
 
The paper in Diabetes is titled “GLP-1 receptor (GLP-1R) agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte (IEL) GLP-1R”. The authors are: Bernardo Yusta, Laurie Baggio, Jacqueline Koehler, Dianne Holland, Xiemin Cao, Lee Pinnell, Kathlene Johnson-Henry, William Yeung, Michael Surette, Annie Bang, Philip Sherman, and Daniel Drucker.
 
About the Drucker lab at the Lunenfeld-Tanenbaum Research Institute
 
Dr. Daniel Drucker and his research team study a family of gut hormones that are produced in the gastrointestinal tract and brain. These hormones control blood glucose and insulin secretion, regulate appetite and control the absorption of nutrients from the food and the conversion of those nutrients to energy. In his lab, Dr. Drucker identifies substances that mimic and enhance the ability of these naturally occurring hormones for use in treating disease. Since enhanced gut hormone action may be beneficial in diabetes, obesity and inflammatory bowel disorders, these substances have real potential to lead to new and better treatments for diseases that afflict millions of people worldwide.
Drucker’s lab has primarily focused on two types of incretin (gut hormones that increase insulin) hormones. When food is ingested, these hormones help the pancreas produce more insulin to help assimilate the energy (glucose) from the food. Diabetes can interfere with the body’s ability to handle glucose, causing blood sugar to spike. By identifying the function of incretin hormones, the Drucker lab has helped to enable the development of two new classes of drugs, GLP-1R agonists and DPP-4 inhibitors, both of which help people with type 2 diabetes produce insulin and control glucose. This work has helped millions of patients around the world.
 

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