Imagine not being able to eat a meal with family or friends. That is the case for people who have a condition known as short bowel syndrome (SBS). When large segments of the intestines are missing, often due to surgery for disease or trauma, patients can be left with insufficient bowel to absorb dietary nutrients and fluids, also called intestinal failure. These processes normally take place in the small intestine (i.e., absorption of ingested carbohydrate, fat, protein and vitamins) and large intestine (i.e., water absorption). Unable to move these essential dietary constituents from the intestines into the bloodstream, individuals with SBS often develop unsustainable diarrhea and malnutrition, resulting in a requirement for nightly intravenous feeding and fluid supplementation in order to survive.
Until recently, there were few treatments for this, fortunately, very rare condition. However, in 1996, a team of researchers at the University of Toronto, of which I was a part, identified an intestinal hormone that stimulates both the growth and the function of the small and large intestines. Known as glucagon-like peptide-2 (GLP-2), this hormone is a peptide composed of 33 amino acids. Although the natural hormone is rapidly destroyed in the circulation, the replacement of amino acid #2 (alanine) with another amino acid (glycine) prevents this degradation while still permitting the biological actions of GLP-2.
With this discovery, clinical trials in humans with SBS were rapidly initiated, and the glycine2-GLP-2 analog was found to improve the ability of these individuals to absorb both nutrients and water, in association with increased growth of the intestines. The success of these trials was so dramatic that this analog, named teduglutide, was approved in 2012 by the FDA and in 2015 by Health Canada for the treatment of adults with SBS who are dependent upon intravenous feeding/fluids; use in children with SBS aged 1 or greater has more recently been approved. Collectively, the findings of clinical trials in patients with SBS, as well as real-world evidence, have shown that teduglutide reduces the need for intravenous nutrients and fluids in ~80% of individuals after 2-years of treatment; excitingly, ~20-30% of these people are able to completely switch to normal, oral feeding and drinking after 2-years, thus enabling them to participate fully in the normal activities associated with daily meals.
The biological effects of GLP-2 (and its analogs) are highly specific for the intestinal tract, as the protein receptors that mediate its actions are almost exclusively located in this organ, resulting in relatively few side-effects associated with the use of this hormone. However, the actual signaling pathways remains somewhat of an enigma, as the GLP-2 receptors are not located in the cells that respond to GLP-2 but, rather, are located in neighbouring cells that release secondary mediators which then act directly on the intestinal cells. As one example, GLP-2 acts on subepithelial cells that lie directly underneath the intestinal cells to cause the expression of a hormone called insulin-like growth factor-1 (IGF-1). IGF-1 then travels the short distance to the intestinal cells where, through its own IGF-1 receptor, it stimulates intestinal growth, nutrient absorption and barrier function (the latter being a physical process by which the intestines prevent the passage of noxious materials from the gut into the bloodstream). Of note, although a variety of different secondary mediators have now been identified for GLP-2 in rodents, how this hormone exerts its actions in humans remains unknown.
Of note, teduglutide is a GLP-2 analog that requires subcutaneous injection every day. Hence, a number of companies are developing novel GLP-2-based therapeutics that will, hopefully, require only weekly or even monthly injection. Additionally, data from rodents and adult humans has shown that the actions of GLP-2 and its analogs are not durable, likely meaning that life-long treatment will be required; whether this will prove to be the case in children treated with GLP-2 remains unknown, although it hoped that children may be able to adapt as they grow and, thus, be weaned off treatment. Furthermore, caution must be taken with the administration of any growth factor to humans, as there remains a possibility of abnormal growth. Studies in rodents have shown that GLP-2 analogs can enhance the growth of intestinal tumours that have been induced chemically, although there is little evidence to date that this is the case in humans.
While not a cure for intestinal failure associated with SBS, the implementation of teduglutide in the clinic has been a game-changer for patients with this rare but debilitating condition. The University of Toronto-based discovery of the biological actions of GLP-2 adds this hormone to the long-list of Canadian scientific innovations that have revolutionized the treatment of devastating conditions, including insulin for type 1 diabetes, pablum for infant malnutrition, and the related hormone GLP-1 for type 2 diabetes and obesity.
Patricia Brubaker, Ph.D., F.R.S.C., is a Professor Emerita, Departments of Physiology and Medicine and a Banting & Best Distinguished Scholar at the聽University of Toronto, Toronto, ON Canada. Dr. Brubaker completed both her undergrad and PhD at 成人VR视频.聽
