The Connection between the Gut, the Brain, and Diabetes
By: Krystal Jacques
The worldwide prevalence of diabetes has almost doubled, from 4.7% of the global adult population in 1980 to 8.5% in 2014 (1). This is thought to reflect increases in obesity, an important risk factor associated with type 2 diabetes. Now, diabetes researchers are taking a closer look at the connection between our gastrointestinal tracts and our brains to understand how gut-brain communication may impact body weight and glucose levels.
Dr. Tony Lam and his team at the Toronto General Hospital Research Institute study how the unique relationship between the gut and the brain regulates blood glucose and body weight homeostasis. After majoring in biochemistry at McMaster University, Dr. Lam completed his PhD in the Department of Physiology at University of Toronto studying liver glucose metabolism with Institute of Medical Science (IMS) faculty, Dr. Adria Giacca, whose lab studies energy excess and diabetes. “It was a challenging time-my first paper only came out towards the end of my PhD in my 5th year,” recalls Dr. Lam. However, the fulfillment of small gains each day, “performing experiments and discovering new things”, inspired him to persevere and go on to complete a postdoc (2003-2006) with Dr. Luciano Rossetti, at the Albert Einstein College of Medicine in New York.
“Dr. Rossetti was the first to posit that the brain could sense nutrients (glucose and lipids) and hormones to subsequently regulate glucose homeostasis,” Dr. Lam explains. During his postdoc, Dr. Lam expanded on his previous PhD work by determining whether the brain plays a role in regulating changes in liver glucose metabolism in rodents with diabetes and obesity. To answer this, he performed the same experiments used during his PhD, but with the addition of blocking molecules and pathways in the brain. His work in Dr. Rossetti’s lab in a relatively new field investigating the brain’s role in diabetes and obesity caught the attention of other scientists. Dr. Lam accredits his research progress to being at the right place at the right time. “I just happened to be fortunate enough to be there to learn from him [Dr. Rossetti], which resulted in my ability to publish a few first-author papers in respectable journals.”
Dr. Lam’s early and exemplary scientific contributions on the neurophysiological profile of diabetes during his postdoc work showed that the brain-liver axis can control blood-glucose levels. In parallel, other researchers in the field had shown that nutrients in the gut activate a negative feedback pathway, via the gut-brain axis, to lower appetite. These two phenomena led Dr. Lam and his own lab in Toronto (started in year 2006) on a mission to discover whether ingested nutrients in the gut-brain communication pathway can also lower glucose levels. Specifically, the Lam lab wanted to know whether nutrients ingested after a meal could activate a negative feedback pathway that stems from the gut to the brain (via the vagus nerve afferent), and whether the brain then relays a signal to the organs of the body (e.g. liver) to regulate glucose levels.
To answer this question, mice and rats are implanted with a catheter tube that stretches from their upper small intestine to an opening in their upper back, via a subcutaneous route. Nutrients, such as glucose and lipids, can then be infused directly into different parts of the upper small intestine, in an attempt to mimic the natural gastric emptying flux of nutrients into the gut that is experienced after a meal. This activates the nutrient sensing pathways in this particular part of the gut.
After 12 years of rigorous research, the Lam lab has shown that nutrients in the gut induce a neuronal signal to the brain, which in turn, can regulate glucose levels in healthy rodents. However, during pathological states, such as when rodents are fed a high fat diet, “a defect in these nutrient sensing mechanisms occurs, leading to a dysregulation of blood glucose levels,” explains Dr. Lam. “Interestingly, our lab has found that metformin and bariatric surgery—the two most common treatments for type 2 diabetes—can partly rescue this nutrient sensing pathway defect in the gut to restore glucose levels.” One of the Lam lab’s most recent findings was published in Cell Metabolism in January 2018 by one of his many exceptional students, Paige Bauer, who is currently pursuing a PhD (2). She performed genetic sequencing of an extract of the microbiome, the community of microbes living in the lumen of the small intestine. This revealed a correlation between the abundance of the Lactobacillaceae family of bacteria and metformin’s antidiabetic effect on the gut nutrient sensing pathway. Subsequent cause-and-effect studies were conducted and the findings indicate that metformin increases Lactobacillus and restores glucose sensing mechanisms in the upper small intestine to lower glucose levels in diabetic/obese rodents.
The basic scientific findings produced by the Lam lab warrants possible future clinical investigation. However, as with all meaningful research, Dr. Lam believes that “It takes time to find out whether your results in the lab can stand the test of time, and whether it’s clinically relevant. Nonetheless, we do have an idea of some molecules in this gut pathway that could work to be as effective as the existing therapies because they mimic the effect of metformin and bariatric surgery, which are both clinically effective to lower blood glucose levels.” In addition, the Lam lab’s findings on Lactobacillus are contributing to the currently exploding field of the microbiome, and to our repertoire of information on how gut bacteria has a significant role to play in several diseases.
Reflecting on his career as a researcher, Dr. Lam stresses the importance for students and scientists to be “open minded in both what you want to pursue as a career as well as in research, because nobody really knows what could happen tomorrow.” Dr. Lam continues by hinting at the philosophy he lives by, which has helped him in the rigorous research career—”It [research] is an extremely rewarding career, because it takes a lot, a lot of effort and time to validate that what you are showing is right to other people. And in exchange, to admit that you are wrong sometimes… it takes a lot of learning. And I love that about academics. It’s an art form—there’s a part of being a researcher that may not only have to do with discovering new things, but how you communicate, how you treat the field, and how you respect others.”
- World Health Organization. Global report on diabetes. [document on the Internet]. 2016 [cited 2018 Jan 10]; Available from: http://apps.who.int/iris/bitstream/10665/204871/1/9789241565257_eng.pdf.
- Bauer P, Duca F, Waise T, et al. Metformin alters upper small intestinal microbiota that impact a glucose-SGLT1-sensing glucoregulatory pathway. Cell Metab. 2018;27:101-117.