Two recent reports on the success of bariatric surgery in treating diabetes associated with obesity have important implications for the field of metabolic disease, including future approaches to the treatment of obesity and diabetes, and broader implications for biomedical research.
First, a bit of history. My research has focused on diabetes and obesity in humans and in animal models. Despite the field’s amazing scientific progress over the past 35 years, which dramatically expanded our understanding of the genetic and biochemical pathways that regulate bodyweight and blood sugar, and despite tremendous investment in basic research and pharmaceutical research and development, obesity and diabetes have become more prevalent, not less. Available treatments remain far less effective than we would like, and the burden of disease continues to increase. Furthermore, the current regulatory environment seems likely to slow development of major new therapies.
Now come two well-conducted studies (Schauer et al. and Mingrone et al.), each of modest size from a single center, comparing the effect of medical therapy vs. bariatric surgery on diabetes in obese patients. The reported results were striking. Surgery, already known to be more effective than medical therapy at inducing durable weight loss, is now shown clearly to be far more effective than medical therapy in improving, and even reversing, diabetes. And the amelioration or reversal of diabetes typically occurs rapidly after surgery, long before substantial weight loss occurs. This strongly suggests that the mechanism by which the procedure(s) improve diabetes must include mechanisms distinct from those associated with weight loss.
How does bariatric surgery produce this effect? Altering the levels of various gut hormones or changing the function of the enteric nervous system seem to be the likely mechanisms, but as of now, we lack a clear explanation. Identifying a mechanism apart from weight loss that explains how surgery ameliorates diabetes should be a research priority, as this could point to future medical therapies that would be effective without the need for surgery. Such research indeed exists, including at HMS, but I suspect it will now accelerate. Meanwhile, pressure will build to offer bariatric surgery to more obese patients with diabetes. It will be necessary to weigh the cost and complications of surgery against the projected long-term benefits to the patient of reductions in obesity and diabetes, while factoring in patient preference for a surgical approach to their “medical” disease.
Here is the irony of this situation. As a fellow and then junior faculty member in the 1970’s and 80’s, I saw patients with severe obesity and diabetes who experienced rapid and durable reversal of diabetes immediately after bariatric surgery. At the time, it was evident that something interesting was going on. Indeed, reports from a number of centers demonstrated this phenomenon, but typically did so without comparing the results of surgery to those in a medically treated group—i.e., a controlled clinical trial. Because we knew of no other treatment that made the disease reverse so reliably without medication, it was evident even then that surgery induced unique and important pathways that we did not fully understand. But controlled trials have power to influence our thinking, and so, these recent findings will have a major effect on the field.
Ten years ago, I was optimistic that effective medical approaches to treating diabetes and obesity would develop out of new molecular research, relegating surgical approaches to the history books. Today, that belief may be viewed as naïve. But we do now have an opportunity to capitalize on the insights gained from bariatric surgery. We can use this treatment to design experiments that will identify currently unknown pathways for the regulation of body weight and diabetes. And this approach may lead to effective medical therapies in patients unwilling or unable to undergo surgery. I believe this represents an excellent opportunity to employ a systems biology approach, which I may address in a future Dean’s Corner.