Curing Type 2 Diabetes with Surgery: It Works -- Now Let's Figure Out Why

During my endocrinology training, I was captivated by a phenomenon I’d seen on the wards, and had just started to read about in the literature: type 2 diabetic patients receiving bariatric surgery exhibiting rapid, seemingly instantaneous improvements in their glycemic control, apparently related to profoundly reduced insulin resistance as a consequence of the surgery. 

The first teaching seminar I gave as a fellow, at Endocrinology Grand Rounds, asked the distinguished medical faculty who gathered in the Ether Dome, “Is Diabetes a Surgical Disease?”

At the time, the answer was, “Yes?”  Now, two recent reports presented today at the ACC, and simultaneously published in the NEJM (here and here), seem to upgrade this answer to “Yes!” 

Both reports conclude that bariatric surgery surpasses medical therapy as a treatment for type 2 diabetes, and are fascinating not only because of the immediate clinical implications (as discussed by Matt Herper here, in an an NEJM editorial comment here), but also because there’s some really cool underlying science that nobody seems to understand.

The fundamental paradox is the same mysterious clinical phenomenon that so intrigued me years ago: the drastic improvement in diabetic function that occurs significantly before most of the weight is lost. 

The authors of the first study note, “Reductions in the use of diabetes medications occurred before achievement of maximal weight loss, which supports the concept that the mechanisms of improvement in diabetes involve physiologic effects in addition to weight loss, probably related to alterations in gut hormones.”  

The authors of the second study were also struck by the rapid improvement in glycemic control they observed, reporting that all patients treated surgically were able to discontinue all their diabetes medicines within fifteen days of their operation – a remarkable result (and entirely consistent with my own clinical experience).  Almost all of the surgically-treated patients remained free of diabetes after two years, while none of the medically-treated patients were as fortunate.

As the authors write, “there was no correlation between normalization of fasting glucose levels and weight loss after gastric bypass and biliopancreatic diversion, findings that are consistent with results of previous studies, which suggests that such surgeries may exert effects on diabetes that are independent of weight.” 

The authors also point out this result is in contrast with gastric banding procedures (which constrict the stomach but don’t otherwise alter the anatomy); the improvement in diabetes seen in those patients does appear to correlate more directly with weight loss.

The intriguing scientific question is how can bariatric surgery result in an almost immediate improvement in the insulin resistance profile of diabetic patients?  To my mind, this is among the most important unanswered questions in endocrinology, and medical science more generally.  While the effect is generally attributed to “gut hormones” (as the authors of the first study write), the biology beyond that gets a bit murky.

To be sure, some companies are working on it – the example that springs first to mind is NGM Biopharmaceuticals, a small Bay-area biotech (with which I have no personal nor professional connection) founded in 2008 as an ambitious science play by The Column Group, Rho Ventures, and Prospect Venture Partners.  I’m sure others are working on this challenge as well.

A final point – as attracted as we are to the view of basic science driving clinical medicine, the experience with gastric bypass surgery arguably exemplifies the reverse, and represents a triumph of empiricism, as well as a reminder of the value of human physiology (see here), and more generally, the importance of studying people (and not just parts of people). 

It also would not be the first (nor will it be the last) time that medical sophisticates learned a valuable lessons from those laboring – often, as in the case of many bariatric surgeons, with inadequate respect – on the front lines of patient care.

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David
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