Medical research: Time to think differently about diabetes

Wow, this is quite amazing. Diabetic people who get bariatric surgery don’t need to be on insulin anymore. This is more than just the effect of the following weight loss. Changes to GI anatomy can directly influence glucose homeostasis! Quite amazing. GI surgery can cure diabetes! 

Wouldn’t it be wonderful if they found knee replacement operations cured bipolar disorder 🙃🙃 guidelines published this week1 announce what may be the most radical change in the treatment of type 2 diabetes for almost a century. Appearing in Diabetes Care, a journal of the American Diabetes Association, and endorsed by 45 professional societies around the world, the guidelines propose that surgery involving the manipulation of the stomach or intestine be considered as a standard treatment option for appropriate candidates. This development follows multiple clinical trials showing that gastrointestinal surgery can improve blood-sugar levels more effectively than any lifestyle or pharmaceutical intervention, and even lead to long-term remission of the diseases. 

As someone who has been investigating the link between gastrointestinal surgery and glucose homeostasis since the late 1990s (see ‘Surgical breakthrough’), I have witnessed first-hand how getting to this point has required many clinical scientists to put aside long-standing preconceptions. Indeed, the guidelines come nearly 100 years after the first clinical observations that diabetes could be improved or even resolved by a surgical operation (see ‘A long road’)2. The evidence that surgery can prompt the remission of a disease that has long been considered irreversible could bolster searches for what causes diabetes and even reinvigorate hopes to find a cure. But future progress will require more thinking outside the box.

Surgical breakthrough
In 1925, a report in The Lancet2 described a ‘side effect’ of a gastrointestinal operation to treat a peptic ulcer. This was the almost overnight resolution of an excess of sugar in the urine (glycosuria) — the chief symptom of diabetes at the time. Similar observations were reported in subsequent decades and became more common after the advent of bariatric or weight-loss surgery in the mid 1950s, which led to more people with diabetes receiving these types of operations. And during the 1980s and 1990s, resolution of diabetes after bariatric surgery was noted on many occasions, including in a landmark report involving more than 120 patients9.
In 1999, while working as a research fellow at Mount Sinai School of Medicine in New York City, I stumbled across a report showing that nearly all people with type 2 diabetes who had undergone a complex bariatric operation (biliopancreatic diversion) had completely normal blood-sugar levels as early as one month after surgery. They had been able to stop taking medication and come off a low-calorie diet. I wondered whether gastrointestinal surgery could influence diabetes directly. If so, surgery could be used to treat diabetes or to understand how it works.
The next day, I persuaded my mentor to seek approval from the institutional review board to run trials in humans. Failing to obtain approval, we turned to rats to investigate whether a modified form of gastric-bypass surgery could directly influence glucose homeostasis. Our experiments confirmed that it could, although it took us more than two years to publish the findings. 
In 2006 and 2007, surgical teams showed that the operation had the same effect in humans, and other groups began to investigate the molecular mechanisms that might be responsible. On the back of these studies, a multidisciplinary group of leading clinicians and scientists at the first Diabetes Surgery Summit in 2007 reviewed the preliminary mechanistic and clinical data available on the effects of surgery on diabetes and established an agenda for research priorities. The summit inspired the randomized clinical trials that now provide the evidence supporting a role of surgery in diabetes. In September 2015, the introduction of surgery into standard care for type 2 diabetes was formally recommended by the participants of the second Diabetes Surgery Summit. 
Clinical shift
The number of adults around the world with diabetes quadrupled from 108 million in 1980 to 422 million in 2014 (ref. 3). About 90% of these people have type 2 diabetes — a major cause of kidney failure, blindness, nerve damage, amputations, heart attack and stroke. Fewer than 50% of people with type 2 diabetes control their blood-sugar levels adequately by changing their diet or exercise regime, or by taking drugs.

Bariatric or weight-loss surgery refers to various procedures. Surgeons may, for instance, remove a portion of the person’s stomach or divide the stomach into two and reroute the small intestine to the upper part (see ‘Gastric bypass’). Since the mid 1950s, people whose body mass index (BMI) is greater than 40 have received bariatric surgery to induce weight loss. Many of these people also had diabetes. The new guidelines advise that such procedures (metabolic surgery) be considered specifically for the treatment of diabetes in people who have not adequately controlled their blood-sugar levels through other means, and whose BMI is greater than 30 (or 27.5 for people of Asian descent). Perhaps more significantly, they also state that the gastrointestinal tract is an appropriate biological target for interventions designed to treat diabetes. 
These recommendations arguably signify the most radical departure from mainstream approaches to the management of diabetes since the introduction of insulin in the 1920s. They are based on findings from a large body of work, including 11 randomized clinical trials conducted over the past decade1. In these studies, most surgically treated people (up to 80% in a recent 5-year follow-up4 of a randomized trial) fall into one of two categories. Either their diabetes goes into apparent remission or their blood-sugar levels can be stabilized using reduced medication or exercise and a calorie-controlled diet (see ‘Big benefits’).
Non-randomized studies, involving people receiving surgery and matched subjects treated with standard interventions, suggest that surgery may also reduce heart attacks, stroke and diabetes-related mortality1. And several economic analyses suggest that the costs of surgery (roughly US$20,000–25,000 per procedure in the United States) may be recouped within 2 years through reduced spending on medication and care. 

  • The effects of surgery on diabetes are dramatic. Yet it has taken nearly a century to unearth them since observations of major improvement or remission of diabetes after surgical operations were first reported. 

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