CLUES FROM THE PAST
Rubino had a hunch that something else was at work. As a research fellow in diabetes at Mount Sinai Hospital in New York in 1999, he was reviewing the medical literature one day for guidance on how to best perform bariatric surgery on a man with a BMI of 80. He found papers from the 1950s and earlier reporting that surgery for peptic ulcers had cured diabetes.

Ulcer surgery removes a portion of the stomach and reconstructs a connection to the intestine, much as gastric bypass does. Few diabetes experts had noticed the old papers; they were published in surgery journals, which endocrinologists seldom read.

His serendipitous find led Rubino to other papers describing operations on the digestive tract that cured diabetes, something that, according to medical textbooks, was unthinkable.

“Within two weeks of surgery and sometimes sooner, these patients were off their insulin, off their diabetes drugs, and with normal blood glucose levels,” said Rubino. “That was too fast to explain by weight loss.”

Yet that’s how experts explained bariatric surgery’s effect on diabetes, especially as the procedure took hold in the 1990s. Few surgeons focused on how quickly the condition disappeared, said Rubino, “or they speculated that patients weren’t eating much after the surgery, and that’s what cured their diabetes.”

He began pursuing the idea that surgery might improve diabetes directly, rather than through weight loss. “I was ignorant of diabetes, so I wasn’t burdened by too much knowledge,” Rubino said. “Something that might have seemed heretical didn’t seem impossible to me.”

Rubino modified the popular gastric bypass surgery, called Roux-en-Y, to test his idea on diabetic lab rodents. In the classic operation, the stomach is pinched off so it can hold less food. Surgical cuts keep the rest of the stomach and the top of the small intestine, called the duodenum, from receiving any food. Instead, the stomach empties directly into the bottom of the small intestine, the jejunum. In Rubino’s variation, called duodenal-jejunal bypass (DJB), the stomach is untouched, but the rest of the procedure is the same.

The rats that Rubino operated on beginning in 2000 were cured of diabetes much more quickly than their weight fell. It was the first rigorous evidence, from a well-controlled study, that gut surgery has an anti-diabetes effect.

In 2006, Rubino was ready to move from rats to people. Two patients, with BMIs of 29 and 30, underwent his procedure. Their blood sugar levels returned to normal within days, though they lost no weight. In his most recent trial, reported in March in the New England Journal of Medicine, Rubino and colleagues at Catholic University in Rome performed standard gastric bypass surgery or a procedure similar to DJB on people with type-2 diabetes. After two years, 15 of 20 bypass patients and 19 of 20 DJB patients no longer had diabetes.

Curiously, although patients shed pounds, there was no correlation between weight loss and blood glucose, the key marker of diabetes. “Bariatric surgery is more effective on diabetes than obesity,” said Rubino. “Patients don’t become lean, but they do not have diabetes anymore.”

FROM GUT TO BRAIN

Research from the University of Toronto, reported online this month in Nature Medicine, may finally explain why. It examined the effects of bypass surgery on rats with type-1 diabetes, which is considered even harder to treat than type-2. Normally the jejunum receives only digested mush, as nutrients have already been absorbed in the duodenum, explained lead researcher Tony Lam.

Bypassing the duodenum allows the jejunum to receive an influx of nutrients for the first time, said Lam. Sensing them, the jejunum sends a “got glucose!” signal to the brain. The brain interprets that as a sign of glucose overabundance and orders the liver to decrease glucose production. Result: The rats no longer have diabetes.