Full Without Food: Drug Therapy May Someday Replace Obesity Surgery

Claire Ainsworth

At 43, New York chef Thomas Pallozzi-Haynes was morbidly obese and close to despair. While his initial weight gain had been triggered by type 2 diabetes, he now found himself in an endless cycle of failed diets and weight gain.

The chef's long commute to work was a misery, thanks to backache and gut cramps from his diabetes medication. Like many overweight people, he ran a daily gauntlet of judgmental comments from other people, and eventually struggled to walk, sleep and even breathe properly.

"My biggest fear was that something would happen to me medically," he recalls. "How would I take care of my wife and child?"

Pallozzi-Haynes's life turned a corner when he watched a TV documentary about gastric bypass surgery, designed to physically limit the amount of food that the stomach can hold and restrict the gut's absorption of nutrients. In April, 2009, he signed up for the operation, which closes off most of the stomach, leaving only a sac about the size of a walnut to receive food. Then the stomach's exit is replumbed so that it connects to the gut further down .

Clearly, these drastic procedures will cut your calorie intake, but here's the strange thing: The operation is much more successful than anyone could have expected. Even though they can't eat as much, people who have undergone surgery are not constantly ravenous, in stark contrast to those dieting through will power alone. It seems the gut normally secretes hormones that make us feel hungry or full, and bypass surgery ramps up production of the ones that make us feel full.

In fact, we're now starting to realize that the gut plays a bigger role in appetite and blood-sugar regulation than previously thought. Several groups are trying to develop drugs that enable people to get the effects of surgery without having to undergo any operation.

"We should, in the end, be able to mimic bypass," says Steve Bloom, an endocrinologist at Imperial College London working on appetite control. "What we call medical bypass."

Obesity is certainly a condition badly in need of better medical treatment. In the U.S., over a third of adults are now classed as obese, while the UK and Australia are not far behind. Ideally, of course, people would lose weight by dieting and preferably doing more exercise, too. The trouble is that dieting is unpleasant and difficult, and despite a multibillion-dollar diet industry, few obese people succeed in losing significant amounts of weight. Perhaps most depressingly, the majority of successful dieters eventually regain most or all of their lost weight.

Once seen as a last-ditch measure for those unable to stop eating themselves to death, obesity surgery, or bariatric surgery as it is also known, is becoming increasingly common, with an estimated 200,000 procedures carried out in the U.S. in 2008 alone. That is partly due to growing numbers of potential candidates, but also to the increasing safety of the surgery, which can now done by keyhole techniques. While any operation is inherently more risky for someone who is overweight, the chance of dying during or just after surgery is quoted at about 0.5 percent, whereas staying obese can cut up to 13 years off life expectancy.

In the normal gut, food is digested in the stomach for around an hour before passing into the first section of the small intestine, the duodenum. It then makes its way down the rest of the small intestine, the jejunum and ileum, and from there into the large intestine.

VARIOUS TYPES OF SURGERY

There are various types of obesity surgery. The simplest merely reduce the useful size of the stomach, for example with a gastric band, an adjustable silicone ring that encircles the top part of the organ.

The most radical procedures surgically reduce the stomach size and connect the exit straight to the ileum. This carries a high risk of malnutrition and other complications, and is now done only rarely. The most common procedure falls between these two extremes. Known as the Roux-en-Y gastric bypass, it combines surgical stomach reduction with bypassing just the first section of the small intestine. This is what Pallozzi-Haynes underwent.

A gastric bypass is no easy ride. In the first few days after the operation, all patients can do is sip liquids. For several weeks they need to stick to tiny portions of mushy foods. As time goes by, they can begin to eat a more varied diet, although some foods, such as steak, will always be hard to digest.

DOUBLE-TAKE

Some people who just have a gastric band fitted are able to "cheat" by grazing constantly or bingeing on high-calorie foods that can slip through the band, such as ice cream. That means fewer people lose significant amounts of weight.

With a bypass, on the other hand, the results are usually dramatic. On average, recipients end up losing around a third of their body weight. This still leaves them overweight, perhaps slightly obese, but not so heavy that their life is in immediate danger, and they can live a much more normal existence.

The question intriguing researchers is why patients are not ravenous after surgery. In hospital surviving on liquids and jelly (jello), Pallozzi-Haynes found the lack of hunger pangs strange. Now he has to keep an eye on his watch to remind himself to eat. Four months down the line, Pallozzi-Haynes has lost 34 kilograms and his weight is still falling. He has seen his blood pressure and cholesterol levels drop back into the healthy zone and, most remarkable of all, he no longer needs to take any diabetes medication. His friends, he says, "are walking by doing a double-take".

So just what is going on in Pallozzi-Haynes's body? Over the past decade, genetic and endocrinological research has pointed to a complex set of hormones and neural signals that control food intake (New Scientist). There seem to be two systems at work: one that aims to keep body-fat stores constant over long periods of time, and another that controls food intake over the course of a day.

It is this short-term control mechanism that has been thrust into the limelight thanks to gastric bypass surgery. "Suddenly, the signaling from the gut has turned out to be much more potent than people believed -- and possibly a better drug target," says Nick Finer, an endocrinologist at University College London.

Our digestive system produces both hormones that make you hungry and those that make you feel full, or sated. Ghrelin, produced by the lower part of the stomach, is a powerful promoter of hunger, while the small intestine releases a number of hormones when it senses the presence of food. These aid digestion as well as producing feelings of satiety, and include cholecystokinin, glucagon-like peptide-1 (GLP-1), oxyntomodulin and PYY.

Current thinking is that changes to the levels of any or all of these hormones could be responsible for the effects of the bypass. Shrinking the stomach seems to reduce ghrelin production, which would curtail hunger signals. A bypass also delivers nutrients to the more distant parts of the small intestine faster and in greater quantities than normal, which would stimulate the release of more satiety hormones.

The other surprising outcome from bypass surgery is its effects on type 2 diabetes, a condition in which people can no longer regulate their blood sugar. After eating, the pancreas normally releases insulin, a hormone that reduces excess glucose in the blood. In type 2 diabetes, though, the body cannot respond to insulin properly or the pancreas fails to make enough of the hormone, or sometimes both.

Type 2 diabetes is much more common in people who are overweight, and it was expected that the weight loss following a bypass would improve symptoms. But doctors have been amazed by just how quickly this happens -- sometimes in a matter of hours and certainly long before any significant weight loss occurs. Many bypass patients, such as Pallozzi-Haynes, have been able to throw away their diabetes drugs.

"If you change the anatomy of the bowel, you improve diabetes like nothing else has ever done," says Francesco Rubino, who operated on Pallozzi-Haynes at Cornell University-New York Presbyterian Hospital in New York. The upshot is that bypass surgery is now being considered for diabetics of lower and lower weight - perhaps even approaching normal weight if their diabetes is severe enough.

The most likely cause of this improvement is a rise in the level of GLP-1, which is known to increase insulin production and enhance the body's response to insulin. It makes sense that hormones released after eating would have this effect. So there are two groups of people -- the overweight and those with type 2 diabetes -- who might benefit from medication that mimics the effect of gut hormones, and a great deal of research is being directed at developing such drugs.

GLP-1 was already seen as a potential lead for new diabetes drugs. One problem, however, is that the hormone itself, as with the other gut hormones so far identified, is just a small protein fragment called a peptide. If taken orally, such peptides would be digested in the stomach, so they have to be given by injection. Even then, most last only a few minutes in the bloodstream, making it hard to achieve long-lasting effects, be it suppressing appetite or enhancing the insulin response. Researchers are working on ways to prolong the action of peptides by tweaking their chemistry or finding ways to block the mechanisms that break them down.

WEIGHT-LOSS DRUGS

Two mimics of GLP-1 have been licensed for treating type 2 diabetes. As well as improving glucose regulation, they do seem to cause modest weight loss, although not as rapidly as a gastric bypass.

For example, trials of exenatide (Byetta), developed by U.S. biotech firm Amylin in partnership with Eli Lilly, have shown it causes people to lose 1 to 1.5 kilograms over three months, with continued slow weight loss for at least two years. This is especially valuable as other diabetes medicines tend to cause weight gain. On the downside, it has to be given by injection twice daily -- although a once-weekly version is in development -- and can cause nausea at first.

Partly thanks to the new findings about the importance of gut signaling, the makers of exenatide and other GLP-1 mimics are now investigating whether they cause weight loss in people who are not diabetic.

Why is the weight loss seen in diabetics taking these drugs less dramatic than that seen after bypass surgery? One issue may be dosage: the drugs were originally developed to treat diabetes, not obesity, and it may be that their insulin-enhancing effects kick in at a lower dose than their satiety-enhancing ones. Higher doses may produce more weight loss, but would risk more side effects too.

A more significant reason may be that something as important as gut signaling, and as complex -- the gut produces more than 50 signaling chemicals -- cannot be controlled by one hormone alone. Using more than one might produce greater effects. Researchers from Indiana University-Bloomington hit the headlines in July 2009 when they reported a weight loss of more than 25 percent in mice given a peptide that, thanks to some chemical tweaking, can act as a mimic of both GLP-1 and a related hormone, glucagon (Nature Chemical Biology).

Another gut hormone undergoing clinical trials is oxyntomodulin, which enhances satiety. In one study, volunteers taking the hormone lost 2 kilograms in four weeks (Diabetes). Bloom's team, which carried out the trial, have made an altered version of the hormone that lasts longer in the bloodstream and is now being developed by pharma company Wyeth. PYY and other combinations of hormones are also being investigated by various teams.

A way to replicate the effects of bypass without undergoing surgery would surely be of benefit as any kind of operation carries risks, particularly for those who are overweight or have diabetes. For people who are morbidly obese, though, the benefits of surgery still outweigh the risks.

Pallozzi-Haynes, for one, feels the transformation in his health and life expectancy clearly outweighs any eating restrictions the procedure has placed on his life. He feels a little weak now and again because he's losing so much weight, including some muscle as well as fat. But for him that's an acceptable trade-off.

"Losing 15 yards on my golf drive pales in comparison to being able to see my son and be around for him when he's in high school, as opposed to being dead," he says. "I have a whole new lease of life."

Claire Ainsworth is a science writer based in Southampton, UK.

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