Diabetes Forecast April 2004

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FOR TYPE 2

A Gut Response

The Next Generation Of Type 2 Drugs

Gut hormones are a new frontier in the race to develop new drugs to treat type 2 diabetes.
By Terri Kordella

When you think of hormones, chances are you think of insulin, estrogen, testosterone, and maybe adrenaline. But did you know that your gut, from your stomach all the way to your colon, makes hormones, too?

These gut hormones exert a lot of influence over your digestion, blood glucose levels, appetite, and weight. That's why they're the subject of hot new research in the development of drugs for type 2 diabetes. In fact, gut hormones could very well be the Next Big Thing in the treatment of type 2.

GLP-1

Glucagon-like peptide-1 (GLP-1) is produced when you eat by the cells that line your gut. It stimulates insulin production in the islet cells of your pancreas.

Type 2 diabetes is caused, in part, by the inability of the pancreas to produce enough insulin to meet the body's needs. Eventually, the insulin-producing islet cells in the pancreas begin to burn out. This might lead you to believe that stimulating the pancreas to produce more insulin would hasten islet-cell burnout. But scientists have discovered that GLP-1 delays damage to the islet cells and thus increases their lifespan.

In one study, researchers in the United States and Italy cultured human islet cells in the lab for five days. Some of the cells were treated with GLP-1, while others were not.

After five days, the researchers noted how many islets were still alive and looked for the presence of cell proteins that would either trigger or delay cell death.

The cells that were treated with GLP-1 lived longer. By the third day, 15.5 percent of untreated cells had died, but only 6.1 percent of the cells treated with GLP-1 had died. At the end of the study, 18.9 percent of the untreated cells had died, but only 8.9 percent of the cells treated with GLP-1 had died. Among the surviving cells, those treated with GLP-1 showed fewer signs of impending cell death. Moreover, when the researchers exposed the surviving cells to glucose, those treated with GLP-1 produced more insulin than their untreated counterparts.

But that's not all. Researchers conducting other studies have found that GLP-1 can also slow the rate at which your stomach empties its contents into your intestines, a process called gastric emptying. This has two benefits. First, you feel fuller, longer, making it easier for you to eat less over the course of the day and therefore lose weight. Second, because glucose from your food is absorbed in your intestines, slowing the rate at which food enters your intestines means slowing the rate at which glucose gets into your blood. That can help prevent after-meal blood glucose spikes.

There's just one glitch with GLP-1: The kidneys break it down and clear it out of the body fairly quickly. This leads us to…

Liraglutide

Researchers at Novo Nordisk Pharmaceuticals are currently studying a substance derived from GLP-1 known as liraglutide. This substance decreases the rise in blood glucose after a meal and remains active in the bloodstream longer than GLP-1.

In one small study involving 11 participants with type 2, researchers found that an injection of liraglutide at bedtime increased insulin secretion overnight and was able to lower blood glucose levels throughout the day.

Exendin-4

Exendin-4 is a hormone much like GLP-1. It's included in the article because it acts like GLP-1; it stimulates insulin secretion in the islets and slows gastric emptying. But even though exendin-4 acts like a gut hormone, it's not found in the gut. In fact, it's not even found in humans. It's found in the saliva of a poisonous lizard from the American southwest called a Gila monster. Gila monsters eat only several times a year. The rest of the time, their pancreases are turned off. When they eat, they secrete exendin-4 to turn their pancreases back on.

Researchers at Amylin Pharmaceuticals, Inc., and Eli Lilly and Co. have derived a synthetic drug from exendin-4 called exenatide. Exenatide does everything GLP-1 does, but it breaks down in humans much more slowly than GLP-1.

In one clinical trial of the drug, researchers gave 63 people with diabetes two shots of exenatide each day for 20 weeks. At the beginning of the study, the participants had an average A1C of 8.6 percent. By the end of the study, the participants' average A1C dropped to 7.2 percent, with more than half of the participants achieving A1Cs below 7 percent. The participants' average fasting blood glucose went from about 217 mg/dl (considered high) to about 187 mg/dl (a marked improvement). Moreover, the participants had an average weight loss of just over five pounds.

Phase III clinical trials of exenatide have been completed, and the companies are expected to submit the drug to the Food and Drug Administration for approval in the first half of 2004. The approval process, however, may take up to two years.

Ghrelin

Ghrelin (pronounced GREY-lin) stimulates your appetite. It's made primarily in your stomach, but smaller amounts of it are also produced in part of your brain called the hypothalamus. Levels of ghrelin increase before a meal and decrease after a meal.

Ghrelin presents a conundrum for scientists. On the surface, it would make sense that people who are obese would have higher levels of ghrelin in their blood plasma, which would account for a greater appetite and heavier weight. But so far, the opposite appears to be true: People who are obese have less ghrelin in their blood plasma than their lean counterparts.

Researchers at the University of Pittsburgh may have found an important clue in solving the mystery. They collected hypothalamus tissue from 24 deceased donors. Eight of the donors were lean, and 16 of them were obese. They found more ghrelin in the hypothalamuses of the obese donors than in the lean donors. So, while ghrelin exists in both blood plasma and brain tissue, high levels in the brain and high levels in the blood may mean very different things.

In another study, the same researchers studied ghrelin in eight living participants. Four were lean and four were obese. The researchers drew blood and measured the ghrelin in the participants' blood plasma. As expected, ghrelin levels were 13 percent lower in the blood plasma of the obese group compared with the lean group.

But then the researchers took samples of cerebrospinal fluid—the fluid that fills the spaces in and around the brain and spinal cord—from the eight participants. They found that levels of ghrelin were 95 percent higher in the obese group than in the lean group. Therefore, ghrelin secreted by the hypothalamus may play a role in obesity, perhaps as much as or more than ghrelin secreted in the stomach.

Researchers at Stanford University in Stanford, Calif., found that blood levels of ghrelin were lower in obese people who have insulin resistance, a precursor to diabetes, than in obese people who had normal insulin sensitivity. People who are insulin-resistant tend to have high levels of insulin in their blood. Therefore, it may be that when there is an excess of insulin in the blood, it somehow interacts with ghrelin to contribute to weight gain in obese people in spite of low blood levels of ghrelin. The researchers also noted that ghrelin levels do not fall after a meal in obese people as much as they do in lean people.

Gut hormone research is a young field, and it may be several more years before there are any new drugs for type 2 diabetes. However, scientists make new discoveries with each passing month, and the future looks promising for a new class of drugs, one that may have its origins right in your own digestive system.

 

Terri Kordella is associate editor of Diabetes Forecast.

Other Contenders

GLP-1, exenatide, and ghrelin are the Big Three in gut hormone research, but they are not the only gut hormones scientists are studying. Two other hormones are the subject of much research with respect to appetite and weight control. Because type 2 is related to obesity, scientists are researching these hormones with an eye toward helping people at risk for type 2 to lose weight.

Oxyntomodulin, a hormone made in the lower gut, has been shown to reduce appetite and food intake. Thirteen lean participants in a British study ate less at a buffet after receiving oxyntomodulin intravenously than at prior meals. They also reported being less hungry, and they ate less, for a full 12 hours after receiving oxyntomodulin.

Peptide YY (PYY), produced in the intestines, has also been shown to decrease appetite and food intake. In a separate British study that included 12 obese and 12 lean participants, researchers noted that natural fasting and after-meal levels of PYY were lower among the obese participants. Then, two hours after receiving PYY intravenously, the obese participants and the lean participants decreased their caloric intake during a lunch buffet by 30 percent and 31 percent, respectively. Both groups also ate less for 24 hours after receiving PYY.
—T.K.