Press Release Source: American Diabetes Association
Gut Hormones Shown to Affect Obesity and Diabetes
Monday June 16, 7:00 pm ET
New Findings May Lead to Exciting Weight and Diabetes Control Drugs
NEW ORLEANS, June 16 /PRNewswire/ -- Exciting research findings about hormones in the gastrointestinal tract that affect appetite and calorie use are leading to new drugs that will help control weight and diabetes, according to reports here at the American Diabetes Association's 63rd Annual Scientific Sessions.
"More than two dozen gut hormones have emerged that affect processes in the brain and elsewhere in the body that control appetite and energy metabolism," said Peter J. Havel, DVM, PhD, Associate Professor of Nutrition at the University of California at Davis and moderator of today's symposium on GI Signals and Energy Balance, in a recent interview. "These represent promising pathways for developing new treatments for obesity and type 2 diabetes."
"This research brings us closer to understanding the many factors that control weight, an important issue in the development of type 2 diabetes, cardiovascular disease, and other diseases," emphasized Richard Kahn, PhD, Chief Scientific and Medical Officer of the American Diabetes Association.
More than 17 million Americans have diabetes, a group of serious diseases characterized by high blood sugar levels that result from defects in the body's ability to produce and/or use insulin. Diabetes can lead to severely debilitating or fatal complications, such as heart disease, blindness, kidney disease and amputations. Diabetes is the fifth-leading cause of death by disease in the U.S.
Type 2 diabetes, the most common form of the disease, usually arises in people who are over 45 and overweight but increasingly afflicts obese children and teens.
Symposia, oral papers and posters presented at the meeting covered a variety of gut hormones, including ghrelin, Apo A IV, PYY 3-36, oxymodulin, GLP-1s, and a drug similar to GLP-1s (synthetic exendin-4), which is closest to reaching the marketplace.
FOOD INTAKE AND ENERGY BALANCE
"Ghrelin is made primarily in the stomach and stimulates appetite," explained Dr. Havel. When infused in people, ghrelin increases hunger and people eat more. Ghrelin levels fall after meals, which may lead to satiety -- feeling full. Surprisingly, ghrelin levels are somewhat lower in obese people than those of normal weight, but they also do not fall after a meal in obese people as they do in lean people. Further, ghrelin levels typically rise when people lose weight, although they don't rise in those who have some types of gastric bypass surgery and lose weight.
"Ghrelin has to have a receptor that it hooks on to in order to stimulate appetite," said Dr. Havel. "So if we could find a drug to block that receptor, it could help reduce obesity."
Researchers at Stanford University reported that ghrelin levels are higher in obese people whose bodies use insulin properly and lower in those who are insulin-resistant, often a precursor of type 2 diabetes. This suggests that insulin may have a role in regulating body weight via its impact on ghrelin.
Apo A IV is made in the small intestine, and its secretion is stimulated to rise by fat intake. In animal studies, it has been shown to inhibit food intake by acting in the brain. It clearly has a role in short-term eating patterns but also may affect long-term intake.
Yet another hormone, PYY 3-36, is made in the colon and also inhibits food intake. When it is infused in people, it produces a long-lasting (12 hours) and profound reduction in food intake. "While it is an interesting potential anti-obesity target, creating a pill would be difficult because it is a small protein that will be digested before it has an opportunity to exert its action," said Dr. Havel. "However, it may be possible to find non-protein activators of the PYY 3-36 receptor."
Researchers at the Imperial College London reported on oxymodulin, a hormone made in the large intestine. Oxymodulin is released after meals, in proportion to caloric intake, and may act as a signal to brain circuits that regulate appetite. When infused into people, it significantly reduced appetite and caloric intake at the meal offered during the infusion -- as well as caloric intake over the next 12 hours. Again, this may be another potential therapeutic target for obesity.
INSULIN SECRETION AND DIABETES CONTROL
Glucagon, a hormone secreted by the alpha cells in the pancreas, helps maintain blood sugar balance by enhancing synthesis and mobilization of glucose in the liver -- increasing the levels of blood glucose. Thus it is a counter-regulatory hormone, opposing the actions of insulin. In people with diabetes, excess glucagon secretion plays a primary role in hyperglycemia.
Another class of hormones produced in the small intestine in response to food intake are glucagon-like peptides, one of which is known as GLP-1. They seem to work in the brain and the stomach. GLP-1 can stimulate insulin production without causing the potentially threatening hypoglycemia (low blood sugar levels) associated with insulin injections and some oral anti-diabetes agents (such as sulfonylureas). These hormones stimulate insulin manufacture and secretion by the pancreas, inhibit glucagon secretion, inhibit food intake, and inhibit gastric emptying, thus slowing the entry of sugar into the blood. Further, mounting evidence suggests that GLP-1 signaling regulates the proliferation of insulin-manufacturing islet cells in the pancreas, thus encouraging the body to make more insulin-producing beta cells.
News on several GLP-1s in drug development were reported at the sessions. Most are not even named yet, going by such identifiers as NN221 and CJC-1131, although another is called albugon.
Exendin-4, a hormone in the saliva of the Gila monster, a lizard native to several Southwestern American states, displays properties similar to human GLP-1. The lizard eats only four times a year and turns its pancreas off the rest of the time. When it eats, it secretes exendin-4 to turn its pancreas on again. Research suggests that exendin-4 exerts its effects through the GLP-1 receptor and is much more potent than GLP-1, with all of the actions of GLP-1 described above.
Researchers at Amylin Pharmaceuticals reported on the progress of clinical trials of a synthetic exendin-4, likely to be the first of this new class of drugs to reach the marketplace for type 2 diabetes. It works by multiple mechanisms of action -- stimulation of insulin secretion, slowing gastric emptying, and inhibiting production of glucose by the liver -- in contrast to most oral drugs that work by only one mechanism. Further, it seems to suppress appetite and promote weight loss.
Synthetic exendin-4 lowers levels of A1C, a long-term measure of glucose control. Its primary drawbacks are that it must be injected -- rather than taken by pill.
The researchers reported on an ongoing open label trial of synthetic exendin-4, and results of a double-blind, placebo-controlled Phase 3 trial are expected within a few months.
The American Diabetes Association is the nation's leading voluntary health organization supporting diabetes research, information and advocacy. Founded in 1940, the Association has offices in every region of the country, providing services to hundreds of communities.
Symposia GI Signals/Energy Balance and Late Breaking Clinical Studies, including abstract #s 560, LB-3, LB-5, LB-6, 479, 486, 498, 534 |
