According to the American Diabetes Association, 25.8 million children and adults in the United States or 8.3% of the population, have diabetes. This presents an economic burden of $174 billion in indirect and direct costs to the health care system.
Diabetes is a metabolic disorder characterized by an inability of the body to manage blood glucose levels adequately. The disease is associated with the progressive damage, and ultimate failure, of vital organs including the eyes, kidneys, nerves, and cardiovascular system. The most prevalent form of diabetes (over 95% of cases), type 2 diabetes mellitus (T2DM), is characterized by the combination of:
These combined effects result in elevated glucose levels after eating, which is a leading cause of subsequent heart disease, blindness, and kidney failure. Obesity is the primary cause of T2DM: about 90% of people with T2DM are obese.
The role of incretins
Although it has long been known that the intestinal epithelium can sense the nutrient composition of GI lumen contents (i.e., food), only recently have the identity and mechanisms of the receptors and transporters underlying this physiological function been elucidated. Those receptors are expressed at the surface of specialized epithelial cells called entero-endocrine cells, which produce and secrete a group of GI peptide hormones called incretins. These hormones, which include GIP, GLP-1, and PYY, are released into the circulation after a meal and enhance the production of insulin, which is needed to metabolize glucose. Incretins, particularly GLP-1, increase digestive secretion, slow down GI transit, adjust gut motility and send signals centrally to the brain to increase the sensation of fullness and satiety.
Ardelyx non-systemic incretin secretagogues
The novel agents being developed by Ardelyx take advantage of these sensing mechanisms by targeting receptors stimulating incretin secretion. These agents should restore normal incretin levels in diabetic patients to improve glucose utilization (normalizing glycemia), elicit earlier satiety, and in the long term, promote weight loss.