Satiogen has completed one clinical study of rectally administered bile acid, and the company is sponsoring a second study now underway.
The completed study is being prepared for publication, so it cannot yet be shown here. Following is the abstract of the data presented at the American Diabetes Association meeting in June 2010:
The Bile Acid Brake: A Novel Target for Treating Diabetes and Obesity.
Adrian TE, Gariballa S, Parekh KA, Thomas SA, Saadi H, Al Kaabi J, Nagelkerke N, Gedulin B, Young AA
Departments of Physiology and Internal Medicine, Faculty of Medicine and health Sciences, United Arab Emirates University, Al Ain, UAE and Satiogen Pharmaceuticals Inc., San Diego CA
Enteroendocrine L-cells produce glucagon gene products (GLP-1 and oxyntomodulin) as well as PYY. All are satiety factors. GLP‑1 is also an incretin. The number of L-cells and hormonal contents increases distally through the gut with highest concentrations in the rectum. We have previously shown that intracolonic infusion of bile salts in humans causes secretion of L-cell hormones, triggered via TGR5 membrane receptors. The present study was designed to investigate the dose-responsive effects of intrarectal sodium taurocholate (ST) on circulating concentrations of GLP-1, PYY, insulin, glucose and on food intake of a subsequent meal.
Ten obese type II diabetic subjects were each studied on five separate occasions after an overnight fast and oral administration of 100 mg sitagliptin 10 hours before the study. They then received an intrarectal infusion of either one of four doses of ST (0.66, 2, 6.66, or 20 mmoles) or vehicle placebo in a random blinded fashion. ST was administered in 20 mL of a 1% carboxymethyl cellulose emulsion over 1 min. Plasma samples for hormone and glucose measurements were collected prior to, and for one hour following the infusion. 75 mins after the infusion, the subjects were invited to eat an unlimited amount of a previously selected favorite meal until satisfied.
ST caused a dose-related increase of GLP-1, PYY and insulin, with peak concentrations ~6, 5 and 3-fold increased, respectively with 20 mmoles ST (all P<.0001). There was a corresponding decrease in circulating glucose concentrations (P< 0.001), with a decrease in glucose of 2.75±0.6 mmol/L with 20 mmoles ST. The ST infusions were also associated with a decrease in caloric consumption of the subsequent meal (P<0.0001), with a maximal inhibition of 44±7 % with 20 mmoles ST. ED50’s for effects on integrated GLP‑1, insulin, PYY, food intake and glucose lowering responses were respectively 8.1, 10.5, 18.5, 24.2 and 25.1 mmol.
Rectally administered ST dose-dependently increased L-cell secretion in association with an incretin response, and reductions in fasting plasma glucose and spontaneous food intake. TGR5 agonists in the distal bowel may be valuable in the treatment of type II diabetes and obesity.
Following are charts displaying the dose responses to rectally administered bile acid: