Orlistat Augments Postprandial Increases in Glucagon-like
Objective: Orlistat leads to improved glycemic control in obese type 2 diabetic patients, which is attributed to decreased insulin resistance associated with weight loss. Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are gut hormones that are secreted in response to food intake, and they both stimulate insulin secretion. Orlistat decreases fat absorption and increases intestinal fat content, which may lead to increased secretion of these peptides. In this pilot study, we tested the hypothesis that increased levels of these intestinal hormones may be involved in the improvement of postprandial hyperglycemia observed previously with orlistat in type 2 diabetic patients.
Research Design and Methods: A total of 29 type 2 diabetic patients, who were not taking insulin or α-glucosidase inhibitors, were enrolled in the study. On a crossover and single-blind design, after an overnight fasting, the patients received 120-mg orlistat or placebo capsules, followed by a standard 600-kcal mixed meal that contained 38% fat. At baseline and 60 min after the meal, blood samples were obtained for the measurement of GLP-1, GIP, insulin, C-peptide, triglycerides, free fatty acids, and glucose.
Results: All measured parameters increased significantly in response to the mixed meal compared with baseline, both with orlistat or placebo. When compared with the placebo, the orlistat administration resulted in a significantly enhanced postprandial increase in GLP-1 and C-peptide levels and attenuated the postprandial rise in glucose and triglycerides.
Conclusions: The results of this study suggest that apart from decreasing insulin resistance as a result of weight loss, orlistat may increase postprandial GLP-1 levels, thereby enhancing the insulin secretory response to the meal and blunting the postprandial rise in glucose in type 2 diabetic patients. Increased GLP-1 levels, which lead to decreased food intake, may also contribute to the weight loss that is associated with the use of this drug.

In normal humans, meal ingestion leads to secretion of gut hormones, which regulate gastric and intestinal motility, absorption of the nutrients, and energy storage. Among these gut hormones, the most important and well studied are the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (gastric inhibitory peptide [GIP]). Both GLP-1 and GIP are potent stimulators of insulin secretion and promote expansion of pancreatic islet β-cell mass. GLP-1 also inhibits gastric emptying and glucagon secretion and suppresses appetite. In type 2 diabetes, basal and postprandial GIP levels are normal, but there seems to be a resistance to the action of GIP. On the other hand, in patients with type 2 diabetes or in individuals with impaired glucose tolerance, postprandial levels of GLP-1 were found to be lower than that of normal subjects. GLP-1 is secreted in two active forms, namely GLP-1 (7-36) amide and GLP-1 (7-37), which are equally potent in terms of stimulation of insulin secretion. Administration of GLP-1 or its agonists has been studied with considerable success in improving metabolic control in type 2 diabetic patients. GIP is predominantly released from the proximal small intestinal K-cells and GLP-1 from more distally located L-cells. Ingestion of a meal rich in fats and complex carbohydrates stimulates secretion of both GIP and GLP-1. This, in turn, leads to increased insulin secretion, thus attenuating postprandial increases in blood glucose levels.

Orlistat, a gastrointestinal lipase inhibitor drug, has been used effectively and safely in the treatment of obesity. By inhibiting lipases, orlistat reduces the absorption of dietary fats by ~30%. In obese type 2 diabetic patients, orlistat treatment is associated with weight loss and improved glycemic control in the long term. In type 2 diabetic patients, orlistat also attenuates postprandial increases in triglycerides, remnant-like particles, cholesterol, and free fatty acids. The antihyperglycemic effect of orlistat has been attributed to weight loss-associated decrease in insulin resistance. However, clinical observations suggest that the improvement in postprandial glucose levels with orlistat is greater in magnitude than could be expected from the decrease in body weight. A hypothetical mechanism could be that orlistat enhances postprandial secretion of certain incretins, particularly GLP-1, due to increased delivery of fats to the distal ileum as a result of inhibition of lipase proximally. If so, such an action of orlistat could lead to suppressed appetite and decreased food intake, as well as improvement in meal-stimulated insulin release. We tested this hypothesis in a single-blind crossover study in a sample of obese type 2 diabetic subjects who took orlistat on a single occasion and placebo on another occasion before ingesting a standardized mixed meal. Our results indicate that stimulation of GLP-1 may indeed play a role in the improvement of postprandial glucose levels observed with orlistat in patients with diabetes.