orlistat and glucagon-like-peptide-1-(7-36)amide

Intestinal lipase inhibition using tetrahydrolipstatin (Orlistat) has been widely used in the pharmacotherapy of morbid obesity. However, the effects of Orlistat on the secretion of appetite regulating gastrointestinal hormones and appetite sensations are still debated. We addressed whether Orlistat alters the secretion of glucagon-like peptide-1-(7-36)-amide (GLP-1), cholecystokinin (CCK), peptide YY (PYY), and ghrelin as well as postprandial appetite sensations.. Twenty-five healthy human volunteers were examined with a solid-liquid test meal after the oral administration of Orlistat or placebo. Gastric emptying, gallbladder volume and the plasma levels of CCK, PYY, GLP-1, and ghrelin were determined and appetite sensations were measured using visual analogue scales.. Gastric emptying was accelerated by Orlistat administration (P < 0.0001), whereas gallbladder emptying was inhibited (P < 0.0001). Plasma levels of CCK (by approximately 53%), PYY (by approximately 40%), and GLP-1 (by approximately 20%) were significantly lowered by Orlistat (P < 0.001), whereas ghrelin levels were unaffected by Orlistat treatment (P = 0.18). Satiety and fullness were lowered by Orlistat (P < 0.0001), whereas appetite and prospective food consumption increased (P < 0.0001). The changes in CCK and PYY levels and the mean hunger ratings after Orlistat treatment were closely related to the inhibition of gallbladder motility.. Orlistat alters gastric and gallbladder emptying and reduces the postprandial secretion of GLP-1, PYY and CCK. These changes in gastrointestinal hormone concentrations may raise appetite sensations and increase food consumption and should therefore be considered as potential side effects when applying lipase inhibitors for the treatment of morbid obesity.

Topics: Administration, Oral; Adult; Animals; Appetite; Cholecystokinin; Enzyme Inhibitors; Gastric Emptying; Glucagon-Like Peptide 1; Humans; Intestines; Lactones; Lipase; Orlistat; Peptide Fragments; Peptide YY; Placebos; Postprandial Period; Rats; Satiety Response; Time Factors

This study examined the effects of the lipase inhibitor, orlistat, on gastric emptying of, and the glycemic and incretin hormone responses to, a drink containing oil and glucose components in patients with type 2 diabetes. Seven patients (aged 58 +/- 5 yr), managed by diet alone, consumed 60 ml olive oil (labeled with 20 MBq (99m)Tc-V-thiocyanate) and 300 ml water containing 75 g glucose (labeled with 6 MBq (67)Ga-EDTA), on two occasions, with and without 120 mg orlistat, positioned in the left lateral decubitus position with their back against a gamma camera. Venous blood samples, for measurement of blood glucose and plasma insulin, glucagon-like peptide-1 and glucose-dependent insulintropic polypeptide were obtained immediately before, and after, the drink. Gastric emptying of both oil (P < 0.001) and glucose (P < 0.0005) was faster after orlistat compared with control. Postprandial blood glucose (P < 0.001) and plasma insulin (P < 0.05) were substantially greater after orlistat compared with control. In contrast, plasma glucagon-like peptide-1 (P < 0.005) and glucose-dependent insulintropic polypeptide (P < 0.05) were less after orlistat. In conclusion, inhibition of fat digestion, by orlistat, may exacerbate postprandial glycemia, as a result of more rapid gastric emptying and a diminished incretin response.

Topics: Autonomic Nervous System; Blood Glucose; Diabetes Mellitus, Type 2; Dietary Fats; Enzyme Inhibitors; Female; Gastric Emptying; Gastric Inhibitory Polypeptide; Gastric Mucosa; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Glucose; Hemodynamics; Humans; Insulin; Lactones; Lipase; Male; Middle Aged; Orlistat; Peptide Fragments; Peptides

Glucagon-like peptide 1 (GLP-1) is the most potent physiological incretin for insulin secretion from the pancreatic beta-cell, but its mechanism of action has not been established. It interacts with specific cell-surface receptors, generates cAMP, and thereby activates protein kinase A (PKA). Many changes in pancreatic beta-cell function have been attributed to PKA activation, but the contribution of each one to the secretory response is unknown. We show here for the first time that GLP-1 rapidly released free fatty acids (FFAs) from cellular stores, thereby lowering intracellular pH (pHi) and stimulating FFA oxidation in clonal beta-cells (HIT). Similar changes were observed with forskolin, suggesting that stimulation of lipolysis was a function of PKA activation in beta-cells. Triacsin C, which inhibits the conversion of FFAs to long-chain acyl CoA (LC-CoA), enhanced basal FFA efflux as well as GLP-1-induced acidification and efflux of FFAs from the cell. Increasing the concentration of the lipase inhibitor orlistat progressively and largely diminished the increment in secretion caused by forskolin. However, glucose-stimulated secretion was less inhibited by orlistat and only at the highest concentration tested. Because the acute addition of FFAs also increases glucose-stimulated insulin secretion, these data suggest that the incretin function of GLP-1 may involve a major role for lipolysis in cAMP-mediated potentiation of secretion.

Topics: Calcium; Cell Line; Enzyme Inhibitors; Glucagon; Glucagon-Like Peptide 1; Glucagon-Like Peptides; Hydrogen-Ion Concentration; Intracellular Membranes; Islets of Langerhans; Lactones; Lipase; Lipolysis; Orlistat; Peptide Fragments; Protein Precursors; Sterol Esterase