Acipimox Acutely Increases GLP-1 Concentrations in Overweight Subjects and Hypopituitary Patients

Context: Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in type 2 diabetes and obesity. The interplay between ambient free fatty acids (FFAs) and GLP-1 remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (also known as HCA(2) and GPR109a) receptor. Objective: To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion. Design: Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and L-cells were incubated with acipimox. Participants: The participants were healthy overweight subjects and hypopituitary adult patients. Interventions: The overweight participants received acipimox 250 mg 60 minutes before an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 hours before and during the metabolic study day, when they were studied in the basal state and during a hyper-insulinemic euglycemic clamp. Results: Acipimox suppressed FFA but did not affect insulin in the clinical trials. In overweight subjects, the GLP-1 increase after the oral glucose tolerance test (area under the curve) was more than doubled [4119 +/- 607 pmol/L x min (Acipimox) vs 19736375 pmol/L x min (control), P = 0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (4.7 +/- 0.8 mg glucose/kg/min (Acipimox) vs 3.1 +/- 0.5 mg glucose/kg/min (control), P = 0.005], and GLP-1 concentrations increased similar to 40%. An inverse correlation between FFA and GLP-1 concentrations existed in both trials. In rat intestine, acipimox did not affect GLP-1 secretion, and L-cells did not consistently express the putative receptor for acipimox. Conclusions: Acipimox treatment increases systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.