Esben Thyssen Vestergaard1,2, Astrid Johanneson Hjelholt1,3, Rune E Kuhre4, Niels Møller1,3, Pierre Larraufie5, Fiona M Gribble5, Frank Reimann5, Niels Jessen1,6,7,8, Jens Juul Holst4, Jens Otto Lunde Jørgensen1,3. 1. Medical Research Laboratories Aarhus University, Aarhus N, Denmark. 2. Department of Pediatrics, Randers Regional Hospital, Randers, Denmark. 3. Department of Diabetes and Endocrinology, Aarhus University Hospital, Aarhus N, Denmark. 4. Department of Biomedical Sciences and NNF Centre for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 5. Metabolic Research Laboratories and Medical Research Council Metabolic Diseases Unit, Wellcome Trust-Medical Research Council Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, United Kingdom. 6. Research Laboratory for Biochemical Pathology, Aarhus University Hospital, Aarhus C, Denmark. 7. Department of Biomedicine, Aarhus University, Aarhus C, Denmark. 8. Steno Diabetes Centre Aarhus, Aarhus University Hospital, Aarhus N, Denmark.
Abstract
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 HCA2 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 hyperinsulinemic 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 × min (Acipimox) vs 1973 ± 375 pmol/L × 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 ~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.
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 HCA2 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 hyperinsulinemic 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 × min (Acipimox) vs 1973 ± 375 pmol/L × 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 ~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.
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