TY - JOUR

T1 - Acipimox Acutely Increases GLP-1 Concentrations in Overweight Subjects and Hypopituitary Patients

AU - Vestergaard, Esben Thyssen

AU - Hjelholt, Astrid Johanneson

AU - Kuhre, Rune E

AU - Møller, Niels

AU - Larraufie, Pierre

AU - Gribble, Fiona M

AU - Reimann, Frank

AU - Jessen, Niels

AU - Holst, Jens Juul

AU - Jørgensen, Jens Otto Lunde

PY - 2019

Y1 - 2019

N2 - Context: Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in T2DM and obesity. The interplay between ambient fatty acids (FFA) and GLP-1, remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (aka HCA2 and GPR109a) receptor.Objective: To investigate if 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 intraarterially and -luminally and L-cell 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 prior to an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 h prior to and during the metabolic study day, where 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 OGTT (AUC, pmol/lxmin) was more than doubled [4,119±607 [Acipimox] vs. 1,973±375 [Control], P=0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (mg glucose/kg/min): 4.7±0.8 [Acipimox] vs. 3.1±0.5 [Control], P=0.005, and GLP-1 concentrations increased approximately 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 enhances systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

AB - Context: Glucagon-like peptide-1 (GLP-1) is an incretin hormone used therapeutically in T2DM and obesity. The interplay between ambient fatty acids (FFA) and GLP-1, remains unclear. Acipimox suppresses adipose tissue lipolysis via activation of the PUMA-G (aka HCA2 and GPR109a) receptor.Objective: To investigate if 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 intraarterially and -luminally and L-cell 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 prior to an oral glucose test. The hypopituitary patients received acipimox 250 mg 12, 9, and 2 h prior to and during the metabolic study day, where 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 OGTT (AUC, pmol/lxmin) was more than doubled [4,119±607 [Acipimox] vs. 1,973±375 [Control], P=0.004]. In hypopituitary patients, acipimox improved insulin sensitivity (mg glucose/kg/min): 4.7±0.8 [Acipimox] vs. 3.1±0.5 [Control], P=0.005, and GLP-1 concentrations increased approximately 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 enhances systemic GLP-1 levels in both obese subjects and hypopituitary patients. Our in vitro data indicate that the underlying mechanisms are indirect.

U2 - 10.1210/jc.2018-02503

DO - 10.1210/jc.2018-02503

M3 - Journal article

C2 - 30726969

VL - 104

SP - 2581

EP - 2592

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 7

ER -