Medical Research Laboratories Aarhus University, Aarhus N, Denmark.
Department of Pediatrics, Randers Regional Hospital, Randers, Denmark.
J Clin Endocrinol Metab. 2019 Jul 1;104(7):2581-2592. doi: 10.1210/jc.2018-02503.
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.
To investigate whether lowering of serum FFA level with acipimox affects GLP-1 secretion.
Two randomized crossover studies were performed in human subjects. Rat intestine was perfused intra-arterially and intraluminally, and l-cells were incubated with acipimox.
The participants were healthy overweight subjects and hypopituitary adult patients.
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.
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.
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.
胰高血糖素样肽-1（GLP-1）是一种肠促胰岛素激素，在 2 型糖尿病和肥胖症的治疗中被应用。环境游离脂肪酸（FFA）与 GLP-1 之间的相互作用尚不清楚。阿昔莫司通过激活 PUMA-G（也称为 HCA2 和 GPR109a）受体抑制脂肪组织脂肪分解。
研究用阿昔莫司降低血清 FFA 水平是否会影响 GLP-1 的分泌。
在人体受试者中进行了两项随机交叉研究。通过动脉内和腔内灌流大鼠肠，并将阿昔莫司孵育于 l 细胞。
参与者为超重的健康受试者和垂体功能减退的成年患者。
超重受试者在口服葡萄糖耐量试验前 60 分钟接受阿昔莫司 250mg。垂体功能减退的患者在代谢研究日的前 12、9 和 2 小时以及在该日期间接受阿昔莫司 250mg 治疗，在基础状态和高胰岛素正常血糖钳夹期间进行研究。
阿昔莫司抑制了 FFA，但在临床试验中并未影响胰岛素。在超重受试者中，口服葡萄糖耐量试验后的 GLP-1 增加（曲线下面积）增加了一倍多[4119 ± 607 pmol/L × min（阿昔莫司）vs 1973 ± 375 pmol/L × min（对照），P = 0.004]。在垂体功能减退的患者中，阿昔莫司改善了胰岛素敏感性[4.7 ± 0.8 mg 葡萄糖/kg/min（阿昔莫司）vs 3.1 ± 0.5 mg 葡萄糖/kg/min（对照），P = 0.005]，GLP-1 浓度增加了约 40%。在两项试验中均存在 FFA 与 GLP-1 浓度之间的负相关。在大鼠肠中，阿昔莫司并未影响 GLP-1 的分泌，而 l 细胞并未一致表达阿昔莫司的假定受体。
阿昔莫司治疗可增加肥胖症患者和垂体功能减退患者的全身 GLP-1 水平。我们的体外数据表明，潜在的机制是间接的。
