Storlien L H, Thorburn A W, Smythe G A, Jenkins A B, Chisholm D J, Kraegen E W
Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia.
Diabetes. 1989 Apr;38(4):499-503. doi: 10.2337/diab.38.4.499.
There is evidence that fenfluramine improves insulin action independently of its anorectic and weight-loss-inducing properties. Chronic d-fenfluramine also reduces hypothalamic noradrenergic tone, which correlates highly with hepatic glucose output. We report that chronic d-fenfluramine (5 mg.kg-1.day-1) ameliorates insulin resistance induced by high-fat feeding. Insulin action was assessed in adult male rats at basal insulin levels and at hyperinsulinemia (approximately 140 mU/L with the euglycemic clamp technique). Hepatic glucose production, peripheral glucose disposal, and individual tissue glucose metabolism were determined from bolus injections of [3H]-2-deoxyglucose and [14C]glucose. Food intake was matched between groups. Basal glucose turnover was reduced 28% (P less than .05) in fat-fed rats receiving d-fenfluramine (fat + fen). The glucose infusion rate to maintain euglycemia was 22.0 +/- 1.1 mg.kg-1.min-1 in the high-carbohydrate-fed rats, 8.2 +/- 1.0 in fat-fed rats, and 15.1 +/- 0.5 in the fat + fen group. Peripheral glucose disposal, reflecting measured skeletal muscle changes, was reduced by fat feeding (from 23.5 +/- 1.0 to 13.8 +/- 0.6 mg.kg-1.min-1) but was improved by d-fenfluramine (16.9 +/- 0.5, P less than .05 vs. fat fed). Impaired suppression of hepatic glucose output by insulin, caused by fat feeding, was totally reversed by d-fenfluramine. Thus, d-fenfluramine counteracted diet-induced insulin resistance, with the predominant effect on the liver. We hypothesize that d-fenfluramine improves insulin action by reducing hypothalamic noradrenergic tone, which in turn reduces the neural drive to hepatic glucose output and improves the hepatic response to insulin.
有证据表明，芬氟拉明可独立于其食欲抑制和减肥特性而改善胰岛素作用。长期使用右旋芬氟拉明还可降低下丘脑去甲肾上腺素能张力，这与肝脏葡萄糖输出高度相关。我们报告，长期使用右旋芬氟拉明（5毫克·千克-1·天-1）可改善高脂喂养诱导的胰岛素抵抗。在基础胰岛素水平和高胰岛素血症（采用正常血糖钳夹技术约为140毫单位/升）下评估成年雄性大鼠的胰岛素作用。通过静脉注射[3H]-2-脱氧葡萄糖和[14C]葡萄糖来测定肝脏葡萄糖生成、外周葡萄糖处置以及各个组织的葡萄糖代谢。各实验组间的食物摄入量相当。接受右旋芬氟拉明的高脂喂养大鼠（高脂+芬氟拉明组）的基础葡萄糖周转率降低了28%（P<0.05）。高碳水化合物喂养大鼠维持正常血糖所需的葡萄糖输注速率为22.0±1.1毫克·千克-1·分钟-1，高脂喂养大鼠为8.2±1.0，高脂+芬氟拉明组为15.1±0.5。反映所测骨骼肌变化的外周葡萄糖处置因高脂喂养而降低（从23.5±1.0降至13.8±0.6毫克·千克-1·分钟-1），但右旋芬氟拉明可使其改善（16.9±0.5，与高脂喂养组相比P<0.05）。高脂喂养导致的胰岛素对肝脏葡萄糖输出抑制作用受损被右旋芬氟拉明完全逆转。因此，右旋芬氟拉明可对抗饮食诱导的胰岛素抵抗，主要作用于肝脏。我们推测，右旋芬氟拉明通过降低下丘脑去甲肾上腺素能张力来改善胰岛素作用，这反过来又减少了对肝脏葡萄糖输出的神经驱动，并改善了肝脏对胰岛素的反应。
