Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs
Causal linkage between insulin suppression of lipolysis and suppression of liver glucose output in dogs
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DOI：
10.1172/jci118846
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发表时间：
1996-08-01
影响因子：
15.9
通讯作者：
Bergman, RN
中科院分区：
文献类型：
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作者：
Rebrin, K;Steil, GM;Bergman, RN
抑制肝脏葡萄糖输出(HGO)主要是由外周胰岛素浓度而不是门脉胰岛素浓度介导的；然而，外周胰岛素抑制HGO的机制尚未确定。我们小组以前的研究结果表明，游离脂肪酸(FFA)和HGO之间存在很强的相关性，这表明胰岛素抑制HGO是通过抑制脂解作用来实现的。为了直接验证HGO的胰岛素抑制与脂肪组织脂解抑制之间的因果联系的假设，我们对清醒的狗(n=8)进行了正常血糖-高胰岛素葡萄糖钳夹，其中FFA被允许下降或通过Liposyn加肝素输注(LI；0.5ml/min 20%Liposyn加25U/min肝素，250U质剂)被阻止下降。用生长抑素(1mU/m in/kg)抑制内源性胰岛素和胰高血糖素，并以0.125或0.5mU/m in/kg的速度输注胰岛素。在0.5mU/min/kg胰岛素剂量下进行另外两个实验：双脂输注(2xLI；1.0ml/min 20%脂肪，肝素，如上)和甘油输注(19 mg/min)。在胰岛素输注0.125 mU/min/kg时，游离脂肪酸下降了40%，HGO下降了33%；用Li阻止FFA下降，完全阻止了HGO的下降。胰岛素输注0.5mU/min/kg时，游离脂肪酸水平下降%，HGO下降62%。在这个较高的胰岛素剂量下阻止FFA的下降在很大程度上阻止了HGO的下降；然而，稳态HGO仍然下降了18%。加倍Li输注量对HGO无进一步影响，提示FFA对HGO的影响是饱和的。升高血浆甘油水平不会改变胰岛素抑制HGO的能力。这些数据直接支持了HGO的胰岛素抑制不是直接的，而是通过胰岛素抑制脂肪组织脂解的观点。因此，肥胖和/或非胰岛素依赖型糖尿病患者对胰岛素控制肝脏葡萄糖产生的抵抗可能反映了脂肪细胞对胰岛素抑制脂解的抵抗。
Suppression of hepatic glucose output (HGO) has been shown to be primarily mediated by peripheral rather than portal insulin concentrations; however, the mechanism by which peripheral insulin suppresses HGO has not yet been determined. Previous findings by our group indicated a strong correlation between free fatty acids (FFA) and HGO, Suggesting that;insulin suppression of HGO is mediated via suppression of lipolysis. To directly test the hypothesis that insulin suppression of HGO is causally linked to the suppression of adipose tissue lipolysis, we performed euglycemic-hyperinsulinemic glucose clamps in conscious dogs (n=8) in which FFA were either allowed to fall or were prevented from falling with Liposyn plus heparin infusion (LI; 0.5 ml/min 20% Liposyn plus 25 U/min heparin with a 250 U prime). Endogenous insulin and glucagon were suppressed with somatostatin (1 mu g/min/kg), and insulin was infused at a rate of either 0.125 or 0.5 mU/min/kg. Two additional experiments were performed at the 0.5 mU/min/kg insulin dose: a double Liposyn infusion (2xLI; 1.0 ml/min 20% Liposyn, heparin as above), and a glycerol infusion (19 mg/min). With the 0.125 mU/min/kg insulin infusion, FFA fell 40% and HGO fell 33%; preventing the fall in FFA with LI entirely prevented this decline in HGO. With 0.5 mU/min/kg insulin infusion, FFA levels fell 64% while HGO declined 62%. Preventing the fall in FFA at this higher insulin dose largely prevented the fall in HGO; however, steady state HGO still declined by 18%. Doubling the LI infusion did not further affect HGO, suggesting that the effect of FFA on HGO is saturable. Elevating plasma glycerol levels did not alter insulin's ability to suppress HGO. These data directly support the concept that insulin suppression of HGO is not direct, but rather is mediated via insulin suppression of adipose tissue lipolysis. Thus, resistance to insulin control of hepatic glucose production in obesity and/or non-insulin-dependent diabetes mellitus may reflect resistance of the adipocyte to insulin suppression of lipolysis.