METFORMIN TREATMENT OF LEAN AND OBESE ZUCKER RATS MODULATES THE ABILITY OF GLUCAGON AND INSULIN TO REGULATE HEPATOCYTE ADENYLATE-CYCLASE ACTIVITY
METFORMIN TREATMENT OF LEAN AND OBESE ZUCKER RATS MODULATES THE ABILITY OF GLUCAGON AND INSULIN TO REGULATE HEPATOCYTE ADENYLATE-CYCLASE ACTIVITY
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DOI：
10.1677/joe.0.1220207
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发表时间：
1989-07-01
影响因子：
4
通讯作者：
HOUSLAY, MD
中科院分区：
文献类型：
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作者：
GAWLER, DJ;WILSON, A;HOUSLAY, MD
胰高血糖素将瘦大鼠 (Fa/Fa) 肝膜中的腺苷酸环化酶活性刺激约 21 倍，将肥胖 (fa/fa) Zucker 大鼠的肝膜中腺苷酸环化酶活性刺激约 20 倍，半最大激活常数（Ka 值）分别为 12.6 和 120.1 nmol/l。用双胍类药物二甲双胍（N'',N''-二甲基双胍）治疗动物，可使瘦动物和肥胖动物的胰高血糖素刺激该酶的能力降低约 16 倍，并将胰高血糖素激活该酶的 Ka 值分别降低至 6.3 和 60.9 nmol/l。在瘦动物的肝膜中，胰岛素抑制胰高血糖素刺激的腺苷酸环化酶活性约 24%，在肥胖动物的肝膜中抑制约 17%，半最大抑制常数（Ki 值）分别为 110 和 160 nmol/l。当胰岛素浓度超过 5 nmol/l 时，肥胖动物（而非瘦动物）的胰岛素抑制腺苷酸环化酶活性的能力会减弱。 用二甲双胍治疗动物极大地改变了腺苷酸环化酶对胰岛素抑制的敏感性，使用瘦或肥胖动物的肝膜时，抑制率增加到约 32%。使用瘦动物和肥胖动物的膜，胰岛素抑制作用的 Ki 值分别为 520 和 500 nmol/l，使用肥胖动物的膜，在浓度超过 5 nmol/l 时，没有观察到胰岛素抑制腺苷酸环化酶活性的能力降低。二甲双胍还改变了胰岛素抑制腺苷酸环化酶的动力学。这些显然是负合作的，使用来自未处理的瘦动物和肥胖动物的膜的希尔系数分别为0.76和0.89，并且是正合作的，对于二甲双胍处理的瘦动物和肥胖动物的希尔系数分别为1.45和1.20。
Glucagon stimulated adenylate cyclase activity some 21-fold in liver membranes from lean (Fa/Fa) and some 20-fold in membranes from obese (fa/fa) Zucker rats, with constants yielding half-maximal activation (Ka values) of 12.6 and 120.1 nmol/l respectively. Treatment of animals with the biguanide drug metformin (N'',N''-dimethylbiguanide) decreased the ability of glucagon to stimulate this enzyme to some 16-fold for both the lean and obese animals and reduced the Ka values for activation of this enzyme by glucagon to 6.3 and 60.9 nmol/l respectively. Insulin inhibited glucagon-stimulated adenylate cyclase activity by some 24% in liver membranes from lean animals and some 17% in liver membranes from obese animals, with constants yielding half-maximal inhibition (Ki values) of 110 and 160 nmol/l respectively. The ability of insulin to inhibit the adenylate cyclase activity, from obese but not lean animals was attenuated when insulin concentrations over 5 nmol/l were employed. Treatment of animals with metformin profoundly altered the sensitivity of adenylate cyclase to inhibition by insulin, with inhibition being increased to some 32% using liver membranes from either lean or obese animals. Values of Ki for this inhibitory action of insulin were 520 and 500 nmol/l using membranes from the lean and obese animals respectively, and no reduction in the ability of insulin, at concentrations over 5 nmol/l, to inhibit adenylate cyclase activity was observed using membranes from obese animals. Metformin also changed the kinetics of inhibition of adenylate cyclase by insulin. These were apparently negatively co-operative, with Hill coefficients of 0.76 and 0.89 using membranes from the untreated lean and obsese animals respectively, and positively co-operative, with Hill coefficients of 1.45 and 1.20 for the metformin-treated lean and obese animals respectively.