Wasner H K, Salge U, Psarakis E, Niktopoulos A
Diabetes-Forschungsinstitut, Düsseldorf, Germany.
Acta Diabetol. 1997 Dec;34(4):257-64. doi: 10.1007/s005920050085.
Reduced ability or failure to stimulate cyclic adenosinemonophosphate (AMP) synthesis on a second addition of hormone 30 min after a first stimulation was taken as an indirect indication of the synthesis of the cyclic AMP antagonist prostaglandylinositol cyclic phosphate (cyclic PIP). In diabetic rats, because of an increased possibility of restimulating cyclic AMP synthesis, the formation of cyclic PIP should be reduced. Additionally, severalfold increased basal cyclic AMP synthesis can be observed in diabetic hepatocytes in comparison with controls. Upon measuring cyclic PIP levels after hormonal stimulation in all organs of diabetic rats, it was found that stimulation of cyclic PIP synthesis by insulin decreased gradually in a time-dependent manner. Plasma membranes were prepared from diabetic Ksj db/db mice and from spontaneously hypertensive rats (SHR), and in a subsequent assay for cyclic PIP synthetase, an up to 60% decrease of enzyme activity was found. Cyclic PIP synthetase can be completely inhibited by preincubation with protein kinase A. It is most likely that this serine phosphorylation reaction by which the enzyme is inhibited also in vivo is a result of increased cyclic AMP levels. The addition of 10(-5)-10(-4) M sulfonylureas to the enzyme assay of liver plasma membrane causes full inhibition, and the addition of 10(-5)-10(-4) M biguanides, a two- to fourfold activation of the enzyme. Activation of cyclic PIP synthetase by biguanides can also be demonstrated in intact cells. It is a fast reaction and additive with respect to the activation by fluoride or guanylyl-imidodiphosphate (GMP-PNP), and it is most likely the effect with which the biguanides produce the correcting changes in metabolism. Furthermore, antihypertensive drugs like captopril, guanethidine, and dihydralazine also activate cyclic PIP synthetase. In contrast to the activation by the biguanides, this effect is not additive to the activation by fluoride. It appears that essential hypertension and type 2 diabetes are connected with or may be the result of a reduction in synthesis of the intracellular messenger cyclic PIP, whose synthesis is stimulated by hormones like insulin and noradrenaline (alpha-adrenergic action).
在首次刺激30分钟后再次添加激素时，刺激环磷酸腺苷（AMP）合成的能力降低或无法合成，这被视为环磷酸腺苷拮抗剂前列腺素肌醇环磷酸酯（环PIP）合成的间接指标。在糖尿病大鼠中，由于再次刺激环磷酸腺苷合成的可能性增加，环PIP的形成应该减少。此外，与对照组相比，在糖尿病肝细胞中可观察到基础环磷酸腺苷合成增加了几倍。在测量糖尿病大鼠所有器官激素刺激后的环PIP水平时，发现胰岛素对环PIP合成的刺激以时间依赖性方式逐渐降低。从糖尿病Ksj db/db小鼠和自发性高血压大鼠（SHR）制备质膜，在随后的环PIP合成酶测定中，发现酶活性降低了高达60%。环PIP合成酶可通过与蛋白激酶A预孵育而被完全抑制。很可能这种在体内也抑制该酶的丝氨酸磷酸化反应是环磷酸腺苷水平升高的结果。在肝质膜的酶测定中加入10^(-5)-10^(-4)M的磺脲类药物会导致完全抑制，而加入10^(-5)-10^(-4)M的双胍类药物会使该酶激活两到四倍。双胍类药物对环PIP合成酶的激活也可在完整细胞中得到证实。这是一个快速反应，与氟化物或鸟苷酰亚胺二磷酸（GMP-PNP）的激活具有加和性，很可能是双胍类药物产生代谢校正变化的作用。此外，卡托普利、胍乙啶和肼屈嗪等抗高血压药物也能激活环PIP合成酶。与双胍类药物的激活不同，这种作用与氟化物的激活不具有加和性。看来原发性高血压和2型糖尿病与细胞内信使环PIP合成减少有关，或者可能是其结果，环PIP的合成受胰岛素和去甲肾上腺素（α-肾上腺素能作用）等激素刺激。
