Antonipillai I, Nadler J, Vu E J, Bughi S, Natarajan R, Horton R
Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033, USA.
J Clin Endocrinol Metab. 1996 May;81(5):1940-5. doi: 10.1210/jcem.81.5.8626861.
Earlier studies in diabetic animal models or ex vivo from diabetics suggest a deficiency in prostacyclin (PGI2) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraenoic acid (12-HETE), which stimulates angiogenesis, mitogenesis, and inhibits renin secretion. We studied the urinary excretion rate of 6-keto-PGF1 alpha (a stable metabolite of PGI2) and 12-HETE in controls and 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with normal renal function and those with micro- or macroalbuminuria/hyporeninemic hypoaldosteronism (HH). The 2 eicosanoids were measured in urine using previously described high pressure liquid chromatography and RIA methods. Normal subjects and patients with NIDDM and microalbuminuria were infused with low dose calcium infusions that stimulate prostacyclin production in normal subjects. The PGI2 excretion rate of NIDDM patients with normal renal function was not different from that of controls (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in those with microalbuminuria (75 +/- 10) and in macroalbuminuria patients (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetics with normal renal function as well as in those with micro- or macroalbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 +/- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI2, but increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI2 (as previously reported), but had increased 12-HETE. HETE/PGI2 ratios further demonstrated these changes in the various groups. In a nondiabetic hypertensive microalbuminuria group, 12-HETE excretion was normal (73 +/- 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HETE is increased early in the diabetic process, whereas PGI2 production is progressively impaired in NIDDM. These changes may play a role in the vascular disease of diabetes and partially explain the HH syndrome.
早期在糖尿病动物模型或糖尿病患者的离体研究表明，前列环素（PGI2）生成不足，而另一种花生四烯酸代谢产物12-羟基二十碳四烯酸（12-HETE）增加，后者可刺激血管生成、有丝分裂并抑制肾素分泌。我们研究了6-酮-PGF1α（PGI2的稳定代谢产物）和12-HETE在对照组以及42例肾功能正常的非胰岛素依赖型糖尿病（NIDDM）患者和有微量或大量蛋白尿/低肾素性低醛固酮血症（HH）患者中的尿排泄率。使用先前描述的高压液相色谱法和放射免疫分析法测定尿液中的这两种类花生酸。对正常受试者以及患有NIDDM和微量蛋白尿的患者输注低剂量钙，低剂量钙可刺激正常受试者生成前列环素。肾功能正常的NIDDM患者的PGI2排泄率与对照组无差异（分别为143±17和118±34 ng/g肌酐），但微量蛋白尿患者（75±10）和大量蛋白尿患者（48±7；P<0.01）的PGI2排泄率降低。相比之下，肾功能正常的糖尿病患者以及微量或大量蛋白尿患者的12-HETE增加（分别为69±18、250±62、226±60和404±131 ng/g肌酐；P<0.01）。与正常受试者不同，钙并未刺激PGI2生成，但却增加了微量蛋白尿糖尿病患者的12-HETE。HH患者排泄的PGI2较少（如先前报道），但12-HETE增加。HETE/PGI2比值进一步证实了各组中的这些变化。在非糖尿病高血压微量蛋白尿组中，12-HETE排泄正常（73±28 ng/g肌酐）。我们得出结论，脂氧合酶产物12-HETE在糖尿病进程早期增加，而NIDDM患者的PGI2生成逐渐受损。这些变化可能在糖尿病血管疾病中起作用，并部分解释了HH综合征。
