A 12-LIPOXYGENASE PRODUCT, 12-HYDROXYEICOSATETRAENOIC ACID, IS INCREASED IN DIABETICS WITH INCIPIENT AND EARLY RENAL-DISEASE

Earlier studies in diabetic animal models or ex vivo from diabetics su ggest a deficiency in prostacyclin (PGI(2)) production and an increase in an alternate arachidonic acid metabolite, 12-hydroxyeicosatetraeno ic acid (18-HETE), which stimulates angiogenesis, mitogenesis, and inh ibits renin secretion. We studied the urinary excretion rate of 6-keto -PGF1(alpha) (a stable metabolite of PGI(2)) and 12-HETE in controls a nd 42 noninsulin-dependent diabetes mellitus (NIDDM) patients with nor mal renal function and those with micro- or macroalbuminuria/hyporenin emic hypoaldosteronism (KH). The 2 eicosanoids were measured in wine u sing 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 prostacycl in production in normal subjects. The PGI(2) excretion rate of NIDDM p atients with normal renal function was not different from that of cont rols (143 +/- 17 vs. 118 +/- 34 ng/g creatinine), but was reduced in t hose with microalbuminuria (75 +/- 10) and in macroalbuminuria patient s (48 +/- 7; P < 0.01). In contrast, 12-HETE was increased in diabetic s with normal renal function as well as in those with micro- or macroa lbuminuria patients (69 +/- 18 vs. 250 +/- 62 vs. 226 +/- 60 and 404 /- 131 ng/g creatinine; P < 0.01). Calcium did not stimulate PGI(2), b ut increased 12-HETE in diabetics with microalbuminuria in contrast to levels in normal subjects. HH patients excreted less PGI(2) (as previ ously reported), but had increased 12-HETE. HETE/PGI(2) ratios further demonstrated these changes in the various groups. In a nondiabetic hy pertensive microalbuminuria group, 12-HETE excretion was normal (73 +/ - 28 ng/g creatinine). We conclude that the lipoxygenase product 12-HE TE is increased early in the diabetic process, whereas PGI(2) producti on is progressively impaired in NIDDM. These changes may play a role i n the vascular disease of diabetes and partially explain the HH syndro me.