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Elevated polyol pathway activity has been implicated in the development of diabetic complications, including neuropathy [1]. In diabetic models, inhibitors of the first enzyme in the pathway, aldose reductase, prevent or correct nerve conduction velocity (NCV) and regeneration deficits [2][3][4][5][6][7][8][9][10][11][12][13]. Clinical trials of aldose reductase inhibitors (ARIs) have shown modest improvements in neurological symptoms, NCV, sensory measures, and an increase in nerve fibre regeneration [14-17] despite a less effective polyol pathway blockade than was found necessary for functional effects in animal studies [6,10,18].Several hypotheses have been advanced to explain the action of ARI. Some putative mechanisms are primarily dependent on the first half of the polyol pathway, conversion of glucose to sorbitol by aldose Diabetologia (1997) 40: 271-281 Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats Summary Aldose reductase inhibitors (ARIs) attenuate diabetic complications in several tissues, including lens, retina, kidney, blood vessels, striated muscle and peripheral nerve. However, it is unclear whether their action in diabetes mellitus depends directly on inhibiting the conversion of glucose to sorbitol by aldose reductase or indirectly by reducing the sorbitol available for subsequent metabolism to fructose by sorbitol dehydrogenase. To identify the polyol pathway step most relevant to complications, particularly neuropathy, we compared the biochemical effects of a sorbitol dehydrogenase inhibitor, WAY-135 706, (250 mg ⋅ kg −1 ⋅ day −1 ) and an ARI, WAY-121 509, (10 mg ⋅ kg −1 ⋅ day −1 ) on a variety of tissues, and their effects on nerve perfusion and conduction velocity. After 6 weeks of untreated streptozotocin diabetes, rats were treated for 2 weeks. Sorbitol was elevated 2.1-32.6-fold by diabetes in lens, retina, kidney, aorta, diaphragm, erythrocytes and sciatic nerve; this was further increased (1.6-8.2-fold) by WAY-135 706 whereas WAY-121 509 caused a marked reduction. Fructose 1.6-8.0-fold elevated by diabetes in tissues other than diaphragm, was reduced by WAY-135 706 and WAY-121 509, except in the kidney. Motor and sensory nerve conduction velocities were decreased by 20.2 and 13.9 %, respectively with diabetes. These deficits were corrected by WAY-121 509, but WAY-135 706 was completely ineffective. A 48.6 % diabetes-induced deficit in sciatic nutritive endoneurial blood flow was corrected by WAY-121 509, but was unaltered by WAY-135 706. Thus, despite profound sorbitol dehydrogenase inhibition, WAY-135 706 had no beneficial effect on nerve function. The data demonstrate that aldose reductase activity, the first step in the polyol pathway, makes a markedly greater contribution to the aetiology of diabetic neurovascular and neurological dysfunction than does the second step involving sorbitol dehydrogenase. [Diabetologia (1997) 40: ...

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The nuclear receptors liver X receptor (LXR) LXR␣ and LXR␤ are differentially expressed ligand-activated transcription factors that induce genes controlling cholesterol homeostasis and lipogenesis. Synthetic ligands for both receptor subtypes activate ATP binding cassette transporter A1 (ABCA1)-mediated cholesterol metabolism, increase reverse cholesterol transport, and provide atheroprotection in mice. However, these ligands may also increase hepatic triglyceride (TG) synthesis via a sterol response element binding protein 1c (SREBP-1c)-dependent mechanism through a process reportedly regulated by LXR␣. We studied pan-LXR␣/␤ agonists in LXR␣ knockout mice to assess the contribution of LXR␤ to the regulation of selected target genes. In vitro dose-response studies with macrophages from LXR␣Ϫ/Ϫ and ␤Ϫ/Ϫ mice confirm an equivalent role for LXR␣ and LXR␤ in the regulation of ABCA1 and SREBP-1c gene expression. Cholesterol-efflux studies verify that LXR␤ can drive apoA1-dependent cholesterol mobilization from macrophages. The in vivo role of LXR␤ in liver was further evaluated by treating LXR␣Ϫ/Ϫ mice with a pan-LXR␣/␤ agonist. Highdensity lipoprotein (HDL) cholesterol increased without significant changes in plasma TG or very low density lipoprotein. Analysis of hepatic gene expression consistently revealed less activation of ABCA1 and SREBP-1c genes in the liver of LXR␣ null animals than in treated wild-type controls. In addition, hepatic CYP7A1 and several genes involved in fatty acid/TG biosynthesis were not induced. In peripheral tissues from these LXR␣-null mice, LXR␤ activation increases ABCA1 and SREBP-1c gene expression in a parallel manner. However, putative elevation of SREBP-1c activity in these tissues did not cause hypertriglyceridemia. In summary, selective LXR␤ activation is expected to stimulate ABCA1 gene expression in macrophages, contribute to favorable HDL increases, but circumvent hepatic LXR␣-dominated lipogenesis.There is great interest in targeting LXR nuclear receptors and their modulation for the treatment of atherosclerosis. These transcription factors play a critical role in the control of cholesterol homeostasis and have been the topic of several recent reviews (Jaye,

Changes in protein kinase (PK) C activity have been implicated in the complications of diabetes mellitus.In retina, blood vessels, kidney and heart, PKC activity is increased [1], perhaps due to raised de novo synthesis of diacylglycerol (DAG). A recent study has shown that PKC inhibitor treatment prevented the development of impaired retinal blood flow, renal glomerular hyperfiltration and microalbuminuria in diabetic rats [2] and this is compatible with the notion that PKC activation contributes to the aetiology of retinopathy and nephropathy.In another complication-prone tissue, peripheral nerve, PKC activity is reduced or unchanged [3±6]. Moreover, one neurochemical explanation of neuro- Diabetologia (1999) AbstractAims//hypothesis. Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151 003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na + ,K + -ATPase, and glutathione deficits in diabetic rats. Methods. Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na + ,K + -ATPase activity were measured in extracts from homogenised sciatic nerves. Results. After 8 weeks of diabetes, sciatic blood flow was 50 % reduced. Two weeks of WAY151 003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20 % diabetic motor conduction deficit, however, at high doses ( > 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na + ,K + -ATPase activity, 42 % reduced by diabetes, was partially corrected by low but not high dose WAY151 003. In contrast, only a very high dose of chelerythrine partially restored Na + ,K + -ATPase activity. A 30 % diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151 003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment. Conclusion/interpretation. Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na + ,K + -ATPase defects. [Diabetologia (1999