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

No abstract

Elevated protein kinase C activity has been linked to the vascular and neural complications of diabetes. The aim of the present study was to examine the involvement of the beta‐isoform of protein kinase C in abnormalities of neuronal function, neural tissue perfusion and endothelium‐dependent vasodilation in diabetes, by treatment with the selective inhibitor LY333531 (10 mg · kg−1 · day−1). Diabetes was induced in rats by streptozotocin; the duration of diabetes was 8 weeks. Nerve conduction velocity was monitored, and responses to noxious mechanical and thermal stimuli were estimated by the Randall‐Sellito and Hargreaves tests respectively. Sciatic nerve and superior cervical ganglion blood flow were measured by microelectrode polarography and hydrogen clearance. Vascular responses were examined using the in vitro mesenteric bed preparation. An 8‐week period of diabetes caused deficits in sciatic motor (20%) and saphenous nerve sensory (16%) conduction velocity, which were reversed by LY333531. Diabetic rats had mechanical and thermal hyperalgesia. LY333531 treatment did not affect mechanical thresholds, but corrected thermal hyperalgesia. Sciatic nerve and superior cervical ganglion blood flow were both reduced by 50% by diabetes; this was almost completely corrected by 2 weeks of LY333531 treatment. Diabetes caused a 32% reduction in vasodilation of the mesenteric vascular bed in response to acetylcholine, mediated by nitric oxide and endothelium‐derived hyperpolarizing factor. When the former was abolished during nitric oxide synthase inhibition, an 80% diabetic deficit in the remaining relaxation was noted. LY333531 treatment attenuated the development of these defects by 64% and 53% respectively. Thus protein kinase Cbeta contributes to the neural and vascular complications of experimental diabetes; LY333531 is a candidate for further study in clinical trials of diabetic neuropathy and vasculopathy.

A sample of 200 healthy subjects, representative of the adult UK population in terms of age, sex and social class distribution, were administered a full-length WAIS-R (UK). Regression equations were built to predict full-length IQ from a series of short-forms. The short-forms ranged from a two-subtest version proposed by Silverstein (1982) to a seven-subtest version proposed by Warrington, James & Maciejewski (1986). Regression equations, their standard errors of estimate and confidence intervals are presented as well as IQ conversion tables. The short-forms are evaluated in terms of their validity in predicting full-length IQ and in terms of their clinical utility. The advantages of regression-based estimates of full-length IQ over those derived from conventional prorating are discussed.

We examined the effects of 2 months of streptozotocin-induced diabetes mellitus in rats on relaxation and contraction of corpus cavernosum and the mesenteric vascular bed in vitro. A further diabetic group was treated from diabetes induction with 10 mg/kg/day of the aldose reductase inhibitor, WAY121509. For corpus cavernosum, maximal acetylcholine-induced relaxation was 35.5% reduced (p < 0.001) by diabetes, and this deficit was completely prevented by WAY121509 treatment. Neither diabetes nor treatment affected contractile responses to field stimulation of noradrenergic nerves; however, nonadrenergic noncholinergic nerve relaxation responses were 32.9% decreased by diabetes and WAY 121509 attenuated this by 84% (p < 0.001). For the mesenteric vascular bed, diabetes depressed maximal endothelium-dependent vasodilation to acetylcholine by 25.2% (p < 0.001), and this was partially (50.6%; p < 0.01) prevented by WAY121509. Nitric oxide synthase blockade revealed endothelium-derived hyperpolarising factor-mediated vasodilation to acetylcholine that was 73.5% (p < 0.001) depressed by diabetes; WAY121509 provided partial (43.4%; p < 0.001) protection. Neither diabetes nor treatment affected endothelium-independent vasorelaxation to the nitric oxide donor, sodium nitroprusside, in corpus cavernosum or mesenteric vessels. Thus the data show protective effects of WAY121509 on nitric oxide-mediated cavernosal vasorelaxation responses and on mesenteric endothelium-derived hyperpolarising factor responses. Together these findings could account for the beneficial effects of aldose reductase inhibition on diabetic complications in experimental models.