Peripheral and autonomic nerve function in 259 diabetic patients with peripheral neuropathy treated with ponalrestat (an aldose reductase inhibitor) or placebo for 18 months. United Kingdom/Scandinavian Ponalrestat Trial.

The potential of the aldose reductase inhibitor ponalrestat (600 mg daily) to ameliorate diabetic neuropathy was evaluated in 259 diabetes mellitus patients with peripheral neuropathy (defined by abnormal vibration perception threshold and abnormal peroneal motor conduction velocity) in a double-blind placebo-controlled clinical trial running for 18 months. Overall, no beneficial effect of ponalrestat on vibration perception thresholds, nerve conduction velocities, and nerve action potential amplitudes was detected. Because vibration perception thresholds and conduction velocities in median, peroneal, and sural nerves did not deteriorate in the placebo group, the potential of ponalrestat to prevent the expected deterioration in peripheral nerve function that occurs with an increased duration of diabetes was not tested. Patients with an abnormal heart rate reaction to standing (abnormal 30:15 ratio; n = 84) on ponalrestat did not deteriorate in this autonomic nerve function test as shown in those on placebo. In conclusion, ponalrestat did not improve peripheral nerve function in diabetes mellitus patients with signs of peripheral neuropathy, although it did ameliorate a deterioration in autonomic nerve function in diabetic patients with signs of autonomic neuropathy.

Aldose reductase in the etiology of diabetic complications: 2. Nephropathy.

The progression of diabetic nephropathy can be arrested by an improvement in diabetic control. High glucose concentrations increase the flux through the aldose reductase pathway, and it has been proposed that this may contribute to renal damage. Aldose reductase is present in both the glomerulus and the renal tubule. Biochemical changes associated with increased sorbitol production have been demonstrated in animal models, including myo-inositol depletion, reduced Na+-K+ ATPase activity, and activation of the pentose phosphate and glucuronate-xylose pathways. Selective inhibition of aldose reductase reverses these biochemical changes and prevents some of the structural and functional abnormalities in diabetic rats. The potential beneficial effects of aldose reductase inhibitors on diabetic kidney disease in man are at present being investigated.

Aldose reductase in the etiology of diabetic complications. 3. Neuropathy.

Aldose reductase has been shown to be present in both autonomic and somatic nerves. Activation of this enzyme and the polyol pathway has been demonstrated in diabetic animal models to cause a range of biochemical, functional, and structural consequences that include the accumulation of sorbitol and fructose; axoglial dysjunction; paranodal demyelination; abnormalities in axonal transport, blood flow, and vascular permeability; and resistance to ischemic transmission of action potentials. These data provide an insight into the range of processes that if activated may either singly or in combination result in altered patterns of nerve function and structural alterations in diabetic neuropathy. In animal models of diabetes, it has been shown that inhibition of aldose reductase can modify these diabetes-induced changes. It is hoped that the results of large-scale controlled trials will provide clinical evidence to support these data.

A study of peripheral diabetic neuropathy. The application of age-related reference values.

The standardization of methodology and the provision of age-related reference values have been addressed for the design of and interpretation of data from a multicentre neuropathy trial. Age-related reference values were generated from 120 healthy volunteers. Vibration perception thresholds (VPT) deteriorated significantly with age (p less than 0.001). Patients were selected on the basis of age-related abnormal VPT and peroneal motor nerve conduction velocity. They were assessed at the beginning and end of a placebo run-in period (baseline data). The coefficients of variation (CV%) for VPT at the medial malleolus (16.81 per cent, n = 316) and great toe (19.23 per cent, n = 313) were lower compared to results in healthy volunteers (29.7 per cent and 20.8 per cent, respectively, n = 49). The CV% for expiratory:inspiratory (E:I) ratio (4.82 per cent, n = 215), Valsalva manoeuvre (10.84 per cent, n = 249) and 30:15 ratio (7.73 per cent, n = 292) from patients corresponded to those recorded in volunteers (7.6 per cent, n = 45 11.0 per cent, n = 49 9.5 per cent, n = 48, respectively). Most patient values for VPT at the great toe fell beyond the 95 centile line for volunteers. E:I ratio for volunteers showed a more variable relationship with age, although patient values appeared to be located below the 5 centile line for volunteer data.