Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy.

OBJECTIVE: To evaluate the efficacy and safety of alpha-lipoic acid given intravenously, followed by oral treatment in type 2 diabetic patients with symptomatic polyneuropathy. RESEARCH DESIGN AND METHODS: In a multicenter randomized double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy [ALADIN] III Study), 509 outpatients were randomly assigned to sequential treatment with 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by 600 mg alpha-lipoic acid three times a day orally for 6 months (A-A; n = 167); 600 mg alpha-lipoic acid once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (A-P; n = 174); and placebo once daily intravenously for 3 weeks, followed by placebo three times a day orally for 6 months (P-P; n = 168). Outcome measures included the Total Symptom Score (TSS) for neuropathic symptoms (pain, burning, paresthesias, and numbness) in the feet, and the Neuropathy Impairment Score (NIS). Data analysis was based on the intention to treat. RESULTS: No significant differences between the groups were noted for the demographic variables and the nerve function parameters at baseline. The TSS in the feet decreased from baseline to day 19 (median [range]) by -3.7 (-12.6 to 5.0) points in the group given alpha-lipoic acid intravenously and by -3.0 (-12.3 to 8.0) points in the placebo group (P = 0.447), but the area under curve on a daily basis was significantly smaller in the active as compared with the placebo group (85.6 [0-219] vs. 95.9 [5.5-220]); P = 0.033). After 7 months, the changes in the TSS from baseline were not significantly different between the three groups studied, which could be due to increasing intercenter variability in the TSS during the trial. The NIS decreased after 19 days by -4.34+/-0.35 points (mean +/- SEM) in A-A and A-P and -3.49+/-0.58 points in P-P (P = 0.02 for alpha-lipoic acid versus placebo) and after 7 months by -5.82+/-0.73 points in A-A, -5.76+/-0.69 points in A-P, and -4.37+/-0.83 points in P-P (P = 0.09 for A-A vs. P-P). The rates of adverse events were not different between the groups throughout the study. CONCLUSIONS: These findings indicate that a 3-week intravenous treatment with alpha-lipoic acid, followed by a 6-month oral treatment, had no effect on neuropathic symptoms distinguishable from placebo to a clinically meaningful degree, possibly due to increasing intercenter variability in symptom scoring during the study. However, this treatment was associated with a favorable effect on neuropathic deficits without causing significant adverse reactions. Long-term trials that focus on neuropathic deficits rather than symptoms as the primary criterion of efficacy are needed to see whether oral treatment with alpha-lipoic acid over several years may slow or reverse the progression of diabetic neuropathy.

Quantitative sudomotor axon reflex test (QSART): a new approach for testing distal sites.

The quantitative sudomotor axon reflex test (QSART) is a useful tool in the evaluation of C-fiber function. Because many neuropathies show a length-dependent loss of nerve function, a new capsule was designed for distal performance of the QSART, allowing measurements on fingers and toes. We investigated 20 healthy volunteers and 15 patients with insulin-dependent diabetes mellitus and normal sensory nerve conduction studies. A QSART was performed on the forearm and on the thumb. The groups showed no differences in the QSARTs on the forearm, but the sweat volume on the thumb was significantly lower in patients. Calculation of the forearm/finger ratio reduced the interindividual variation and showed the highest sensitivity for detecting C-fiber dysfunction in the patient group. We conclude that the distal measuring device and the forearm/finger ratio are more sensitive tools for the early detection of distal-onset neuropathies than are the commonly used proximal testing sites.

Platelet aggregation in type 1 diabetes without microvascular disease during continuous subcutaneous insulin infusion.

The effect of metabolic control on platelet activities was studied in eleven insulin-dependent diabetic patients during six months of continuous insulin infusion (CSII) treatment in comparison to three months of conventional therapy. Diabetic patients chosen for the study were free of microvascular disease. Glycemia control was improved during CSII treatment and a significant hemoglobin A1c reduction from 8.26 +/- 1.78 to 6.16 +/- 0.46%, p < 0.001, was achieved. The accompanying improvement in platelet aggregation in response to two agonists was only observed with the achievement of glycemia control (ADP: 20.84 +/- 4.61 vs 14.84 +/- 3.03%, p < 0.001; arachidonic acid: 22.04 +/- 4.26 vs 16.0 +/- 3.15%, p < 0.01). The synthesis of proaggregatory thromboxane B2, as a response to arachidonate, was lower during the CSII period (TxB2: 415 +/- 51 vs 382 +/- 36 micrograms/l.10(6) platelets), but with no statistical significance. Inspite of the fact that in all patients, lipoprotein concentrations were of normal values both before and after intensified therapy (HDL-c: 1.48 +/- 0.5 vs 1.52 +/- 0.4 mmol/l, NS; LDL-c: 3.2 +/- 1.3 vs 2.7 +/- 1.0 mmol/l, NS), a significant correlation was observed between the atherogenic lipoprotein fraction and aggregation parameters. Thus, in all patients, LDL-cholesterol before and during CSII showed a significant correlation with platelet sensitivity to ADP (r = 0.61, p < 0.002), whereas at the same time its correlation with the corresponding values of HDL-cholesterol (r = -0.52, p < 0.01) was negative. Our results suggested that intensive insulin treatment reduced platelet aggregation in patients without microvascular disease when strict glycemia control was maintained and indicated that changes in platelet aggregation could directly result from changes in plasma glucose concentrations.

Blood glucose and free insulin levels after the administration of insulin by conventional syringe or jet injector in insulin treated type 2 diabetics.

UNLABELLED: The levels of blood glucose and free insulin were compared in 20 diabetic subjects (type 2) receiving one dose of a combination of fast-acting and intermediary-acting insulins in the morning by means of a needle syringe or a jet injector (SICIM, Italy), using minimum possible injecting power. A shift to the left in the free insulin profile, consequential to different pharmacokinetic characteristics of insulin when administered by means of a jet injector, was observed, although no significant differences were seen for free insulin levels. Statistically significantly higher blood glucose values (P less than 0.05) were recorded 6 and 9 h after insulin administration by means of a jet injector, as well as statistically significant higher MBG values (P less than 0.05), thus indicating a faster and shorter effect achieved in comparison to that produced by the syringe injected insulin. CONCLUSIONS: 1. When switching the method of insulin administration in patients from needle syringe to jet injections the power of the jet injector should be increased (it can be set in three different levels). If that is not possible, because of patient skin characteristics then the dose of intermediary acting insulin should be slightly increased. 2. No local or general side-effects were registered using minimum injecting power of jet injector. 3. The results of the controlled poll have shown that this method of insulin administration is less painful and simpler for patients. The great majority of the patients would like to possess a jet injector.