The Diabetic Neuropathies
Aggressive glycemic control has been shown in large, well-designed clinical trials to reduce the neuropathy risk in type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) randomized 1441 patients with type 1 diabetes to intensive or standard glucose control. During the long-term follow-up, glycemic control was similar between patients initially randomized to the different treatment groups. Despite this fact, those who had 5 years of intensive control during the DCCT were less likely to have neuropathy 14 years later than those who had standard therapy (25% vs 35%, p < 0.001). Similar data supporting a benefit for aggressive glycemic control in type 2 diabetes are lacking. The ACCORD study, which randomized 10,251 early diabetic subjects (HgbA1c of > 7.4%) to either intensive (HgbA1c goal of 6.5%) or standard (goal 7.0–7.9%) therapy found no reduction in the risk of incident clinical neuropathy. A recent Cochrane Review of this topic concludes that aggressive glycemic control does not reduce clinical neuropathy risk.
The Steno-2 trial provides the best data on potential neuroprotective effects of metabolic syndrome control in patients with diabetes. Patients with type 2 diabetes were randomized to receive standard treatment or aggressive multimodal therapy to normalize weight, hypertension and lipid abnormalities, together with smoking cessation. Those in the multifactorial treatment arm were significantly less likely to develop coronary, cerebral, or peripheral vascular occlusive disease, but also nephropathy, retinopathy, and autonomic neuropathy. Somatic neuropathy and associated pain were not evaluated.
An evolving literature supports a role for exercise in neuropathy prevention and therapy. One prospective study compared neuropathy incidence in 78 type 2 diabetes patients randomized to supervised treadmill walking 4 hours weekly or bland counseling. HgbA1c did not improve significantly for either cohort, but exercise subjects improved fitness doubled VO2 max and reduced waist circumference. Clinical neuropathy developed in 30% of nonexercisers compared with 7% of exercisers (p < 0.05). A smaller unrandomized study in subjects with DSP found 10 weeks of supervised exercise significantly improved reported neuropathic pain, as well as cutaneous axon sprouting. These results suggest that exercise may impact neuropathy through a mechanism other than improvement in glucose control.
Generally, however, once DSP is established, it has proved remarkably resistant to treatment. No human clinical trial has demonstrated reversal or improvement of DSP even with complete resolution of diabetes. Patients with type 1 diabetes who underwent pancreatic transplant were compared with matched subjects who received best medical therapy. Compared with medical therapy subjects, who experienced unrelenting decline in clinical measures of peripheral nerve function, transplant recipients showed a stabilization of neuropathy progression, but minimal improvement over many years. With neuropathy progression, reversible metabolic factors tend to be supplanted by irreversible structural injury. Even in rodent models, spontaneous reversion to normoglycemia does not result in significant improvement of chronic diabetic neuropathy. These observations suggest future therapeutic efforts should focus on very early disease or even neuropathy prevention.
Treatment of Hyperglycemia and Metabolic Syndrome
Aggressive glycemic control has been shown in large, well-designed clinical trials to reduce the neuropathy risk in type 1 diabetes. The Diabetes Control and Complications Trial (DCCT) randomized 1441 patients with type 1 diabetes to intensive or standard glucose control. During the long-term follow-up, glycemic control was similar between patients initially randomized to the different treatment groups. Despite this fact, those who had 5 years of intensive control during the DCCT were less likely to have neuropathy 14 years later than those who had standard therapy (25% vs 35%, p < 0.001). Similar data supporting a benefit for aggressive glycemic control in type 2 diabetes are lacking. The ACCORD study, which randomized 10,251 early diabetic subjects (HgbA1c of > 7.4%) to either intensive (HgbA1c goal of 6.5%) or standard (goal 7.0–7.9%) therapy found no reduction in the risk of incident clinical neuropathy. A recent Cochrane Review of this topic concludes that aggressive glycemic control does not reduce clinical neuropathy risk.
The Steno-2 trial provides the best data on potential neuroprotective effects of metabolic syndrome control in patients with diabetes. Patients with type 2 diabetes were randomized to receive standard treatment or aggressive multimodal therapy to normalize weight, hypertension and lipid abnormalities, together with smoking cessation. Those in the multifactorial treatment arm were significantly less likely to develop coronary, cerebral, or peripheral vascular occlusive disease, but also nephropathy, retinopathy, and autonomic neuropathy. Somatic neuropathy and associated pain were not evaluated.
An evolving literature supports a role for exercise in neuropathy prevention and therapy. One prospective study compared neuropathy incidence in 78 type 2 diabetes patients randomized to supervised treadmill walking 4 hours weekly or bland counseling. HgbA1c did not improve significantly for either cohort, but exercise subjects improved fitness doubled VO2 max and reduced waist circumference. Clinical neuropathy developed in 30% of nonexercisers compared with 7% of exercisers (p < 0.05). A smaller unrandomized study in subjects with DSP found 10 weeks of supervised exercise significantly improved reported neuropathic pain, as well as cutaneous axon sprouting. These results suggest that exercise may impact neuropathy through a mechanism other than improvement in glucose control.
Generally, however, once DSP is established, it has proved remarkably resistant to treatment. No human clinical trial has demonstrated reversal or improvement of DSP even with complete resolution of diabetes. Patients with type 1 diabetes who underwent pancreatic transplant were compared with matched subjects who received best medical therapy. Compared with medical therapy subjects, who experienced unrelenting decline in clinical measures of peripheral nerve function, transplant recipients showed a stabilization of neuropathy progression, but minimal improvement over many years. With neuropathy progression, reversible metabolic factors tend to be supplanted by irreversible structural injury. Even in rodent models, spontaneous reversion to normoglycemia does not result in significant improvement of chronic diabetic neuropathy. These observations suggest future therapeutic efforts should focus on very early disease or even neuropathy prevention.
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