Diabetic Neuropathy. Friedrich A. Gries

and renal transplantation on NCV after four years of normoglycemia. The initial improvement in motor NCV observed in these patients was also noted in diabetic patients receiving a renal transplant only, and was most likely due to the elimination of uremia. However, further improvement was seen only in the euglycemic pancreas graft recipients. Muller-Felber et al. [150] have shown modest improvement in neuropathic symptoms and increase in motor but not sensory NCV after three years in patients who underwent successful pancreas and kidney transplantation as compared to those with early pancreas rejection and functioning kidney graft. None of the beneficial effects described in these three studies were demonstrable after two years, and none of these studies could demonstrate an effect on HRV as an index of cardiovascular autonomic dysfunction, while the effects on clinical measures were variable (Table 4.3). These findings are confirmed in the more recent studies shown in the last three columns of Table 4.3 [151–153]. Thus, periods of normoglycemia of more than two years following pancreas transplantation retard the further progression of deficits in motor and sensory NCV, but no such clear effect is noted for neuropathic symptoms and deficits, while no beneficial effect is seen on cardiovascular autonomic dysfunction. The reasons for this divergent effect are not known but may be due to a different susceptibility of the autonomic nerves to metabolic changes or to methodological factors.

Is There a Glycemic Threshold for the Risk of Diabetic Complications?

      Two retrospective studies suggested the existence of a glycemic threshold at a HbA_1c level of approximately 8% for microalbuminuria and retinopathy, below which there is no further reduction in risk [154,155]. This would imply that improving glycemic control below this level is unnecessary, thereby potentially reducing the risk of hypoglycemia in some type 1 diabetic patients [156]. In contrast, the DCCT could not identify such a HbA_1c threshold. The risks of retinopathy progression and of developing microalbuminuria and neuropathy were found to be continuous but nonlinear over the entire range of HbA_1c values. As HbA_1c was reduced below 8% there were continuing relative reductions in the risk of diabetic complications, whereas the rate of increase in the risk of hypoglycemia was slower [157,158]. Likewise, in the Pittsburgh Epidemiology of Diabetes Complications Study no definitive threshold was found after six years for any complication in type 1 diabetic subjects [159].

Conclusions

      1. The large randomized long-term clinical trials such as the DCCT and UKPDS were not designed to evaluate the effects of intensive diabetes therapy on diabetic polyneuropathy, but rather to study the influence of such treatment on the development and progression of the chronic diabetic complications. Thus, only a minority of the patients enrolled in these studies had symptomatic polyneuropathy at entry. In type 1 diabetic patients these studies show that intensive diabetes therapy retards but does not completely prevent the development of polyneuropathy and autonomic neuropathy. In contrast, in type 2 diabetic patients, who represent the vast majority of people with diabetes, the results were variable. Intensive diabetes therapy either had no effect or only partially slowed the progression of polyneuropathy, and the effect on autonomic neuropathy was largely lacking. Moreover, improved glycemic control was achieved at the expense of increased risk of hypoglycemia and weight gain.

      2. Only a few small studies have evaluated the effects of intensive diabetes therapy on established polyneuropathy in type 1 diabetic patients. They indicate that improved glycemic control may improve some aspects of diabetic neuropathy, but imperfect study designs and methodology hamper the validity of most of these small trials. At more advanced stages improvement is still possible for some measures of nerve function such as motor NCV, but is less likely for autonomic dysfunction. This may be due to the fact that true normoglycemia could not be achieved in many patients. No large, randomized, controlled trial has been performed specifically to show favorable effects of intensive diabetes therapy on diabetic polyneuropathy.

      3. In type 1 diabetic patients with the most advanced stages of peripheral neuropathy, progression of nerve conduction deficits is halted after three to four years of normoglycemia following pancreas transplantation, but no effect is seen in autonomic neuropathy. However, successful pancreas transplantation results in long-term normoglycemia. Hence, the effect on nerve function that can be achieved with this method cannot be extrapolated to the widely used current methods of intensive diabetes therapy, since for various reasons the majority of diabetic patients in whom these methods are used do not achieve sustained normoglycemia.

      4. Although observational studies suggested a glycemic threshold for the development and progression of long-term complications in type 1 diabetes, the DCCT data do not support such an assumption. Thus, attempts to achieve optimal glycemic control should not aim at a particular HbA_1c threshold within the diabetic range, but should follow “the goal of achieving normal glycemia as early as possible in as many IDDM patients as is safely possible” [158].