Oslo Study, a difference in HbA1 of 1% was associated with changes in peroneal motor NCV of 1.2 m/s, in tibial motor NCV of 1.3 m/s, and in sural sensory NCV of 1.4 m/s during the eight-year follow-up period [139], In the SD1S the mean differences in NCV between the IT and CT groups after 10 years were 5.1 m/s for the peroneal nerve. 6.0 m/s for the tibial nerve, and 8.9 m/s for the sural nerve. Pin-prick sensitivity deteriorated significantly in the CT vs the IT groups, and the rates of neuropathic symptoms were 14% vs 32% after 10 years for IT vs CT, respectively [138], However, these studies do not provide information about the reversibility of established nerve conduction deficits. Fur-thermore, in the Oslo Study the original randomization to the three treatment groups was abolished, and the patients were retrospectively allocated to new groups according to their mean HbA1 over eight years. A certain degree of deterioration and development of deficits in NCV was also observed in the well-controlled groups, suggesting that, using the current methods of intensive insulin therapy, complete prevention of neuropathy is difficult to achieve. Moreover, in the DCCT, intensive therapy was associated with a three-fold increased risk of severe hypoglycemia and mean weight gain of 4.6 kg within five years. In the SDIS, a two-fold increased risk of severe hypoglycemia was observed for intensive therapy (Table 4.2).
Long-term Trials In Type 2 Diabetic Patients
The UKPDS showed a lower rate of impaired vibration perception threshold (VPT>25 V) after 15 years for IT with a sulfonylurea or insulin vs CT with diet (31% vs 52%). However, only 217 patients were available for assessment of VPT after 15 years, out of 3836 available at baseline. Thus, a bias due to the small sample size may have influenced this result. Moreover, the only additional time point at which VPT reached a significant difference between IT and CT was the nine-year follow-up, whereas the results after three, six, and 12 years did not differ between the groups. Likewise, the rates of absent knee and ankle reflexes as well as the heart rate responses to deep breathing did not differ between the groups. IT was associated with an increased risk of weight gain and hypoglycemia [110] (Table 4.2).
In the Kumamoto Study of insulin-treated type 2 diabetic patients, after six years NCV in the median motor and sensory nerves was significantly slower in patients given conventional insulin injection therapy (CT) compared with those given multiple insulin injections (IT), but unfortunately NCV was not measured in the lower limbs, where it would be more likely to reflect an effect on polyneuropathy. This is particularly important in view of the fact that VPT in the upper but not the lower limbs was significantly improved in IT as compared with CT. Similar to the findings of the UKPDS. HRV at rest and during deep breathing and posture-related change in blood pressure did not differ between the groups after six years [143]. The 10-year follow-up of the Kumamoto Study showed a relative risk reduction in the progression of clinical neuropathy by 64% in the IT group compared to the CT group. Moreover, IT prolonged the period in which patients were free of clinical neuropathy by 2.2 years, and was more cost-effective, mainly because of reduced costs for management of diabetic complications [144].
In the Steno type 2 Study, intensified multifactorial intervention including the use of intensive diabetes treatment, ACE inhibitors, antioxidants, statins, aspirin, and smoking cessation in patients with microalbuminuria had no effect on the progression of polyneuropathy after 3.8 years. By contrast, a positive effect of this approach was seen on HRV. It cannot be deduced from this study that this effect was due to improved glycemic control, because any of the other interventions, particularly the administration of ACE inhibitors and antioxidants, or even smoking cessation, may have been responsible for this result [145].
In the Veterans Administration Cooperative Study on type 2 diabetes mellitus (VA CSDM), no significant effect of IT (four-step plan of multiple insulin injections) compared to CT (one morning insulin injection per day) on peripheral neuropathy, abnormal Valsalva ratio and/or R-R interval variation, or erectile dysfunction could be demonstrated after two years, despite a difference in HbA1c between the groups comparable with those in the above studies [146].
In conclusion, these trials have shown heterogeneous effects of intensive diabetes therapy on the progression of distal symmetric polyneuropathy and autonomic neuropathy. It cannot be concluded unequivocally from these results that improved glycemic control prevents the development or retards the progression of polyneuropathy in type 2 diabetic patients treated for periods of 2-15 years. In the UKPDS intensive therapy was associated with an increased risk of weight gain and mild or severe hypoglycemia.
Pancreas Transplantation in Type 1 Diabetic Patients
Pancreas transplantation is the most effective method of achieving long-term normoglycemia in type 1 diabetic patients, but is usually limited to patients with end-stage diabetic nephropathy in combination with a renal graft. Other indications have been questioned [147]. Several long-term studies in patients with established diabetic polyneuropathy who underwent successful pancreatic transplantation have been published (Table 4.3). Kennedy et al. [148] have shown that 42 months after transplantation the neuropathy was only slightly improved, but a significant difference was seen in the mean motor and sensory nerve conduction in the transplanted group compared with a control group who did not have a functioning graft after 42 months. Improvement was more pronounced when only mild dysfunction was present initially.
Solders et al. [149] have demonstrated beneficial effects of combined pancreatic 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 HbA1c 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 HbA1c threshold. The risks of retinopathy progression and of developing microalbuminuria and neuropathy were found to be continuous but nonlinear over the entire range of HbA1c values. As HbA1c 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
