in motor nerve conduction velocity (NCV), which has been shown to improve significantly as soon as one week following the elimination of ketosis and hyperglycemia by insulin treatment [116–118]. Similarly, other findings of neural dysfunction, such as increased resistance to ischemia in the diabetic nerve [118] or impaired retinal neurophysiologic function [119] were rapidly reversible within one to three weeks of improved glycemic control after the diagnosis of type 1 diabetes. In hyperglycemic patients with various durations of diabetes, who were treated with an artificial endocrine pancreas, H-reflex conduction velocity or motor and sensory conduction increased significantly during two or three days of normoglycemia [120,121]. Metabolic derangement resulting in diabetic ketoacidosis is often associated with nerve conduction slowing which has been shown to be reversible following insulin treatment for three months or less [122].
The aforementioned studies suggest that the acutely reversible changes in nerve function observed after improvement in glycemic control are attributable to functional rather than structural alterations in the diabetic nerve during episodes of metabolic derangement. Experimental studies have shown a marked reduction of the compound nerve action potential in isolated dorsal rat spinal roots incubated in 25-mM extracellular glucose and transiently exposed to hypoxia. This electrophysiologic alteration appeared to be caused by acidosis, because it was prevented when bicarbonate-containing solutions were used [128].
Although the rapidly reversible abnormalities in nerve function are related to restoring near-normoglycemia, acute painful neuropathy associated with the initiation of tight glycemic control has been reported in some patients [129]. Caravati [130] first described this rare phenomenon, which he called “insulin neuritis,” in 1933 (see Chapter 5, page 306-309). This effect has been observed in poorly controlled patients with markedly raised HbA1 levels and occurred within several weeks of lowering of blood glucose by intensive insulin treatment but without evidence for frequent hypoglycemic episodes. Continuation of insulin treatment and maintenance of good glycemic control leads to a recovery from the painful symptoms after periods of up to six months. Sural nerve biopsy in one case during the acute phase revealed predominant small-fiber loss and regenerating axon sprouts [129].
Role of Intensive Diabetes Therapy in Treatment and Prevention of Diabetic Neuropathy
Earlier Small Trials in Type 1 Diabetic Patients
Earlier uncontrolled short-term studies including relatively small numbers of patients with diabetic neuropathy have reported that neuropathic symptoms or abnormal nerve function tests seen during hyperglycemic conditions may be more or less ameliorated following improvement of glycemic control [131–134]. Previous randomized controlled studies have assessed the influence of improved glycemic control on peripheral nerve function for periods of up to two years. However, several shortcomings are apparent in these studies: (1) two studies have used retinopathy as the primary selection criterion for entry and provided no information as to the prevalence and severity of clinical neuropathy [123,127], (2) only one study used reliable and clinically meaningful criteria for the diagnosis of neuropathy [126], (3) three studies did not measure nerve conduction [123,125,127], which is thought to be the most objective, sensitive, and reliable test in the evaluation of diabetic neuropathy [135], and (4) intensified insulin treatment did not lower the elevated HbA1 values to the normal range. In addition, in most of these studies the differences in mean HbA1 between the conventionally and intensively treated patients were relatively rather small to result in meaningful differences in peripheral nerve function. According to Dyck and O'Brien [136], the following degrees of changes in motor and sensory NCV that are associated with a change in the Neuropathy Impairment Score (NIS) of two points can be regarded as meaningful in controlled clinical trials: median motor NCV: 2.5 m/s, ulnar motor NCV: 4.6 m/s, peroneal motor NCV: 2.2 m/s, median sensory NCV: 1.9 m/s, and sural sensory NCV: 5.6 m/s. A change in NIS of two points corresponds to, e.g., bilateral change in dorsiflexor muscle strength of 25%, or change in ankle reflexes, or pin-prick perception from normal to decreased and vice versa.
Ziegler et al. [137] conducted a prospective study in 55 initially poorly controlled type 1 diabetic patients who were treated with continuous subcutaneous insulin infusion (CSII) or intensive conventional therapy (ICT) for four years. Patients were divided into three groups according to their mean HbA1 levels during the study. Group 1 (n = 19) had mean HbA1 during months 3-48 in the normal range of less than 7.8% (near-normoglycemic control), group 2 (n = 18) showed moderately elevated mean HbA] between 7.8% and 8.5% (satisfactory control), and group 3 (n = 18) had clearly elevated mean HbA1 of 8.6% or above (poor control). In the three groups studied, the changes in median and peroneal motor NCV over baseline as well as median and ulnar sensory NCV after four years were inversely related to the mean HbA1 levels of months 3-48 (P<0.05). No significant associations with mean HbA1 were noted for ulnar motor NCV, sural sensory NCV, and heart rate variability (HRV) as an index of autonomic dysfunction. Thus, near-normoglycemia maintained for four years in type 1 diabetic patients was associated with an increase in NCV in the upper limbs but not sensory NCV in the lower limbs and HRV. These results indicate that the susceptibility of different nerve fiber populations to long-term improvement in blood glucose control may be variable.
Long-Term Trials in Type 1 Diabetic Patients
Three pivotal long-term prospective studies that included type 1 diabetic patients either with mild retinopathy or without evidence of diabetic complications have been published (Table 4.1). The results of the Stockholm Diabetes Intervention Study (SDIS) over 10 years [138], the Oslo Study over eight years [139], and the DCCT over five years [140] demonstrate that long-term near-normoglycemia retards the deterioration in motor and sensory NCV. In the DCCT, intensive insulin therapy reduced the appearance of nerve conduction deficits after five years by approximately 50%. The risk for the development of clinical neuropathy was reduced by 64% within five years (5% vs 13% for the intensive therapy [IT] vs the conventional therapy [CT] group) [109]. Most attributes of nerve conduction remained stable or showed modest improvement in patients on IT, whereas they generally deteriorated in those on CT. Among patients in the primary prevention cohort (for retinopathy) without neuropathy at baseline, the IT group had significantly higher NCVs at five years compared with the CT group, the most prominent difference being noted for the peroneal motor NCV, which was 4.1 m/s faster [140]. A comparable effect was observed in the subgroup of patients with possible or definite neuropathy at baseline and in the secondary intervention cohort. Thus, the magnitude of treatment effect was relatively independent of the presence or absence of clinical neuropathy at baseline. Abnormal R-R interval variation at deep breathing as a measure of cardiovascular autonomic neuropathy (CAN) was significantly more frequent in the CT group than the IT group (14.8% vs 7.6%) in the secondary intervention cohort at 5-6 years [141]. The corresponding percentages for any abnormality among R-R interval variation, Valsalva ratio, and postural testing in the secondary intervention cohort at 5-6 years were 16.2% and 8.2%, respectively. These differences were considerably smaller and did not reach statistical significance in the primary prevention cohort. Overall, less than 3% of the DCCT subjects reported symptoms consistent with autonomic dysfunction. Thus, intensive therapy can slow the progression and development of autonomic dysfunction in type 1 diabetic patients with retinopathy.
The Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term observational continuation of the DCCT in which the CT patients were offered IT, showed that the reduction in the risk of progressive retinopathy and nephropathy resulting from IT persists for four years, despite a narrowing in the difference in mean HbA1c between the groups, which decreased from 9.1% to 8.2% in the original CT group and increased from 7.2.% to 7.9% in the IT group [142]. However, no data were reported for neuropathy.
In
