Pathogenetic Mechanisms
The terminal aspects of autonomic axons appear to be preferentially targeted in diabetes. Ganglionic neuroaxonal dystrophy may represent an abnormal outcome of synaptic turnover, which may normally sub-serve synaptic plasticity, or the synaptic detachment/reattachment process that follows postganglionic sympathetic axotomy [104]. Other possible pathogenetic mechanisms have been previously described in detail [105].
Pathobiochemistry and Pathophysiology
D. Ziegler
Introduction
It was as early as in 1864 when Marchal de Calvi established that neurologic symptoms reflect the consequence rather than the cause of diabetes mellitus [106], However, one of the most intriguing questions in clinical research in diabetes during the past decades was whether long-term near-normoglycemia may retard or improve the chronic diabetic complications, including diabetic neuropathy [107,108]. The recent publications of the two largest and longest studies in the history of diabetes research, the Diabetes Control and Complications Trial (DCCT), conducted in type 1 diabetic patients, and the United Kingdom Prospective Diabetes Study (UKPDS), performed in type 2 diabetic patients, have been interpreted as providing evidence of the benefit of intensive diabetes therapy on the development and progression of the chronic diabetic complications [109–111]. However, while in both studies the effects of improved glycemic control on the microvascular endpoints were unanimously considered as being favorable [107,112], the effects on macrovascular endpoints in the UKPDS have also been interpreted as showing a clinically important benefit on macrovascular endpoints only in patients treated with metformin, but not those treated with sulfonylureas or insulin. Because metformin provided blood glucose levels similar to those of sulfonylureas or insulin, the benefit from metformin appeared to be independent of its blood-glucose-lowering effect [113]. Moreover, in both studies microvascular or macrovascular rather than neuropathic endpoints were used as the primary outcome measures.
Numerous previous short-term studies have shown that neuropathic symptoms or abnormal nerve function tests occurring during periods of metabolic derangement can be ameliorated within several days or weeks following improvement of blood glucose control [114–122]. However, possible long-term effects have been difficult to study due to the following problems: (1) the progression of diabetic polyneuropathy is relatively slow, so that expected changes may take place over several years, (2) the various nerve fiber populations might be affected at different rates, (3) minor changes may not be detected due to a low reproducibility of some methods, (4) glycemic control or the risk factor profile may fluctuate over time, and (5) even with the modern intensive diabetes therapy regimens, long-term near-normoglycemia is difficult to achieve in some patients. These problems may in part account for the conflicting findings in the earlier reports, with some showing improvement of peripheral nerve function [123–125], while others have failed to demonstrate any changes [126,127].
Rapidly Reversible Nerve Dysfunction After Correction of Metabolic Derangement
Untreated, newly diagnosed type 1 diabetic patients show slight reduction 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