Original Article
Effects of Pancreatic Transplantation on Diabetic Neuropathy
N Engl J Med 1990; 322:1031-1037April 12, 1990
- Abstract
- Abstract
Reestablishment of the euglycemic state by successful transplantation of the pancreas might halt or reverse diabetic neuropathy. To test this possibility we evaluated neurologic function by clinical examination, nerve conduction studies, and autonomic-function tests in patients with insulin-dependent (Type I) diabetes mellitus before and after successful pancreatic transplantation. Sixty-one patients were studied before and 12 months after transplantation, 27 again after 24 months, and 11 again after 42 months. A control group of patients with Type I diabetes treated with insulin underwent the same studies at similar intervals — 48 patients before and after 12 months had elapsed, 21 again after 24 months, and 12 again after 42 months.
In the control group, neuropathy tended to worsen during the follow-up period. The scores on the clinical examination indicated increased impairment after 12 months. Composite indexes of the degree of abnormality found on neurophysiologic testing of the function of peripheral motor, sensory, and autonomie nerves indicated decreased autonomie function after 12 months. The examination score and the three index values worsened slightly but not significantly in the patients followed for 24 and 42 months. In contrast, in the patients who had received pancreatic transplants, the neuropathy tended to improve. There was significant improvement in the motor and sensory indexes 12 months after transplantation and in the sensory index 24 months after transplantation. The other measures improved slightly but not significantly at these times, as did all four measures in the patients studied 42 months after transplantation.
We conclude that the progression of diabetic polyneuropathy may be halted through the restoration of a euglycemic state by successful pancreatic transplantation. (N Engl J Med 1990; 322:1031–7.)
Article Activity
- Article
POLYNEUROPATHY affecting the somatic and autonomie nervous systems is a common complication of diabetes mellitus. Although many attempts have been made to halt or reverse diabetic neuropathy by improved metabolic control, the use of pharmacologic agents, and organ transplantation, it is still uncertain whether strict control of hyperglycemia can prevent the occurrence and progression of polyneuropathy.1 2 3 Minimal improvement in nerve conduction velocity has been demonstrated in short-term studies of patients undergoing intensive intermittent insulin therapy,4 5 6 7 and the improvement of nerve conduction velocity and possibly cardiorespiratory reflexes and the sense of vibration has been reported in patients treated with a continuous infusion of insulin8 9 10 11 12 or with aldose reductase inhibitors.13 14 15 Treatment with aldose reductase inhibitors also improves the biochemical and morphologic abnormalities in the peripheral nerves of patients with diabetes.16 , 17 However, these studies only rarely lasted for more than 12 months, the degree of improvement in nerve conduction was usually minimal, and clinical signs or symptoms changed little. Our own 15-year follow-up study of patients with insulin-dependent diabetes indicated that kidney transplantation for chronic renal failure did not halt the progression of neuropathy.18 , 19
Replacement of functioning islet beta cells is the most logical treatment for diabetes mellitus and therefore its complications, including neuropathy. In our institution the most effective method of replacing islet cells and restoring lasting euglycemia is pancreatic transplantation. Limited information has been published about the influence of pancreatic transplantation on the neuropathy of diabetes mellitus. Our preliminary results suggested that pancreatic transplantation might halt the progression of neuropathy,20 , 21 in agreement with other reports.22 23 24 25 26 Recently however, Solders et al.27 found that renal transplantation alone and combined renal and pancreatic transplantation had similar, slight effects on nerve-conduction values and no effect on cardiorespiratory reflexes.
This report describes the results of clinical examinations, nerve-conduction studies, and cardiorespiratory-reflex tests in patients with insulin-dependent (Type I) diabetes before and 1, 2, and 3 1/2 years after successful pancreatic transplantation.
Methods
Patients and Management
The study group consisted of 61 patients with Type I diabetes (21 men and 40 women; mean [±SD] age, 32 ±6 years; mean duration of diabetes, 21±6 years) who received pancreatic transplants between July 1978 and June 1987 and retained the grafts for more than 12 months. All the patients were studied before and approximately 12 months after transplantation, 27 of them were studied again after 24 months, and 11 again after 42 months. Follow-up was not complete for the following reasons: death (2 patients), graft failure (11 patients), the fact that less than 24 months (21 patients) or between 24 and 42 months (8 patients) had passed since transplantation, and missing evaluations (8 patients). Cadaveric donors were the source of 34 grafts, and living related donors the source of 27. Nineteen patients had previously received a renal allograft for the treatment of end-stage diabetic nephropathy, and seven patients underwent renal and pancreatic transplantation at the same time. The other 35 patients did not have uremia and therefore had not undergone renal transplantation. No patient required hemodialysis or renal transplantation during the study.
The control group consisted of 48 patients with Type I diabetes (16 men and 32 women; mean age, 31±5 years; mean duration of diabetes, 20±6 years). The neurologic characteristics of this group at the time of entry into the study did not differ from those of the study group. The controls were evaluated while awaiting pancreatic transplantation (n = 33) or after the graft had failed (n = 15) if it had functioned for no more than three months (mean, 1.6). Of the 48 controls, 21 had previously undergone successful renal transplantation. All 48 patients in the control group were studied at entry and after 12 months, 21 were studied again after 24 months, and 12 again after 42 months. Follow-up was not complete for the following reasons: death (3 patients), pancreatic transplantation (17 patients), the fact that less than 24 months (5 patients) or between 24 and 42 months (2 patients) had passed since the entry into the study, and missing evaluations (9 patients).
The surgical techniques and case management have been described elsewhere.28 , 29 Immunosuppressive therapy consisted of combinations of cyclosporine, azathioprine, and prednisone. Rejection episodes were treated with increased doses of prednisone and with antilymphocyte globulin in some patients. All patients with functioning pancreatic transplants became persistently normoglycemic and no longer required insulin therapy. Their mean (±SE) total glycosylated hemoglobin (A1c) values were 9.6±0.4 percent at entry into the study and within the normal range (5.4 to 7.4 percent) thereafter, with the exception of the value at 42 months. The mean values were 7.2±0.2 percent after 12 months (P<0.001 for the comparison with paired values before transplantation), 7.4±0.3 percent after 24 months (P<0.001), and 8.0±1.0 percent after 42 months (P<0.05). The control patients were dependent on insulin throughout the follow-up period. They were treated according to conventional, nonintensive insulin regimens. Their glycosylated hemoglobin levels averaged 11.2±0.5, 9.8±0.5, 9.9±0.2, and 10.6±1.0 percent at the respective times studied.
Clinical Evaluation
A complete neurologic examination (excluding the cranial nerves) was performed at each visit by the same neurologist. Each part of the examination was subjectively graded from 0 to —4 (normal function to complete impairment). A neurologic examination score was constructed by adding the scores of all the examination items (Table 1Table 1
Protocol Used for the Clinical Evaluation of Neuropathy.) to determine the evolution of neuropathy during the study intervals.Nerve Conduction Studies
The motor-nerve conduction velocity of an ulnar, median, peroneal, and tibial nerve was measured at each visit. Evoked muscle action potentials were recorded from the hypothenar, thenar, extensor digitorum brevis, and abductor digiti minimi muscles, respectively. Orthodromic sensory-nerve conduction was measured in the median and sural nerves, the latency and amplitude of the nerve action potential being recorded. The sensory-nerve conduction velocity in the forearm segment of the median nerve was measured antidromically. If there was no response to nerve stimulation, the amplitude was recorded as zero and the conduction velocity and latency as missing values. During these studies the skin temperature was maintained between 33.5 and 35°C in the upper extremities and between 32 and 34°C in the lower extremities.
Cardiorespiratory-Reflex Tests
Cardiorespiratory reflexes were measured at the same times in a smaller number of patients (Tables 2Table 2
Mean (±SE) Neurophysiologic-Test Results Immediately before and 12, 24, and 42 Months after Transplantation in the Patients with Diabetes Who Received a Pancreatic Transplant.* and 3Table 3
Mean (±SE) Neurophysiologic-Test Results in the Control Patients with Diabetes at Entry into the Study and after 12, 24, and 42 Months of Follow-up.*). The variation in the heart rate during deep breathing at a rate of six breaths per minute was recorded as the mean of the differences between the maximal and minimal heart rates measured during three trials of seven respiratory cycles each. The Valsalva ratio was calculated as follows: the highest heart rate during a Valsalva maneuver in which expiratory pressure was maintained at 40 mm Hg for 10 seconds, divided by the lowest heart rate within 30 seconds after the maneuver.30 Analysis
To assess the degree of nerve-function involvement, we calculated indexes of neuropathy.31 The motor index was calculated as the mean of the deviations of the values of motor-nerve conduction velocity and amplitude of the muscle action potentials measured in each patient from the mean values of normal subjects. Slower-than-normal velocities, longer-than-normal latencies, or lower-than-normal amplitudes, which are usually found in such patients, were thus considered negative deviations. Similarly, the sensory index was calculated as the mean of the deviations of the five sensory-nerve conduction values, and the autonomie index as the mean of the deviations of the values of the two cardiorespiratory reflexes.
The paired two-tailed t-test was used for comparisons of the clinical and electrophysiologic results over time within each group. The unpaired t-test was used for comparisons between the study and control groups after each interval. For variables that did not follow a normal distribution (the results of cardiorespiratory-reflex tests and the neurologic-examination scores), the Wilcoxon signed-rank and Wilcoxon rank-sum tests were used. The chi-square test was used for comparison of variations in the evolution of each group. Because of multiple testing, P values of less than 0.01 were considered to indicate significant differences, and P values of less than 0.05 were considered to indicate differences approaching significance.
Results
Clinical Evaluation
All the patients had abnormal results on neurologic examination at the time of entry into the study. The mean initial examination score was –22.0 in the study group. No significant changes in the examination results were recorded 12, 24, and 42 months after pancreatic transplantation (Table 4Table 4
Mean (±SE) Neurophysiologic-Examination Scores and Indexes of Severity of Motor, Sensory, and Autonomie Neuropathy in the Patients with Diabetes with a Pancreatic Transplant (Study Group) and the Control Patients with Diabetes (Control Group) at Entry into the Study and after 12, 24, and 42 Months of Follow-up.). In the control group the mean initial score was –25.7, and the mean score was similarly low after each of the three succeeding intervals.Neurophysiologic Studies
All but one patient in the study group had neurophysiologic evidence of polyneuropathy when evaluated before transplantation. The mean motor-nerve conduction velocity in the ulnar, median, peroneal, and tibial nerves was near or slightly below the respective mean values minus 2 SD in normal subjects (Table 2). The recorded mean amplitudes of the muscle action potentials were in the low normal range in the hand muscles and slightly below the normal range in the foot muscles. Sensory-nerve conduction was slowed in the median and sural nerves, and the amplitudes of the nerve action potentials were below normal. The mean cardiorespiratory-reflex values were far below the respective normal ranges. The indexes of neuropathy were therefore all less than zero (Table 4).
Twelve months after pancreatic transplantation, the mean motor-nerve and sensory-nerve conduction velocities were significantly improved (about 2 m per second in the upper-extremity nerves and 1.5 m per second in the lower-extremity nerves). The mean amplitudes of the muscle action potentials and nerve action potentials increased slightly in the upper extremity, but they did not change in the lower extremity. In the autonomie tests, the Valsalva ratio improved slightly (P<0.05), whereas there was no change in the difference between maximal and minimal heart rates during deep breathing. The motor and sensory indexes improved significantly, but the autonomie index did not improve (Table 4).
Twenty-four months after pancreatic transplantation, the nerve conduction values and the evoked responses increased slightly but not significantly in the upper-extremity nerves (Table 2). All three indexes of neuropathy improved slightly, but only in the sensory index did the increase approach significance. Forty-two months after pancreatic transplantation the trends were similar, but none of the differences were significant, because we studied only a small number of patients with functioning grafts at that time.
All but three patients in the control group had neurophysiologic evidence of neuropathy on initial examination, and the severity of the abnormalities in this group was similar to that in the study group (Table 3). The neurophysiologic tests showed mild deterioration in this group after 12 months — a significant decrease in the amplitude of the muscle action potentials and a decrease that approached significance in the nerve action potentials and in one autonomie test; on the other hand, the nerve conduction velocity did not change. The results were similar after 24 and 42 months. The mean motor and sensory indexes (Table 4) were slightly but not significantly more abnormal at 24 and 42 months than initially.
When comparing the study and control groups, we found several differences (P values are shown in Table 3), especially at the 12-month examination, that indicated the worsening of neuropathy in the control group. Among the 45 pairs of mean results shown in both Table 2 and Table 3, the values improved in 38 pairs in the study group and in only 10 in the control group. The indexes of neuropathy, which were similar at entry into the study, tended to improve with time in the group with functioning pancreatic transplants but to worsen in the control group. Figure 1Figure 1
Mean (±SE) Variations in the Indexes of Motor, Sensory, and Autonomie Neuropathy in the Study (○) and Control (●) Groups at Entry into the Study and after 12, 24, and 42 Months. shows the variations in the three indexes among the patients who were followed up for 42 months.In considering the patients individually, we discovered that with respect to the indexes of neuropathy, a higher percentage of the patients with functioning pancreatic transplants tended to improve and a lower percentage to worsen, as compared with the controls. In the study group, 70 percent of the patients had improved results on motor-nerve tests, nearly 60 percent had improved results on sensory tests, and 45 percent had improved results on autonomie tests 12 and 24 months after pancreatic transplantation. In contrast, in the control group at the same periods, only 30 percent of the patients had improved results on motor and sensory tests, 12 percent had improved results on autonomie tests, and in nearly 50 percent the values had deteriorated.
To assess the possible influence of the correction of uremia by kidney transplantation (simultaneous or earlier), we examined the longitudinal results in the 35 patients with functioning pancreatic transplants who did not have uremia and who had not undergone kidney transplantation. The indexes of neuropathy improved to the same degree in these patients as in the entire study group (Table 4).
Discussion
This prospective study of repeated neurologic evaluations during a 42-month follow-up period demonstrated that in patients who became normoglycemic after successful pancreatic transplantation, peripheral-nerve function had a tendency to improve. This finding contrasts with the natural history of polyneuropathy in patients with Type I diabetes of long duration, which is one of progression. Improvement was most obvious during the first year after pancreatic transplantation, possibly because of the correction of metabolic factors thought to affect peripheral-nerve function.32 These results corroborate the conclusion of a preliminary study.21 They differ from the results of Solders et al.,27 who found no differences between the evolution of neuropathy in a small group of patients who underwent simultaneous renal and pancreatic transplantation and its evolution in a group that underwent only renal transplantation. Other authors have also described improvement of diabetic polyneuropathy after pancreatic transplantation.22 23 24 25 26 In their reports the small numbers of patients studied and the short study periods precluded statistical analysis and definite conclusions. Pancreatic-islet transplantation in rats with streptozocin-induced diabetes has also been reported to improve motor-nerve conduction33 and autonomic-nerve function34 and to prevent histologie nerve lesions.35 , 36
We studied patients who did not have uremia, including some who had their own kidneys and some who had received a kidney transplant before or at the time of entry into the study. The results shown in Table 4 are in agreement with those reported for a smaller subgroup of patients without uremia who had not received a kidney transplant.37 We therefore attribute the changes in the course of diabetic polyneuropathy in our patients to the transplanted pancreas. In a prospective study of patients with Type I diabetes who retained a renal transplant for more than 15 years, we found a progression of neuropathy, as evidenced by a decrease in amplitudes of the muscle action potentials and increased electromyographic abnormalities.18 , 19 We found similar progression, but to a lesser degree, in the control patients with diabetes in this study. These results suggest that the ongoing neuropathic lesions of diabetes were halted by the restoration of normoglycemia produced by successful pancreatic transplantation. Nevertheless, the neuropathy was only slightly improved 42 months after transplantation (Table 4). Therefore, many of the pathological effects of long-standing diabetes on peripheral nerves are either irreversible or require more time for improvement.3 , 27 In the subgroup of 11 patients who were followed up for 42 months, the changes in the severity of polyneuropathy were most evident at the final evaluation (Fig. 1). These results suggest that short-term studies of the effect of treatment on diabetic neuropathy are not adequate to detect slowly evolving neuropathic changes that have progressed during the long course of diabetes.
The effects of pancreatic transplantation and the resulting normoglycemia on the different types of nerve fibers involved in diabetic neuropathy are difficult to ascertain without parallel histologie studies. The results of other treatments indicate that motor-nerve function is more likely to improve than sensory or autonomie function.5 , 15 We found that improvement was more noticeable in the indexes that were initially only mildly abnormal, such as nerve conduction in the upper extremities, and that the results of autonomie tests did not change appreciably, as others have also observed.26 , 27 , 38
The increase in sensation and endurance reported by most patients after pancreatic transplantation usually did not correspond to any change in objective clinical and electrophysiologic results. This phenomenon may be due to a sense of well-being, to which prednisone therapy, freedom from the need for insulin treatment, the absence of the mental changes associated with fluctuating blood glucose levels, and the easing of dietary restrictions all may contribute.
Better control of hyperglycemia can be attained with pancreatic transplantation than with conventional insulin treatment.28 , 29 Other prospective studies have demonstrated that pancreatic transplantation and subsequent prolonged normoglycemia can prevent the development of renal lesions,39 , 40 reverse angiopathic abnormalities,26 , 41 and arrest the progression of retinopathy in some26 but not all42 patients with diabetes.
Our findings suggest that the progression of diabetic polyneuropathy can be halted and polyneuropathy slightly improved by successful pancreatic transplantation. However, the degree of improvement was small, probably because of previous structural damage to the peripheral nervous system. The effect of pancreatic transplantation may be greater if it is performed at an earlier stage of the disease.
Supported in part by a grant (NS R01 26348) from the Public Health Service and a Clinical Research Center grant (RR-400) from National Institutes of Health.
We are indebted to Ms. Lois Balloge, Ms. Julia Spiry, Mr. Frederick Sahinen, and Ms. Kay Moudry-Munns for technical assistance, to Dr. Ruth B. Loewenson for advice in the statistical analysis, and to the nursing staff of the University of Minnesota Hospital Clinical Research Center.
Source Information
From the Departments of Neurology (W.R.K., X.N.), Medicine (F.C.G.), and Surgery (D.E.R.S., J.S.N.), University of Minnesota, Minneapolis. Address reprint requests to Dr. Kennedy at the Department of Neurology, University of Minnesota, Box 187 UMHC, 420 Delaware St., S.E., Minneapolis, MN 55455.
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