- Email: [email protected]
Diabetic neuropathy and plasma glucose control
Diabetic Neuropathy
DANIEL PORTE, JR.. M.D. RONALD J. GRAF, M.D. JEFFREY B. HALTER, M.D. MICHAEL A. PFEIFER. M.D. EUGEN HALAR, M.D. Seattle, Washington
and Plasma Glucose Control
Diabetic neuropatby is defined, and theories of its pathogenesis are reviewed. Recent studies designed to investigate the influence of plasma glucose on nerve function in noninsulin-dependent diabetic patients are summarized. Motor nerve conduction velocities in the median and peroneal nerves were measured using a double-stimulus technique, and sensory conduction velocity was measured by conventional methods before and after therapy with oral agents or insulin. The degree of hyperglycemia was assessed by measurement of fasting plasma glucose and glycosylated hemoglobin concentrations. The degree of slowing in motor nerve conduction velocity in untreated patients was found to correlate with the fasting plasma glucose and glycosylated hemoglobin concentrations, but sensory nerve function, although abnormal, did not show such correlation. Reduction of hyperglycemia was associated with improvement in motor nerve conduction velocity in the peroneal and median motor nerves of these patients, but sensory nerve conduction velocity showed no such improvement. Improvement in median motor nerve conduction velocity was directly related to the degree of reduction in fasting plasma glucose concentration. These findings suggest that metabolic factors related to hyperglycemia are important in the impaired motor nerve function seen in noninsulin-dependent patients with maturity-onset diabetes. Over the past few years we have studied the relationship between plasma glucose concentration and diabetic nerve disease. Many of the hypotheses regarding the causes of such disease have suggested some direct effect of serum glucose concentration on the nerve conduction system. However, direct evidence to support such hypotheses was not available from studies in man. In this report we summarize our understanding of this disorder and recent preliminary findings regarding the nse of nerve conduction velocity to assess peripheral nerve function [VI.
From the Departments of Medicine and Rehabilitation Medicine, University of Washington School of Medicine, and the Veterans Administration Medical Center, Seattle, Washington. The study was supported by National Institutes of Health Grants AM-12829, AM-20754 and AM-00788, by the Diabetes Research Center of the University of Washington (Grant AM-17047) and by the Veterans Administration. It was presented at a Symposium on Diabetes Management, sponsored by the Upjohn Company, held in Miami, Florida, February 29-March 1. 1980. Requests for reprints should be addressed to Dr. Daniel Porte, Jr., VA Medical Center (151). 4435 Beacon Avenue South, Seattle, Washington 98108.
PATHOGENESIS OF DIFFUSE POLYNEUROPATHY Table I lists the various types of diabetic neuropathies. In this report we shall not discuss autonomic neuropathy, amyotrophy or the mononenropathies. Rather, we shall focus on diffuse impairment of neural function or diabetic polyneuropathy. It is possible that all of these types may be related to the same pathophysiologic abnormality, but this is not certain. They may be somewhat different in their responses to treatment, and they may even have different causes. Because of these uncertainties, we limited our studies to one type of diabetic neuropathy. We also chose to study somatosensory somatometric neuropathy because its diffuse nature is more consistent with a metabolic cause. There are several hypotheses relating to the cause of this disease. At one time it was believed that vascular infarction or &hernia might play a role, but the morphologic evidence for this has been very poor.
January 1981
The American Journal of Medicine
Volume 79
195
DIABETIC
TABLE I
NELJROPATHY
AND
PLASMA
GLUCOSE
CONTROL-PORTE
Types of Diabetic Neurapathy
A. Diffuse polynewopathy B. Mononeuropathy-radiculopathy C. Motor neuropathy-amyotrophy D. Autonomic neuopathy Motor Sensory
At present, only diabetic mononeuropathy is believed to be related to sudden ischemia; this is because of its very sudden onset and because it is sometimes associated with vascular abnormalities [3]. The two major hypotheses concerning the cause of diffuse polyneuropathy are (1) that there is a metabolic injury that leads to malfunction of the nerves or (2) that there is an intrinsic cellular abnormality in the peripheral nerves of diabetic subjects that is part of the over-all diabetic syndrome. The primary site of this nerve damage was formerly believed to be in Schwann cells, because segmental demyelination was found to be the characteristic lesion of diabetic polyneuropathy [4]. However, the hypothesis that the Schwann cell is the primary cell of injury is being challenged now because of two findings: (1) There is axonal dwindling and loss of axonal function prior to the loss of Schwann cells and segmental demyelination [5]; and (2) the swelling that occurs in nerves in experimentally-induced diabetes seems to occur between the Schwann cells and the axons, not in the Schwann cells themselves [S]. Therefore, there is still some question whether the Schwann cell defect is a primary or secondary abnormality in diabetic nerve disease. There are several variants to the metabolic theory. One suggests that glycosylation of neural proteins may occur secondary to hyperglycemia, leading to abnormal function such as is found in hemoglobin and red cell membrane proteins (71.Another is the polyol pathway hypothesis [8,9], which states that the conversion of glucose to sorbitol by aldose reductase and the conversion of sorbitol by sorbitol dehydrogenase to fructose are accelerated in hyperglycemia, leading to an increase in intracellular osmolality because of accumulation of two compounds that are unable to be transported out of cells. This eventually leads to swelling and disruption of cellular function. These enzymes are present only in Schwann cells, not in axons. Therefore an alternative theory related to myoinositol deficiency has been proposed [lo]. It holds that the polycyclic alcohol, myoinositol, is deficient in diabetic nerves because its transport is disrupted by hyperglycemia. It is believed that this deficiency is toxic to nerves. Low myoinositol concentrations have been found in the nerves of experimental animals with diabetes [lO,ll], and a similar deficiency is probably present in people with diabetes [12,13]. Deficiency of this key metabolic intermediate may be secondary to increased polyol pathway activity, or it may be related to hyperglycemia in some other way and may lead to disordered nerve function. Finally, it
166
January 1661 The American Journal of Medicine
ET AL,
has been hypothesized that a defect in myelin synthesis may be at fault. Such a defect has been described in experimentally induced diabetes (141. This defect is related to insulin deficiency and can be reversed with insulin treatment. In this case, the lesion would be due to insulin deficiency rather than being directly related to hyperglycemic damage. This has very important clinical implications, because one can treat patients by diet or oral agents without necessarily increasing their insulin concentrations. In the cellular abnormality theory it has been hypothesized that increased cell death and turnover in diabetic neuropathy occur independent of hyperglycemia [l5]. Vracko [15] suggested that damage to the Schwann cell leads to increased turnover of basement membrane and thickening by reduplication. In fact, he used the observation of basement membrane thickening in Schwann cells as evidence for increased cell turnover in diabetes. NERVE FUNCTION AND METABOLIC CHANGES IN DIARETES We considered it important for the metabolic hypothesis to see if we could relate abnormalities in nerve function to metabolic parameters in diabetes. There was evidence that this might be a productive line of investigation, for as early as 1971Ward et al. [16] in England had shown that nerve function improved when diabetic patients were treated. They measured motor nerve conduction velocity in two motor nerves: the lateral popliteal and the median. Despite clinical findings that most of the problems that patients complained of were in the legs, the median nerve was as abnormal as the popliteal. This finding in itself is good evidence that diabetic polyneuropathy is a metabolic disorder, because a metabolic defect would hardly be limited to the leg or the arm nerves. Figure 1 shows the response to treatment in the group of patients they studied. They treated their patients with insulin or with oral agents and observed motor nerve conduction velocities over periods of six weeks to six months. There was rapid improvement, which certainly lent support to the metabolic hypothesis. However, there were no controls in this study, and these investigators commented on the fact that no relationship was found between the degree of abnormal carbohydrate metabolism and nerve conduction velocity prior to treatment, or between the change in conduction velocity and the improvement in carbohydrate metabolism after treatment. Also, there was no measure of sensory nerve function, which is the usual clinically important disorder of nerve function. It should be pointed out that in 1971 control of diabetes was still assessed on the basis of measurements of urinary glucose excretion. In retrospect, it is clear that if one is looking for a direct toxic effect of plasma glucose concentration on some body function, urinary glucose excretion is the wrong thing to measure. It may be very useful from a clinical point of view, but urinary
Volume
70
DIABETIC
NEUROPATHY
glucose cannot damage any organ directly. Thus, it is perhaps not surprising that these investigators found no relationship between carbohydrate metabolism as they assessed it and motor nerve conduction velocity. Therefore, we believe that urinary glucose excretion should be ignored as an index of glucose control when trying to relate hyperglycemia to pathologic changes in the organism. Further support for the metabolic theory came in 1975. Animal experiments showed that shortly after the induction of experimental hyperglycemia there was a measurable abnormality of motor nerve conduction velocity in the rat [lo]. This abnormality was abolished by treatment with insulin, and conduction velocities became indistinguishable between the treated animals and normal controls. It was thought that segmental demyelination did not occur in rats, and this troubled the investigators greatly, because they could not make a clinical correlation. However, it is now known that if one waits long enough, segmental demyelination does develop in the rat, but this is probably a late and possibly irreversible stage of the illness [li’]. One other problem with this study was that many of these insulin-treated rats died of hypoglycemia. This was because tight glucose control was necessary in order to reverse the neuropathy, and hypoglycemia became a frequent complication of treatment. This apparent need for very tight control concerned many of us who thought that these studies might have some practical clinical applicability. Again, in none of these studies was there a direct correlation between any measure of glucose control and improvement in nerve function. Because treatment alters metabolism in many ways in addition to decreasing glucose concentration, it is difficult to know whether or not glucose concentration is the critical causative variable. Therefore, in our studies we chose patients in whom treatment was not necessary (at least in the short-term) and who could be followed at various steady-state glucose concentrations over time. METHODS
AND
PLASMA
GLUCOSE
CONTROL-PORTE
ET AL.
607
MCV (meterslsec)
1’
1
Lateral
popllteol
nerve
11/I1~lNorrnol range (%+2 S D f
Diabetics
(n&SD.,
, n=4.1
)
n=39)
60
MCV (meters/set)
50
(1
A
Median
nerve
40 Pretreatment From
Ward
6th~.
6Wks. et al,
Lancet
i:428,1971
lgure 1. Effects of diabetes treatment on motor nerve conduction velocities (MCV) in recently diagnosed diabetic patients. From Ward et al. [ 161.
207
v=.o33x
.
+ 5.37
1816-
OF STUDY
14-
Patients with noninsulin-dependent diabetes characteristically regulate their plasma glucose concentrations without ketosis, just as normal people do, although at much higher values. Therefore, although many are quite hyperglycemic, their plasma glucose concentrations remain steady, and their weights remain reasonably stable. To assess serum glucose control, we measured fasting plasma glucose and glycosylated hemoglobin concentrations. This was carried out either colorimetrically [18] or by column chromatography [XI]. In our hands, the results of these two methods correlated very well [18]. We found that basal hyperglycemia in such stable patients is clearly correlated with glycosylated hemoglobin concentration [19] (Figure 2). Thus, results of a method for short-term assessment of diabetes control
? 0 8
12IO8Diabetics n=24
6-
80
120
160
200 FPG,
240 mg /dl
280
320
360
400
Figure 2. Steady-state relationship between fasting plasma glucose (Fffi) and glycosylated hemoglobin (GHb) concentrations in maturity-onset noninsulin-dependent diabetic patients. Upper limits of normal are 10.5 percent of total hemoglobin as glycosylated hemoglobin and 115 mg/dl for glucose. Modified from [ 191.
January 1981 The American Journal of Medicine
Volume 79
197
DIABETIC NEUROPATHY
AND
PLASMA
GLUCOSE
CONTROL-PORTE
50 1
!
50 5 +al ”
45
4’: z= 40 a >es I
35
30
Pre Rx
3mo
Pre Rx 6 mo
Pre Rx 12mo
lgure 3. Effects of diabetes treatment for three, six and 12 months on motor nerve conduction velocity (NCV). The group of patients diminishes, as not all patients completed 12 months at the time of the preliminary evaluation.
t50
0
-50
F (j -100 k a
-150 -200 -250
“;I6
07
t-5 1
a -15
I
P~O.001 “:I6
PC0 005
0
n:,e
3
07 MONTHS
‘igure 4. Effects of diabetes treatment (oral agent, d/et or insulin) on fasting plasma glucose (FPG) and glycosylated hemoglobin (GHb) concentrations in diabetic patients treated for three, six and 12 months. Note the wide range of responses in this group of patients.
198
(fasting plasma glucose concentration) and a method for long-term assessment of diabetes control (glycosylated hemoglobin concentration] correlate well if the measurements are made in a group of stable maturity-onset diabetic patients. The tests for nerve conduction velocity, like many other functional tests, are somewhat difficult and variable. The method ordinarily used is quite variable: stimulating the nerve and then recording at a distance by estimating impulse arrival from timing of the take-off of the evoked motor potential. Fortunately we had available an improved technique [20] in which motor nerve conduction velocity could be measured with less variability. It is called the superimposed wave response technique. Alternating stimuli are used from two separate electrodes fixed to a rigid bar. With this method the distance between the electrodes always stays the same. Thus, one can record both responses on an oscilloscope, then electronically superimpose them and accurately calculate the latency between them. One does not have to identify the peak point, which is one major potential source of error. Our maturity-onset diabetic patients ranged from those in whom the diagnosis was made recently [within a month or two] to those in whom the diagnosis had been made several years earlier. They did not have symptomatic neuropathy, and none had either the pain or dysesthesia that one associates with clinical diabetic neuropathy. PRELIMINARY
0
\
ET AL.
January 1981 The American Journal of Medicine
RESULTS AND COMMENTS
Baseline Findings. We found that all motor and sensory nerves that we tested were abnormal. However, the magnitude of the change was greater in motor nerves than in sensory nerves and, in contrast to the findings of clinical neuropathy, the changes were present equally in the upper and lower limbs. We do not know if this was because the abnormality was greater in motor nerves or if our method of the double-stimulus technique was better for determining motor nerve velocity than the traditional single-stimulus technique used for the sensory nerves. We also found proportionate reductions in motor nerve conduction velocities in the median motor nerve, the tibia1 motor nerve, the peroneal nerve and the H reflex [a measure involving both the sensory and motor nerves). All of these changes were inversely correlated with fasting plasma glucose concentrations and glycosylated hemoglobin concentrations measured prior to diabetes treatment [l]. To our knowledge these are the first data showing a relationship between the degree of hyperglycemia and the degree of nerve impairment. This is probably because we studied the types of patients in whom traditionally these measurements had not been made but in whom serum glucose concentrations are stable over periods sufficiently long to establish a stable baseline. Thus, those with the highest fasting plasma glucose and glycosylated hemoglobin concentrations
Volume
70
DIABETIC NEUROPATHY
had the poorest motor nerve conduction velocities, and those in whom these concentrations were closer to the normal range had less slowing of conduction velocity. In contrast, the sensory nerve abnormalities did not correlate with fasting plasma glucose or glycosylated hemoglobin concentrations, despite the fact that sensory and motor nerve conduction velocities correlated with one another. Treatment Effects. The patients in this group were treated variably; that is, some were given insulin, some were given oral agents, and some were treated with diet only. We deliberately wanted to get a spectrum of responses in terms of plasma glucose concentrations because we considered it important for the metabolic hypothesis that any treatment to lower the plasma glucose concentration should relate glucose response to nerve function. Therefore we thought it important to determine if patients with minimal treatment and minor lowering of plasma glucose concentrations would respond in a different manner than those who had major changes in plasma glucose concentrations. The effects of treatment at three, six and 12 months are shown in Figure 3. In both the peroneal and median motor nerves there were increases in conduction velocities that became statistically significant at three months, although in many patients we saw such a change at one month. After the three-month point we did not observe any progressive changes over time, and plasma glucose concentrations in the treated patients tended to remain relatively constant. Figure 4 shows the spectrum of changes in fasting plasma glucose and glycosylated hemoglobin concentrations. Notice that some patients showed no change, and the concentrations in a few even increased. Those whose concentrations decreased from 100 to 200 mg/dl were treated either with insulin or with oral agents. Over-all, the mean values of hemoglobin and plasma glucose were lower at three months and stayed down. However, many patients (even those who responded to therapy) were still hyperglycemic at the end of the treatment period. Our next concern was to determine if those patients who showed the greatest improvement in conduction velocity also showed the greatest lowering of plasma glucose concentrations, and to determine if those who did not do so well or whose condition worsened showed any changes in their plasma glucose concentrations. When we analyzed the median motor nerve conduction velocities at three and 12 months, we found that there was a significant linear relationship between the change in fasting plasma glucose concentration and the change in nerve conduction velocity (Figure 5). Thus, those who had the greatest decreases in fasting plasma glucose concentrations had the greatest improvements in motor nerve conduction velocities, and those who showed either no change or some increase in their fasting plasma glucose concentrations tended to show no change in motor nerve conduction velocity. In this group of
AND
PLASMA
GLUCOSE
CONTROL-PURTE
ET AL.
:/y
. .
t25
0
. r=066 PC0 05 “Zll
-50
-100
A FPG, mg/dl
-150
t
-250
-200
-1
Relationship between change in fasting glucose & concentration (AFPG) and change in median motor nerve conduction velocity (ANCV) after 12 months of therapy in 11 diabetic patients.
patients, fasting plasma glucose concentration was better correlated with conduction velocity than was glycosylated hemoglobin concentration, This is the first study in which any relationship between degree of glucose response to treatment and degree of change in some function related to nerve performance has been shown. By contrast, sensory nerve impairment did not correlate with plasma glucose or glycosylated hemoglobin concentration prior to treatment, and showed no change over 12 months of treatment in the median sensory or sural nerves. SUMMARY
AND ANALYSIS
Our findings show that both sensory and motor nerve conduction velocities are diffusely abnormal in the mamrity-onset type of diabetes and that these abnormalities occur early in the course of the disease. The motor nerve conduction abnormality is related to the degree of hyperglycemia and the degree of glycosylation of hemoglobin. In a preliminary study we can show that some abnormalities of motor nerve conduction velocity are reversible with treatment. Sensory nerve function is not related to the degree of hyperglycemia or glycosylated hemoglobin concentration, and in the same preliminary study these conduction abnormalities were not reversible with treatment. Two questions arise: Why sensory nerve function does not relate to glucose control, and why sensory nerves do not get better? At present we do not know. There are several possibile answers. One is that sensory nerve abnormalities and motor nerve abnormalities really are pathophysiologically different. There is some evidence for this in recent work with myoinositol [Zl]. Patients treated with myoinositol showed improved conduction velocities in sensory nerves but not in motor nerves.
January 1981
The American Journal of Medicine
Volume
70
199
DIABETIC NEUROPATHY
AND PLASMA GLUCOSE
CONTROL-PORTE
it may be a complex lesion: we must keep an open mind. It should also be pointed out that we did not treat all of our patients effectively. We treated most of them as we usually do in the clinic. In some there was considerable improvement where as in others there was very little improvement. Because of a tendency for paGents with marked reductions in plasma glucose concentrations to show some change in sensory nerve Therefore,
ET AL.
conduction velocity, it is possible that we simply have to do better in lowering their glucose concentrations. Finally, it is possible that the lesion is not reversible in sensory nerves, and this would account for its greater clinical impact. It is clear that additional study will be necessary to resolve the differences found between the responses of peripheral motor and sensory nerve functions during the treatment of diabetes.
REFERENCES 1. Graf RJ, Halter JB, Halar E, Porte D Jr: Nerve conduction
2.
3. 4. 5. 6. 7.
8. 9.
10.
11.
200
abnormalities in untreated maturitv-onset diabetes: relation to levels of fasting plasma glucose and glycosylated hemoglobin. Ann Intern Med 1979; 90: 298-303. Graf RJ, Halter JB, Pfeifer MA, Halar E, Brozovich F, Porte D Jr: Glycemic control and nerve conduction abnormalities in-no&insulin-dependent diabetic subjects. Ann Intern Med (in press). Raff MC, Sangaland V, Asbmy AK: Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 1968: 18: 487-499. Thomas. PK. Lascelles RG: The pathology of diabetic neuropathy. Q J Med 1966; 35: 489-505. Behse F, Buchthal F, Carlsen F: Nerve biopsy and conduction studies in diabetic neuropathv. 1 Neurol Neurosurg _ Pmchiatry 1977: 40: 1072-1082. _ ’ Jakobsen J: Peripheral nerves in early experimental diabetes: exnansion of endoneurial suace as a cause of increased wa’ter content. Diabetologiai978; 14: 113-119. Bunn HF. Gabbay KH, Gallop PM: The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 1978; 200: 21-27. Gabbay KH, Merola LO, Field RA: Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 1966: 151: 209-210. Gabbay KH: Role of sorbitol pathway in neuropathy. In: Camerini-Davalos RA and Cole HS, eds. Vascular and neurologic changes in early diabetes. New York: Academic Press, 1973; 417-424. Greene DA, De Jesus PV, Winegard AI: Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 1975; 55: 1326-1336. Palmano KP, Whiting PH, Hawthorne JN: Free and lipid myoinositol in tissues from rats with acute and less severe
January 1981
The American Journal of Medicine
streptozotocin-induced 229-235.
diabetes.
Biochem J 1977; 167:
12. Brown MJ, Iwamori M, Rapoport B: Human diabetic
13. 14.
15. 16. 17.
18.
neuronathv: a moruhometrical and neurochemical studv.” I, Neuropathol Exp Neuroll976; 35: 336. Gregerson G, Borsting H, Theil P, et al.: Myoinositol and function of peripheral nerves in human diabetics. Acta Neurol Stand 1978; 58: 241-248. Spritz N, Singh H, Marinan B: Metabolism of peripheral nerve myelin in experimental diabetes. J Clin Invest 1975; 55: 1049-1056. Vracko R: Basal lamina layerin in diabetes mellitus: evidence for accelerated rate of ccl P death and cell regeneration. Diabetes 1974; 23: 94-104. Ward JD, Fisher DJ, Barnes CG, et al.: Improvement in nerve conduction followine treatment in newlv diannosed diabetics. Lancet 1971; 5 428-430. ” v Powell H. Knox D. Lee S. et al.: Alloxan diabetic neurooathv: electron micro&opic studies. Neurology (Minneapj 197?; 27: 60-66. Pecoraro RE. Graf RJ, Halter JB, et al.: Comparison of a calorimetric assay for glycosylated hemoglobin with ion-exchange chromatography. Diabetes 1979; 28: 1120-
1125. 19. Graf’ RI. Halter
IB. Porte D Ir: Glvcosvlated hemoalobin in n&al subjkc’ti and mat&y onset &iabetics. Evaence for a saturable svstem in man. Diabetes 1978; 27: 834839.
20. Halar EM, Venkatesh ME: Nerve conduction velocity measurements: improved accuracy using superimposed response waves. Arch Phys Med Rehabil 1976; 57: 451457. 21. Clements R, Vourganti B, Kuba T, Oh SJ, Darnell B: Dietary myoinositol intake and peripheral nerve function in diabetic neuropathy. Metabolism 1979; 28: 477-483.
Volume 70
DANIEL PORTE, JR.. M.D. RONALD J. GRAF, M.D. JEFFREY B. HALTER, M.D. MICHAEL A. PFEIFER. M.D. EUGEN HALAR, M.D. Seattle, Washington
and Plasma Glucose Control
Diabetic neuropatby is defined, and theories of its pathogenesis are reviewed. Recent studies designed to investigate the influence of plasma glucose on nerve function in noninsulin-dependent diabetic patients are summarized. Motor nerve conduction velocities in the median and peroneal nerves were measured using a double-stimulus technique, and sensory conduction velocity was measured by conventional methods before and after therapy with oral agents or insulin. The degree of hyperglycemia was assessed by measurement of fasting plasma glucose and glycosylated hemoglobin concentrations. The degree of slowing in motor nerve conduction velocity in untreated patients was found to correlate with the fasting plasma glucose and glycosylated hemoglobin concentrations, but sensory nerve function, although abnormal, did not show such correlation. Reduction of hyperglycemia was associated with improvement in motor nerve conduction velocity in the peroneal and median motor nerves of these patients, but sensory nerve conduction velocity showed no such improvement. Improvement in median motor nerve conduction velocity was directly related to the degree of reduction in fasting plasma glucose concentration. These findings suggest that metabolic factors related to hyperglycemia are important in the impaired motor nerve function seen in noninsulin-dependent patients with maturity-onset diabetes. Over the past few years we have studied the relationship between plasma glucose concentration and diabetic nerve disease. Many of the hypotheses regarding the causes of such disease have suggested some direct effect of serum glucose concentration on the nerve conduction system. However, direct evidence to support such hypotheses was not available from studies in man. In this report we summarize our understanding of this disorder and recent preliminary findings regarding the nse of nerve conduction velocity to assess peripheral nerve function [VI.
From the Departments of Medicine and Rehabilitation Medicine, University of Washington School of Medicine, and the Veterans Administration Medical Center, Seattle, Washington. The study was supported by National Institutes of Health Grants AM-12829, AM-20754 and AM-00788, by the Diabetes Research Center of the University of Washington (Grant AM-17047) and by the Veterans Administration. It was presented at a Symposium on Diabetes Management, sponsored by the Upjohn Company, held in Miami, Florida, February 29-March 1. 1980. Requests for reprints should be addressed to Dr. Daniel Porte, Jr., VA Medical Center (151). 4435 Beacon Avenue South, Seattle, Washington 98108.
PATHOGENESIS OF DIFFUSE POLYNEUROPATHY Table I lists the various types of diabetic neuropathies. In this report we shall not discuss autonomic neuropathy, amyotrophy or the mononenropathies. Rather, we shall focus on diffuse impairment of neural function or diabetic polyneuropathy. It is possible that all of these types may be related to the same pathophysiologic abnormality, but this is not certain. They may be somewhat different in their responses to treatment, and they may even have different causes. Because of these uncertainties, we limited our studies to one type of diabetic neuropathy. We also chose to study somatosensory somatometric neuropathy because its diffuse nature is more consistent with a metabolic cause. There are several hypotheses relating to the cause of this disease. At one time it was believed that vascular infarction or &hernia might play a role, but the morphologic evidence for this has been very poor.
January 1981
The American Journal of Medicine
Volume 79
195
DIABETIC
TABLE I
NELJROPATHY
AND
PLASMA
GLUCOSE
CONTROL-PORTE
Types of Diabetic Neurapathy
A. Diffuse polynewopathy B. Mononeuropathy-radiculopathy C. Motor neuropathy-amyotrophy D. Autonomic neuopathy Motor Sensory
At present, only diabetic mononeuropathy is believed to be related to sudden ischemia; this is because of its very sudden onset and because it is sometimes associated with vascular abnormalities [3]. The two major hypotheses concerning the cause of diffuse polyneuropathy are (1) that there is a metabolic injury that leads to malfunction of the nerves or (2) that there is an intrinsic cellular abnormality in the peripheral nerves of diabetic subjects that is part of the over-all diabetic syndrome. The primary site of this nerve damage was formerly believed to be in Schwann cells, because segmental demyelination was found to be the characteristic lesion of diabetic polyneuropathy [4]. However, the hypothesis that the Schwann cell is the primary cell of injury is being challenged now because of two findings: (1) There is axonal dwindling and loss of axonal function prior to the loss of Schwann cells and segmental demyelination [5]; and (2) the swelling that occurs in nerves in experimentally-induced diabetes seems to occur between the Schwann cells and the axons, not in the Schwann cells themselves [S]. Therefore, there is still some question whether the Schwann cell defect is a primary or secondary abnormality in diabetic nerve disease. There are several variants to the metabolic theory. One suggests that glycosylation of neural proteins may occur secondary to hyperglycemia, leading to abnormal function such as is found in hemoglobin and red cell membrane proteins (71.Another is the polyol pathway hypothesis [8,9], which states that the conversion of glucose to sorbitol by aldose reductase and the conversion of sorbitol by sorbitol dehydrogenase to fructose are accelerated in hyperglycemia, leading to an increase in intracellular osmolality because of accumulation of two compounds that are unable to be transported out of cells. This eventually leads to swelling and disruption of cellular function. These enzymes are present only in Schwann cells, not in axons. Therefore an alternative theory related to myoinositol deficiency has been proposed [lo]. It holds that the polycyclic alcohol, myoinositol, is deficient in diabetic nerves because its transport is disrupted by hyperglycemia. It is believed that this deficiency is toxic to nerves. Low myoinositol concentrations have been found in the nerves of experimental animals with diabetes [lO,ll], and a similar deficiency is probably present in people with diabetes [12,13]. Deficiency of this key metabolic intermediate may be secondary to increased polyol pathway activity, or it may be related to hyperglycemia in some other way and may lead to disordered nerve function. Finally, it
166
January 1661 The American Journal of Medicine
ET AL,
has been hypothesized that a defect in myelin synthesis may be at fault. Such a defect has been described in experimentally induced diabetes (141. This defect is related to insulin deficiency and can be reversed with insulin treatment. In this case, the lesion would be due to insulin deficiency rather than being directly related to hyperglycemic damage. This has very important clinical implications, because one can treat patients by diet or oral agents without necessarily increasing their insulin concentrations. In the cellular abnormality theory it has been hypothesized that increased cell death and turnover in diabetic neuropathy occur independent of hyperglycemia [l5]. Vracko [15] suggested that damage to the Schwann cell leads to increased turnover of basement membrane and thickening by reduplication. In fact, he used the observation of basement membrane thickening in Schwann cells as evidence for increased cell turnover in diabetes. NERVE FUNCTION AND METABOLIC CHANGES IN DIARETES We considered it important for the metabolic hypothesis to see if we could relate abnormalities in nerve function to metabolic parameters in diabetes. There was evidence that this might be a productive line of investigation, for as early as 1971Ward et al. [16] in England had shown that nerve function improved when diabetic patients were treated. They measured motor nerve conduction velocity in two motor nerves: the lateral popliteal and the median. Despite clinical findings that most of the problems that patients complained of were in the legs, the median nerve was as abnormal as the popliteal. This finding in itself is good evidence that diabetic polyneuropathy is a metabolic disorder, because a metabolic defect would hardly be limited to the leg or the arm nerves. Figure 1 shows the response to treatment in the group of patients they studied. They treated their patients with insulin or with oral agents and observed motor nerve conduction velocities over periods of six weeks to six months. There was rapid improvement, which certainly lent support to the metabolic hypothesis. However, there were no controls in this study, and these investigators commented on the fact that no relationship was found between the degree of abnormal carbohydrate metabolism and nerve conduction velocity prior to treatment, or between the change in conduction velocity and the improvement in carbohydrate metabolism after treatment. Also, there was no measure of sensory nerve function, which is the usual clinically important disorder of nerve function. It should be pointed out that in 1971 control of diabetes was still assessed on the basis of measurements of urinary glucose excretion. In retrospect, it is clear that if one is looking for a direct toxic effect of plasma glucose concentration on some body function, urinary glucose excretion is the wrong thing to measure. It may be very useful from a clinical point of view, but urinary
Volume
70
DIABETIC
NEUROPATHY
glucose cannot damage any organ directly. Thus, it is perhaps not surprising that these investigators found no relationship between carbohydrate metabolism as they assessed it and motor nerve conduction velocity. Therefore, we believe that urinary glucose excretion should be ignored as an index of glucose control when trying to relate hyperglycemia to pathologic changes in the organism. Further support for the metabolic theory came in 1975. Animal experiments showed that shortly after the induction of experimental hyperglycemia there was a measurable abnormality of motor nerve conduction velocity in the rat [lo]. This abnormality was abolished by treatment with insulin, and conduction velocities became indistinguishable between the treated animals and normal controls. It was thought that segmental demyelination did not occur in rats, and this troubled the investigators greatly, because they could not make a clinical correlation. However, it is now known that if one waits long enough, segmental demyelination does develop in the rat, but this is probably a late and possibly irreversible stage of the illness [li’]. One other problem with this study was that many of these insulin-treated rats died of hypoglycemia. This was because tight glucose control was necessary in order to reverse the neuropathy, and hypoglycemia became a frequent complication of treatment. This apparent need for very tight control concerned many of us who thought that these studies might have some practical clinical applicability. Again, in none of these studies was there a direct correlation between any measure of glucose control and improvement in nerve function. Because treatment alters metabolism in many ways in addition to decreasing glucose concentration, it is difficult to know whether or not glucose concentration is the critical causative variable. Therefore, in our studies we chose patients in whom treatment was not necessary (at least in the short-term) and who could be followed at various steady-state glucose concentrations over time. METHODS
AND
PLASMA
GLUCOSE
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ET AL.
607
MCV (meterslsec)
1’
1
Lateral
popllteol
nerve
11/I1~lNorrnol range (%+2 S D f
Diabetics
(n&SD.,
, n=4.1
)
n=39)
60
MCV (meters/set)
50
(1
A
Median
nerve
40 Pretreatment From
Ward
6th~.
6Wks. et al,
Lancet
i:428,1971
lgure 1. Effects of diabetes treatment on motor nerve conduction velocities (MCV) in recently diagnosed diabetic patients. From Ward et al. [ 161.
207
v=.o33x
.
+ 5.37
1816-
OF STUDY
14-
Patients with noninsulin-dependent diabetes characteristically regulate their plasma glucose concentrations without ketosis, just as normal people do, although at much higher values. Therefore, although many are quite hyperglycemic, their plasma glucose concentrations remain steady, and their weights remain reasonably stable. To assess serum glucose control, we measured fasting plasma glucose and glycosylated hemoglobin concentrations. This was carried out either colorimetrically [18] or by column chromatography [XI]. In our hands, the results of these two methods correlated very well [18]. We found that basal hyperglycemia in such stable patients is clearly correlated with glycosylated hemoglobin concentration [19] (Figure 2). Thus, results of a method for short-term assessment of diabetes control
? 0 8
12IO8Diabetics n=24
6-
80
120
160
200 FPG,
240 mg /dl
280
320
360
400
Figure 2. Steady-state relationship between fasting plasma glucose (Fffi) and glycosylated hemoglobin (GHb) concentrations in maturity-onset noninsulin-dependent diabetic patients. Upper limits of normal are 10.5 percent of total hemoglobin as glycosylated hemoglobin and 115 mg/dl for glucose. Modified from [ 191.
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50 1
!
50 5 +al ”
45
4’: z= 40 a >es I
35
30
Pre Rx
3mo
Pre Rx 6 mo
Pre Rx 12mo
lgure 3. Effects of diabetes treatment for three, six and 12 months on motor nerve conduction velocity (NCV). The group of patients diminishes, as not all patients completed 12 months at the time of the preliminary evaluation.
t50
0
-50
F (j -100 k a
-150 -200 -250
“;I6
07
t-5 1
a -15
I
P~O.001 “:I6
PC0 005
0
n:,e
3
07 MONTHS
‘igure 4. Effects of diabetes treatment (oral agent, d/et or insulin) on fasting plasma glucose (FPG) and glycosylated hemoglobin (GHb) concentrations in diabetic patients treated for three, six and 12 months. Note the wide range of responses in this group of patients.
198
(fasting plasma glucose concentration) and a method for long-term assessment of diabetes control (glycosylated hemoglobin concentration] correlate well if the measurements are made in a group of stable maturity-onset diabetic patients. The tests for nerve conduction velocity, like many other functional tests, are somewhat difficult and variable. The method ordinarily used is quite variable: stimulating the nerve and then recording at a distance by estimating impulse arrival from timing of the take-off of the evoked motor potential. Fortunately we had available an improved technique [20] in which motor nerve conduction velocity could be measured with less variability. It is called the superimposed wave response technique. Alternating stimuli are used from two separate electrodes fixed to a rigid bar. With this method the distance between the electrodes always stays the same. Thus, one can record both responses on an oscilloscope, then electronically superimpose them and accurately calculate the latency between them. One does not have to identify the peak point, which is one major potential source of error. Our maturity-onset diabetic patients ranged from those in whom the diagnosis was made recently [within a month or two] to those in whom the diagnosis had been made several years earlier. They did not have symptomatic neuropathy, and none had either the pain or dysesthesia that one associates with clinical diabetic neuropathy. PRELIMINARY
0
\
ET AL.
January 1981 The American Journal of Medicine
RESULTS AND COMMENTS
Baseline Findings. We found that all motor and sensory nerves that we tested were abnormal. However, the magnitude of the change was greater in motor nerves than in sensory nerves and, in contrast to the findings of clinical neuropathy, the changes were present equally in the upper and lower limbs. We do not know if this was because the abnormality was greater in motor nerves or if our method of the double-stimulus technique was better for determining motor nerve velocity than the traditional single-stimulus technique used for the sensory nerves. We also found proportionate reductions in motor nerve conduction velocities in the median motor nerve, the tibia1 motor nerve, the peroneal nerve and the H reflex [a measure involving both the sensory and motor nerves). All of these changes were inversely correlated with fasting plasma glucose concentrations and glycosylated hemoglobin concentrations measured prior to diabetes treatment [l]. To our knowledge these are the first data showing a relationship between the degree of hyperglycemia and the degree of nerve impairment. This is probably because we studied the types of patients in whom traditionally these measurements had not been made but in whom serum glucose concentrations are stable over periods sufficiently long to establish a stable baseline. Thus, those with the highest fasting plasma glucose and glycosylated hemoglobin concentrations
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had the poorest motor nerve conduction velocities, and those in whom these concentrations were closer to the normal range had less slowing of conduction velocity. In contrast, the sensory nerve abnormalities did not correlate with fasting plasma glucose or glycosylated hemoglobin concentrations, despite the fact that sensory and motor nerve conduction velocities correlated with one another. Treatment Effects. The patients in this group were treated variably; that is, some were given insulin, some were given oral agents, and some were treated with diet only. We deliberately wanted to get a spectrum of responses in terms of plasma glucose concentrations because we considered it important for the metabolic hypothesis that any treatment to lower the plasma glucose concentration should relate glucose response to nerve function. Therefore we thought it important to determine if patients with minimal treatment and minor lowering of plasma glucose concentrations would respond in a different manner than those who had major changes in plasma glucose concentrations. The effects of treatment at three, six and 12 months are shown in Figure 3. In both the peroneal and median motor nerves there were increases in conduction velocities that became statistically significant at three months, although in many patients we saw such a change at one month. After the three-month point we did not observe any progressive changes over time, and plasma glucose concentrations in the treated patients tended to remain relatively constant. Figure 4 shows the spectrum of changes in fasting plasma glucose and glycosylated hemoglobin concentrations. Notice that some patients showed no change, and the concentrations in a few even increased. Those whose concentrations decreased from 100 to 200 mg/dl were treated either with insulin or with oral agents. Over-all, the mean values of hemoglobin and plasma glucose were lower at three months and stayed down. However, many patients (even those who responded to therapy) were still hyperglycemic at the end of the treatment period. Our next concern was to determine if those patients who showed the greatest improvement in conduction velocity also showed the greatest lowering of plasma glucose concentrations, and to determine if those who did not do so well or whose condition worsened showed any changes in their plasma glucose concentrations. When we analyzed the median motor nerve conduction velocities at three and 12 months, we found that there was a significant linear relationship between the change in fasting plasma glucose concentration and the change in nerve conduction velocity (Figure 5). Thus, those who had the greatest decreases in fasting plasma glucose concentrations had the greatest improvements in motor nerve conduction velocities, and those who showed either no change or some increase in their fasting plasma glucose concentrations tended to show no change in motor nerve conduction velocity. In this group of
AND
PLASMA
GLUCOSE
CONTROL-PURTE
ET AL.
:/y
. .
t25
0
. r=066 PC0 05 “Zll
-50
-100
A FPG, mg/dl
-150
t
-250
-200
-1
Relationship between change in fasting glucose & concentration (AFPG) and change in median motor nerve conduction velocity (ANCV) after 12 months of therapy in 11 diabetic patients.
patients, fasting plasma glucose concentration was better correlated with conduction velocity than was glycosylated hemoglobin concentration, This is the first study in which any relationship between degree of glucose response to treatment and degree of change in some function related to nerve performance has been shown. By contrast, sensory nerve impairment did not correlate with plasma glucose or glycosylated hemoglobin concentration prior to treatment, and showed no change over 12 months of treatment in the median sensory or sural nerves. SUMMARY
AND ANALYSIS
Our findings show that both sensory and motor nerve conduction velocities are diffusely abnormal in the mamrity-onset type of diabetes and that these abnormalities occur early in the course of the disease. The motor nerve conduction abnormality is related to the degree of hyperglycemia and the degree of glycosylation of hemoglobin. In a preliminary study we can show that some abnormalities of motor nerve conduction velocity are reversible with treatment. Sensory nerve function is not related to the degree of hyperglycemia or glycosylated hemoglobin concentration, and in the same preliminary study these conduction abnormalities were not reversible with treatment. Two questions arise: Why sensory nerve function does not relate to glucose control, and why sensory nerves do not get better? At present we do not know. There are several possibile answers. One is that sensory nerve abnormalities and motor nerve abnormalities really are pathophysiologically different. There is some evidence for this in recent work with myoinositol [Zl]. Patients treated with myoinositol showed improved conduction velocities in sensory nerves but not in motor nerves.
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it may be a complex lesion: we must keep an open mind. It should also be pointed out that we did not treat all of our patients effectively. We treated most of them as we usually do in the clinic. In some there was considerable improvement where as in others there was very little improvement. Because of a tendency for paGents with marked reductions in plasma glucose concentrations to show some change in sensory nerve Therefore,
ET AL.
conduction velocity, it is possible that we simply have to do better in lowering their glucose concentrations. Finally, it is possible that the lesion is not reversible in sensory nerves, and this would account for its greater clinical impact. It is clear that additional study will be necessary to resolve the differences found between the responses of peripheral motor and sensory nerve functions during the treatment of diabetes.
REFERENCES 1. Graf RJ, Halter JB, Halar E, Porte D Jr: Nerve conduction
2.
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abnormalities in untreated maturitv-onset diabetes: relation to levels of fasting plasma glucose and glycosylated hemoglobin. Ann Intern Med 1979; 90: 298-303. Graf RJ, Halter JB, Pfeifer MA, Halar E, Brozovich F, Porte D Jr: Glycemic control and nerve conduction abnormalities in-no&insulin-dependent diabetic subjects. Ann Intern Med (in press). Raff MC, Sangaland V, Asbmy AK: Ischemic mononeuropathy multiplex associated with diabetes mellitus. Arch Neurol 1968: 18: 487-499. Thomas. PK. Lascelles RG: The pathology of diabetic neuropathy. Q J Med 1966; 35: 489-505. Behse F, Buchthal F, Carlsen F: Nerve biopsy and conduction studies in diabetic neuropathv. 1 Neurol Neurosurg _ Pmchiatry 1977: 40: 1072-1082. _ ’ Jakobsen J: Peripheral nerves in early experimental diabetes: exnansion of endoneurial suace as a cause of increased wa’ter content. Diabetologiai978; 14: 113-119. Bunn HF. Gabbay KH, Gallop PM: The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 1978; 200: 21-27. Gabbay KH, Merola LO, Field RA: Sorbitol pathway: presence in nerve and cord with substrate accumulation in diabetes. Science 1966: 151: 209-210. Gabbay KH: Role of sorbitol pathway in neuropathy. In: Camerini-Davalos RA and Cole HS, eds. Vascular and neurologic changes in early diabetes. New York: Academic Press, 1973; 417-424. Greene DA, De Jesus PV, Winegard AI: Effects of insulin and dietary myoinositol on impaired peripheral motor nerve conduction velocity in acute streptozotocin diabetes. J Clin Invest 1975; 55: 1326-1336. Palmano KP, Whiting PH, Hawthorne JN: Free and lipid myoinositol in tissues from rats with acute and less severe
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streptozotocin-induced 229-235.
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12. Brown MJ, Iwamori M, Rapoport B: Human diabetic
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neuronathv: a moruhometrical and neurochemical studv.” I, Neuropathol Exp Neuroll976; 35: 336. Gregerson G, Borsting H, Theil P, et al.: Myoinositol and function of peripheral nerves in human diabetics. Acta Neurol Stand 1978; 58: 241-248. Spritz N, Singh H, Marinan B: Metabolism of peripheral nerve myelin in experimental diabetes. J Clin Invest 1975; 55: 1049-1056. Vracko R: Basal lamina layerin in diabetes mellitus: evidence for accelerated rate of ccl P death and cell regeneration. Diabetes 1974; 23: 94-104. Ward JD, Fisher DJ, Barnes CG, et al.: Improvement in nerve conduction followine treatment in newlv diannosed diabetics. Lancet 1971; 5 428-430. ” v Powell H. Knox D. Lee S. et al.: Alloxan diabetic neurooathv: electron micro&opic studies. Neurology (Minneapj 197?; 27: 60-66. Pecoraro RE. Graf RJ, Halter JB, et al.: Comparison of a calorimetric assay for glycosylated hemoglobin with ion-exchange chromatography. Diabetes 1979; 28: 1120-
1125. 19. Graf’ RI. Halter
IB. Porte D Ir: Glvcosvlated hemoalobin in n&al subjkc’ti and mat&y onset &iabetics. Evaence for a saturable svstem in man. Diabetes 1978; 27: 834839.
20. Halar EM, Venkatesh ME: Nerve conduction velocity measurements: improved accuracy using superimposed response waves. Arch Phys Med Rehabil 1976; 57: 451457. 21. Clements R, Vourganti B, Kuba T, Oh SJ, Darnell B: Dietary myoinositol intake and peripheral nerve function in diabetic neuropathy. Metabolism 1979; 28: 477-483.
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