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Does improved control of glycemia prevent or ameliorate diabetic polyneuropathy.

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Does Improved Control
of Glycemia Prevent or Ameliorate
Diabetic Polyneuropathy ?
Committee on Health Care Issues, American Neurological Association”
Whether improved control of glycemia can prevent or
ameliorate neuropathy is of importance to patients,
neurologists, and diabetologists because neuropathy is
common, may be associated with prolonged morbidity,
may become more frequent as people live longer, and
may be preventable or reversible with the improved
methods for the control of glycemia that are becoming
available [2, 5, 14, 26, 32, 347.
An unequivocal answer to the question posed in the
title cannot yet be given. There is suggestive evidence
that improved control of glycemia at least partially improves such expressions of neuropathy as abnormal
nerve conduction, resistance to ischemic block, and
abnormality of vibratory threshold. Because the demonstrated beneficial effects seem to be small, long-term
studies using several sensitive and reliable indicators of
neuropathy in many patients are now needed to determine the degree to which various types of neuropathy
can be prevented or improved.
It is generally agreed that the conventional management of diabetes does not prevent the complications of
retinopathy, nephropathy, or polyneuropathy [lS}.
Euglycemia cannot yet be predictably and reproducibly
attained except for short periods and then only with a
complex, closed-loop artificial pancreas [ 19, 271. Improvement of glycemic control over that gained by
conventional treatment has been achieved using either
continuous subcutaneous insulin infusion (CSII, an
open loop system) r21, 22, 301 or multiple daily injections of insulin {17). In either case, daily patient monitoring of plasma glucose levels and intensive surveillance and encouragement by health care personnel are
Four lines of evidence suggest that the development
and severity of neuropathy can be related to glycemic
control. The first is based on retrospective studies [lo,
15, 241. Patients with poor control of glycemia tended
to develop diabetic complications at an earlier age and
more severely than did patients with better control.
These studies are weak in two respects. The degree of
glycemia and the presence, severity, and characteristics
of neuropathy were inadequately ascertained. The
studies were retrospective and variables other than degree of glycemia control may have accounted for the
higher complication rate.
The second line of evidence comes from evaluation of the neuropathic status before and after institution of diabetic therapy. In newly diagnosed insulindependent diabetic patients, reducing the level of
glycemia is reported to be associated with improved
motor nerve conduction velocity { l l , 16, 23, 337, resistance to ischemic block {317, and vibratory
threshold of the toe 137. As it is unlikely that there
would have been improvement in these end-points
without treatment, improved control of glycemia may
have been responsible. Usually motor and not sensory nerve conduction velocity is improved and improvement may not be demonstrated until after six
months of treatment [33}. In a series of patients with
acute painful neuropathy associated with rapid weight
loss, institution of glycemic control was associated with
rapid weight gain and recovery of neuropathy in 8 of 9
patients [l]. Painful diabetic neuropathy has been reported to improve after institution of improved glycemic control using CSII 141. Complete normalization
of plasma glucose for 72 hours using the artificial pancreas did not improve nerve function [271.
The third line of evidence is based on studies performed on non-insulin-dependent diabetic men with
stable diabetes who were not receiving treatment 112,
251. In these patients, the fasting plasma glucose (FPG)
and glycosylated hemoglobin (GHb) levels provided a
reasonable index of glycemia control [20, 251. The
levels of both FPG and G H b were inversely associ-
*This report was authored by Peter James Dyck, MD, Mark Brown,
Greene, MD’ Johannes Jakobsen’ MD’
Pfeifer, MD, Daniel Pone, MD, and P. K. Thomas, MD; it was
developed for the American Neurological Association Committee
on Health Care Issues. Members of the ANA Committee on Health
Care Issues are: Peter James Dyck, MD (Chairman),Jerome Posner,
MD, Roger N. Rosenberg, MD, and Joseph J. Volpe, MD.
Received Aug 21, 1985. Accepted for publication Aug 21, 1985.
Address reprint requests to Dr Dyck, Mayo Clinic, Peripheral
Nerve Laboratov, Rochester, MN 55905,
ated, to highly significant levels, with motor conduction velocity 1127. In a later study, an improvement in
FPG or G H b after institution of therapy was found to
be statistically associated with improved motor conduction velocity of the median, tibial, and peroneal
nerves C13, 251. These studies provide further support
favoring a relationship between chronic glycemic control and abnormality of nerve conduction.
The fourth line of evidence has come from controlled clinical trials in which the neuropathic effect
from manipulation of the one variable, hyperglycemia,
has been assessed. The first requirement for conducting such trials is that there must be a statistically
significant difference in glycemia, which is of sufficient
magnitude and for a long enough period. The difficulty
of obtaining statistically significantly different levels of
glycemic control has been demonstrated in a trial conducted at the Mayo Clinic 1287. Failure of compliance
by some patients in the rigorous control group and
improved glycemic control in the conventional group
prevented these investigators from attaining improvement of glycemic control that was statistically significant.
In a study El87 from the Radcliffe Infirmary, Oxford, 74 insulin-dependent diabetic patients with background diabetic retinopathy were randomized into two
groups: one (Group U) continued with usual diabetic
care, and the other (Group A) underwent more intensive therapy. The study lasted for two years. Group A
was taught and encouraged to take multiple injections
of insulin and to monitor the plasma glucose level. At
entry, glucose control was comparable in the two
groups. Group A attained better glycemic control
throughout most of the study than did Group U. The
vibratory threshold of the toe became significantly better for Group A than that for Group U patients. Unfortunately, only vibratory threshold was evaluated and
by less than optimal methods. These investigators also
found that some of the Group U patients adopted
practices that put them into Group A.
Service and co-workers {29) completed a prospective randomized clinical trial in a small group of insulin-dependent diabetic patients with mild retinopathy.
Patients were assigned randomly to CSII or conventional insulin therapy (CIT). Despite significantly improved mean plasma glucose levels (95 mg/dl and 179
mg/dl in CSII and CIT, respectively; p = 0.002) and
total G H b vahes (8.5% and 10.7%, respective1y;p =
0.002), significant differences in neuropathy symptoms; results of a quantitated neurological examination; computer-assisted sensory examination of vibratory threshold, touch-pressure, and thermal cooling;
and nerve conduction
groups were not found at four months 17, 97. By eight
months, however, statistically significant differences in
nerve conduction and vibratory threshold were found,
favoring the CSII group. The vibratory system used
employs precisely quantitated stimuli, tests multiple
grid points, employs a forced-choice approach to minimize response bias, follows a predetermined computer
algorithm of testing, and prints out results as a percentile response specific for site, age, and sex based on
evaluation of more than 300 screened healthy persons
181. These results appear to show that control of glycemia leads to improved nerve conduction and vibratory sensation but that it may take more than four
months for them to develop.
Thus, the balance of evidence favors the premise
that hyperglycemia is an important determinant of diabetic neuropathy and improved glycemic control is
beneficial for nerve function. The latter is true whether
assessed by electrophysiological or functional (vibratory threshold) criteria. Whether these findings can
be translated into a noticeable clinical response or
whether prevention of clinical disease can be demonstrated awaits the outcome of large-scale clinical trials
such as the Diabetes Complications and Control Trial
now under way 163.
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