1-4-252.pdf

Special Article
Diabetes Mellitus and Its
Degenerative Complications:
A Prospective Study of 4,400 Patients
Observed Between 1947 and 1973
JEAN PIRART
This article was originally published in French in Diabete et
Metabolisme (vol. 3: 97-107, 173-182, 245-256; 1977).
The Editors of DIABETES CARE thank the author, and the editors
and publisher of Diabete et Metabolisme for granting permis-
sion for us to print this English translation. The paper was trans-
lated by Marjorie Levin of Miami, Florida.
Part I of this translation appeared in the May-June
issue of DIABETES CARE (vol. I: 168-188).
Part 2
DISCUSSION
B
ased on a longitudinal follow-up of 4,400 patients,
our prospective study has shown that the two
essential factors which determine the risk of
degenerative complications are the duration and
the intensity of diabetes. Neither diabetic heredity nor
obesity seems to play a direct role. Neither sex nor age modify
the risk of the specific complications so often associated in
a triopathy, although their role in the development of
coronary and peripheral atherosclerosis is evident. All this is
in agreement with the data in the literature. The controversy
is essentially over the effects of duration and intensity of
diabetes, especially the latter. Now, this intensity can be
considerably diminished by treatment. It is this actual
intensity (glycemic control) and not the inherent severity of
diabetes that seems related to the development of specific
lesions. By contrast, glycemic control does not seem to slow
down accelerated atherosclerosis related to diabetes. A
moderate degree of attenuation of diabetes by treatment
seems already efficacious in the prevention of the specific
microvascular and nervous lesions. It can be achieved in
most diabetic patients, although with a bit of effort.
The pathogenesis of the complications of diabetes in man is
still conjectural for the reasons set forth in the introduc-
tion. Although very suggestive, our statistical correlation ob-
viously cannot furnish proof of a causal link between pro-
longed hyperglycemia and the complications. This causality
has been strongly disputed. The objections generally pre-
sented can be grouped under the following headings:
(1) The specific lesions of diabetes are an integral part of
idiopathic diabetes and are not observed in secondary
diabetes. Therefore "complications" would be considered
concomitants of a constitutional illness which would affect
the insulin-secreting cells, the fibroblasts, the small blood
vessels, and the nerves.39
'169
'179
'197
(2) Since they do not always evolve parallel to the dura-
tion of diabetes, the degenerative lesions that accompany
it can be observed from the onset of diabetes and can even
precede it.
(3) The specific lesions evolve independently of the in-
tensity of the diabetes and are influenced little if at all by the
treatment of the metabolic disorder; viz., a protective effect
of reduction of hyperglycemia has never been demonstrated
by any convincing statistical evidence.
Clinical and experimental work done over the past 10
years has produced a large amount of data that permits the
three objections to be refuted.
(1) Lesions of the kidney, retina, and nerves similar to
those of human diabetes can be obtained in animals in which
diabetes is induced by pancreatectomy, beta-cytotoxic
agents, or growth hormone (table 2). Typical features of
retinopathy, of glomerulosclerosis (even nodular), and of
neuropathy have been observed in human long-term cases of
secondary diabetes, resulting from hemochromatosis, chronic
pancreatitis, or pancreatectomy (table 2).
A careful review of the literature will uncover no argu-
ment in favor of a hereditary predisposition to neuropathy,151
nephropathy,20
'67
'100
'159
'202
or retinopathy4
'19
'100
'123
'159
'161
'166
with the sole exception of the beautiful study by Pyke and
Tattersall.153
These authors studied 13 pairs of identical
twins both of whom had diabetes and 10 pairs of identical
twins of whom only one had diabetes. In those 26 twins of
concordant pairs they found a family history of diabetes in
252 DIABETES CARE, VOL. 1 NO. 4, JULY-AUGUST 1978
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DIABETES MELLITUS AND ITS DEGENERATIVE COMPLICATIONS / JEAN PIRART
addition to retinopathy (in particular severe retinopathy)
more frequently than in the 10 diabetic twins of the dis-
cordant pairs. In our cases, overall prevalence (all durations)
and annual prevalence show no correlation whatever with a
family history of diabetes. It is striking to note that whatever
TABLE 2
Complications arising in cases of nonidiopathic diabetes
its origin, hereditary or not—and half of the idiopathic cases
are not hereditary187
—idiopathic diabetes, like secondary
diabetes, leads to specific complications which are a function
of the duration of hyperglycemia (table 2).
(2) Our study demonstrates a strict correlation between the
Animals: Experimental diabetes produced by pancreatectomy, beta-cytotoxins, or growth hormone
Retinopathy Nephropathy Neuropathy
Hausler et al., 1963
Hausler et al., 1964
Engerman and Bloodworth, 1965
Gibbset al., 1966
Osterby'Hansen and Orskov, 1967
Toussaint, 1968
Bloodworth et al., 1969
Bloodworth and Engerman, 1971
Mann and Goddart, 1949
Mann et al., 1951
Janes, 1969
Greenberg, 1962
Beaser et al., 1963
Beaser et al, 1964
Osterby-Hansen et al., 1966
Gibbset al., 1966
Bloodworth et al., 1969
Bloodworth and Engerman, 1971
Tseng et al., 1972
Mauer et al, 1972
Hagg, 1974 (p. 211)
Mauer et al., 1975
Preston, 1967
Hildebrandet al., 1968
Sahgaletal, 1972
Jakobsen, 1975
Fox et al., 1975
Man: Secondary diabetes resulting from various pancreatic and extrapahcreatic diseases
Retinopathy Nephropathy Neuropathy
Pancreatectomy
Chronic pancreatitis
Hemochromatosis
Cushing's syndrome or
acromegaly
Intense and prolonged
corticosteroid therapy
Rynearson, 1957 (cited by Duncan, 1958)
Burton et al, 1957
Duncan etal, 1958
Dec/cert, 1960
Dett^ler, 1964
Turin et al., 1967
Lubetzki et al., 1968
Seveletal., 1971
Geevarghese and Mathew, 1973
Verbonfcetal., 1975
Wellmann and Volk, 1976
Hudson, 1953
Dunlop, 1957 (cited by Duncan, 1958)
Dec/cert, i960
Gallon, 1965
Turin et al., 1967
Pirart and Barbier, 1971
Gri#thsetal., 1971
Simon et al., 1973
Passaet al., 1975
McCulIagh, 1956
Goto and Yamagata, 1964
Toussaint and Famir, 1966
Doyle et al., 1964
Duncan etal, 1958
DecJcert, 1960
Shapiro and Smith, I960
Dettwyler, 1964
Ireland etal, 1967
Turin et al., 1967
Enniset al., 1969
Wellmann and Volk, 1976
Becker and Miller, I960
Turin et al., 1967
Ireland etal., 1967
Simon et al., 1967
Doyle et al., 1964
Deckert, 1960
Dettwykr, 1964
Lubetzki et al., 1968
Galton, 1965
Turin et al., 1967
Dymocketal., 1972
Pirart, 1976
Recordier et al., 1976
McCulIagh, 1956
References in italics refer to long-term cases.
DIABETES CARE, VOL. 1 NO. 4, JULY-AUGUST 1978 253
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known duration of hyperglycemia on the one hand and the
prevalence and incidence of nervous and vascular complica-
tions on the other. Thus we confirm the impression gleaned
from review of numerous clinical studies. Most of these,
however, pertain only to one or two of the three specific
complications and to large subgroups of duration (more than
20 years, more than 30 years, etc.). None, except for
the one by Knowles et al. ,86
provides figures for annual
prevalence and annual incidence as we do.
The observations that cast doubt on the effect of duration
concerning neuropathy have to do with some severe pre-
cocious cases, often reversible once the treatment of diabetes
has been initiated (reference in Pirart, 1970139
)144
; or they
have to do with some subclinical cases studied by electro-
physiologic techniques.125
The clinical observations, in
general, show correlations between known duration of dia-
betes and glomerulosclerosis (frequency and severity). The
rare disagreements concern only a small number of clinical
cases observed after the 10th year of childhood diabetes.90
Morphological studies on the other hand show frequent
discordance between the known duration of diabetes and the
intensity of the lesions demonstrated by light micros-
copy76
'144
'147
'148
or electron microscopy.141
'147
'148
Some very
careful quantitative studies82
'110
have shown, nevertheless,
that the initial glomerular lesions—a thickening of the capil-
lary basement membrane—did not exist at the beginning of
diabetes except in middle-aged subjects. In addition they
have shown that this lesion could develop rapidly, and
that its progression is clearly a function of the duration of
diabetes.164
No discordance appears for retinopathy in the 43 studies
dealing with it. Finally, the duration factor is a determinant
in the development of nervous and vascular complications
of secondary diabetes, whether clinical or experimental
(table 2).
The discovery of specific lesions at the time of diagnosis is
not a serious argument against the theory which makes those
lesions authentic complications of a metabolic disorder evolv-
ing as a function of its intensity and duration. None of the
26 reports concerning "precocious complications" bear proof
of the absence of diabetes, not even in the year preceding
the simultaneous discovery of hyperglycemia and complica-
tions. To the contrary, some authors emphasize the need
for a careful search into the medical records which might
uncover proof of diabetic antecedents which the patient
had hidden, ignored, or forgotten.
The experience in all diabetes centers agrees with the
results of detection drives: when accompanied by typical
symptoms, diabetes can go unrecognized for a long time,
and even much longer in the case with no glycosuria. This
is frequent in the elderly, who pay a higher price for
ii • M 1* • 17 $n 17^1
precocious complications.1
''o<J
'i
'J
We put forward three additional arguments suggesting
that the underestimation of duration could be the artifact
responsible for the "precocious" lesions: (a) These are all
the more frequent in patients who were more obese before
the discovery of diabetes; (b) middle-aged subjects had a
higher glycemia at the discovery of diabetes, if the illness
was already accompanied by complications; (c) in the first
years of diabetes, the "old" patients already had more compli-
cations (prevalence) than the "young" ones, although those
who were still unaffected by complications did not develop
them any sooner (incidence) than the "young" ones. This
is compatible with the idea of an unrecognized long dura-
tion responsible for the precocious complications. Extrap-
olation towards the left of our ascending curves for the
prevalence of the three specific complications (figures 14 and
15) as a function of duration of diabetes in the "old" is
reminiscent of extrapolation to the left of the gentle slope
of increasing thickness of basement membrane of the
glomerular capillaries in adults as compared with the steep-
ness of this rise in children and adolescents (Lazarow,97
see
his figure 3). The development of specific lesions before the
appearance of hyperglycemia will not be discussed here. A
meticulous analysis of the publications that do mention this
shows that almost all such cases can be explained by at least
one of the two following possibilities: either the complica-
tion was not specific, or diabetes was probably preexistent.
In an overwhelming majority of the 60 reports dealing
with the subject (table 3), the authors found a correlation
between poor control of diabetes and the prevalence of its
complications. However, it must be recognized that none of
them offers statistical data that fulfill most of the require-
ments set forth in the introduction. Some even conclude that
they did not find any correlation.86
Our study is the only
one that satisfies 22 of the 23 criteria defined above. In fact,
the only problem we could not solve was that of dropouts.
The present study has specific features: magnitude, dura-
tion, continuity, homogeneity, use of objective criteria to
estimate the degree of chronic hyperglycemia, effort to sepa-
rate the two aspects of diabetic intensity (inherent severity
and degree of glycemic control), and careful statistical
analysis. This study, which Spiro182
has called ambitious,
could in such a way add more convincing original data to
the studies as yet published.
Magnitude of the Present Study
The particular circumstances in which our subjects came to
us allowed us for a long time to avoid a highly selective
recruitment, which is the norm in renowned clinics. We have
reasons to believe that our material constitutes a representa-
tive sample of the diabetic population of the Brussels
area (age, sex, duration of diabetes, severity of diabetes,
complications, etc.). All the patients whom we were able
to care for were questioned and examined. No one was ex-
cluded and no file was left out of the collection.
The broad range of the study is unique: 21,000 annual
neurovascular evaluations on 4,400 patients. Our material is
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TABLE 3
Comparison of the Brussels study with the U.G.D.P. study (retinopathy only)
U.G.D.P. Brussels
Period of observation
Admission criteria
Incipient cohort (no. of cases followed since
year one)
Erosion of subject pool
Still followed at year 5
Still followed at years 5—8
Retinal examination
Place of examination
Observers
Goals of the study
Evaluate a certain type of treatment
Evaluate the effect of hyperglycemia
Methods
Random allocation of one treatment to
randomized groups
Systematic effort to obtain better control
1961-1974
Borderline and overt diabetes
Known for <1 year
Not insulin-dependent
716*
1947-1973
Overt diabetes
All durations
All degrees of severity
2,795
499T
211"
None
None
Photograph of the central part
of the right retina
12 clinics
±40 doctors
Yes
Secondary goal
Yes
No
547
360
219
97
Direct opthalmoscopy
of both eyes, dilated
2 clinics
2 private practices
±2 doctors
No
Main goal
No
Yes
* Diabetes (Suppl. 2) 19: 771 (table 28), 1970.
t J. Am. Med. Assoc. 218: 1402 (table 2), 1971.
11
J. Am. Med. Assoc. 217: 783 (table 6), 1971.
N.B. —The data published in Article V of the U.G.D.P. Study (Diabetes 24 (Suppl. 1), 1974) are useless because duration of diabetes is not defined (see pp.
101, 102, tables 21, 22, and on p. 128, table B17. This holds true also for table 9, p. 1139 of Article VI (Diabetes 25: 1129, 1976) which concerns the first
appearance of a retinal abnormality (see p. 1131, paragraph 2) with no mention of the duration of diabetes at that moment.
more extensive than that of 15 longitudinal studies published
to date: their subject populations range from 21 to 990. Our
260 patients who had diabetes before 21 years of age and
our 497 patients who had diabetes before 31 are to be com-
pared with the 132 "children" of Hardin et al.62
and to
the 78 "children" of Knowles et al.,86
which are the largest
groups of cases of juvenile diabetes followed for several years.
Our cross-sectional study of long-term cases, whether fol-
lowed up or not, also prevails over the majority of others
with respect to the number of patients. At the 15th year of
diabetes, we have 339 patients of whom 298 could be studied
for the degree of control, while Dunlop,36
Lestradet and
Billaud,100
and Lundbaek103
mention, respectively, 167,
86, and 234 cases of various durations greater than 15 years.
By contrast, at the 20th year of diabetes, we have only 164
cases of whom 138 can be studied for the degree of control,
while Pense et al.135
and Constam25
had, respectively,
180 and 434 cases with duration of 20 years or more. It must
be added that the degree of cumulative control could not be
estimated on all the patients observed by these authors,
whose denominators are sometimes much lower than the
number of subjects.
No continuous longitudinal study (inception cohort) has
been pursuedfor as long a time as ours, since the one by Spoont
et al.183
was on 50 cases followed for more than 10 years
and those of the U.G.D.P. published to date195
are on 211
cases in which follow-up on the retina continued for from five
to eight years and on 379 cases with follow-up on the
kidneys for the same amount of time. All such cases were ob-
served from the beginning of diabetes (table 3).
We have simultaneously studied, year by year, neuropathy,
microangiopathy in two areas, macroangiopathy in two
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other areas, and various clinical and biological parameters.
Most of the published studies dealt only with one or two
kinds of complications, and only seven of them concerned
the three specific complications. No longitudinal study has
evaluated, for a prolonged length of time, both the triopathy
and the arteriopathies.
Kaplan and Feinstein81
pointed out that in most published
studies the denominator is not stable: not all the cases were
studied for each of the various complications reported on. In
the longitudinal studies that were more or less continuous,
the "denominator," i.e., that fraction of the subject popula-
tion in which a complication was observed, is variable not
only from one complication to another but from one year to
the next. We believe that we accomplished the rarely at-
tained maintenance of the denominators at roughly 100 per
cent of our available population for all complications, for
all durations of diabetes, and at all years of the continuous
follow-up. It was a rare exception if any examinable patient
was left out of the denominator by omission of a periodic ex-
amination, and this reinforces the homogeneity of our statis-
tics. The study of the annual incidence of the five compli-
cations could not have been carried out otherwise, and that is
why we are the only ones to have done it. The denomina-
tors of our studies of incidence are naturally always much
lower than those of our studies of prevalence, because once
a patient had escaped from us one year, he became definitively
lost from the study of incidence.
Prevalence of Diverse Complications in our Series
At the discovery of diabetes we observed prevalences of 7.5
per cent for neuropathy, 7.2 per cent for retinopathy, and
1 per cent for nephropathy, which agree with the observa-
tions made in other diabetes clinics in industrialized
countries.
After 20 to 25 years of diabetes, our whole population
(the two cohorts pooled) show neuropathy only in about 45
per cent of cases, retinopathy only in about 55 per cent of
cases, and nephropathy only in about 15 per cent. This could
be compared with the figures commonly found in the litera-
ture (table 5, p. 205 in Lestradet, 1959; table 22, p. 263
in Knowles, 1965; table 10, p. 312 in Burditt, 1958; figures
6.1 to 6.4 in Caird, Pirie, and Ramsell, 1969, among others).
The reported figures go from 30 to 60 per cent for neuropathy,
50 to 100 per cent for retinopathy, and 20 to 40 per cent
for nephropathy.
Our "inception cohort," consisting of patients whom we
personally cared for since the discovery of their diabetes,
shows for these same durations of 20 to 25 years about 60 per
cent neuropathy, about 60 per cent retinopathy, and about 5
per cent nephropathy. These figures are therefore less favor-
able than those of the additional cohort, which doubtless
reflects my inexperience at the beginning of my career and/
or a selection bias that made us keep the more difficult cases
for a longer time.
Continuity of Observations
In almost all diabetes clinics, record-keeping is delegated to
interns or medical students or to temporary assistants who
are little interested in a long-term study and poorly qualified I
in the practice of diabetes care. They are the ones who ex-
amine and really treat the patients under the supervision of a
small number of senior physicians who, unfortunately, no
longer have much contact with the patients. We have suc-
ceeded in avoiding this particular snag so as to attain greater *
value and homogeneity in our observations. Undoubtedly it
is also the continuity of personal doctor-nurse-patient rela-
tionships which explains the relatively slow attrition of our
subject population, especially of the insulin-dependent per-
sons who were much more motivated than the mild cases.
Table 3 compares our study with that of the U.G.D.P.
which was carried out with a deployment of personnel
and financial means incomparably superior to ours. Inci-
dentally, this table underlines some differences in the proto-
col adopted and in the way in which it was carried out. To
simplify the table, only retinopathy was considered from
the multiple "non-fatal events" that occurred to the
U.G.D.P. patients since their entry into the study.195
Criteria of Intensity of Diabetes
We are convinced of the variability of the degree of inherent
severity and of its durable attenuation by the slow effects
of treatment in numerous cases, especially in the first years
of evolution. That is why we cannot agree with Miki et al.m
who adopt as an index of diabetes severity the mean fasting
blood glucose before the treatment starts.
In any case, we have carefully avoided the confusion that
often arises between insulin treatment and true insulin
dependence.
The degree of glycemic control was measured by objective
and continuous methods and assessed year by year, which
makes our study much more reliable than the majority of the
preceding ones, as table 4 shows.
The methods used to estimate the degree of glycemic control
observed throughout the patient's career and/or the results of
this estimate are not made clear in 16 out of the 60 studies
analyzed in this table. In certain studies, it was based on very
subjective data, such as discipline and desire to cooperate
on the part of the patient and those around him, the degree
of initiative he takes in the management of insulin, his feel-
ing of well-being, and his place in society. There are, on
the other hand, objective data such as body weight, values
of glycemia and glycosuria, etc., recorded episodes of
ketoacidosis or hypoglycemia, frequency of medical visits and
urine tests performed between visits, and whether the diet
was actually followed. Many authors do not clearly separate
the means prescribed (and supposed to be applied) from the
results obtained. What do the means matter (whether diet was
followed, insulin or pills taken, dosage adjusted, lapses in
treatment rapidly corrected, frequency of visits and urine
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and blood tests recorded) if the results are poor! It is evident
that the state of the susceptible tissues cannot be influenced
by the goals, the methods, and the applications of treatment,
but only by metabolic results—glycemia, lipemia, in-
sulinemia, etc. —which are largely independent of these. Our
own observations agree with those of Francois et al.44
on their
children: there is not necessarily any correlation between the
degree of control obtained and the means used to obtain it,
in particular the intensity of supervision. Now what is
important to derive from these tests is some kind of con-
tinuous "film" record showing as continuously as possible the
variations of glycemia, glycosuria, and acetonuria (includ-
ing during acute episodes) and of body weight, and other
measurements during the life of the diabetic patient. The
frequency and the reliability of observations made by the
patient and by the doctor furnish a certain number of
"snapshots" more or less representative of this continuing
picture.
Such factors as lifestyle, appetite, and mildness or intrinsic
stability of the diabetes play an important role in obtaining
good or poor control, either one often undeserved. Even
when the objective means of estimating the degree of control
were identified in a text, the evaluation sometimes seemed
unreliable because of the intrusion of subjective judgment,
hazardous extrapolation of punctual observations over long
periods,122
or because of the "penalization" of a habitual agly-
cosuria if it is accompanied by frequent hypoglycemia or by
rare episodes of hyperglycemia that is serious but of short
duration.
The correlation with the control of diabetes has been
studied for the three specific complications in 10 published
studies, in which three report partially on the same sample.
Only two complications, most often microangiopathy, were
studied in 18 publications; only one complication, usually
retinopathy, was studied with relation to the degree of control
in 33 publications, of which seven have to do with groups of
patients selected precisely because they had this complica-
tion. The control group not affected was more or less well
defined.
Among the 41 reports in which the relationship between
poor control and complication(s) seems to have been studied
fairly seriously, the only one that concludes that there is no
correlation between retinopathy and degree of control is the
one by Knowles et al.86
But the glycemic control was so
poor among all patients in that study that it was impossible to
oppose two groups of patients, good control and poor control.
Two others among the least reliable conclude a doubtful
positive correlation. All the others show that good metabolic
control (reflected by blood and urine glucose) prevents
specific complications.
We have attempted to detect statistical bias in the recruit-
ment and the maintenance of our subject pool or in estimating
the degree of control. Such bias could have influenced the
correlation between control and complications in our ma-
terial. Recruitment and maintenance of subjects could have
gained us some cases with poor control suffering from complica-
tions (who were seeking help from those whom they believed
qualified to give it) and could have lost us cases with
complications and however good control. This is unlikely be-
cause of our connections with the ophthalmology and surgery
clinics and the various in-patient departments. We see no
reason to have drawn patients with good control and no
complications. We may have lost some cases who had no
complications and did not accept our restrictions, believing
that they were all right. Maybe we have also drawn easy-
to-control patients with complications and some unstable
cases who were poorly controlled but who escaped com-
plications.
As for biases in estimating the degree of control, we suspect
that there are three: (1) Had we estimated the metabolism of
those patients suffering from diabetic complications only
while they were hospitalized for complications—which in-
cluded infection or trauma (artery occlusion for example) —
we could have believed their degree of control to be worse
than it was as a rule. This is not the case, as our judgment
on glycemic balance was based principally on ambulatory
periods outside of acute episodes. (2) We could also have
underestimated hyperglycemia in the patients with an ele-
vated renal threshold, but it is precisely these patients
who are inclined to show complications of arteriosclerosis
and diabetic nephropathy, such that this bias worked against
our hypothesis. (3) We feel that our patients tended
consciously or not, to make us overestimate the quality
of their glycemic control (cheating in the notation of urine
tests, treatment followed more rigorously prior to the visit)
but we do not see why this error of estimation would have
been more frequent in those patients free of any complications.
It is impossible for us to evaluate the importance of these
statistical biases on the final evaluation. Our impression is
that they could have cancelled each other out in such a way
that the correlations we found correspond to reality.
It has often been emphasized that the patient who obtains
good glycemic control is often more careful of his health
and for this reason has better general hygiene, which could
prevent him from getting certain complications. This is true
for gangrene and infections (not studied here) and possibly
for atherosclerosis (a poor diet of saturated fats), but one
cannot understand how better hygiene and better care of
health could protect the patient from retinopathy, glomerulo-
sclerosis, or neuropathy. As it turns out, our study demon-
strates the correlation between good glycemic control and
the three specific complications, precisely those not
believed to be influenced by general hygiene, and the
study shows no correlation between good glycemic control
and atherosclerosis.
Atherosclerosis
Peripheral and coronary atherosclerosis in our diabetic patients
increased very strongly in prevalence and in incidence with
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TABLE 4
Prevalence of one, two, or all three specific complications as a function of chronic hyperglycemia and its control (if any)
Reference
No.
of
patients
Ages
at
onset
Dura-
tion of
diabetes
(yrs.)
Method of estimating degree of control
Subjective
(S)or
objective
(Ob)
Based on
means (M)
or on
results (R)
Annual and
cumulative
(AC) or
global (G) Validity
Effect on
Neur. Neph. Retin. Remarks
Root et al.
Dunlop
Matthews
Matthews
Pirart and Schoys-
man-De Boek
1954
1954
1954
1955
155 Juv.
1955
Rogers and Holcomb 1960
Aagenaes
Pirart
Constant
1963
1965(a)
1965
Constam m
Pirart and Coers 1969
Constam
Dolger
Wilson et al.
Keiding et al.
Jordan
1972
1947
1951
1952
1936
167
545
1,145
114
33
1,135
300
623
434
247
451
200
All
All
All
All
All
All
All
All
All
<50
<30
<30
All
(137)
All
All
>25
Long
All
>20
>20
>20
All
All
S & Ob M & R
Ob R
(Not defined)
Ob
S&Ob
S
Ob
Ob
Ob
Ob
S&Ob
S&Ob
S&Ob
S&Ob
R G
M & R G
(Not defined)
M G
R G
R
M&R G
(Poorly defined)
M&R
M&R
M & R G ?
(Degrees of control not defined)
Rundles
Martin
Fry et al.
Greenbaum
Pirart
Noel et al.
Root et al.
Appel
Spoont et al.
Mellinghoff
Schwarz
Lundbaek
Lambie and
McFarlane
Hardin et al.
Mohnike
El Mahallawy
and Sabour
McNeal and Rogers
Sauer
Skouby
Buschmann et al.
Paul and Presley
Downie and Martin
1945
1953
1962
1964
1965(a)
1971
1959
1950
1951
1953
1953
1953
1955
1956
1957
1960
1955
1956
1956
1958
1958
1959
125
150
62
80
58
22
840
370
50
22
43
234
120
132
2,600
391
103
58
286
1,547
29
47
All
All
All
All
All
All
All
All
All
All
All
All
All
<15
All
All
*
<40
All
Juv.
Juv.
All
All
All
All
All
All
All
All
>10
>9
>10
>15
All
>10
All
All
All
>10
All
All
>25
>20
Ob
?
Ob
Ob
S & O b
Ob
Ob
Ob
Ob
Ob
Ob
Ob
Ob
Ob
S & O b
Ob
S & O b
(Not defined)
(Not defined)
R G
7
?
±
? G ?
(Degrees of control not defined)
R
R
M & R
(Not defined)
R
R
R
R
R
R
R
R
R
G
G
G
AC
G
G
G
G
AC
G
AC
G
(Poorly defined)
M & R G
(Not defined)
M & R G
(R not defined)
R G
±
±
±
0
+
±
±
±
±
±
+
±
0
0
7
0
±
• A
A A
A A
A A
Selected: all affected with triopathy
Taking into account fluctuations of control
over the years
Selection: all suffering from neuropathy
Selection: all suffering from proliferative
retinopathy
Large initial cohort
Out of 267 patients, duration >10 years
Autopsies; glycemic control known in 78 cases
According to their data, but not their
conclusions
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TABLE 4 (Continued)
Reference
Lestradet
Markman et al.
1959
1959
No.
of
patients
420
210
Ages
at
onset
<15
All
Dura-
tion of
diabetes
(yrs.)
All
All
Subject™
(S)or
objective
(Ob)
Ob
Ob
Method of estimating degree of control
Based on Annual and
means (M) cumulative
or on (AC) or
results (R) global (G) Validity
Effect on
Neur. Neph. Retn Remarks
Cugudda and
Stramignoni
Johnsson
Collyer and Hazlett
Lestradet and Billaud
Thieffry et al.
Leonetti,
Francois et al.
1959
1960
1961
1968
1972
19731
1976 1
373
159
100
86
269
204
All
<40
<16
<15
<15
<16
All
All
Schlesinger et al.
Mulder et al.
Munck et al.
Darnaud et al.
Knowles et al.t
Thomsen
Olaffesson and
Petersen
Gamstorp et al.
Szabo et al.
Burditt et al.
Caird et al.
Balodimos et al.
Miki et al.t
Goto et al.
Jarrett
Jarrett and Keent
Miki et al.
Pense et al.
Lauvauxt
Pirartt
(present study)
1960
1961
1961
1963
1965
1965
1966
1966
1967
1968
1969
1969
1969
1970
1972
1975
1973
1973
1976
1976
41
103
419
76
78
102
66
107
324
990
299
152
289
285
207 1
248 J
333
180
398
<40
All
±40
<18
<16
All
<15
<17
All
All
All
**
*
All
*
*
**
All
All
All
>10
All
All
>10
>10
All
All
All
>10
All
>10
>8
All
All
5
10
All
>20
All
>15
(339)
>20
(164)
R G ±
R G ±
(Weakened by penalty for hypoglycemia)
S & Ob M & R
S M
Ob M & R G
(Criteria of control not defined)
Ob
S &Ob
R
0
(Vague)
Ob R G ±
(Criteria of good control undemanding and
weakened by penalty for hypoglycemia)
Ob R G ±
(Not defined) 0
Ob R ?
(Extrapolated from observations in the hospital)
Ob M&R G +
0
0
Ob
&Ob
Ob
Ob
Ob
Ob
Ob
Ob
R
M & R
(Not defined)
R
R
R
R
R
R
G
G
G
G
G
G
G
G
(Not defined)
(Only initial glycemia)
Cannot
be ex-
trapolated
Ob R
Ob R
Ob R
G
iy 5-yr.
classes
AC
A
0
A
A
A
A
+
+
A
A
A
A
A
+
A
A
A
A
A
A
0
A
A
A
A
A
A
A
A
A
+
A
±
+
0
A
A
A
+
+
+
+
+
A
+
Initial cohort of 93 cases
Two groups treated successively
were compared
Questionnaires sent to several centers
Selection for neuropathy
Selection: all insulin-dependent
All poor control, so comparison is impossible
Renal biopsies
Subclinical neuropathy
Comparison of first five years with
following years
Prospective for evolution, retrospective for
prevalence
Pinpointed cases of limited diabetes
Cases with borderline diabetes compared
with 116 true diabetes all screened in a
detection drive
Retrospective for prevalence
Continuous follow-up
Continuous follow-up, large initial cohort
Neur., neuropathy; Neph., nephropathy; Retin., retinopathy.
* Especially middle age.
** Middle age.
t Those few studies that were prospective.
" Number of patients in parentheses.
A Complications not studied.
The validity of the affirmed or denied relationship between glycemic control and complication was assessed according to objective (reproducible) value of the estimated control (reliability, frequency,
and schedule of blood sugar and urine sugar tests), statistical methods (in particular the constitution of comparable groups), and validity of the conclusions drawn from the data as presented. No judgment is
implied either of the quality of care given or of the observations. A severe critique does not necessarily contradict the authors' opinion of their own work, which could have been pursuing other
principal goals other than the study of control or could have met with insurmountable difficulties in the evaluation of glycemic control.
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age whatever the duration of diabetes, which agrees with
all that is known about vascular disease in both the general
and diabetic populations.12
'53
*80
*101
'103
*175
The effect of age
cannot be studied except in large samples not biased by selec-
tive recruitment of diabetic patients or by the selective
research of vascular disease among those who complain of it.
A comparison of the mean ages of appearance of an occlusive
arteriopathy in juvenile diabetes and in maturity-onset
diabetes102
or between insulin-dependent and mild cases does
not make any sense unless both groups are of comparable
age at the time of the study, which is generally not the
case. Besides, it is difficult to eliminate the duration fac-
tor in juveniles when observed at middle or advanced age.
The development of arteriopathy increases with the dura-
tion of diabetes12
*101
'158
'184
but so slowly that this rise is not
discernible in small samples53
'154
'175
especially if these are
heavily loaded with a great number of "precocious" cases,
i.e. those suffering from nonspecific complications either
before diabetes or at "onset." And this is all the more so
as the discovery of one of the two illnesses often entails the
discovery of the other. In our series, arteriopathy is more fre-
quent in cases of mild diabetes since the onset of the illness,
and it appears later more often in mild cases than in insulin-
dependent ones. This agrees with the consensus of a greater
frequency of arterial lesions in diabetes, even in mild
cases, than in the control population,131
and of a correlation
between coronary atherosclerosis and mature age.204
Arteriopathy is more frequent in diabetes, even in mild or
borderline diabetes, than among subjects whose glucose tol-
erance is normal. Numerous studies of glucose tolerance in
patients with atherosclerosis as well as studies of athero-
sclerosis in subdiabetic and diabetic subjects have shown
this with perfect agreement.77>81
*83
*93
*102
~103
*131
Artery dis-
ease seems to be more frequent in cases of true diabetes
than in cases of borderline diabetes, as much in prevalence82
as in incidence.49
'71
However, among the clearly hyperglycemic subjects,
arteriopathy is not in any way related to the severity of
diabetes. On the contrary65
'88
'158
'175
-184
-188
'198
peripheral
artery disease and coronary insufficiency are therefore very
often related to mild diabetes.
This relationship between atherosclerosis and mild dia-
betes is only in part explicable by middle age, which is a
common feature of both, for we have found it at all ages and
at all durations of diabetes. It is not explained by obesity
either, for we have found only a weak correlation with
maximum weight reached before diabetes and no correlation
between arterial disease and present obesity (in spite of the
frequent association between obesity and hypertension and in
spite of the effect of overweight on the appearance of angina
on exertion, which facilitates the detection of it). We thus
confirm diverse studies on coronary artery101
'198
and on
peripheral artery12
*65
disease. Nevertheless, in cases of long-
term diabetes, almost all of which have been treated with
insulin, two groups135
-159
have observed a clearly unfavor-
able effect of present obesity, which was not explainable by
a lesser degree of glycemic control. Isolated obesity (dis-
sociated from hypertension, from high cholesterol, and from
old age) plays a reduced role in the general population, as
Yater et al. ,206
Spain et al. ,181
and the extended research of
the Framingham study78
'79
have shown.
Finally, we were not able to show the least favorable ef-
fect of good glycemic control on the prevalence and the
incidence of both arterial lesions, which confirms the majority
of previous observations.31
'65
-106
-119
-135
'154
'172
That does not at all exclude an effect of the intensity of
diabetes (severity and degree of glycemic control) on the
development of Monkeberg's nonocclusive medial sclerosis.
We did not study it. It shows up on X-rays of the most distal
arteries of the upper and lower limbs in long-term severe
diabetes84
'103
-123
-202
-205
and as a reduced arterial elasticity
measurable by an increased speed of propagation of the pulse
in diabetic patients, even without hypertension, and even
more so in insulin-dependent diabetic patients.171
In patients with juvenile diabetes for more than 15 years84
and among diabetic patients of middle age affected for more
than five years,171
medial sclerosis is related to poor glycemic
control. There are some correlations (same arteries in the
same subjects) between medial sclerosis and atherosclerosis54
in the same way that there is a correlation between micro-
and macroangiopathy in young, long-term diabetic pa-
tients.104
It is, therefore, possible that arteriosclerosis in its
diverse forms can be influenced by the treatment of diabetes,
but its multifactorial origin49
*79
and its strong association
with aging render a demonstration of this difficult. It stands
out clearly from our work as well as from that of Pense et al.135
that the three specific complications on the one hand and the
two localizations of atherosclerosis on the other hand behave
very differently with regard to the intensity of diabetes.
Everything indicates that arteriopathy, either in the presence
or the absence of diabetes, is determined by factors much
more complex (genetic or not) than the specific complica-
tions of diabetes. These latter seem to have a similar fre-
quency in all the populations of the world, while artery
disease is distributed very unequally in the diverse diabetic
populations so far studied.71
'201
CONCLUSIONS
A
fter careful analysis of the enormous literature
dedicated to the specific and nonspecific
complications of diabetes, two impressions
emerge: (1) The rigor of most of the statistics
leaves something to be desired particularly in the contro-
versial sphere of the effects of metabolic control. No one
satisfies most of the methodological requirements set out in
the introduction. (2) Despite the apparent chaos resulting
from the study of different populations examined by dif-
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ferent methods, one finds however a general agreement on
the relationship between the three specific lesions and the
duration and intensity of diabetes.
Our study fulfills 22 of the 23 criteria of validity re-
quested by the most severe critics. It conclusively proves
that diabetic triopathy and not atherosclerosis is a func-
tion of the duration and intensity of diabetes and more
precisely of hyperglycemia.
Of course, this can be lessened by treatment. This fact
should encourage physicians to strive toward normoglycemia
in diabetes therapy, while at the same time recommending
various methods of hygiene which could slow down the
development of atheromatosis and of hypertension.
A
C
K
N
O
W
L
E
D
G
M
E
N
T
S
: It is impossible for us to acknowledge each
of the many people whose collaboration enabled us to
achieve a study of this magnitude. Therefore, the names
of the many assistants who helped at our clinics will not
necessarily appear on the articles to be published on
each of the problems dealt with in this survey. We were
fortunate enough to have access to valuable records which
our predecessors had carefully kept at their practices:
at the Cesar De Paepe Clinic (Dr. Purnal), at the Brugmann
Hospital (Dr. Rutman), and at the Saint-Pierre Hospital
(Doctors Mahaux and Corvilain). We have relied on the
precise ophthalmological descriptions from the two uni-
versity hospitals (Prof. Danis) as well as on those from the
Cesar De Paepe Clinic (Dr. Claessen). It is thanks to the
diligence of our nurses that we were able to keep ourfilesup to
date. Some of these nurses have welcomed our patients for
more than 20 years. Numerous colleagues responded with
precision to our requests for information on the medical
history of our patients or on the hiatus of their curriculum
vitae. Finally, the regularity of our periodic examinations is
due in large part to the punctuality of our patients, even
those who followed our advise poorly. It is their discipline
and their goodwill which made this research possible.
From the Cesar de Paepe Hospital, Brussels, Belgium.
Reprints are not available from the author.
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