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By Guillaume
Charpentier
H�pital Sud Francilien, Corbeil, France
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Diabetes has become a major global public
health problem. The reasons for the fast expansion of this pandemic
is partly to be found in urbanisation and a general acceptance of
so called "Western Life Style". The patients suffering from
this disease are exposed to the risk of very serious complications.
These are, however, avoidable if the patients are given appropriate
care. The disease shortens life expectancy by about 10 years and
even more if the disease has had an early debut. The concept of
diabetes contains two very different pathological entities,
diabetes type 1 and diabetes type 2, both having in common the
chronic elevation of the blood glucose concentration and the risk
of complications related to the hyperglycaemia .
TYPE 1 DIABETES
Type 1 diabetes is the less frequent than Type 2: about 10% of
the total number in the western world. The global prevalence is
from 0.25% in Great Britain. This type preferentially affects young
adults but sometimes also occurs in children. There are great
regional differences in incidence. The annual incidence in Europe,
before the age of 16, varies between 40�2 and 3�2 per 100 000
inhabitants, with a pronounced north-south gradient.
Physiopathology
Type 1 diabetes is an autoimmune disease. The
islets of Langerhans in the pancreas, containing the �-cells that
specialise in the production of insulin, is the site of an
inflammation which eventually will lead to their irreversible
destruction.
There is a genetic predisposition for this
disease and it is significantly more frequent in subjects carrying
the haplotypes HLA DR3 and DR 4. Subjects carrying HLA Dq b-57
ala/val are at risk whereas the HLA Dq b-asp has a protecting role.
The possible benefit of the research on these markers has so far
not been put to practicable use. But, on the other hand, it has
been of great interest for epidemiological studies. The role of the
genetics in the occurrence of the disease is secondary: as shown by
the weak concordance for this disease in homozygous twins, <30%,
in contrast to the situation for diabetes, type 2.
Triggering environmental factors, are
ill understood, but seem to play a decisive role; e.g. it has been
shown that the occurrence of type 1 diabetes can be linked to
coxacki B4 viral infection or to the ingestion of cow's milk before
the age of two months. The proposed explanation is that there
exists an antigenic kinship between certain antigenic constituents
of the �-cell and these infectious or alimentary agents: between
the epitopes of glutamic acid decarboxylase (GAD), a
constituent of the � cell, and the coxacki B4 virus or the islet
cell antigen, ICA 69, and the albumin of cow's milk. The normal
immunological rejection of such uninvited guests, infectious or
alimentary, may in certain genetically predisposed persons result
in a chronic pathological auto-immune reaction which may, several
years later, when 90% of the �-islet tissue is destroyed result in
the clinically overt phase of the disease.
Clinical
manifestations
The patients suffers, apparently unexpectedly,
from an intensive increase of the blood glucose concentration which
provokes polyuria, thirst, loss of weight followed by acidosis and
coma. At this stage the diagnosis is evident and a fasting blood
glucose concentration well above 11 mmol/L (2 g/L) only confirms
the diagnosis.
The signs of this auto-immune aggression can
be noticed in the blood at an early stage well before the clinical
phase in the shape of antibodies; anti-islet tissue (ICA),
anti-insulin (IIA), anti-tyrosinephosphatase (IA2) and above all
anti-GAD, the earliest detectable antibody (Fig 1). Further research in this field
may be of interest in two situations: in discovering people at risk
for developing type 1 diabetes. This would only be of interest if
there was a specific immunomodulating treatment available, which is
effective and not iatrogenic and capable of interrupting the
auto-immune disease at such an early stage that the main part of
the �-islet tissue would be preserved. This means it has to
instituted well before the clinical stage after which it is
definitely too late. This type of treatment is at present not
available. But several clinical trials are under way (ant-CD 3,
DIAPEP 277).
The research on these markers has an interest
for the individualisation of LADA or slow type 1 diabetes. This
type of diabetes presents itself in the beginning as a type 2
diabetes but transforms rapidly, during a few years, into a stage
of underproduction of insulin and requires an early treatment with
this hormone. Among 1360 subjects participating in the UKPDS and
tested at the time of diagnosis, 11�8% showed the presence of
anti-GAD and 7�8% anti-islet cell with variable
concentrations1.
The treatment of type
1 diabetes:
In the clinical phase of the disease the
therapeutic strategy is aimed at preventing acute metabolic
accidents like acidosis and also preventing late-occurring chronic
complications: complications connected to the retinal or renal
microangiopathy or neuropathy. But also non-specific complications,
frequently occurring in diabetics, like peripheral macroangiopathy
or coronary angiopathy. It generally takes about ten years of badly
controlled blood glucose concentration to create these
complications. There is, however, a pronounced individual
variation, which in the case of at least the nephropathy is
probably connected to genetic factors that are still poorly
known.
The lesson
learned from the DCCT
The multicentre prospective study by the
Diabetes Control and Complication Trial (DCCT)2
published in 1993 showed that intensive insulin treatment could
reduce the appearance of specific diabetes complications or at
least slow their evolution. This study was performed on 1441 type 1
diabetic patients, half of them not suffering from retinopathy and
the other half showing a mild retinopathy. The patients were
treated for 1 - 15 years before they were randomly divided into two
groups.
The first group was treated in a conventional
way (at that time) with one to two injections per day, and
self-monitoring of the blood or urine glucose concentration and
with the goal of the absence of functional signs of the
disease.
The second group was treated in a more
aggressive way with three to four injections per day or an external
pump (40% of the subjects at the time of the study); at least four
blood glucose concentration controls per day; daily adjustment of
the insulin dose; monthly consultation with specialists; and
interactive telephone contacts. This treatment brought the mean
HbA1c down to less than 7�5% with the goal set at reaching the
normal range (<6�05%). The mean HbA1c of the conventionally
treated patients remained at about 9%. There was a reduction of the
adjusted mean risk of developing retinopathy by 76% in the
intensively treated patients in the primary prevention group and
its progression was reduced by 54% in the patients treated in the
same way in the secondary prevention group. Comparable results were
obtained for nephropathy and neuropathy.
The DCCT has in this way clearly shown that
the appearance of diabetes-specific complications is directly
correlated with the HbA1c percentage. This will consequently be the
key test to follow and adjust the therapy in these patients (Fig 2). This study has also shown that
there is a price to pay for obtaining a normal glucose
concentration; the appearance of severe hypoglycemia is inversely
correlated to the HbA1c percentage (Fig 3). The use of ultra-rapid insulin
analogues (and soon the slow analogues) and the more frequent use
of insulin pumps, should, at least in theory, permit the use of
intensive therapeutic schedules of the type basal bolus with
insulin therapy functionally adapted to food intake. This
therapeutic schedule ought to make it easier to obtain good
glycaemic control, i.e. the HbA1c at less than 7% and also a lower
risk for hypoglycaemia.
In practice, due to the lack of consensus
regarding therapeutic principles, and probably also the lack of
human resources for education and intensive follow-up of these
patients, the situation will stay heterogeneous and not always
satisfactory even in those countries that are blessed with a strong
public health infrastructure. Thus, a recent French survey showed
that in France less than 1/3 of the patients suffering from type 1
diabetes had HbA1c at less than 7�5% even though 36 different
insulin schedules were utilised and without showing any correlation
between number of injections and HbA1c.
TYPE 2 DIABETES
Type 2 diabetes poses radically different
problems.
Pathophysiology
Three mechanisms compete in this disease to
increase the hyperglycemia: peripheral insulin resistance leading
to a diminished muscular glucose up-take, an increased hepatic
glucose production which is the principal reason for the fasting
hyperglycaemia at the end of the night and, lastly, diminished
insulin production. All these anomalies deteriorate progressively
with time, resulting in an incapacity to withstand the insulin
resistance and the progressive aggravation of the metabolic
disorder. The precise origin of these metabolic anomalies is not
known. They are clearly "genetically programmed": the concordance
for type 2 diabetes is more than 90% in homozygous twins. The
history of this type of diabetes is clearly familial and this is
even more evident if the disease affected the parents at a young
age. The gene, or rather the genes, responsible are not known,
(except perhaps Capsain-10). But it is assumed that type 2 diabetes
is genetically heterogeneous involving a few genes, which suggests
heterogeneity in the clinical phenotype. This disease is thought to
be provoked by a combination of several genetic variants, where
none of these alone is sufficient to produce the disease. It is
very possible that these individual genes are not pathogenic on
their own. The genes involved could be genes of "energy storage"
and type 2 diabetes could be induced by "thrifty genotypes": genes
favourable in an ancestral situation of severe famine and turned
unfavourable in a situation of food in surplus and physical
idleness leading to obesity and later diabetes.
Environment
factors
There are, however, some factors that play a
major role in the genesis of the disease: the prevalence of type 2
diabetes in the Japanese living in Japan is not higher than 1% but
increases to 10% if the same ethnic group moves to Hawaii or to the
west coast of the USA adopting the so called "American way of life"
with food containing a large intake of glucose and lipids and
little physical activity. The same phenomenon is observed with the
Chinese living in China (1�6%) or living on island of Mauritius
(13�1%) and the same phenomenon has been described in several
analogue situations. The role of these genetic and environment
factors is well illustrated by the great difference in the
prevalence of the disease in ethnic groups living in the United
States, genetically different but living under the same
circumstances with over-eating and reduced physical activity (Fig 4).
An other important environment factor is the
increased life expectancy as the prevalence of this type of
diabetes increases with age.
Thus, the fact that the population is getting
older in the "developed countries" as well as in many "developing
countries", the universal urbanisation with a sedentary way of life
with little physical activity and eating foods rich in lipids and
refined sugar can well explain the alarming global increase of the
diabetes pandemic. The number of diabetics was estimated to 145
millions in the year 2000 and is expected to surpass 300 millions
in the year 2025. This expansion is found principally in the 45-60
year age group in the "developing countries" and in the age group
> 65 in the "developed countries" (Fig 5).
Clinical
manifestations of type 2 diabetes
The diagnostic criteria are given in Fig 6. The early clinical picture of this
disease is rather treacherous as, in contrast to type1diabetes, the
increase in hyperglycemia is very slow and the patients can stay
unsymptomatic for several years. If there is no screening program
for diabetes it may well happen that the diagnosis is not made
before the appearance of the cardinal symptoms like (thirst,
polyuria, and loss of weight) and when the fasting blood glucose
concentration is above14 mmol/L (2�5 g/L). It may well be that the
clinical diagnosis is not made before 10 years after the biological
first appearance. In that situation diagnosis is often made at the
occurrence of micro-or macro vascular complications. In the United
Kingdom Prospective Diabetes Study (UKPDS) 50% of the patients had
at least one complication at the time of diagnosis! In order
to make the diagnosis as early as possible before the complications
are overt the checking, on at two occasions, if the fasting plasma
glucose concentration is above 7� 0 mmol/L is of great importance.
Unfortunately there is no international consensus about the rules
for a systematic screening procedure. However, it is certain that
that subjects having a family history of diabetes run a big risk as
well as obese people or those having waist/hip ratio >0�8 for
women and >1 for men. The same holds true for women having a
history of gestational diabetes. In certain ethnic groups this risk
is considerable where people just over 60 years of age have the
same prevalence as the aged. The age when to begin a screening
procedure or the frequency of sampling is so far not defined.
Subjects having a blood glucose concentration
below the threshold defining diabetes (Fig 6) but having a value above the mean or
slightly higher are those who run the highest risk of developing
diabetes. The DPP3 study showed that 30% of the patients
having a fasting plasma glucose concentration of between 5�3 and
7�0 mmol/L (0�95 and 1�25 g/L) and between 7�8 and 11�0 mmol/L
(1�40 and 1�99 g/L) after glucose load developed diabetes within
the next three years. The same study showed that if you could
detect these subjects through a simple blood sample and modifying
their "life style" one could reduce the incidence by 58%
during the three year period.
The treatment
of type 2 diabetes, the lesson learned from UKPDS
The UKPDS1 consists of 5000 patients suffering
from a recently diagnosed type 2 diabetes. These patients were
randomly grouped into two groups. One group treated with rather
slack therapeutic objectives and the other treated with strict
therapeutic goals.
This study demonstrated two fundamental facts that are essential to
know about the effective treatment of type 2 diabetes.
- A
reduction of 0�9% of the group mean value for HbA1c in the strictly
treated group resulted in a 21% reduction of retinopathy during a
10 year period, a 33% reduction of nephropathy and there was
evidence of 16% reduction of coronary infarcts. There exists a
correlation between the appearance of micro- or macro-vascular
complications and the period mean HbA1c value.
- Each of
the drugs used initially (insulin, sulfonylurea, or metformin - for
the obese) in single drug therapy failed, after a transitory
effective phase, without one being better than the other in
controlling the glycaemia. This phenomenon was parallel to the
diminishing insulin secretion.
The therapeutic strategy for type 2 diabetes
should evidently be a strategy in which new therapeutic
modes/agents are added whenever the glycemic goals are not
achieved: the first step based on diet and physical activity, after
that Metformin or Sulfonylurea is added, then both together and
then perhaps a tri-therapy with ascarbose or thiazolidinedione (no
consensus). As a final step a change to insulin and to begin
with a mixed treatment with insulin NPH at bed time and then after
a few years when this mixed treatment fails one can use treatment
with several injections per day and stop of oral
anti-diabetics using therapeutic schedules very similar to those
used in the treatment of type 1 diabetes (no consensus)
.
Glycaemia
goals
There exist several rather similar national
and international recommendations. The French National Agency for
Evaluation, ANAES, recommends an optimal threshold value for HbA1c
of 6.5% (with a normal range of < 6%). This is very ambitious
with the aim of eliminating the diabetic complications. The
treatment must be modified if the HbA1c is above 8%. In the
interval between these two levels, the treatment should be
strengthened in accordance with the expected advantages and
disadvantages.
The value of HbA1c is the decisive parameter
for deciding the therapeutic course to be taken by the physician.
This makes it necessary that the result is correct, reproducible
and comparable to other laboratories. Nevertheless the
standardisation of this test is not always realised; in France in
1999 the inquiry DIABEST made it clear that there were at least 28
different standards, 56% of upper reference ranges given were
higher than 6%.
The treatment of type2 diabetes is not based
only on the blood glucose concentration but includes also the
active consideration of other vascular risk factors.
-
High blood pressure is present in more than 50%
of the patients. The UKPD study showed that the active treatment of
this complication gave a better result on morbidity/ mortality in
cardiovascular complications than correction of the
hyperglycaemia. The therapeutic goals must be stricter for
these patients as compared to a non-diabetic population (running a
lower risk of cardio-vascular disease). A number of very similar
recommendations have been published. We keep to the ANAES which
recommends the resting blood pressure should be below 140/80
mmHg.
-
Type 2 diabetes is very often associated with
dyslipidaemia. The serum LDL cholesterol concentration ought to be
kept below 1�30 g/L (primary prevention) or below 1�0 g/L
(secondary prevention) by dietary restrictions or if necessary by
drug therapy. Also the serum triglycerides , atherogenic in
diabetics, should be kept at below 2 g/L (primary prevention) or
below 1�5 g /L (secondary prevention) by dietary restriction or
eventually with the addition of fibrates.
-
all this should be coupled to fighting smoking
and sedentary life style.
Paying this price it may be possible to avoid
the chronic diabetic complications. It would be advantageous to
perform a very early thorough check up on these patients. It is
frequently recommended to make this check up annually in the
future.
This check up should include the search for
signs of retinopathy by retinal examination, the nephropathy by
determining the 24 h microalbumin excretion the serum creatinine
concentration and the neuropathy by clinical examination (diapason
or monofilament) looking for carotid arteritis or thermo by
palpating the pulse and auscultation over the arteries and in the
case anomalies supplemented by a Doppler examination.
Discovering coronary insufficiency is more problematic, it is often
silent in diabetics and clinical examination and ECG taken at rest
add little. However, coronary accidents are responsible for
more than 50% of the increased mortality in type 2 diabetes.
Physical exertion tests and pharmacological tests could be used in
a situation of particular risk. Unfortunately, there is no evident
consensus concerning these situations. The risk equations ought to
be a useful aid for the definition of patients to be further
examined.
CONCLUSION
In type 1 and type 2 diabetes the therapeutic
decisions and the clinical prognosis rely to a very large extent on
laboratory test results. It is of great importance for the
clinician to have a correct and reliable determination of the blood
glucose concentration, and the HbA1c which ought to be
standardised, the urine microalbumin excretion rate, the serum
creatinine, the serum LDL cholesterol and the triglyceride
concentrations.
Concerning type 2 diabetes systematic
screening of the general population or at least of risk groups for
fasting blood glucose concentration would be suitable for making an
early diagnosis and permit a real prevention of diabetic
complications.
REFERENCES
1. UK Prospective
Diabetes Study (UKPDS) Group : Intensive blood glucose control with
sulphonylrureas or insulin compared with conventional treatment and
risk of complications in patients with type 2 diabetes. Lancet, 352
: 837-853, 1998.
2. The diabetes
control and complications Trial Research Group : the effect of
intensive treatment of diabetes on the development and progression
of long-term complications in insulin-dependent diabetes mellitus.
N Engl J Med, 329 : 997-986, 1993.
3. Diabetes
Prevention Program Research Group : reduction in the incidence of
type 2 diabetes with lifestyle intervention or metformin. N Engl J
Med, 346 : 393-403, 2002.
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