Diabetes Treatments

Diabetes in itself doesn’t cause deaths directly, but it has common Diabetes is a very significant disease and it is far away the most common of the …

DIABETES

Dufour

Today, we will talk about the pathology of diabetes and diabetic
complications Now what is the significance of diabetes? Diabetes is one
of the more common causes of death It is the 6th leading cause of death
and it is estimated that it affects about 10 million people in United
States With the prevalence of obesity and the prevalence of relative
physical inactivity increasing, it has been estimated that over the next 20-
30 years, the prevalence of diabetes will double and that is mostly type 2
diabetes

Diabetes in itself doesnt cause deaths directly, but it has common
complications that affect the site, that affect the heart, the kidney, the
legs and the nervous system For this reason through these complications,
diabetes becomes a 6th leading cause of death and diabetes is also a major
cause of morbidity It causes a lot of hospitalizations for treatment of
these complications even before it causes death

Diabetes is a very significant disease and it is far away the most common
of the endocrine diseases Now in terms of glucose
metabolism, there are
number of things that affect glucose level First of all, glucose levels
in the bloodstream initially after a meal reflect food ingestion and
glucose from food keeps it going for only a few hours So after that we
rely on stored glucose in the form of glycogen and depending on our liver
status, muscle status and on physical activity, this may last as for 8-12
hours After that when we are eating then we have to relay upon
gluconeogenesis, producing glucose from amino acid

Insulin is produced by the beta cells in the pancreas and it is initially
produced as a compound called proinsulin When signals come from high
glucose levels, there is a transport mechanism for moving glucose into the
islet cells and then a signaling mechanism and that initially signals the
cleavage of insulin or proinsulin to release insulin in inactive C peptide
Then it also stimulates the production of additional insulin

Insulin in the circulation has a half-life of about 4 minutes and C peptide
has a half-life about 20-30 minutes Remember of course that insulin as we
get it in injectable form doesnt have C peptide in it, so we
didnt start
with proinsulin In fact, when we have a patient with hypoglycemia and we
are worried whether they might be injecting themselves with insulin or they
have insulin-producing tumor, measurement of C peptide is very helpful for
making that distinction

This is how the system works, so if we look at typical cells like
hepatocyte, what we see is that glucose levels are affected by the influx
of glucose into cells stimulated by insulin and the release of glucose from
cells stimulated by a number of hormones:

1 Glucagon
2 Cortisol
3 Epinephrine
4 Growth hormone

Most of the hormones have their effect on either gluconeogenesis, glucagon,
cortisol and growth hormone stimulate gluconeogenesis or on glycogenolysis
for example glucagon and epinephrine stimulate glycogenolysis But another
compounds over here ethanol, which inhibits gluconeogenesis and it also
inhibits glycogen synthesis So alcoholics are very prone to develop
hypoglycemia

Insulin on the other hand allows glucose entry in the cells by allowing
transport mechanisms for glucose to be expressed by the cell and inhibit
glycogenolysis and glyconeogenesis and
stimulate storage of excess energy
as fat So those are the actions that we have with insulin and if we dont
have insulin then we also breakdown triglycerides as an energy source and
that is where we get ketoacidosis

Generally speaking, it takes less insulin to maintain normal serum glucose
levels then it goes to prevent ketoacidosis So people with type 2
diabetes, who usually have some insulin will have high glucose, but not
ketoacidosis People with type 1 diabetes, which usually absolutely
insulin deficient develops ketoacidosis when they dont take their insulin

Glucose measurements are often done using a test called glucose oxidase and
when we do fingerstick glucose on a patient when they do it at home, most
have this particular enzyme and there are couple of things that will affect
this It is affected by the oxygen content to the blood So when we have
people in the hospital that are sick, they may be either very anemic or
hypoxemic

Also vitamin C inhibits the measurement of glucose by this enzyme and this
is particularly problematic in urine and people taking a lot of vitamin C
can give us a falsely low urine glucose or
inhibit the reaction with
glucose in the urine So remember that in people who are critically ill,
whole blood glucose may not be very accurate because of these factors

There are some other things that affect blood glucose level for example
after meals, venous glucose is about 15 lower than capillary glucose would
be because the insulin stimulates uptake of glucose by the tissues So we
dont want to use fingerstick glucose to do a glucose tolerance test for
example In short, glucose is often used up in venous glucose levels,
which reflect what is leftover after the tissue uses it may be very low

Finally, it is important that if we draw a blood sample and dont
centrifuge it down, they separate the serum from the cells and then either
use one of those two of the gel in it, which makes the separation between
them or centrifuge and remove the serum from the cells Glucose is going
to continue to be used by the cells and glucose levels with fall So we
dont want to let samples for glucose sit around for a long time because
they would very low

Another test for evaluating glucose metabolism is Glucose Tolerance Test
The ADA no
longer recommends this is a first line test for diagnosing
diabetes except in pregnancy So a large bolus of glucose is given and we
test the ability of the pancreas to produce insulin in response to this
Typically multiple samples are drawn, but only the value at two hours is
considered diagnostic There are a lot of things that can affect glucose
tolerance The patient has to be fasting overnight, it should be done in
the morning rather than the afternoon Caffeine affects it so we want to
make sure, we tell our patients not to drink coffee in the morning even if
it is just black coffee because caffeine stimulates catecholamine
production Catecholamines breakdown glycogen and increase glucose levels

The patient has to be told that they are going to have to sit around in the
lab or in our office for two hours, they cant be running around doing
things because the exercise will change cortisol and catecholamine levels
and can effect that as well So it requires a lot of preparation and it is
not very reproducible in the same person from one day to the next, which is
why it is no longer the primary test that we use for
diagnosing diabetes
except in pregnancy

The other thing we have learned about as we can measure levels of
hemoglobin AIc and glycation of proteins is one of the major mechanisms of
tissue injury in people who have diabetes Now the way that this works is
that amine group on proteins can bind glucose and in fact some other
chemicals as well, and initially this is reversible, but eventually becomes
irreversible

With certain types of proteins not with hemoglobin or serum protein like
albumin, it can lead to protein deposition and cross-linking and this is
part of how glucose levels that are high cause the complications of
diabetes Now this process occurs after synthesis of proteins and it is
proportional to the glucose concentration over the lifespan of the
proteins If we look at hemoglobin AIc generally, it increases 1, normal
hemoglobin AIc is between about 4 and 6 have an increase by about 1 for
every 30 mg increase/dL in average glucose concentration

If we have a patient who has hemoglobin AIc of 8 that tells us their
average glucose concentration is about 60 mg/dl above normal or about a
160 If they
have 9, they have an average of about 190 for example So
that is how we could use this

However, it is important to remember there are some other things that could
effect this First of all, if we have a very rapid rise in glucose and it
goes very, very high, it measures the average glucose concentration over
the life of the protein So we are going to attach a lot of glucose on the
protein in a short period of time If we have somebody who comes in with
glucose of 600, hemoglobin AIc is going to be very high even if their
glucose was in good control up until a week ago so not really helpful in
that situation

Secondly, it is important that hemoglobin AIc refers to this compound where
glucose attaches to the end terminal valine of the beta chain of hemoglobin
and this represents about 80 of the total carbohydrate that is attached on
to hemoglobin molecules But what if we have a patient who doesnt have
hemoglobin A? What if we have a patient who has got hemoglobin S/C disease
or some other hemoglobinopathy in a homozygous form? Are they going to
have any hemoglobin AIc? No they wont because they dont have any
hemoglobin A So to
get hemoglobin AIc, we have to have hemoglobin A

It is important to remember if we have a patient, who has a
hemoglobinopathy, they may have reduced or no hemoglobin AIc just because
they dont have hemoglobin A Now other things can also attach on to that
same place, salicylates, urea in people with renal failure, acidaldehyde in
alcoholics So depending on the method that we use that is used in the
laboratory, these compounds might be measured as hemoglobin AIc

So when we get out and start our practice, we want to know how the
laboratory is measuring hemoglobin AIc? Is it using a method that is
specific for hemoglobin AIc? Would it measure glycated hemoglobins as
avert hemoglobin A for example, some methods do that or would it measure
some of these other compounds in which cases we could get false elevations?
So remember those important points about how we need to know what method
the lab is using for measuring hemoglobin AIc

There are other things that could affect hemoglobin AIc as well For
example, we said that integrate theory under the curve of glucose
concentration versus the lifespan of the
protein What if the lifespan of
the protein is altered? When the cells are very small like an iron
deficiency anemia or thalassemia, they last for considerably longer in the
circulation

So even if we have a nondiabetic or a diabetic who is under good control,
if they develop iron deficiency, the hemoglobin AIc will go up
Splenectomy can also do the same thing If the patient has a shortened red
cell lifespan, if they have a hemolytic anemia or they have a bleeding
episode that could give us falsely low hemoglobin AIc So understand other
things that can affect hemoglobin AIc besides just a level of diabetic
control so that is an important thing to be aware of

We now talk a little bit about what diabetes is in the different
classifications of diabetes Now the term diabetes is from the Greek word
diabainein, which means to pass through and so it refers to people who have
a high urine output We have talked about two kinds of diabetes:

1 Diabetes mellitus where the urine is sweet
2 Diabetes insipidus where the urine has no taste to it

This is a good reason We dont do this anymore, but we think about it
that
how its distinction was originally made between diabetes mellitus and
diabetes insipidus, so somebody must have done this somewhere along the
lines

What is the pathogenesis of diabetes mellitus? We are going to use the
shorthand diabetes to refer the diabetes mellitus for the rest of talk So
diabetes is a disorder in which there is deficiency of insulin that causes
hyperglycemia and that deficiency may either be relative or absolute Now
as a result of the deficiency of insulin, there is cellular starvation
Cells do not have the ability to get glucose and in fact people with
diabetes often lose weight because they cant metabolize glucose as an
energy source and other sources of energy are already deficient

So one of the symptoms of diabetes is often weight loss There is often
also an osmotic diuresis, which causes polyuria and that leads to
polydipsia Despite the fact that they have an increased appetite because
their cells are starving, they do lose weight So these are the things
that we often see in people with diabetes

Type 1 Diabetes:

Type 1 diabetes is the lesser common of the two forms So type 1 diabetes
is
an absolute deficiency of insulin that is cause by autoimmune
destruction of the beta cells in the islets of Langerhans Now at the time
of the presentation about 25 of people with type 1 diabetes still have
some insulin production and there may a brief period of time where they
dont need insulin They may still make enough insulin because what often
tips them over to go out of control as if they become sick And what
happens in illness, our cortisol goes up, growth hormones goes up,
epinephrine goes up and these increase glucose production So the amount
of insulin that we have cant handle it

In adults, this honeymoon period will actually last for several years In
children, it is usually only a few months What causes type 1 diabetes?
What leads to this autoimmune destruction? What we know that there are
both T cells mediated and has B cell markers There are specific HLA types
that are specifically associated with type 1 diabetes particularly type D3
and D4 and it is associated with the presence of antibodies to various
islet cell antigens that are generally present for years before the
clinical
appearance of diabetes

In fact in some studies where they look at this in twins, so if one twin
develops diabetes and then they follow the other twin It has been found
that these antibodies can be detected as long as 10 years before the
clinical onset of diabetes

The most common antibodies are against the signaling mechanism in the islet
cells These are antibodies against glutamic acid decarboxylase or against
tyrosine phosphatase, which is also called islet antigen 2 and also against
insulin So many of the proteins that are found in the islet cells are the
targets of this autoantibody destruction

In fact we have met few patients in Japan that had antibodies against
acinar cells, the exocrine pancreas and have not had islet cell antibodies
who has presented with a picture that look likes type 1 diabetes as well

While the autoantibodies are typically present at the time of diagnosis,
they may disappear a number of years later So if we a patient who has had
diabetes for 10 years, we want to know, were they have type 1 or type 2
diabetes and we want to measure autoantibodies and it may not be very
helpful at that point But at the
time of presentation, the autoantibodies
are typically present

The destruction of the islet does not actually come from these
autoantibodies rather there are T cell infiltrates in the islets of
Langerhans that actually destroy the beta cells It is specific for the
beta cells The other cells in the islets are not effected and whole we
can see this insulitis, this inflammation in the islets in the early stages
just like the autoantibodies years after diagnosis, they may disappear

So here is a normal islet of Langerhans, but this was sustained with
special stain It highlights the beta cell, which are primarily around the
outside This is a patient who has recently been diagnosed with type 1
diabetes and actually died and we can see marked inflammation of the islets
and they are all lymphocytes And if we did typing on these, these would
be primarily T lymphocytes This is what we might see years later So we
dont have any other beta cells left This is using special stains against
insulin and immunoperoxidase stains there is no beta cells left and all we
see is often delta cells in the other cells that are present in the
islets
Many years later, we see a much smaller islet normally about 60 of the
cells in the islets are beta cells So the islets are very much smaller,
but we wont see inflammation anymore

Type 2 Diabetes:

Type 2 diabetes is the disorder in which there is a relative insulin
deficiency as well as insulin resistance In fact insulin resistance seems
to be the major initial factor involved in the pathogenesis of type 2
diabetes in most patients However over years, insulin production declines
and in fact in the later stages the patient has had type 2 diabetes for
years, the main problem may be insulin deficiency, not insulin resistance
anymore

This constitutes about 90 of diabetes and currently most cases occur in
people over the age of 40 However, there has been a rising prevalence of
type 2 diabetes in people in their teens in 20s related to this epidemic
obesity and physical inactivity that is going on

People with type 2 diabetes because they typically do produce some insulin
dont develop ketoacidosis, although about 10-20 ultimately end up
requiring insulin to maintain a normal serum glucose level Now we dont
know the
exact defects that are involved in the pathogenesis of type 2
diabetes and in fact that is probably a polygenic disorder

However, we do know that there is a very strong genetic component If we
look at individual who has an identical twin who develops type 1 diabetes,
what we know that there is inherited linkage to the HLA D antigens About
50 of the identical twins will develop type 1 diabetes

If we have an adult, who develops type 2 diabetes and they have an
identical twin, there is a 90 concordance for type 2 diabetes Now this
is not solely related to the fact that they may have similar body habitus
because if we look at twins, they were reared separately by different
parents and they might have different body habitus, the same thing happens
So it is not purely environmental, it is not purely genetic, but there is
a major genetic component

We also know that obesity is a major factor In fact obesity causes
insulin resistance and in a very recently publish study in the General
American Medical Associate about a month ago It will show that an
individual who had impaired glucose tolerance that by having them in
the
age and very moderate weight loss and exercise and exercise was about 15
minutes three times a week They could improve them from having impaired
glucose tolerance to having normal glucose tolerance and in fact prevent
the development of diabetes over a relatively short 2-3 follow-up period
when compared to those individuals that didnt have that intervention done

So clearly obesity is a major factor in the pathogenesis of type 2 diabetes
in most individuals Weight loss and engaging in exercise both which tend
to improve insulin responsiveness and decrease when resistance as it is
very important in the management of an individual with type 2 diabetes

What is happening morphologically in type 2 diabetes? In the early stages,
the islets are normal, but overtime the islets become gradually destroyed
by two different processes First of all, we tend to see an increase in
fibrous tissue within the islets and we are sure what actually the
pathogenesis of that is, but we also see the deposits of amyloid

Amyloid just refers to the way that it stands, it doesnt tell us what the
protein is In this case, the protein is amylin, which is
called amylin
because it was derived from and it was found in the amyloid Amylin is a
normal product of the islet cells, which seems to be involved in insulin
responsiveness in peripheral tissues

This fibrosis and amyloid deposition induce atrophy of the islets that
often leads to decreased beta cell masses So in the late stages, people
with type 2 diabetes may functionally behave like type 1 diabetics that if
they have inadequate insulin production This shows that we an opportunity
to see this in laboratory today at different stages in different islet, but
this is kind of the endstage where we have the amyloid deposition which is
markedly enlarging the islets, but replacing the normal islet cells

Gestational Diabetes:

Gestational diabetes refers to hyperglycemia that develops during pregnancy
and the excess glucose delivery causes enlargement of the baby It causes
what we call macrosomia and it also increases the risks of premature
delivery, perinatal death, birth defects and as we might except from the
islets in the baby undergoing hyperplasia and neonatal hypoglycemia

It has been clearly shown that the risks of these
complications can be
lowered by improving glucose control There is clearly an increased
association with birth defects whether it causes birth defects or not is
another question, but there is clear data showing that there is an
increased prevalence of birth defects in infants of mothers who have
gestational diabetes Whether that reflects another factor is not known
for example, it is thought that one of the factors that may have a role in
the pathogenesis of glucose intolerance in pregnancy is high level of human
chorionic somatomammotropin HCS which is the product of the placenta
That tends to be higher in women who have glucose intolerance Now it also
is higher in genetically abnormal infants

So perhaps it is the association with birth defects rather than it causes
birth defects, but it is hard to really tell for sure, but there is a clear
association of gestational diabetes with birth defects whether it is
causative association result is not clear

Other things can also cause diabetes Hyperglycemia can be caused by
endocrine diseases for example Cushings syndrome, hyperthyroidism,
acromegaly or
pheochromocytoma not surprisingly increases the levels of
these hormones They increased glucose production can trigger diabetes
If we can treat the underlying disease process, we may be able to put the
diabetes into remission

Diabetes may also be caused by pancreatic injury for example following
surgical removal of the pancreas or recurrent episodes of pancreatitis or
with the drug pentamidine, which we use very commonly for treating
pneumocystic pneumonia With endocrine diseases if that is the cause
treatment of the endocrine disease may get rid of the diabetes

Diagnosis:

The criteria for diagnosing diabetes that we use in this country are those
established by the American Diabetes Association and initially published in
1997 There are that we have to have two or more of these findings Now
it could be the same finding on two or more occasions and the important
thing to remember is that it should be when the patient is in the usual
state of health Why they are in there usual state of health? Because with
illness we see increased levels of cortisol, growth hormone and
catecholamine which can increase glucose
levels

The three criteria are:
1 Random glucose over 200 in a patient who has signs or symptoms of
diabetes
2 Fasting glucose over 126 mg/dl
3 An abnormal glucose tolerance test and by we made a glucose level more
than 200 mg/dl two hours after glucose congestion

They dont recommend the use of hemoglobin AIc for diagnosis Now that is
only because of some of the problems that we told about the different
things interfering it really depends what method the lab uses and that the
results are not very well standardized for one lab to the next But in
fact if we have a patient who has elevated hemoglobin AIc unless they have
iron deficiency or thalassemia, they probably are diabetic

Why do we worry about diabetes? It is mainly because of its complications
and we could have two major kinds of complications:

1 Direct Metabolic Complications Of Diabetes:

These are such as ketoacidosis, hyperosmotic coma and tissue damage

Tissue Damage:

Tissue damage in diabetes is caused by four major mechanism:

a Protein glycation
b Polyol sorbitol accumulation
c Hyperlipidemia which commonly accompanies diabetes
d Altered white cell
function, which is induced by the high glucose
level

Ketoacidosis:

Ketoacidosis is associated with state of severe insulin deficiency which
leads to prevention of utilization of glucose by cells and use of fatty
acids for an energy source Now the ketone bodies, which are derivatives
of fatty acid metabolism, cause the marked acidosis that often seen in
these people can trigger abdominal pain and tend to present fairly quickly
So ketoacidosis often dont have a really high glucose If normal glucose
is up to 126 fasting, their glucose is may be 300 or 400 typically in
ketoacidosis, because they feel really bad and they get really sick with
ketoacidosis

Our body doesnt tolerate acidosis very well The two major things that
tend to trigger ketoacidosis are if the patient develops infection So
they are taking the same amount of insulin, but they have more glucose
production by the tissues in response toward stress hormones or they stop
taking their insulin and therefore they dont have enough insulin So
either way it is a severe insulin deficiency

Hyperosmotic Coma:

Hyperosmotic coma is associated with moderate
insulin deficiency and
moderate insulin deficiency is enough to prevent ketoacidosis, but not to
keep normal serum glucose and the increase glucose levels cause water loss
through osmotic diuresis and this tends to lead to cellular dehydration
In severe cases, dehydration of brain may cause coma

People with hyperosmolar comas may have much higher glucose The highest
one we have ever seen in a patient with hyperosmolar coma was 2100 mg/dl
So it can get really high in people who have hyperosmolar coma In
general, if we look at glucose levels in people with hyperosmolar coma,
they are significantly higher than what we would see in people with
ketoacidosis

Protein Glycation:

There are three major ways that protein glycation can cause problems

First of all protein glycation in certain tissue proteins may cause cross
linkage in the proteins and cross linkage in the proteins may prevent
normal turnover of that protein and so the protein can accumulate This is
thought to be one of the mechanisms by which this occurs

Secondly in the basal membrane of the blood vessels, glycation may alter
the charge on the protein and may cause
the blood vessels to become leaky
We remember one of the earliest manifestations of diabetic nephropathy is
microalbuminuria, finding protein showing up in the urine indicating lack
of normal basal membrane function Then finally circulating glycated
proteins may directly deposit in tissues particularly in places where the
endothelium is fenestrated like in the kidney and may be responsible for
the damage And in fact in an animal model if we take serum from
individuals who are diabetics and have high glucose levels and we infuse
that into dogs, we can produce glomerular injuries similar to what we see
in diabetes

So probably all three of these mechanisms are important in the pathogenesis
of many of the diabetic complications A protein glycation can also alter
the function of proteins For example low-density lipoprotein can be
glycated and when glucose is attached to low-density lipoprotein there is
increased uptake of LDL by the scavenger pathway, which is what macrophages
use cholesterol into the blood vessel walls So it is a very important
part of the pathogenesis is increased atherosclerosis that occurs
in
diabetics and of course we can improve that by lowering glucose levels

The other mechanism that may be involved in injury and specific tissues and
what we call the polyol sorbitol pathway Some cells in the body are
capable of taking up glucose in the absence of insulin Red cells for
example, which is why we can use hemoglobin A1C and the Schwann cells,
which are myelin producing cells in the peripheral nervous system Now the
enzyme aldose reductase, which is present in these cells, is capable of
converting glucose to sorbitol Sorbitol accumulation lowers levels of
myoinositol, which are needed for cellular energy generation and for
coupling the sodium potassium ATPase pump So as a result in cells where
there is accumulation of the sorbitol and depletion of myoinositol will
have impaired pumping of sodium out of the cells and as a result those
cells will swell This is thought to be important in the pathogenesis of
diabetic neuropathy and also in the development of cataracts in diabetic
individuals

How to Prevent Diabetic Complications:

That is very important to note that it has been conclusively proven
that
lowering glucose levels in improving diabetic control can reduce the
incidence of the eye and renal injuries It is not so clear that lowering
glucose levels and improving diabetic control can reduce the incidence of
the eye and renal injuries It is not so clear that lowering glucose
levels is effective in presenting some of the other complications of
diabetes and in fact the diabetes control in complication problems in this
country was only working at type 1 diabetics So it may be that insulin
resistance is also important in some of the other complications of diabetes
and it may be that we need to do other things And obviously we can look
at the early detection of damage such as finding microalbuminuria and if we
can improve glucose control at that point, we can prevent progression to
overt nephropathy so important point in preventing diabetic complications
is normalizing glucose

Systemic Diabetic Complications:

Systemic diabetic complications are where most of the problems ultimately
are common in diabetics and one of the major complications is accelerated
atherosclerosis And we find that people who have
diabetes they have
higher levels of lipoproteins particularly the LDL, but also to some extent
LDL to have glycated LDL, which increases up take by the tissues, by the
scavenger pathway And diabetic is also to be of higher levels of
lipoprotein-A which also increases uptake by the scavenger pathway As a
result diabetics have remarkably increased risk of myocardial infarction
and stroke and in generally develop these complications about 10 years
earlier than the general population Moreover in women who have diabetes,
they have the same pattern of atherosclerotic complications as men do So
they loose the protective effect from estrogen underneath that, they
developed these complications 20 years earlier the women who are not
diabetic So part of our target for treatment is to make sure that we try
to normalize levels of lipoproteins which we use usually in the medications
and we are usually using the same target value for LDL that is in the 100
mg/dl that we do for people who have known coronary artery disease, because
they are such at high risk of atherosclerosis Now in addition to having
problems in their big blood
vessels, diabetes also causes microvascular
disease We have already learned this back in the renal block where we saw
that hyalin arteriolar sclerosis that narrowing of the medium size to small
size blood vessels So that occurs not only in the kidney, but also
throughout the body We also have glycation of the basement membrane and
we also have loss of pericytes and these things together tend to cause
leakage in the blood vessels They tend to cause particularly in the
retina proliferation of new blood vessels And so we can see these small
vessel changes directly in the retina just like we saw that hyalin
arteriolosclerosis in the kidney, but these changes are happening
throughout the body So diabetics have problems with delivery of blood to
the tissues both at the macrovascular level and the big arteries from
atherosclerosis and in the smaller blood vessels due to the basement
membrane injury that occurs and due to the hyalin arteriolosclerosis that
is involving the small to medium size arteries Now this shows what is
happening at the level of an individual capillary

Here is a normal capillary and
in addition to the endothelial cells, there
are also these pericytes, which seem to be important for maintaining the
normal function of the blood vessel Here is the endothelial cell and here
is the pericyte and we can see that it produces a membrane that surrounds
the capillary Here is all we see in people who have diabetes and you look
that there are no pericytes left anymore This capillary is making a
little bud right over here We talk about eye damage a little bit This
is very important in the pathogenesis of eye damage

Now the combination of the big vessel disease and the small vessel disease
tends to be the most severely evident in the legs and in fact leg ischemia
is a very significant problem in people who have diabetes They develop
both of these and they also developed neuropathy Now when we buy a pair
of shoes How do we know that they are not fitting quite right? They
hurt People with diabetes often develop neuropathy and attempts to be
most severe peripherally and it tends to most characteristically affect the
sensory nerves So if we have diabetics who have neuropathy in their feet,
how did they tell that their
shoes are not fitting correctly? They cannot
and they can big blisters Now what happens, we can have infection
developing if that blister ruptures We have impaired white cell function
if the glucose is high, the white cells do not get there and we have
impaired tissue perfusion, because of the small vessel and large vessel
disease that occurs So as a result even minor injury to the feet can lead
to major problems and gangrene of the extremities occurs predominantly in
the individuals who have diabetes with these complications And in this
country over 90 of nontraumatic amputations, ie not caused by car
accidents or getting run over by something, are related to diabetes So
diabetes is the major cause of limb loss in this country This is what
happens because they do not have any tissue perfusions to speak of, they
have impaired perfusion, they have impaired white cell functions
Infections can spread very readily and once that reaches this stage, we
really do not have much choice, but to do an amputation so obviously it is
very problematic in diabetics

Diabetic Nephropathy:

We have already talked a lot
about diabetic nephropathy It is a common
cause for renal failure probably the number 2 or number 1 cause of renal
failure in this country along with hypertension And so what are the
mechanisms for production of renal failure in diabetes? The macrovascular
disease is involved these people have ischemic injury and the microvascular
disease as well is important They developed specific glomerular injures
They have impaired white cell functions so there is increased risk for
infection and rarely we can see renal papillary necrosis occurring as a
result of these complications

The earliest change that we see is damage to the basement membrane that
causes leakage In the earlier stages we see proteinuria and we see
hyperfiltration, the GFR actually goes up This hyperfiltration tends to
set off and an irreversible cascade where the glomeruli become damaged,
which puts more pressure on the remaining glomeruli, which causes further
hyperfiltration and we just continue to get this cycle That is why it is
so important to catch it early on before the hyperfiltration really sets
in

In addition, we also see accumulation of
protein within the mesangium,
which can cause a very diffuse glomerulosclerosis and if we just look at
this at a light microscopic level, it can look very similar to focal
sclerosis Then finally we can see nodular intercapillary
glomerulosclerosis We see nodular deposits in the mesangium and we call
this Kimmelstiel-Wilson disease
Papillary Necrosis:

This can occur in diabetics Here is kind of more diffuse
glomerulosclerosis generally affecting the glomerulus And here we see the
nodular intercapillary glomerulosclerosis and this time it is also the
hyalin arteriolosclerosis So it is the combination of these things that
tend to cause the development of diabetic nephropathy

Retinal Damage:

Retinal damage is one of the most common causes of the blindness in this
country and retinal damage to the diabetes is a most common cause of
retinal blindness Now retinal injury in diabetics usually follows
glomerular injury So if we have an individual who has proteinuria, we
need to check them and refer them to an ophthalmologist for retinal imaging
studies to see if they have evidence of retinal
damage Then the early
stages that damage to the small blood vessels causes protein leakage and
this often causes symptoms of blurred vision But as this damage occurs,
new blood vessels start to spring off from there and we get little aneurism
formation

Now when bleeding occurs in the region of the retina, it bleeds in to the
area between the retina and the vitreous and when that forms a clot and
that clot retracts We can pull the retina away from the nerve layers and
so gradually that this process effects a lot the eye, we can see how the
individual could loose visual activity And here is what we would see;
this is the early stage to see all these yellow spots on the retina They
represent areas of leakage of protein

Now the more severe damage is when we get these little microaneurysms
That is when they tend to run into problem So if we catch these early, we
can use photocoagulation therapy to burn them to sclerose them up and
prevent them from bleeding and prevent the complications that they develop
from this This is what can happen at the end stage we normally remove the
eyes in autopsy, but this patient have given
permission to have their eyes
removed for study, because they developed blindness due to diabetic
retinopathy We can see the retina is just totally pulled the way from the
nerve layers This is the retina right here and it should not be like this
and it should be applied to the inner surface of the eye So it should not
be doing that

Now the other problem that can occur in the eye is cataract formation and
that seems to again be directly related to glucose levels

Diabetic Neuropathy:

Finally, neuropathy is very common in people who have had diabetes from
many years We think the mechanism for this is the polyol sorbitol pathway
we talked about before What happens as a result of this and due to the
damage to the Schwann cells is that there is decreased myelin in nerve
fibers and this can affect both motor and sensory nerves In terms of
motor nerves, it often affects the internal motor nerves So for example
it often affects bowel and may cause problems with ileus from poor movement
of food through the intestinal tract It can affect the bladder and cause
neurogenic bladder, diabetic neuropathy is thought to be a very major cause
of
erectile dysfunction

It can also cause sensory neuropathy so the sensory neuropathy is very
important in the legs particularly in predisposing to development of
gangrene So one of the things we always want to do in your diabetic
patients is to check them for evidence of neuropathy There is a little
test It is called the filament test and we have a very thin filament
fiber and you use that to touch the patients foot and see if they become
sensory to touch and this is a very sensitive way to pick up the neuropathy
that can affect these diabetic patients

SLIDE REVIEW

Latham

We have a few slides for this afternoon and they are these three

Slide 1:

The first one is an example of the amyloid deposition in a patient with
type 2 diabetes and we can see the islets are standing up very clearly
because of the deposition of the amyloid in these slides Then there is a
hyalin material so it is a flat pink coloration now very distinctive of
amyloid in order to detect that it was truly amyloid we need to do some
special stain But we can easily see
that it has displaced and replaced
the islet cells themselves in this case So many of these islets are
totally destroyed

Slide 2:

This is simply an example of the hypertrophy and hyperplasia that we might
expect to see in a baby that is born of a diabetic mother and that is the
example in the slide today So this one is fairly quick The islets are
increased in both number and in the number of cells within each islet so we
see particularly in contrast to the field we showed before at the higher
power, which had a couple of islets and that there are at least three very
well seen ones and another one that is a little more vague in this field
alone When we look at higher power the islet cells themselves are more or
less normal, but do have some changes at the cellular level They appear
larger and polymorphic and some of the nuclei in the cells themselves may
show what is referred to as cytomegaly or simply looking like a very big
change, just an enlarged nucleus and enlarged cells The cells are
increased both in number within the islets as well in the increase in the
number of the islets We may also see, although it is
difficult to
appreciate here an increase in inflammatory cells occasionally in these
islets and we may see some eosinophils This photograph as a lot of pink
and red color in it so they are little more difficult to pick up

Slide 3:

The last example is the major manifestation of diabetes and the picture
under the microscope is very distinctive and we remember this could be a
cause of nephrotic syndrome And so there is a leakage of protein and here
we see the reason why in a more dramatic way where we have got the
accumulation of mesangial matrix, the protein that is exuded from the
capillaries accumulates in the mesangial matrix and basically squashes the
little capillaries in between so that we get the nodule like appearance
This is a very distinctive nodular eosinophilic deposit in the glomerular
tuft It is very characteristic of Kimmelstiel-Wilson disease, which is
the characteristic renal manifestation at the glomerular level of diabetes

Of course the other feature that we will see is vascular disease This is
a close up showing us again these glomerular tuft filled in the mesangium
with protein matrix, but the other
features that we see in conjunction with
hypertension as we have gone through this year and many of the autopsy
cases we have, we have noticed that the majority of the autopsy cases we
have seen have granular scarring and pitting to the capsular surface of the
kidneys And of course that is related to small and larger vessel disease
and little granules representing arteriolar involvement And the deeper
pits representing that the scarring is associated with medium sized artery
involvement and that is a sign of vascular disease in the majority of
cases In the majority of cases it is hypertensive related and also found
in ultimately by atherosclerosis but diabetes is a major cause of the
vascular disease in this country and of course contributory to
atherosclerosis

The scarring under the microscope, if we look at the capsular surface of
the kidneys, we will be able to appreciate the scarring under the
microscope As we look at our slide and at the capsular surface we will
see that the little areas of scarring are actually tiny infarcts and we can
still make out a slit like, or wedge like shape right
underneath the
capsule as that artery has been affected and that area has become
sclerotic The glomeruli are going to become sclerotic too as they are
involves and we will see an increase in interstitial fibrosis, and we may
see some chronic inflammatory cells very typical of an area of old infarct
As we look around the glomeruli, we see again the nodular accumulation,
but we will also notice that the arteries that are feeding this glomerulus
called the afferent and efferent arterioles are involved with
arteriosclerosis, because of the damage to the basement membrane and the
deposition of glycated proteins as well perhaps is the mechanism of
sorbitol

In the average case of hypertension, where we have an effect on the small
arterioles as we might imagine the hypertension is going to effect the
afferent arteriole that is coming into the glomeruli, but the mechanism of
the effect upon the arterioles in diabetes is more uniformed and
consequently both the afferent and efferent arterioles are going to be
involved Therefore, if we find the glomerulus where we can see both small
arterioles, we will
find them either right at the edge of the glomerulus
itself or as we see here just outside of it depending on the cut of
dissection

In the case of hypertension for the most part, we will see that there is
just one of those arteries involved But in the case of diabetes, we will
see that they both are involved and that is very characteristic If both
the afferent and the efferent arterioles both small arteries feeding the
glomerulus show arterial sclerotic change that is a virtually pathognomonic
of diabetes So it is a feature that we want to look for and we see it on
our slides where we see the arteriosclerotic change in the small arteries
and the second hyalin deposit in the wall of these small vessels, two of
them adjacent in the glomerulus

Source:gwu.edu