Diabetes Treatments

That is probably ten folds more than the numbers with Type-I diabetes. So the overwhelming majority of patients that we encounter are patients with Type-II diabetes. …

TYPE II DIABETES

Cohen

Type-II diabetes is far more common than is Type-I diabetes Current
figures are that there are about sixteen or eighteen million people in the
United States with Type-II diabetes That is probably ten folds more than
the numbers with Type-I diabetes So the overwhelming majority of patients
that we encounter are patients with Type-II diabetes

We are in what could fairly be described as an epidemic of Type-II
diabetes In addition to the cases that are diagnosed, there are estimated
to be millions of additional individuals who remain undiagnosed This is a
very important issue, because when these patients do ultimately present, we
can reasonably suspect that they have had diabetes for many years, and are
presenting with complications of diabetes rather than presenting with the
sequelae of acute hypoglycemia or as a result of screening

One of the most important epidemiologic factors that underlies this
epidemic of diabetes has been the increase in obesity in the United States,
and again in much of westernized cultures The BMI body
mass index is a
standard measure in dealing with weight BMI is calculated as a patients
weight divided by their height square The units should be in kilograms
and meters, so that a patients BMI is their weight in kilograms divided by
their height in meters square

From a perspective of health concerns, the general recommendation is for
the BMI to be between 22-26 It is probably considered to be the ideal
range of BMI BMI above 26-30 are classified as being overweight BMI of
above 30 are classified as being obese We are in an era of tremendous
amount of overweight and obesity in this country, and diabetes is actually
only one of the ways that this is manifesting itself clinically There are
several epidemiologic studies and more basic studies as well, which has
pointed to the linkage between obesity and the risk of development of
diabetes This is data that comes from the nurses health study, a long-
standing periodic health survey of nurses For BMI above 26 or so, there
is a progressive increase in risk of developing diabetes

Diabetes is not hitting all our various ethnic groups equally There are
groups that are considerably
more at risk than others Among the highest
risk groups are Native American populations The American Pima Indians
have been studied extensively as a kind of a model The risk for the
American Pima Indians living in Southwest United States of developing
diabetes is approaching 80 or so The risk of diabetes has increased in
other ethnic subcultures as well, very importantly including Latino
American groups and African American groups There is also an increased
risk of diabetes in pacific islanders and in some Asian populations

The prevalence of diabetes in China is quite low, but the expectation is
that there are going to be under going their own diabetes epidemic over the
coming years as well

One of the ideas that underlies the questions in terms of different ethnic
group risks of the development of diabetes has been proposed as the so
called threat to gene hypothesis The idea is that populations that
initially populated North America and Europe, may have had metabolic
systems that were optimized for fuel efficiency, that in a hunter gatherer
society, evolutionary pressure would have selected for individuals
who were
very efficient at fuel storage during times of famine Now in our modern
culture of more plentiful food and less exercise As was mentioned, one of
the examples of this relates to the Pima Indians, there are actually two
populations of Pima Indians in North America who are genetically identical,
but live under different circumstances There is a group of Pima Indians
that have settled in Southwest Arizona and lead extremely sedentary lives
They live on a reservation, with all the problems associated with that,
have high fat diet In this population about over 50 of the men and 40
of the women are diabetic

There is another population of Pima Indians that has settled near Mexico
City, we can see compared to the United States Pima Indians, the Mexican
Pima Indians are thinner Their body mass index is considerably lower and
we can also see that their risk of diabetes is considerably lower When we
look further in terms of differences in their diet and activities, the
American Pima Indians about 40 of their diet is from carbohydrate and as
much as 40 or more is fat In comparison, the Mexican Pima Indians, a
greater percentage
is carbohydrate and a considerably lower percentage as
fat The other cultural difference is in terms of their energy
expenditure The Pima Indians living on the reservations are basically
very sedentary In comparison, the ones living in Mexico have to work
quite hard This is just an example of how with virtually identical
genetic background, the kind of environmental pressures that we currently
live in, are manifesting themselves as far as increased risk of obesity and
diabetes

Diagnosis of Type-II diabetes:

The official criterion for diabetes, which was revised, was fasting blood
glucose of 126 or greater We would like to see that replicated on more
than one occasion We want to be sure that the patient does not have some
significant intercurrent illness at the time that the measurement was done
But if some body routinely has a blood glucose of 126 or greater, that is
diabetes

The other criterion that could be used is that the blood glucose measured
two hours after a 75 gram glucose load of 200 mg/dl or greater So in
certain circumstances a patient might come in, may be their blood sugar is
not reaching this
126 threshold, but for various reasons, they are still
concerned that they might have Type-II diabetes, so we might do a glucose
tolerance test On the other hand, a patient comes in with fasting blood
glucose of 168, we dont need to do a glucose tolerance test to confirm
that that person has diabetes They are making it on the basis of their
fasting blood glucose alone

A random blood sugar is not necessarily diagnostic of diabetes in an
individual So some body might come in shortly after a high carbohydrate
lunch, and we might check their blood sugar in the office and find it to be
220 or in that range That does not necessarily diagnose diabetes,
although one has to be suspicious of it On the other hand, that same
person comes in and says I have really been thirsty, I have been losing
weight, my vision has been blurred for the last month We measure the
blood glucose and find it to be 290 or something rather like that That
person has diabetes We dont need to tell that person to come back the
next day far a fasting blood glucose check, or a glucose tolerance test
There are two points here, the first is that
there are specific criteria to
enable us to categorize somebody as having diabetes or not We should know
those criteria and we should use them

There was a study done among a group of patients in Virginia, the patients
were asked if they had diabetes or not They fell into three groups, there
were patients who said they did not have diabetes There were patients who
said, yes their doctor told them they had diabetes There were patients
whose response went along the lines of saying something like, my doctor
told me that I have a touch of sugar, but I dont really have diabetes
They then looked at various parameters of metabolic control, hemoglobin
A1C, lipids, all sorts of different things The patients who had been told
and self classified themselves as having a little bit of sugar were in poor
glycemic control than the folks who had been told and classified that they
have diabetes These criteria are out there and we should use them

Why these numbers? Why 126, why not 140? Or why not 110? There is a lot
of debate about that, but at a certain level, the reason for these
particular numbers relates to the fact that in epidemiologic
studies, the
risk of developing the characteristic microvascular complications of
diabetes, the retinopathy and the nephropathy increases for levels that are
above these criteria So in fact the diagnosis is defined on the bases of
the risk of the characteristic microvascular complications So this is
just sort of a comparison of the different diagnostic criteria, based on
fasting blood glucose 126, based on a two-hour postprandial blood glucose
200 What are normal levels? A normal fasting blood glucose is considered
to be up to about 110, some people might argue even that is a little high
and a normal two-hour postprandial blood glucose up to 140

There are intermediate levels here of individuals who might have a fasting
glucose between 110-126, or individuals whose postprandial blood glucose is
above 140, but less than 200 The individual with this sort of
intermediate level of fasting blood glucose is now being called IFG
impaired fasting glucose Those with an intermediate postprandial level
are being referred to as IGT or impaired glucose tolerance
Major risk factors for Type-II diabetes:

Family history, obesity,
sedentary life style, ethnic background,
previously identified IGT or IFT ie pervious mild abnormalities, history of
gestational diabetes, or a history of polycystic ovary syndrome Certain
specific dyslipidemia, particularly in folks with high triglyceride levels,
decreased HTL levels and hypertension These last three categories, poly
cystic ovary syndrome, dyslipidemia and hypertension, all are things that
are suggestive of an underlying state of insulin resistance Insulin
resistance is, as we will see not enough to produce diabetes alone in most
individuals, again it is certainly an important part of the pathogenesis

Gestational diabetes:

This develops in 2-13 of screened populations, depending upon their
ethnicity, their weight and other factors These are women who have no
history of diabetes prior to pregnancy, who develop alterations during
pregnancy and most typically during the third trimester of pregnancy All
women undergo some metabolic changes during pregnancy, and in particular
during the later stages of pregnancy, there is a tendency among women for
insulin resistance, probably related to increased
production of placental
hormones For most women these are not clinical things For woman with
gestational diabetes, there are some specific neonatal complications that
can develop This can include macrosomia, a large size baby What happens
here is that the mothers sugar is elevated during this last trimester, as
a result of that the baby develops hyperinsulinism, in order to help
dispose off the increased sugar that is being presented to the baby across
the placenta The increased levels of insulin have anabolic effects, they
increase fat storage in the baby Whenever we end up with a large baby, we
end up with risks of trauma at the time of delivery

Few other metabolic complications associate with gestational diabetes,
hypoglycemia, probably related to the neonatal hyperinsulinism One thing
that is not on this list in terms of gestational diabetes is fetal
malformations The reason for that is that fetal malformations are not a
common feature in gestational diabetes For the most part gestational
diabetes will develop during the third trimester of pregnancy, and major
organogenesis is complete by that time During the
first trimester when
the major organs are forming, the blood sugar levels in woman who is
ultimately going to develop gestational diabetes is still likely to be
normal So we do not typically see fetal miscarriage or malformation
related to gestational diabetes The problems that we see are later on

A woman with gestational diabetes is going to be asymptomatic, she is not
going to present with a blood sugar level that is so high as to be causing
those symptoms of hyperglycemia So gestational diabetes is diagnosed as a
result of screening and diagnostic tests There are specific diagnostic
criteria for gestational diabetes, in terms of the blood sugar response to
a glucose load They actually are different than the criteria in the non-
pregnant woman Not long it was recommended that all women be screened for
gestational diabetes as a matter of routine Now the recommendation is
that women who fit into a very low risk group, which basically means women
who are below twenty five or thirty, who have none of the risk factors for
diabetes that we mentioned, that those women do not need to be screened for
gestational diabetes, but
otherwise women should

Treatment of gestational diabetes:

Often times we can treat it by dietary attention and perhaps encouragement
to exercise We generally do not use oral agents in the treatment of
diabetes in women who are pregnant So a woman with gestational diabetes
if her blood sugar control is not adequate on diet alone, we are probably
going to recommend treating her with insulin She will not need to take
that insulin after she delivers Most women who even with a history of
gestational diabetes will revert to normal glucose tolerance after
delivery Although as indicated gestational diabetes probably is a marker
that this is a woman who has other things going on that are putting her at
risk of further development of diabetes

Impaired glucose tolerance and impaired fasting glucose these days are
referred to as so called pre-diabetes The importance is that there have
been research studies that have been published with in the last year, which
have suggested that intervention among individuals at this level of pre-
diabetes can be very effective in reducing the risk that these individuals
will go on to develop frank
Type-II diabetes

There was a study called the diabetes prevention program, the DPP, and the
finding in that study was that individuals who fell into this prediabetes
group, if they were encouraged to lose weight, and started on an exercise
program, they dropped their risk of developing diabetes by about 50 or so,
over the time period of the study, which was about three or four years
There was also a medication treatment group that also showed a benefit
The treatment group that was encouraged to exercise and lose weight
actually did better as far as reducing their risk of diabetes, than the
group treated with medication

Classifying individuals with impaired glucose tolerance or impaired fasting
glucose is largely of academic interest, there is going to be more
attention paid to identifying these folks and trying to intervene to
prevent them from developing Type-II diabetes

Clinical presentations of Type-II diabetes:

Asymptomatic screening, and there are recommendations that individuals
should be screened for diabetes by measurement of their fasting blood
sugar, starting in roughly their forties, perhaps at an
earlier age if they
have some of these risk factors present There can be yeast infections,
urinary tract infections etc

Patients with type-II diabetes can present with complications Prevalence
of complications at the time of diagnosis of diabetes in this study, which
comes out of the United Kingdom, 50 of the patients had manifestations of
some complications of diabetes at the time that they were diagnosed The
figure of 21 presenting with retinopathy is a very interesting figure,
because in folks with type-I diabetes, in whom we are fairly confidently
able to define when they actually develop diabetes, it typically takes on
the order of ten years or more, before patients with Type-I diabetes will
show evidence of retinopathy In this study 20 of the individuals had
retinopathy at the time that they presented So clearly these are folks
who are out there and either they are not being screened or even with
testing they are not being recognized and appropriately classified and
treated

For the most part, we can distinguish Type-II from Type-I diabetes on the
basis of the clinical features regarding age, body habitus, risk
factors
all those sorts of things Those remain the most important criteria for
typically distinguishing patients A few other things can be used in the
patients with Type-II diabetes, this is not an autoimmune disorder, so
these patients will not have the antibodies, the evidence of autoimmunity
that is seen in patients with Type-I diabetes Indeed there are a certain
number of patients, who are classified as type-II diabetes largely on the
basis of the age at which they present, who upon antibody testing are found
to have antibodies Indeed, these individuals have been mis-classified,
these represent a variant form of Type-I diabetes that sometimes is
referred to as latent autoimmune diabetes of adults The point being that
there are a group of individuals who present with a subclinical
presentation, who are thought to have type-II, but actually have Type-I
diabetes, based on the presence of autoimmune markers

The other potential distinguishing thing that one could look at is insulin
production Insulin production in individuals with Type-I diabetes is
severely impaired As far as DKA is concerned, by no means do all
patients
with Type-I diabetes necessarily present with DKA Now a days it is
probably the exception Diabetes develops over time, even folks with type-
I diabetes, will typically go through a period of what might be weeks or
even months in which they have symptoms of hyperglycemia without having
frank diabetic ketoacidosis Perhaps their very last bit of pancreatic
beta cells are still producing enough insulin to prevent them from
producing ketones In certain circumstances we can measure indices of
endogenous insulin to distinguish Type-II from Type-I diabetes C-peptide
is the intervening sequence in proinsulin that gets cleaved out during the
conversion on proinsulin to insulin So C-peptide is an endogenous marker
of insulin production It has a longer half-life than insulin it self, it
is also not confounded in individuals who are taking exogenous insulin So
we can use measures of either the basal C-peptide levels or maximal
stimulated C-peptide level as a measure of insulin production Somebody
with type-II diabetes would be expected to have at least some insulin
production, perhaps a lot even Patients
with Type-I have nearly none
Pathogenesis and natural history:

Insulin resistance means the situation in which there are impaired cellular
responses to the physiologic effects of insulin, for example decreased
glucose uptake in muscle in response to insulin As we can see, greater
than 90 of patients with Type-II diabetes have insulin resistance

Insulin resistance alone is probably not enough to cause somebody to
develop diabetes There are many situations in which patients can be
profoundly insulin resistant, but the initial compensatory response by the
pancreas is to secrete more insulin, although the patient is insulin
resistant, the feedback regulates blood glucose and keeps it still
affectively intact So it is likely that even in the setting of severe
insulin resistance alone, if the pancreas is able to respond, the patient
will not be frankly diabetic Is there something wrong with that patient?
The answer is yes That patient we could then classify as being insulin
resistant and hyperinsulinemic Even in the absence of diabetes in these
patients, it is felt that that combination of insulin resistance
and
hyperinsulinemia is a significant risk factor for atherosclerosis etc

Again showing the compensation concept that in a group of non-diabetic
individuals, as ones insulin sensitivity declines or one is becoming more
and more insulin resistant, then the insulin levels are rising in response
to that There are a number of different ways in which we can measure
insulin resistance, but unfortunately one of the problems we have now a
days is we are approaching a situation in which we are very interested
clinically in insulin resistance and yet in terms of a clinical test that
we could do on patients coming into the office, we really dont have any
good direct measures of insulin resistance So often times when we talk
about insulin resistance, the measurements are done in research studies and
model systems The point here being that using one such measure of insulin
resistance, we saw a progressive loss of insulin sensitivity from normal
individuals to individuals with impaired glucose tolerance, to individuals
with frank Type-II diabetes

Another kind of manifestation of the effects of the compensation is if we
look first at the
individual who is a normal thin individual, and a normal
individual, nondiabetic who is markedly obese and who has become insulin
resistant as a result of that obesity We can see how much higher both the
basal and the stimulated insulin levels are in the normal individual If
we look at the diabetic obese individual, that individual actually is also
hyperinsulinemic, certainly compared to the normal thin individual On the
other hand, when we compare that obese individual to the obese individual
who has managed not yet to develop diabetes, we can see that particularly
in the early time period that the individual who has diabetes has a
relative insulin deficiency So in the context of insulin resistance, our
scales in terms of what are the appropriate levels of insulin, and not are
in effect changing

Hypertension can be associated with insulin resistance, possibly because
hyperinsulinism has effects on the vascular system that will alter blood
pressure control As mentioned that there was a specific dyslipidemia
associated with insulin resistance, with high triglyceride levels and low
HDL

Why polycystic ovary syndrome has also
insulin resistance? Thoughts are
that one of the major factors deriving increased ovarian androgen
production in women with PCOS is hyperinsulinism Ovarian androgen
production is in part insulin dependent, so in the setting of an individual
who has developed insulin resistance, they become hyperinsulinemic, the
high levels of insulin act on the ovaries to stimulate androgen production
Indeed in certain specific circumstances we are now using insulin-
sensitizing agents, drugs that enhance the body sensitivity to insulin to
treat poly cystic ovary syndrome In certain situations it has been very
helpful as an adjunctive therapy for fertility in women with PCOS

Acanthosis Nigricans:

Is a finding of a hyperpigmented area that has a velvety sense to it, it
tends to be a little bit raised and it occurs most typically in
intertriginous areas, in skin folds of the neck or sometimes the axilla
Acanthosis nigricans is a marker of hyperinsulinism and particularly
mediated through non-insulin receptor pathways This is a physical finding
that is commonly seen in diabetic patients with severe insulin
resistance,
and in nondiabetic patients with severe insulin resistance, and
hyperinsulinism Hyperinsulinism is by no means the only cause of
acanthosis nigricans and so it can be seen in other conditions, it can be
seen as a paraneoplastic syndrome and other things as well The patients
with insulin resistance are, even in the absence of diabetes, at a high
risk for other complications

If insulin resistance alone is not enough to account for diabetes, what
else is needed And the other thing that appears to be needed is some beta
cell lesion, perhaps independent of the insulin resistance, that leads to
some degree of impairment in the beta cells ability to produce insulin in
response to a load

A data on Pima Indians who were investigated perceptively, and some people
went on to develop diabetes, the Progressors Some individuals went on
not to develop diabetes, the non-progressors

Looking mainly at this thirty-minute point and looking at the plasma
insulin concentrations, minutes after a glucose load, you can see that the
insulin response of the progressors was impaired compared to the insulin
response of the
non-progressors We are working towards a two lesion model
in which in individuals who have insulin resistance, the folks who have an
additional pancreatic defect, or develop an additional loss of bets cell
responsiveness are the ones who will goon to develop diabetes

Another kind of data, this is looking at the very early response of insulin
to an intravenous glucose load The very early spike in insulin in
response to intravenous glucose load is referred to as the Phase-1 insulin
release It would appear that in folks with Type-II diabetes, it is very
specifically and very early on this Phase-1 release of insulin that is very
selectively lost Phase-1 response probably relates to easily releasable
insulin pool with in pancreatic beta cells Some people feel that this
Phase-1 response is very important in terms of the immediate responses to a
glucose load as far as suppression of hepatic glucose out put So this is
the sort of two head model that we come to, insulin resistance which
effects glucose uptake in the muscle and fat cells, and glucose production
in the liver, together with a progressive insulin secretory defect at
the
level of the pancreas

Another in terms of the natural history of diabetes, that insulin
resistance arguably develops early on, and some of the factors leading to
insulin resistance are genetic, they may be present from birth Initially
the pancreas compensates, but at some point that compensation is failing,
the patient begins to develop a relative insulin deficiency and than an
absolute insulin deficiency Initially their fasting blood glucose is
maintained but the postprandial blood glucose has become elevated With
time the fasting blood glucose becomes elevated as well This is process
that is occurring over the course of years When a patient presents with
clinical diabetes, that might be long after the evolution of these changes
began in that individual

There is an important difference in terms of the natural history of Type-I
versus type-II diabetes, after it is diagnosed, which is the Type-II
diabetes is a disease the progresses in a way different than the
progression of Type-I diabetes This is from a study referred to as the
DCCT, what was done in this study was to take individuals with
Type-I
diabetes, and to randomize them to different insulin treatment programs
And there were differences in the Hemoglobin A1C So there was a so called
conventional, for that age treatment group, and a more intensively treated
group The important point was that hemoglobin A1C in these different
treatment groups remain fairly constant, they establish a treatment, they
got patients into control or not, and that level of control remained fairly
stable for the duration, in this case ten years of the study

In contrast the results from a comparable but identical study that was done
in folks with Type-II diabetes There was a conventional and an intensive
treatment group For both the treatment groups, the disease was not stable
over time, there was a progressive worsening of Hemoglobin A1C, as an index
of control over the course of the study This is an area of very intense
research

With early intervention we can potentially prevent people from developing
diabetes If the people do develop diabetes, what we would like to do is
at least be able to prevent the progression of diabetes that we see in the
typical individual over the time course of
action

Treatment:

Treatment of Type-II diabetes is a little bit different, than our treatment
of Type-I Although there certainly are relations, we focus a lot in terms
of life style intervention in terms of issues of weight loss, encouraging
exercise, things like that As opposed to Type-I diabetes in which insulin
is an absolute requirement for treatment

Treatment of Type-II diabetes tends to be more staged So the initial
treatment and perhaps sufficient, might be life style interventions to
encourage weight loss, exercise, limit other risk factors of
atherosclerosis With greater degrees of weight loss, there was successive
improvement in terms of hemoglobin A1C, and lowering of insulin levels So
life style interventions can be very affective in controlling Type-II
diabetes, and altering the underlying pathophysiology

Another study showing the benefits of exercise as far as diminishing the
risk of cardiovascular events, this goes back to the nurses study in
diabetic women But in general for women with type-II diabetes, their risk
of cardiovascular events was to some extent protected by vigorous
physical
activity

As far as glucose control strategies, we can start with oral agents There
are a number of different classes of oral agents that have different
effects on various parts of the glucose control system There are agents
like metformin that tend to enhance insulin sensitivity There are other
agents such as sulfonylureas and some other classes that tend to enhance
endogenous insulin release So often times from a pharmacologic
perspective in treating folks with Type-II diabetes we might use
combinations of different classes of oral agents to attack the different
lesions If the progressive beta cell failure does progress, than many
although not all patients with Type-II diabetes are going to go on to
require insulin in their own endogenous secretory capacity gets to be
sufficiently low So the treatment for Type-II diabetes tends to be
staged, depending upon the degree of involvement of these different
lesions

We have also over the last few years gotten to be very much more aware of
the importance of co-treating the other cardiovascular risk factors in
folks with diabetes,
and so put a lot of attention now not just in terms of
blood sugar control, but also in terms of a very tight control of blood
pressure and of lipid levels The standards for blood pressure control
would be blood pressure less than 130/80 mmHg Stricter criteria that we
would have for blood pressure control in somebody without diabetes As far
as lipids are concerned, in certain ways diabetes has been called a
coronary artery disease equivalent If somebody has diabetes, and we dont
know any thing at all about their cardiac status, we would non the less say
that over all the prognosis of that patient from a cardiac stand point is
quite similar to what it would be in a nondiabetic individual, who we knew
to have coronary artery disease So diabetes is almost considered to be a
coronary artery disease equivalent So our criterion in terms of lipid
control likewise are stricter than they would be in a nondiabetic
individual who was not known to have cardiac disease The general
recommendation now is for folks with diabetes to target to achieve an LDL
level of less than a hundred Something comparable to what you would
be
treating for an individual who had previously had a heart attack

The treatment programs for these patients have to be multimodel in origin
This is not a disease that you could treat simply by telling the patient to
take this pill or that medication These are patients that require very
intensive intervention and follow up