August 13, 2012

Diabetes: Overview,
Diagnosis, Classification
Dr. Araceli Panelo

I.

II.

III.

IV.

Outline
Overview
A. Introduction
B. Epidemiology
C. Risk Factors for Diabetes
D. Classic Symptoms of Diabetes
E. Complications of Type 2 Diabetes
Criteria for Diagnosing Diabetes
A. Suggested Algorithm for Diagnosing
Diabetes
a. Random Blood Sugar
b. Fasting blood sugar
c. Two-Hour Post Glucose Blood
Sugar
B. HbA1c
C. Summary of Criteria for the Diagnosis of
Diabetes
Etiologic Classification of Diabetes
A. Type 1 Diabetes
B. Type 2 Diabetes
C. Gestational Diabetes Mellitus
D. Other Specific Types
Prevention/Delay of Diabetes

systems that impose a tremendous burden on the

individual with diabetes and on the health care system.

EPIDEMIOLOGY
Global diabetes epidemic

OVERVIEW
INTRODUCTION
Diabetes Mellitus

Ancient disease
o Ancient Greek diabetes means to flow
through
o Latin word mellitus sweetened or
honeylike
o Medical descriptions of diabetes date back
to at least 1500 BC, nearly 3,500 years
ago.
o Writings from ancient cultures in China and
the Middle East describe the classic signs
of diabetes, such as passing large
quantities of urine through the body.

A group of metabolic diseases characterized by

hyperglycemia due to defects in insulin secretion,
insulin action, or both.

Resulting in defects in carbohydrate, protein, and

fat metabolism

The chronic hyperglycemia of diabetes is

associated with long-term damage, dysfunction,
and failure of various organs, especially the eyes,
kidneys, nerves, heart, and blood vessels.

Complications
o Acute
o Chronic

International
Diabetes Federation

We face a global epidemic of type 2 diabetes in the

coming decades.
The latest data from the International Diabetes
Federation (IDF) were presented at the 18th Meeting
of the IDF, held in Paris, France, 2429 August
2003, by Sir George Alberti.
The number of people worldwide who have
diabetes will increase from 194 million to 333
million by 2025.
o In 2003, there were only 194M diabetics in
the world. In the year 2025, it is projected
that there will be a 72% increase in the
number of diabetics in the world.
Ninety percent of cases of diabetes will be the type
2 form of the disease, with an even higher
percentage in developing countries.

Increased burden of diabetes will affect the

developing world the most

Harrisons:

Several distinct types of DM exist and are caused by a

complex interaction of genetics and environmental
factors.

Depending on the etiology of the DM, factors contributing

to hyperglycemia include reduced insulin secretion,
decreased glucose utilization, and increased glucose
production.

The metabolic dysregulation associated with DM causes

secondary pathophysiologic changes in multiple organ

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Most of the increase in diabetics will be coming

from our part of the world.

In the year 2025, 226 million are expected to come

from the developing countries.

Worldwide estimates project that in 2030 the greatest

number of individuals with diabetes will be 4564 years of
age.

1.

Family history (i.e., parent or sibling with type 2

RISK FACTORS FOR DIABETES

diabetes [Harrisons])

2.

The presence of the members of the metabolic

syndrome in your family would mean that you are
also candidates for type 2 diabetes.
Race Asians (e.g., African American, Latino, Native
American, Asian American, Pacific Islander [Harrisons])

Developing countries will bear the burden of the

diabetes epidemic

3.
4.
5.

This shows the percentage increase from the

present day to 2025 in the number of people
expected to have diabetes, by region.
o It is projected that in the year 2025, Asia
will contribute 91 million diabetics.
Increasing rates of obesity and sedentary lifestyles
against a background of increasing lifespan will
continue to push up the prevalence of type 2
diabetes in North America.
However, developing countries in the Middle-East,
Asia, Central and South America, and Africa will
bear the brunt of the global diabetes epidemic.

DIABETES on the rise!

As seen in the list of countries with most

number of diabetics, if you are an Indian, you
have a very, very high risk of developing
diabetes. Whether the Indians stay in India or
go to other countries, they will still be the ones
at most risk for diabetes.

Being a Filipino is also a risk factor for

developing diabetes.
Age > 30
The older you get, the higher is the chance to get
it.
Overweight/obesity (BMI>23kg/m2 )
Previous history of IFG/IGT (prediabetes)
Poor obstetrical history in women (history of
gestational diabetes) (or delivery of baby >4 kg (>9 lb
[Harrisons])

6.
7.

Hypertension (blood pressure 140/90 mmHg

[Harrisons])

Dyslipidemia (HDL cholesterol level <35 mg/dL (0.90

mmol/L) and/or a triglyceride level >250 mg/dL (2.82
mmol/L) [Harrisons])

8. Coronary artery disease

9. Cerebrovascular accidents
10. Physical inactivity

High risk presence of 2 or more risk factors

With 2 or more risk factors, you then become a good
candidate for development of diabetes, but ONLY IF
you are not careful since diabetes can now be
prevented and delayed.

Harrisons:
Other risk factor for type 2 diabetes mellitus:

Polycystic ovary syndrome or acanthosis nigricans

CLASSIC SYMPTOMS OF DIABETES

Right now, China and India are the top 2 producers

of diabetes.
In 2000, it was India. Now, China has already
overtaken India in being the country with the most
number of diabetics in the whole world.
The Philippines is expected to be in the top 10
among countries with the most diabetics in the
world.

Harrisons:

The prevalence is similar in men and women throughout

most age ranges (10.5% and 8.8% in individuals >20
years) but is slightly greater in men >60 years.
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Polyuria
Polydipsia
Unexplained weight loss (in spite of a very good
appetite)

COMPLICATIONS OF TYPE 2 DIABETES

Type 2 diabetes is associated with serious
complications

The microvascular complications of both type 1 and type

2 DM result from chronic hyperglycemia.
Evidence implicating a causative role for chronic
hyperglycemia in the development of macrovascular
complications is less conclusive.
However, coronary heart disease events and mortality are
two to four times greater in patients with type 2 DM.
These events correlate with fasting and postprandial
plasma glucose levels as well as with the A1C.
Other factors (dyslipidemia and hypertension) also play
important roles in macrovascular complications.

Type 2 diabetes reduces life expectancy

Serious microvascular and macrovascular

complications of type 2 diabetes have a
devastating effect on quality of life and impose a
heavy burden on healthcare systems.
Diabetic retinopathy: present in 21% of people
at the time type 2 diabetes is diagnosed, diabetic
retinopathy is the leading cause of new blindness
among adults aged 2074 years.
o Diabetic retinopathy is the leading cause of
blindness in the US and in other developed
countries. We do not have the exact data
in the Philippines because at the moment,
it is not considered a reportable case.
Diabetic nephropathy: present in 18% of people
diagnosed with diabetes; diabetes is a leading
cause of end-stage renal disease.
o In Metro Manila, the number one cause of
the need for dialysis is diabetic
nephropathy.
Stroke: diabetes is associated with a 2- to 4-fold
increase in cardiovascular mortality and stroke.
Cardiovascular disease: 75% of individuals with
type 2 diabetes die from cardiovascular causes.
o Eight out of ten (8/10) of diabetics die from
cardiovascular eventseither myocardial
infarction or stroke.
Diabetic neuropathy: present in 12% of people at
diagnosis, diabetic neuropathy affects
approximately 70% of people with diabetes and is a
leading cause of non-traumatic lower extremity
amputations (2nd only to trauma as a cause in the
US).
In the UKPDS, 50% of individuals with diabetes
already had complications at diagnosis.
Early detection and treatment of diabetes is
essential in order to reduce the impact of its
serious complications.

Harrisons:

Chronic complications can be divided into vascular and

nonvascular complications.

The vascular complications of DM are further subdivided

into microvascular (retinopathy, neuropathy,
nephropathy) and macrovascular complications
[coronary artery disease (CAD), peripheral arterial
disease (PAD), cerebrovascular disease].

Nonvascular complications include problems such as

gastroparesis, infections, and skin changes. Longstanding diabetes may be associated with hearing loss.

Since type 2 DM often has a long asymptomatic period of

hyperglycemia, many individuals with type 2 DM have
complications at the time of diagnosis.
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This shows the expected reduction in future life

expectancy in adult patients given a diagnosis of
diabetes at different ages.
o It shows the number of years that you lose
depending on the age that you were
diagnosed with diabetes.
A survey of three observational studies in this area
shows that a diagnosis of type 2 diabetes is
associated with significant loss of life expectancy.
Patients diagnosed in middle age (highlighted on
the slide) lose a substantial portion f their
remaining life expectancy, with a potential loss of
58 years of life consistently found across three
studies.
o If you were diagnosed to have diabetes at
ages 40-49, you may lose 7-10 years. At
ages 50-59, you may lose 6-7 years.
o The older you get, the less the number of
years that you lose from diabetes.
There is no doubt that type 2 diabetes causes loss
of a significant proportion of patients lives.
It is a good strategy to delay the onset of diabetes.
It has been shown in many studies that you can
either prevent the onset of diabetes among
individuals at high risk for developing the disease,
or you can delay at least the onset of diabetes.
In a family where there is a very strong history of
type 2 diabetes, if you work on them before they
become diabetics, there is a good chance that you
may be able to delay the onset, and that will be
good for these particular individuals.

Hospitalizations account for the majority of the

costs of managing type 2 diabetes

In the Cost of Diabetes in Europe Type 2 (CODE-2)

study, the total direct medical costs of type 2
diabetes in Belgium, France, Germany, Italy, the
Netherlands, Spain, Sweden and the UK were
estimated at 29 billion a year (1999 values) and
the estimated annual costs per individual were
2,834.
Hospitalizations accounted for the majority of
overall costs (55%), with ambulatory care
contributing 18%, antidiabetic drugs 7%, and all
other drugs 21%.
o As you can see, hospitalizations occupy
more than half of the pie in the expenses
for the management of type 2 diabetes.
The strategy now is to treat them well in the
outpatient, try to diagnose as early as we can, and
then be aggressive during the early years of their
diabetes, so that well be able to prevent the
complications; thus, minimizing the cost of
treatment of type 2 diabetes.

Managing complications accounts for most of the

cost of managing type 2 diabetes

Medical cost of diabetes

Health economic analyses from the UK Prospective

Diabetes Study are available for both the main
cohort (randomly assigned to conventional, dietbased treatment or to intensive glycaemic
management with a sulphonylurea or insulin) and
from the study in overweight patients randomised
to receive diet-based treatment or intensive
glycaemic management with metformin.
o This is a study among 5,000 newly
diagnosed with type 2 diabetes at the time
of recruitment. They were followed up for
10 years.
In each case, the costs associated with the
management of diabetic complications accounted
for the majority of the costs associated with the
patients overall treatment (calculated to be
relevant to the procedures and costs encountered

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in the routine, day-to-day management of type 2

diabetes).
o Looking at the cost of managing type 2
diabetes, it shows that whether the patient
is underweight or overweight, the cost is
the same. The complications are what
drive the cost of management of diabetes
upward.
Controlling the complications of type 2 diabetes
holds the key to both improving patient outcomes
and to limiting the growth of the burden of diabetes
on healthcare systems.

Diabetes-related complications account for a major

part of healthcare budgets in the USA alone they
accounted for about US$100 billion in 1997.
Medical, behavioural public health and policy
changes that can delay the onset or slow the
progression of diabetes have tremendous potential
to mitigate the costs associated with the disease.
Diabetes is now considered a cardiovascular
disease based on many studies.
In this study, cardiovascular disease accounts for
the highest cost. It is the most common cause of
death, and more than 80% of patients with
diabetes are affected.
This study was published in 2003. Now, doctors are
able to prevent the onset of cardiovascular disease
in some patients, and are able to prolong the lives
of the patients. With that, some of them will have
renal disease, and that will add to the cost of
management of type 2 diabetes as well.

Reaching glucose goals is important to reduce

macrovascular complications

Overall, 75% of people with type 2 diabetes die

from cardiovascular disease.
Meeting and maintaining good glycemic control is
also important for the prevention of diabetesrelated macrovascular complications, which include
cardiovascular disease and stroke.
o Reaching glucose goals can decrease both
microvascular and macrovascular
complications of type 2 diabetes.
Cardiovascular disease: 75% of individuals with
type 2 diabetes die from cardiovascular causes.
Stroke: diabetes is associated with a 24-fold
increase in cardiovascular mortality and stroke.

HbA1c reduction of 3% delivers an

approximately 63% reduction in risk
Therefore, the greater the reduction in HbA1c, the
greater the protection against complications.
o

CRITERIA FOR DIAGNOSING DIABETES

Lessons from UKPDS: Better glucose control
means fewer complications

The UKPDS study has demonstrated that intensive

glycemic control is strongly associated with
significant clinical benefits for patients with type 2
diabetes.
In an epidemiological analysis of the UKPDS cohort,
every 1% decrease in HbA1c was associated with
clinically important reductions in the incidence of:
o Diabetes-related death (mean decrease
21%, p<0.0001)
o Myocardial infarction (mean decrease 14%,
p<0.0001)
o Microvascular complications (mean
decrease 37%, p<0.0001)
o Peripheral vascular disease (mean
decrease 43%, p<0.0001)
For example, the patient started with HbA1c of 11,
if you are able to reduce it to 10, that will already
amount to a 21% reduced risk in deaths from
diabetes, 14% reduction in heart attacks, 37%
reduction in microvascular complications, and 43%
reduction in peripheral vascular disease.
With that, it is indeed very important to manage
the hyperglycemia of these patients. There is no
doubt that lowering the blood sugar can decrease
the complications in type 2 diabetes.
The correlation is bigger with the microvascular
complications, and lowering of the blood sugar, but
there is still some correlation between
hyperglycemia lowering and the macrovascular
complications. If you look at peripheral vascular
disorder, which is considered a macrovascular
disease, there is a 43% reduction. If the patient
then started on HbA1c of 11 and you are able to
lower it to 9, you will be able to reduce the chance
of this patient going into amputation by 86%, and
myocardial infarction by 28%. This is very
significant.
There is no lower limit beyond which reductions in
HbA1c cease to be of benefit.
Taking diabetes-related death as an example, this
means that:
o HbA1c reduction of 2% delivers an
approximately 42% reduction in risk

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NOTE: THIS IS VERY IMPORTANT. REMEMBER THE

CRITERIA. MEMORIZE THE VALUES. According to
Dr. Panelo, in the exam it will be cases, and
these values will be the bases.
1. Random blood glucose 200mg/dl
(11.1mmol/L) + classic symptoms, OR
2. FPG (fasting plasma glucose) 126mg/dl
(7.0mmol/L), OR
3. Two-hour PG (postprandial glucose)
200mg/dl (11.1mmol/L) on OGTT (oral glucose
tolerance test)

In the absence of unequivocal hyperglycemia with

acute metabolic decompensation (classic
symptoms), these criteria should be confirmed by
repeat testing on a different day (you need more
than one value).

It takes 7-10, or even 14 years, before a diabetic

will be symptomatic. Do not test people with signs
and symptoms only. You have to test everybody
who has the risk factors, whom you suspect to
have diabetes.
FPG

Normal
<100mg/dl

2-hour PG

<140mg/dl

IFG/IGT
100125mg/dl
140199mg/dl

DM
126mg/dl
200mg/dl

IFG impaired fasting glucose; IGT impaired glucose tolerance

IFG/IGT - Prediabetes

In the past, in the absence of technology to detect

presence of high blood sugar or high urine spillage,
the scientists used to taste the urine of their
patients. If it is sweet, then sugar is present in the
urine.

SUGGESTED ALGORITHM FOR DIAGNOSING

DIABETES
Based on: Report of the Expert Committee on the Diagnosis and
Classification of Diabetes Mellitus. Diabetes Care 2003; 26 (Suppl 1):
s12; ADA. Screening for Type 2 Diabetes. Diabetes Care 2003; 26
(Suppl 1): s21-s24

RANDOM BLOOD SUGAR (RBS)

In the presence of classic symptoms of diabetes

(polyuria, polydipsia, weight loss, do a RBS (done at
any time of day, regardless of time of last meal). Doing
a capillary blood sugar (CBG) is not an official way of
diagnosing, so you have to send the patient to the
laboratory (Note: CBG can be done for self-screening,
but this is not official.)

If RBS is <200, do a 2-hour PGBS. Among

nonpregnant individuals, that means 75 g of
glucose.

If the RBS is < or = to 200, that is diagnostic for

type 2 diabetes. REMEMBER, the classic signs
and symptoms of diabetes have to be there.

You may do a FBS, and if it is normal (<100),

request for a 2-hour PGBS.
If the reading is > or = 126, you should do
another FBS to be able to make a diagnosis.
If you have a repeat FBS and it was able to
duplicate the first result, or the result was even
higher than the first, that is now diabetes.
If you repeat the FBS and the reading is <126, do a
2-hour PGBS.
Which is more important to do, FBS or 2-hour
PGBS? Many experts would agree that taking the 2hour PGBS could enable you to detect more
diabetics than FBS. This is why many experts
would rather have a 2-hour PGBS screening test
than a FBS.
However, there are now other studies that would
show that there are individuals whose FBS may be
high and can be diagnosed with diabetes using
FBS, and there are individuals whose FBS are
normal but whose 2-hour PGBS may be elevated.
It seems like the ones who present first with the
increased FBS, and those who present first with
increased 2-hour PGBS have different
characteristics. You can see from here that type 2
diabetes is really a very heterogenous disorder.
If you may, it would be best do both FBS and 2hour PGBS to uncover everybody who has
diabetes.
However, if you already get a (+) reading on your
FBS, theres no reason for you to go on ahead with
a 2-hour PGBS. (Example: Patients FBS is 300 mg,
theres no sense in doing 2-hour PGBS. The patient
is diabetic already.)

FASTING BLOOD SUGAR (FBS)

TWO-HOUR POST GLUCOSE BLOOD SUGAR

(2 PGBS)

For example, you have a patient who is a Filipino,

obese, but asymptomatic (with no polyuria, polydipsia,
or weight loss). Having 2 risk factors makes him at
high risk for diabetes. This should make you think of a
diagnostic test already.
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When you treat a diabetic patient, make sure that

you also go for the other members of the family.
This is good practice that will help prevent the
spread of type 2 diabetes. (This will also be good
for you financially because you will have more
patients than just the diabetic member of the
family.)

June 7, 2009 (New Orleans, Louisiana): ADA, IDF,

and EASD joined forces to recommend the use of
A1c assay for the diagnosis of diabetes.
Diagnostic value of 6.5%
This cut-point is where risk of retinopathy
substantially increases
HbA1c testing
o This test should be performed in a
laboratory using a method that is NGSP
(National Glycosylated Standardization
Program) certified and standardized to the
DCCT (Diabetes Control and Complications
Trial) assay
They suggest that the diagnosis should be
confirmed with a repeat A1c test, unless the
patient is symptomatic with plasma glucose levels
above 200mg/dl (above 11.1mmol/L).
They point out that if A1c testing is not possible
(because of cost or convenience), previously
recommended diagnostic methods (fasting or 2hour post-prandial glucose levels, with
confirmation) would remain as acceptable ways to
make the diagnosis.
Advantages
o A1c is a more stable chemical moiety (low
variability from day to day; not affected by
stress and illness)
o Its more convenient (not required to fast)
o Correlates tightly with the risk of
developing retinopathy
Disadvantages
o Cost
o Certain conditions: hemoglobinopathy
(HbS, HbF HbC HbE), changes in RBC
turnover (hemolytic anemia, chronic
malaria, major blood loss, or blood
transfusion will lead to spurious A1c
results; even pregnancy when changes in
rbc turnover occurs)
American Diabetes Association Revised Diabetes
Guidelines:
o A1c level of 6.5% or higher indicates the
presence of diabetes
o A1c level of 5.7% to 6.4% = prediabetes
o A1c level of 5% = absence of diabetes
o Other revisions:
Diagnosis of Prediabetes is now named
Categories of Increased Risk for Diabetes
Antiplatelet (aspirin) agent for moderate or
low risk patients is questionable for primary
prevention
You only give aspirin now to those who
already have manifest atherogenesis.

HbA1c

If you are to do a 2-hour PGBS using a 75 g anhydrous

glucose load, the patient should have fasted for 8
hours, and he should be eating his regular
carbohydrate load in the previous 3 days (You are not
supposed to make the patient fast and avoid
carbohydrates in preparation).

If the reading is <140, it is normal.

If the reading is > or = 200, it is diabetes.

If the reading is 140-199, it is impaired glucose

tolerance.
o In people with IGT, after 10 years1/3 will
continue to have IGT, 1/3 will revert to
normal, and 1/3 will become diabetics. (If
you have IGT, your chance of becoming a
diabetic is very high, so after 10 years,
they may still be IGT, but the chance of
becoming a diabetic is higher.
o Aside from that, even if the IGT does not
progress to type 2 diabetes, they are
already at risk for developing the
macrovascular complications of diabetes
(atherosclerosis).

They say that there are 2 clocks that tick in

diabetes. One clock is the clock for microvascular
complications, which starts ticking only at the
onset of hyperglycemia, so when the patient
becomes diabetic for the first time (real onset of
diabetes), thats the time that hyperglycemia
affects the small blood vessels (microvascular
bed).
The atherogenesis starts earlier. The patient may
not even be IGT, and he may have dyslipidemia
already. If the patient is overweight or has a family
history of type 2 diabetes, even if he doesnt have
hyperglycemia, he will already develop
atherogenesis. The clock for macrovascular
disease starts earlier than the clock for
microvascular complications.
This is the reason it is easier to prevent the
microvascular complications than the
macrovascular complications.
That is why the campaign now is to be able to get
to individuals at high risk for diabetes, and these
are the family members of diabetic patients.

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Diabetes care in the hospital now questions

the benefit of very tight glycemic control
goals in critically ill patients

The study measured Hba1c in blood samples from

more than 11,000 people, black and white adults,
who had no history of diabetes.
The samples were obtained between 1990 and
1992 as part of the Atherosclerosis Risk in
Communities (ARIC) Study
The samples have been in cold storage since their
collection. "It is amazing to be able to use blood
samples collected over a decade ago."
The current analysis demonstrates that HbA1c is
not only an extraordinarily strong predictor of who
will develop diabetes, its also an important marker
of cardiovascular risk.
HbA1c is being used as a tool in many clinical
trials.
As HbA1c increases, even if its still within the
normal values, the risks for cardiovascular disease
also increases.

Incidence of new diabetes and hazard ratio (95%

CI) for diabetes and other clinical outcomes (14year median follow-up), by baseline glycated
hemoglobin level, in nondiabetics

1. A1C 6.5%. The test should be performed in a

laboratory using a method that is NGSP certified
and standardized to the DCCT assay.*
OR
2. FPG 126 mg/dl (7.0 mmol/l). Fasting is
defined as no caloric intake for at least 8 h.*
OR
3. Two-hour plasma glucose 200 mg/dl (11.1
mmol/l) during an OGTT. The test should be
performed as described by the World Health
Organization, using a glucose load containing the
equivalent of 75 g anhydrous glucose dissolved in
water.*
OR
4. In a patient with classic symptoms of
hyperglycemia or hyperglycemic crisis, a
random plasma glucose 200 mg/dl (11.1 mmol/l).
*In the absence of unequivocal hyperglycemia, criteria
13 should be confirmed by repeat testing

However, two tests that reach the expected

diabetes values are enough. If you have an
increased FBS and increased HbA1c, or an
increased FBS and an increased 2-hour PGBS, this
will be enough.

ETIOLOGIC CLASSIFICATION OF DIABETES

MELLITUS

Type 1 diabetes
Type 2 diabetes
More than 90% of diabetics in the Philippines are
type 2 diabetics.
Gestational diabetes mellitus
Other specific types

TYPE 1 DIABETES

Eleven thousand ninety-two (11 092) were white or

African American, nondiabetic, and without a
history of cardiovascular disease and yielded blood
samples sufficient for measuring HbA1c.
They were followed for development of diabetes
and clinical events for a median of about 14 years.
The risks of incident diabetes, coronary heart
disease events, and death were significantly
increased for all HbA1c values higher than the
reference range of 5.0% to <5.5%; the ischemic
stroke risk went up significantly at levels >6.0%.
The analysis controlled for patient features and
conventional CV risk factors.

SUMMARY OF CRITERIA FOR THE DIAGNOSIS

OF DIABETES
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Results from autoimmune destruction of pancreatic

beta-cells
Absolute insulin deficiency (reason for this is
destruction is almost 100%)
Patients typically dependent on insulin for survival
Patients may present with ketoacidosis as initial
sign of the disorder.
o The younger the onset, the higher is the
chance to develop DKA (diabetic
ketoacidosis) because of more destruction
of beta-cells.
o It is very important to recognize the early
signs of diabetic ketoacidosis.

Harrisons:
Manifestations of diabetic ketoacidosis:

Symptoms: nausea/vomiting, thirst/polyuria, abdominal

pain, shortness of breath

Precipitating events: inadequate insulin administration,

infection (pneumonia/UTI/gastroenteritis/sepsis),
infarction (cerebral, coronary, mesenteric, peripheral),
drugs (cocaine), pregnancy

Physical findings: tachycardia, dehydration/hypotension,

tachypnea/Kussmal respirations/respiratory distress,
abdominal tenderness (may resemble acute pancreatitis
or surgical abdomen)

Lethargy/obtundation/cerebral edema/possibly coma

diagnosis, patients are already started on

insulin, and they will be on insulin forever.

From genetic susceptibility to beta cell destruction.

o Everybody is born with a 100% beta cell
mass, which is the normal. However, there
are genes in some families that will
predispose individuals to type 1 diabetes.
(If there are twins or siblings of a type 1
diabetic, these children should be followed
up as well.)
Usually precipitated by a certain agent, usually a
viral infection, that triggers off a host of
immunologic response leading to the
autodestruction of beta cells.
o Having the genes is not enough. There has
to be a precipitating agent. The union of
the genes and the precipitating agent will
lead to the destruction of beta cells.
o In most studies, the number one most
common precipitating agent for the onset
of type 1 diabetes is a virus (measles,
chicken pox virus, other common viruses).
There are some characteristics of the virus
that are very similar to some structures in
the wall of the beta cell. The immune
system mistakes these structures in the
wall of the beta cell for the virus
themselves. The immune cells (T cells)
fight off these structures in the beta cells
there is a destruction of the cell wall of the
beta cell, and the beta cell dies. When the
beta cell dies, there is a reduction in the
beta cell mass.
Overtime developed progressive loss of insulin
release eventually to overt diabetes
o After exposure to the precipitating agent,
there will be overt immunologic
abnormalities leading to reduction in beta
cell mass.
o However, the other remaining beta cells
tend to overwork themselves to be able to
keep the blood sugar normal. There is a
progressive loss of insulin release because
of progressive decline in beta cell mass.
o When beta cell mass reaches overt
diabetes level, you will be presenting with
the signs and symptoms of diabetes. At
this point, there is already no insulin. At

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Harrisons:
Pathogenesis of type 1 DM:

Pathologically, the pancreatic islets are infiltrated with

lymphocytes (in a process termed insulitis).

After all beta cells are destroyed, the inflammatory

process abates, the islets become atrophic, and most
immunologic markers disappear.

Studies of the autoimmune process in humans have

identified the following abnormalities in the humoral and
cellular arms of the immune system: (1) islet cell
autoantibodies; (2) activated lymphocytes in the islets,
peripancreatic lymph nodes, and systemic circulation; (3)
T lymphocytes that proliferate when stimulated with islet
proteins; and (4) release of cytokines within the insulitis.

Beta cells seem to be particularly susceptible to the toxic

effect of some cytokines [tumor necrosis factor (TNF-),
interferon, and interleukin 1 (IL-1)].

The precise mechanisms of beta cell death are not known

but may involve formation of nitric oxide metabolites,
apoptosis, and direct CD8+ T cell cytotoxicity.

The islet destruction is mediated by T lymphocytes rather

than islet autoantibodies, as these antibodies do not
generally react with the cell surface of islet cells and are
not capable of transferring DM to animals.

Suppression of the autoimmune process (cyclosporine, T

lymphocyte antibodies) at the time of diagnosis of
diabetes slows the decline in beta cell destruction, but
the safety of such interventions is unknown.

TYPE 2 DIABETES

Insulin resistance and relative insulin deficiency

Patients may or may not need insulin treatment to
survive
o May go on with hyperglycemia for years
and not develop immediate emergency
complications like DKA (so they may not
need insulin to survive)
May remain undiagnosed for many years, as
hyperglycemia develops slowly
Associated with strong genetic predisposition
o Correlation of type 2 diabetes with genes is
stronger than type 1.
Heterogenous

Natural History of Diabetes

point when type 2 diabetics will have no

insulin anymore. (Before that time, use of
exogenous insulin is already recommended
to prevent increase in blood sugar levels,
and development of complications of type
2 diabetes.)

Orange line above postprandial glucose; yellow line

fasting plasma glucose; red line insulin resistance;
orange line below insulin secretion

Early on, increasing insulin resistance leads to

compensatory increases in circulating insulin,
which prevents an increase in glucose levels.
o If you are born with the genes for insulin
resistance, as you get older, your insulin
resistance increases. As you gain more
weight, it also increases. As you become
less physically active, it also increases.
As time progresses the insulin resistance reaches a
peak and stabilizes, while the compensatory
increase in insulin continues to prevent fasting
glucose levels from becoming abnormal.
There is a temporal relationship between insulin
resistance, insulin secretion and the development
of diabetes.
In the early stages, as insulin resistance rises,
there is a compensatory increase in insulin
secretion and the individual remains
normoglycemic.
o At the time that the beta cell is still normal,
it will try to compensate and produce more
insulin than the normal. In the early stage
of type 2 diabetes, type 2 diabetics are
actually hyperinsulinemic to make up for
the insulin resistance. As long as the beta
cells can do this, there will be no diabetes.
However, the beta cells cannot do this
forever.
In the long term, as the -cells begin to fail, insulin
secretion falls, hyperglycemia becomes apparent
and frank type 2 diabetes develops.
o After some time, the beta cells give up and
show signs of decline in function. When
this happens, even at this point that the
insulin level is still higher than normal, you
will see a rise in postprandial glucose. Note
in the diagram that postprandial glucose
becomes abnormal earlier than fasting
plasma glucose. (So if you do 2-hour PGBS
rather than doing FBS alone, you will be
able to diagnose diabetes earlier).
o As the beta cell function declines, there is
a continuing increase in blood sugar levels.
This decline is progressive, and will reach a

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Another way to explain it--- inability to utilize

insulin efficiently because of insulin resistance--and inadequate insulin level because of beta cell
dysfunction
Early on when a genetically susceptible individual
to type 2 diabetes developed insulin resistance
Insulin resistance and impaired beta-cell function
are primary defects that occur early in the course
of development of type 2 diabetes.
Insulin resistance leads to an obligatory
hyperinsulinemia in order to maintain normal
glucose tolerance.
In most cases of type 2 diabetes, beta-cell
dysfunction develops subsequent to the
development of insulin resistance, and it is not until
such beta-cell dysfunction develops that any
abnormality in glucose tolerance is seen.
The condition that results is termed impaired
glucose tolerance (IGT). In some cases beta-cell
dysfunction may develop in the absence of early
insulin resistance.
However, exposure of tissues to hyperglycemia in
the face of
beta-cell dysfunction increases resistance to the
effects of insulin whether or not insulin resistance
was present to begin with.
Ultimately, type 2 diabetes is the result of
worsening beta-cell function, either in the most
common situation of chronic pre-existing insulin
resistance or, in the less common scenario of
decreased beta-cell function without pre-existing
insulin resistance.

Harrisons:

Type 2 DM is characterized by impaired insulin secretion,

insulin resistance, excessive hepatic glucose production,
and abnormal fat metabolism.

Obesity, particularly visceral or central (as evidenced by

the hip-waist ratio), is very common in type 2 DM.

In the early stages of the disorder, glucose tolerance

remains near-normal, despite insulin resistance, because

the pancreatic beta cells compensate by increasing

insulin output.
As insulin resistance and compensatory hyperinsulinemia
progress, the pancreatic islets in certain individuals are
unable to sustain the hyperinsulinemic state. IGT,
characterized by elevations in postprandial glucose, then
develops.
A further decline in insulin secretion and an increase in
hepatic glucose production lead to overt diabetes with
fasting hyperglycemia.
Ultimately, beta cell failure may ensue.

GESTATIONAL DIABETES MELLITUS (GDM)

Any degree of glucose intolerance with onset or

first recognition during pregnancy
If a patient is diabetic before she got pregnant, and
was not recognized before she became pregnant,
she will still be diagnosed to have gestational
diabetes.
Associated with increased perinatal morbidity and
mortality
Six weeks or more after pregnancy ends, the
woman should be reclassified
o There should be reclassification because
after delivery, true gestational diabetes will
have normalized sugar (which starts
already during labor).
o Overt diabetes before pregnancy remains
to have hyperglycemia even after delivery.
High risk for type 2 DM.
o More than 80% of these women will have
type 2 diabetes.
o After delivery, if they do not breastfeed,
they are given some pharmacologic agents
already. It has been shown that intervening
after delivery by giving Pioglitazone even if
the blood sugar level is still normal will
reduce the risk of these women becoming
type 2 diabetics.

Harrisons:

Insulin resistance is related to the metabolic changes

of late pregnancy, and the increased insulin
requirements may lead to IGT.

Most women revert to normal glucose tolerance postpartum but have a substantial risk (3060%) of
developing DM later in life.

SCREENING FOR PREGNANT WOMEN

The recommendation now is any woman who wants to
become pregnant should be tested to be able to
uncover those who may be diabetic, but are not
diagnosed yet. It has been shown that even the ovum
can become glycosylated. The baby may have some
defectsmay not be physical, may be on intelligence.

Diagnosis of GDM with a 100-g or 75-g glucose

load

In the 75-g glucose load, all you need is 1 value to

be able to diagnose gestational diabetes.

In the 100-g glucose load, you need 2 values.

WHO Criteria for GDM

One out of 2 cut-off is diagnostic of GDM:

o Two-hour PG using 75 gm glucose
FBS of 126mg/dl
Value of 140mg/dl
Diagnostic Test

The recommendation now is any woman who

wants to become pregnant should be tested to be
able to uncover those who may be diabetic, but are
not diagnosed yet. It has been shown that even the
ovum can become glycosylated. The baby may
have some defects, which may not be physical, but
on intelligence.

OTHER SPECIFIC TYPES

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Genetic defects of B cell function (MODY)

Genetic defects in insulin action (Leprechaunism

and the Rabson-Mendenhall syndrome)
Diseases of the exocrine pancreas (pancreatitis,
pancreatectomy, neoplasia, hemochromatosis)
Endocrinopathies (acromegaly, Cushing disease,
glucagonoma, pheochromocytoma)
Drug - or chemical - induced (Vacor, Pentamidien,
Nicotinic Acid, steroid, Thyroid hormone, Diazoxide,
Thiazide)
Infections (Cong. rubella, CMV)
Uncommon forms of immune-mediated diabetes
(stiff-man syndrome)
o Stiff-man syndrome - an autoimmune
disorder of the central nervous system
characterized by stiffness of the axial
muscles with painful spasms
Patients usually have high titers of the GAD
(glutamic acid decarboxylase)
autoantibodies, and approximately onethird will develop diabetes
Other genetic syndromes sometimes associated
with diabetes (Down Syndrome, Turner Syndrome
etc.)

PREVENTION/DELAY OF DIABETES

If you get a figure of 100-125mg/dl, you are within

the range of IFG --- a condition which may take a
little time to develop into frank diabetes. In such
case consult a competent diabetes clinic.
If you get a figure of 126mg/dl and over, consult a
competent diabetes clinic for confirmation and
treatment. You probably are diabetic.
The best way to prevent diabetes in high risk
individuals and to prevent complications among
confirmed diabetics is to consistently keep FBS
below 100 &126mg/dl respectively and PBG below
140mg/dl.

LIFESTYLE CHANGES

Dont get fat or overweight

Exercise daily
Avoid sweets, salts, fat, alcohol, and cigarettes
Keep in touch with a good diabetes clinic

Harrisons:
The Diabetes Prevention Program (DPP) demonstrated that
intensive changes in lifestyle (diet and exercise for 30 min/day
five times/week) in individuals with IGT prevented or delayed
the development of type 2 DM by 58% compared to placebo.
Individuals with a strong family history of type 2 DM and
individuals with IFG or IGT should be strongly encouraged to
maintain a normal BMI and engage in regular physical activity.
Pharmacologic therapy for individuals with prediabetes is
currently controversial because its cost-effectiveness and
safety profile are not known.
Nice to know:
In the painting of The Last Supper, portion sizes also gradually
grew. Size of the main dish grew by 69%, size of the plate by
66%, and the bread by 23% between the years 1000-2000.

END
OF PART I :)

Barbosa, Bautista C, Bautista MF

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