Diabetes Mellitus
Dr: Wael H.Mansy, MD
Assistant Professor
College of Pharmacy
King Saud University
Diabetes Mellitus
Study Objectives
• List the effects of insulin and glucagon in the body.
• List the factors that put an individual at risk for developing diabetes.
• Discuss the possible etiology of type I and type II diabetes.
• Define the three “ploys.” Why do they occur?
• What are the manifestations of diabetic ketoacidosis? Why does it occur?
• What is hyperosmolar -hyperglycemic syndrome? Why does it occur?
• Discuss pharmacologic and nonpharmacologic treatment for diabetes .
• Discuss possible mechanisms of tissue injury in diabetes mellitus.
• List the major effects of chronic diabetes mellitus. Why does each occur?
• Define gestational diabetes
Diabetes Mellitus

Group of metabolic disorders characterized by
hyperglycemia resulting from either or both:



insufficient insulin secretion
resistance to the action of insulin
Abnormalities in carbohydrate, fat, protein
metabolism
Effects of Insulin on Various Tissues
Adipose Tissue
Increased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K+ uptake
Muscle
Increased glucose entry
Increased glycogen synthesis
Increased amino acid uptake
Increased protein synthesis in ribosomes
Decreased release of gluconeogenic amino acids
Increased ketone uptake
Increased K+ uptake
Liver
Decreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased
glycolysis
General
Increased cell growth
4
Insulin stimulates hepatic glucose storage as glycogen; in adipose tissue as triglycerides; and amino acid storage
in muscle as protein; it also promotes utilization of glucose in muscle for energy. These pathways, which also are
enhanced by feeding, are indicated by the solid blue arrows. Insulin inhibits the breakdown of triglycerides,
glycogen, & protein and conversion of amino acids to glucose (gluconeogenesis), as indicated by the white 5
arrows. These pathways are increased during fasting and in diabetic states. Conversion of amino acids to glucose
& glucose to fatty acids occurs primarily in the liver.
6
Diabetes Classification

Majority of diabetics classified in 2
categories:



Gestational diabetes


type 1: absolute deficiency of insulin
type 2: presence of insulin resistance with
reduced insulin secretion
triggered by stress of pregnancy
Other specific types:

infections, drugs, endocrinopathies, pancreatic
destruction, genetic defects
7
7
Type 1 DM

Autoimmune destruction of pancreatic β-cells




~90% of patients have markers of immune β-cell
destruction at diagnosis
children & adolescents often have rapid β-cell
destruction & present with ketoacidosis
may occur at any age
Known as latent autoimmune diabetes in
adults (LADA)


slowly progressive
sufficient insulin secretion to prevent ketoacidosis
for many years
9
9
LADA



Latent Autoimmune Diabetes in Adults (LADA) is
a form of autoimmune (type 1 diabetes) which
is diagnosed in individuals who are older than
the usual age of onset of type 1 diabetes.
Alternate terms that have been used for "LADA"
include Late-onset Autoimmune Diabetes of
Adulthood, "Slow Onset Type 1" diabetes, and
sometimes also "Type 1.5
Often, patients with LADA are mistakenly
thought to have type 2 diabetes, based on their
age at the time of diagnosis.
LADA (cont.)
(Islet Cell Antibodies)
(Glutamic Acid Decarboxylase Autoantibodies)
Type 1 DM Pathogenesis
1.
Preclinical period


2.
Hyperglycemia

3.
80 to 90% of β-cells destroyed
Transient remission

4.
immune markers present
β-cell destruction
honeymoon phase
Established disease
12
12
Type 2 DM


Insulin resistance, relative lack of insulin
secretion
Usually presents with cluster of abnormalities
known as metabolic syndrome:





abdominal obesity
hypertension
dyslipidemia
elevated PAI-1 (plasminogen activator inhibitor-1)
levels
Increased macrovascular complication risk
13
13
NCEP ATP III: Components of the
Metabolic Syndrome (> 3 for diagnosis)
Risk Factor
Abdominal obesitya
Defining Level
Men (waist circumference)b
> 102 cm (> 40 in.)
Women
> 88 cm (> 35 in.)
Triglycerides
> 1.7 mmol/L (> 150 mg/dL)
HDL cholesterol
Men
< 1.0 mmol/L (< 40 mg/dL)
Women
< 1.3 mmol/L (< 50 mg/dL)
Blood Pressure
≥ 130/≥ 85 mmHg
Fasting glucose
> 6.1 mmol/L ( > 110 mg/dL)
NCEP-ATP: National Cholesterol Education Program Adult Treatment Panel
14
Screening

Type 1



not recommended
low prevalence, acute symptoms
Type 2


fasting plasma glucose (FPG) recommended
alternative: oral glucose tolerance test (OGTT)



more costly, less convenient, less reproducible
HbA1c (HbA1c reflects glucose levels for the previous 2 to 3 months)
not recommended


no gold standard assay
useful in monitoring glycemic control after diagnosis
15
15
Glucose Tolerance Test
Blood glucose curves of a
normal and a diabetic person
after oral administration of 1 g
of glucose/kg body weight.
Note the initial raised
concentration in the fasting
diabetic.
A criterion of normality is the
return of the curve to the initial
value within 2 hours.
16
Type 2 DM Screening
ADA Type 2 Diabetes Screening Recommendations
Children & Adolescents
Every 3 years at age 10 or onset of puberty if
overweighta with two additional risk factorsb
Adults
Every 3 years in adults ≥ 45 years of age or earlier
if overweightc & additional risk factors present
aBMI
> 85th percentile for age & sex, > 85th percentile weight for height, or >
120% of ideal weight for height
bFamily history of DM2 in 1st or 2nd degree relative; high risk ethnic group; signs
of insulin resistance; maternal history of gestational diabetes during child’s
gestation
c BMI ≥ 25kg/m2
17
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
Type 2 DM Risk Factors




BMI ≥ 25

Physical inactivity

1st degree relative with 
DM
High risk ethnic group 
(Latino, African American, 
Native American, Asian
American, Pacific
Islander)


IFG, IGT
HTN: ≥ 140/90 mmHg or


CV disease
HDL < 35 mg/dL
Triglycerides > 250
mg/dL
Delivery of > 9 lb baby
History of GDM
Insulin resistance
Polycystic ovary
syndrome
on therapy for HTN
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
18
Screening for Gestational DM


Risk assessment at 1st prenatal visit
Screen high risk women as soon as possible






family history of DM
history of GDM
marked obesity
presence of glycosuria
diagnosis of PCOS
If initial screening negative, retest high risk
women at 24 to 28 weeks gestation
19
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
19
Diabetes Mellitus
Gestational diabetes mellitus

Any degree of glucose intolerance with onset or first recognition
during pregnancy, most commonly seen during the third trimester of
pregnancy (in about 1 to 6% of pregnancies).

More common among obese women and women with a family
history of diabetes.

Resolves itself in most patients after birth but in certain
percentage (50 to 60%) type 2 diabetes will develop within 10 yrs
of initial diagnosis.

May be associated with an increased risk of fetal abnormalities.

Currently recommended that all pregnant women be screened for
the presence of gestational diabetes.
Diagnosis

Normal



Impaired fasting glucose (IFG)


FBG = 100 to 125 mg/dL
Impaired glucose tolerance (IGT)


FPG < 100 mg/dL
2 hr postload plasma glucose < 140 mg/dL
2 hr postload plasma glucose = 140 to 199 mg/dL
Diabetes mellitus


FPG ≥ 126 mg/dL
2 hr postload plasma glucose ≥ 200 mg/dL
21
Diagnosis
ADA Criteria for DM Diagnosis
1
Fastinga plasma glucose (FBG) ≥ 126 mg/dL
2
Symptoms of diabetesb & casualc plasma glucose ≥ 200 mg/dL
3
2-hour plasma glucose ≥ 200 mg/dL during OGTTd
In absence of unequivocal hyperglycemia: confirm on different day
a
Fasting: no caloric intake for at least 8 hours
b Classic symptoms: polyuria, polydipsia, unexplained weight loss
c Causal: any time of day without regard to last meal
d Oral glucose tolerance test: equivalent to 75-g anhydrous glucose in H2O;
not recommended for routine clinical use
22
DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 7th Edition:
http://www.accesspharmacy.com
23
Clinical Presentation of Diabetesa
Characteristic
Age
Onset
Body habitus
Insulin resistance
Autoantibodies
Symptoms
Ketones at diagnosis
Need for insulin therapy
Acute complications
Type 1 DM
< 30 yearsb
Abrupt
Lean
Absent
Often present
Symptomaticc
Present
Immediate
Diabetic
ketoacidosis
Microvascular complications at No
diagnosis
Macrovascular complications at Rare
or before diagnosis
aClinical
Type 2 DM
> 30 yearsb
Gradual
Obese or history of obesity
Present
Rarely present
Often asymptomatic
Absentd
Years after diagnosis
Hyperosmolar hyperglycemic state
Common
Common
presentation can vary widely. bAge of onset for type 1 DM is generally < 20
years of age but can present at any age. The prevalence of type 2 DM in children,
adolescents, and young adults is increasing. This is especially true in ethnic and
minority children. cType 1 can present acutely with symptoms of polyuria, nocturia,
polydipisia, polyphagia, weight loss. dType 2 children and adolescents are more
likely to present with ketones but after the acute phase can treated with oral agents.24
Prolonged fasting can also produce ketones in individuals.
Diabetes Mellitus
Manifestations:
• Symptoms of diabetes appear when the levels of glucose
are either very high or very low.
• Many persons with diabetes and all those with pre-diabetes
do not have symptoms.
• Children may also feel very tired all the time.
Diabetes Mellitus
Manifestations:
Weight loss.
The three “ploys” : Polydepsia (increased thirst),
Polyphagia (increased appetite),
Polyuria (increased urine output).
Weakness and fatigue due to poor energy
utilization and skeletal muscle catabolism .
Diabetes Mellitus
Why do the three “polys” occur?
Polyuria :Excess blood glucose filtered by the kidneys
cannot be reabsorbed and is eliminated at the expense of
water.
Polydepsia : Excessive thirst caused by the osmotic
diuresis of glucose and subsequent tissue dehydration. The
thirst response is mediated by the hypothalamus.
Polyphagia: Poor utilization of carbohydrates (due to the
lack of insulin) results in depletion of stored fats, proteins
and carbohydrates.
Diabetes Mellitus
Manifestations:
Diabetic ketoacidosis
Accumulation of acidic ketone bodies in the blood due to a
lack of insulin stimulated fatty acid utilization. Much more
common in type I than type 2
Ketone Bodies
•(β-hydroxybutyrate)
•(acetoacetate)
•(acetone)
- INSULIN
Fatty Acids
INSULIN+
Energy
Diabetes Mellitus
Manifestations:
Manifestations of Diabetic Ketoacidosis

Decreased blood pH levels.

Ketonuria — Appearance of excess ketones in the urine.

Lethargy.

Nausea and vomiting

Severe dehydration.

Markedly increased respiratory rate as an attempt to correct decreased blood pH.

Acetone breath — Acetone is a volatile ketone body that is eliminated via the lungs;
may be noticeable in the exhaled air during diabetic ketoacidosis.

Coma and possible death.
Diabetes Mellitus
Manifestations:
Hyperglycemic Hyperosmolar Syndrome

A syndrome of type I diabetes mellitus that can result from acute
insulin deficiency.

It may often accompany diabetic ketoacidosis.
The manifestations include:

Severe dehydration

Extreme thirst

Serum osmolarity over 300 mOsm due to excessive glucose in the
blood

Osmotic diuresis of glucose

Depressed neurologic function

Possible shock, coma and death
Complications
Diabetes: Complications
Macrovascular
Stroke
Microvascular
Diabetic eye disease
(retinopathy and cataracts)
Heart disease and
hypertension
2-4 X increased risk
Renal disease
Peripheral
vascular disease
Erectile Dysfunction
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Diabetes Mellitus
Complication:
1.Vascular Diseases

Chronic diabetes mellitus is associated with significant
increases in the incidence of coronary artery disease,
cerebrovascular disease and peripheral vascular disease.

May be due to a number of factors including elevated serum
lipid levels, vascular injury, and enhanced atherogenesis
(formation of atherosclerotic lesions).

Coronary artery disease and stroke are significant sources of
mortality and morbidity in patients with diabetes. Peripheral
vascular disease can lead to gangrene and amputations
(particularly of the toes and feet) in people suffering from
diabetes.
Diabetes Mellitus
Complication:
2.Diabetic neuropathy

Abnormality of nerve conduction and function.

Often affects peripheral nerves.

Can involve sensory or motor neurons.

May manifest as numbness, pain or sensory/motor impairment.

Often progressive and irreversible.

Although the exact cause is unknown, the neuropathy may be
related to ischemia or altered nerve cell metabolism.
Diabetes Mellitus
Complication:
3.Diabetic Retinopathy
Pathogenesis of DR:

The most serious consequence of long-term diabetes in terms of the
eye is retinal damage.

The retina is a highly metabolic tissue that is especially vulnerable to
the effects of chronic hypoxia and diabetes.

Hemorrhage of eye capillaries and chronic inflammation is common
and can lead to increases in intraocular pressure that scar the retina
and impair vision. This phenomenon is usually progressive and can
lead to blindness.

Diabetes is also associated with an increased incidence of glaucoma
and cataract formation.
Complication:
Diabetes Mellitus
Diabetic Retinopathy
Diabetes Mellitus
Complication:
4.Diabetic Nephropathy
It is a progressive kidney disease caused by angiopathy of
capillaries in the kidney glomeruli.
The glomerular injury is characterized by thickening of the glomerular
basement membrane and glomerulosclerosis.
Although the exact etiology is unclear, trapping of glycosylated proteins
in the glomeruli appears to be a key contributing factor.
 The appearance of protein (albumin) in the urine is an early indicator of
altered glomerular permeability (Microalbuminuria).
Renal function may continue to deteriorate as glomerular filtration decreases.
Signs and symptoms of renal failure will appear as renal function continues to
decline.
Diabetes Mellitus
Complication:
5. Impaired healing
and
increased infections

As a result of peripheral vascular disease, injuries in patients
with diabetes do not heal properly. Poor blood flow limits the
delivery of leukocytes and oxygen to the injured area while
impairing removal of debris and infectious organisms.

The high glucose levels serve as a nutrient to support the
growth of microorganisms.

Patients with diabetes might also be more susceptible to
physical injuries as a result of impaired vision and sensory
perception.
Erectile dysfunction


Erectile dysfunction (ED, "male impotence") is sexual
dysfunction characterized by the inability to develop or
maintain an erection of the penis during sexual
performance.
Since penile erection is neurovascular process, diabetic
patients usually suffer from vascular complications that
affect penile blood flow as well as neuropathies that
disturb the nervous control of penile erection.
Diabetes Mellitus
Complication:
6. Diabetic Foot
Pathogenesis:

Loss of protective sensation.

Starts distally and migrates proximally in
“stocking” distribution.

Mostly affects forefoot ulceration.

It results from repeated improper shoe ware,
deformity or injury by glass or any other objects.
Diabetes Mellitus
Complication:
Possible Mechanisms of Tissue Injury in Chronic D M
Glycosylation of proteins : Attachment of glucose to proteins in the eye, blood
vessel walls, and kidney membranes will change their structure and may lead to
altered function and eventual damage of these tissues. Circulating glycosylated
proteins may also be trapped in the glomeruli of the kidney, leading to
inflammation and injury.
Formation of alcohol sugars e.g. sorbitol : Unlike glucose, alcohol sugars do
not easily diffuse out of tissues. Because these alcohol sugars are osmotically
active, they can lead to swelling and damage of tissues. The accumulation of
other sugars such as galactose might also contribute to this phenomenon
Poor blood flow and oxygen delivery to tissues :Glycosylation of
hemoglobin alters its affinity for oxygen while progressive vascular disease can
reduce overall blood flow to tissues, leading to ischemic injury
Diabetes Mellitus
Diagnosis :
Diagnosis Criteria
Normal
Pre diabetes
Diabetes
Fasting Blood Glucose
Test (FBG)*
Less than
100
Between
100 - 125
More than or equal
to 126
Glucose Tolerance Test
(GTT) **
Less than
140
Equal to or more
than 140 but
less than 200
More than or equal
to 200
* FBG
blood test is done after fasting 8 hours.
** GTT results are repeated after 2 hours. A person drinks a 75 mg glucose solution
before test. 100 mg for Pregnant women.
Diabetes Mellitus
Treatment
Optimal diabetes control is a careful balance of Diet, Exercise, and Insulin
and/or oral medication
GOAL:
To maintain target
blood glucose
Diabetes Self-management
what a person with diabetes should do
by her/himself to maintain control
meal
plan
(always
eating
healthy)
exercise
moderately
(eg.
walking 30 minutes a day),
Exercise may enhance glucose
utilization and improve glucose
control in patients with type II
diabetes, thus reducing the risk
of diabetic complications.
Treatment of diabetes mellitus
The key to optimal diabetes control
is a careful balance or juggling of
food, exercise, and insulin and/or
exercise
oral medication.
As
a
general
medication
and
insulin
and/or
oral medication
rule,
insulin/oral
exercise/activity
makes blood glucose levels go
down.
food
Maintaining good blood glucose control is a constant
juggling act, 24 hours a day, 7 days a week.
2 to 3 portions
Less
than one
portion
2 to 3
portions
3 to 5
portions
6 to 11
portions
2 to 4 portions
Diabetes Mellitus
Type I of diabetes mellitus
Treatment:
Insulin replacement.
Insulin must be administered by injection because an oral form would be
degraded in the gastrointestinal tract.
Insulin is generally available in three preparations:
Short-acting form : Peak action in 2–4 hours, duration 6–8 hours.
Intermediate-acting form :Peak action in 6–12 hours, duration 12–24 hours.
Long-acting form : Peak action 8–24 hours, duration 24–36 hours.
Diabetes Mellitus
Type II of diabetes mellitus

Oral therapy: prescribed after dietary control has
been proven insufficient or if the client is highly
symptomatic

Classifications:

Sulfonylureas

Meglitnide analogs

Biguanides

Alpha-glucosidse inhibitors

Thiazolidinedione antidiabetic agents
Monitoring of DM
Frequent measurement of blood glucose levels
Measurement of glycosylated hemoglobin (Hb A1c,
hemoglobin that has glucose bound to it) that forms at a
rate that increases with increasing blood glucose, which is
a useful measure of blood glucose control in patients with
diabetes.
Why should we educate diabetics about diabetes?
BECAUSE…
☺Controlling Glucose Levels through Self Management
Every 1% drop of A1C significantly reduces the risk of eye, kidney,
and nerve complications
☺Controlling Blood Pressure  Will reduce the risk of heart
disease or stroke by 33% to 50%.
☺Controlling Lipids (fats)  Will reduce cardiovascular
complications by 20% to 50%.
☺Careful foot care  Will reduce amputations rates by 45% to
85%.
☺Careful eye care  Will reduce the development of severe
vision loss by 50% - 60%.
☺Careful kidney care  Will reduce the decline in kidney
function by 30% - 70%.
THANK YOU