Dr: Wael H.Mansy, MD

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Diabetes Mellitus
Dr Wael H.Mansy, MD Assistant Professor College
of Pharmacy King Saud University
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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
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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

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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
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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 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.
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Diabetes Classification

• Majority of diabetics classified in 2 categories
• type 1 absolute deficiency of insulin
• type 2 presence of insulin resistance with
  reduced insulin secretion
• Gestational diabetes
• triggered by stress of pregnancy
• Other specific types
• infections, drugs, endocrinopathies, pancreatic
  destruction, genetic defects

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Type 1 DM

• Autoimmune destruction of pancreatic ß-cells
• 90 of patients have markers of immune ß-cell
  destruction at diagnosis
• children adolescents often have rapid ß-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

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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.

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LADA (cont.)
(Islet Cell Antibodies)
(Glutamic Acid Decarboxylase Autoantibodies)
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Type 1 DM Pathogenesis

• Preclinical period
• immune markers present
• ß-cell destruction
• Hyperglycemia
• 80 to 90 of ß-cells destroyed
• Transient remission
• honeymoon phase
• Established disease

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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

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NCEP ATP III Components of the Metabolic
Syndrome (gt 3 for diagnosis)
Risk Factor Defining Level
Abdominal obesitya
Men (waist circumference)b gt 102 cm (gt 40 in.)
Women gt 88 cm (gt 35 in.)
Triglycerides gt 1.7 mmol/L (gt 150 mg/dL)
HDL cholesterol
Men lt 1.0 mmol/L (lt 40 mg/dL)
Women lt 1.3 mmol/L (lt 50 mg/dL)
Blood Pressure 130/ 85 mmHg
Fasting glucose gt 6.1 mmol/L ( gt 110 mg/dL)
NCEP-ATP National Cholesterol Education Program
Adult Treatment Panel
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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

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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.
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Type 2 DM Screening
ADA Type 2 Diabetes Screening Recommendations 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 gt 85th percentile for age sex, gt 85th
  percentile weight for height, or gt 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 childs gestation
• c BMI 25kg/m2

American Diabetes Association. Standards of
medical care in diabetes -2009. Diabetes Care
200932S13-S61.
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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 on therapy for HTN

• CV disease
• HDL lt 35 mg/dL
• Triglycerides gt 250 mg/dL
• Delivery of gt 9 lb baby
• History of GDM
• Insulin resistance
• Polycystic ovary syndrome

American Diabetes Association. Standards of
medical care in diabetes -2009. Diabetes Care
200932S13-S61.
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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

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American Diabetes Association. Standards of
medical care in diabetes -2009. Diabetes Care
200932S13-S61.
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• 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.

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Diagnosis

• Normal
• FPG lt 100 mg/dL
• 2 hr postload plasma glucose lt 140 mg/dL
• Impaired fasting glucose (IFG)
• FBG 100 to 125 mg/dL
• Impaired glucose tolerance (IGT)
• 2 hr postload plasma glucose 140 to 199 mg/dL
• Diabetes mellitus
• FPG 126 mg/dL
• 2 hr postload plasma glucose 200 mg/dL

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Diagnosis
ADA Criteria for DM 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

DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells
BG, Posey LM Pharmacotherapy A Pathophysiologic
Approach, 7th Edition http//www.accesspharmacy.c
om
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Clinical Presentation of Diabetesa
Characteristic  Type 1 DM  Type 2 DM 
Age lt 30 yearsb gt 30 yearsb
Onset Abrupt Gradual
Body habitus Lean Obese or history of obesity
Insulin resistance Absent Present
Autoantibodies Often present Rarely present
Symptoms Symptomaticc Often asymptomatic
Ketones at diagnosis Present Absentd
Need for insulin therapy Immediate Years after diagnosis
Acute complications Diabetic ketoacidosis Hyperosmolar hyperglycemic state
Microvascular complications at diagnosis No Common
Macrovascular complications at or before diagnosis Rare Common
aClinical presentation can vary widely. bAge of
onset for type 1 DM is generally lt 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. Prolonged fasting
can also produce ketones in individuals.
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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.

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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 .

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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.

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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
• (ß-hydroxybutyrate)
• (acetoacetate)
• (acetone)

- INSULIN Fatty Acids INSULIN
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• 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.

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• 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

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Diabetes Complications
Complications
Macrovascular
Microvascular
Diabetic eye disease (retinopathy and cataracts)
Stroke
Heart disease and hypertension 2-4 X increased
risk
Renal disease
Peripheral vascular disease
Erectile Dysfunction
Peripheral Neuropathy
Foot problems
Meltzer et al. CMAJ 199820(Suppl 8)S1-S29.
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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.

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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.

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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.

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Diabetic Retinopathy
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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.

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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.

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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.

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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.

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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

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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.
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Diabetes Mellitus
Treatment Optimal diabetes control is a careful
balance of Diet, Exercise, and Insulin and/or
oral medication
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Diabetes Self-management
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Treatment of diabetes mellitus
The key to optimal diabetes control is a careful
balance or juggling of food, exercise, and
insulin and/or oral medication. As a general
rule, insulin/oral medication and
exercise/activity makes blood glucose levels go
down.
Maintaining good blood glucose control is a
constant juggling act, 24 hours a day, 7 days a
week.
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2 to 3 portions 2 to 4 portions
Less than one portion 2 to 3 portions 3 to 5
portions 6 to 11 portions
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• 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 24 hours, duration 68
hours. Intermediate-acting form Peak action in
612 hours, duration 1224 hours. Long-acting
form Peak action 824 hours, duration 2436
hours.
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• 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

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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.

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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.

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THANK YOU