Dr: Wael H.Mansy, MD Assistant Professor College of Pharmacy King Saud University Diabetes Mellitus Diabetes Mellitus
Dr: Wael H.Mansy, MDAssistant Professor
College of Pharmacy
King Saud University
Diabetes Diabetes Mellitus Mellitus
• 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 MellitusDiabetes Mellitus Study Objectives
Diabetes MellitusDiabetes 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
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Adipose TissueIncreased glucose entry
Increased fatty acid synthesis
Increased glycerol phosphate synthesis
Activation of lipoprotein lipase
Inhibition of hormone-sensitive lipase
Increased K+ uptake
MuscleIncreased 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
LiverDecreased ketogenesis
Increased protein synthesis
Increased lipid synthesis
Decreased glucose output due to decreased gluconeogenesis, increased glycogen synthesis, and increased glycolysis
GeneralIncreased 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 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
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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
LADA (cont.)
(Islet Cell Antibodies)(Glutamic Acid Decarboxylase Autoantibodies)
Type 1 DM Pathogenesis
1. Preclinical period immune markers present β-cell destruction
2. Hyperglycemia 80 to 90% of β-cells destroyed
3. Transient remission honeymoon phase
4. 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 (> 3 for diagnosis)
Risk Factor Defining LevelAbdominal obesitya
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
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
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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
aBMI > 85th percentile for age & sex, > 85th percentile weight for height, or > 120% of ideal weight for heightbFamily 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
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
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
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 < 35 mg/dL Triglycerides > 250
mg/dL Delivery of > 9 lb baby History of GDM Insulin resistance Polycystic ovary
syndrome
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Type 2 DM Risk Factors
American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
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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19American Diabetes Association. Standards of medical care in diabetes -2009. Diabetes Care 2009;32:S13-S61.
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.
Diabetes MellitusDiabetes Mellitus Gestational diabetes mellitus
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Diagnosis
Normal FPG < 100 mg/dL 2 hr postload plasma glucose < 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
In absence of unequivocal hyperglycemia: confirm on different day
a Fasting: no caloric intake for at least 8 hoursb Classic symptoms: polyuria, polydipsia, unexplained weight lossc Causal: any time of day without regard to last meald 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.com
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
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Characteristic Type 1 DM Type 2 DM
Age < 30 yearsb > 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
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Clinical Presentation of Diabetesa
aClinical 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. Prolonged fasting can also produce ketones in individuals.
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 Diabetes MellitusMellitus
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 MellitusDiabetes 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 MellitusDiabetes Mellitus
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
- INSULIN Fatty Acids INSULIN+
Energy
Ketone Bodies•(β-hydroxybutyrate)
•(acetoacetate)•(acetone)
Diabetes MellitusDiabetes Mellitus ManifestationsManifestations::
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 MellitusDiabetes Mellitus ManifestationsManifestations::
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
Diabetes MellitusDiabetes Mellitus ManifestationsManifestations::
Macrovascular Microvascular
Stroke
Heart disease and hypertension
2-4 X increased risk
Foot problems
Diabetic eye disease(retinopathy and cataracts)
Renal disease
Peripheral Neuropathy
Peripheral vascular disease
Diabetes: Complications
Meltzer et al. CMAJ 1998;20(Suppl 8):S1-S29.
Complications
Erectile Dysfunction
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 MellitusDiabetes Mellitus Complication:Complication:
1.Vascular Diseases 1.Vascular Diseases
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.
2.Diabetic neuropathy2.Diabetic neuropathy
Diabetes MellitusDiabetes Mellitus Complication:Complication:
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.
3.Diabetic Retinopathy3.Diabetic Retinopathy
Diabetes MellitusDiabetes Mellitus Complication:Complication:
Pathogenesis of DR:
Diabetes MellitusDiabetes Mellitus Complication:Complication:
Diabetic RetinopathyDiabetic Retinopathy
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 MellitusDiabetes Mellitus Complication:Complication:
4.Diabetic Nephropathy4.Diabetic Nephropathy
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.
Diabetes MellitusDiabetes Mellitus Complication:Complication:
5. Impaired healing 5. Impaired healing and and
increased infectionsincreased infections
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.
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 MellitusDiabetes Mellitus Complication:Complication:
6. Diabetic Foot6. Diabetic Foot
Pathogenesis:
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
Possible Mechanisms of Tissue Injury in Chronic D M
DiabetesDiabetes MellitusMellitus Complication:Complication:
Normal Pre diabetes
Diabetes
Fasting Blood Glucose Test (FBG)*
Less than100
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
Diagnosis Criteria
* 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 MellitusDiabetes Mellitus Diagnosis :Diagnosis :
Diabetes MellitusDiabetes Mellitus
Treatment
Optimal diabetes control is a careful balance of Diet, Exercise, and Insulin
and/or oral medication
GOAL:
To maintain target blood
glucose
DiabetesDiabetes Self- Self-managementmanagement
meal plan (always eating meal plan (always eating healthy)healthy)
exercise moderately (eg. exercise moderately (eg. walking 30 minutes a day), walking 30 minutes a day), Exercise may enhance glucose Exercise may enhance glucose utilization and improve glucose utilization and improve glucose control in patients with type II control in patients with type II diabetes, thus reducing the risk diabetes, thus reducing the risk of diabetic complications.of diabetic complications.
what a person with diabetes should do what a person with diabetes should do by her/himself to maintain controlby her/himself to maintain control
insulin and/or
oral medication
food
exercise
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.
Treatment of diabetes mellitus
Maintaining good blood glucose control is a constant
juggling act, 24 hours a day, 7 days a week.
Less than one portion
2 to 3 portions
3 to 5 portions
6 to 11 portions
2 to 3 portions
2 to 4 portions
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 MellitusDiabetes Mellitus
Type I of diabetes mellitus
Treatment:
Insulin replacement.
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
Diabetes MellitusDiabetes Mellitus
Type II of diabetes mellitus
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.
Monitoring of DM
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%.
Why should we educate diabetics about diabetes?
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