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


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.


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.


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


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


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


Pathogenesis of DR:


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.


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.


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.


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 :


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.


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


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?

THANK YOUTHANK YOU

Documents

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