Yunita Linawati, M.Sc.

, Apt

1
 What is diabetes?

▪ Diabetes mellitus (DM) is a chronic condition

that is characterised by raised blood glucose
levels (Hyperglycemia).

2
Regulation of Plasma
Glucose Level

3
How Insuline Decrease
Plasma Glucose Level?

4
 Carbohydrate Metabolism

– Carbohydrates are metabolized in the body

to glucose.
– CNS uses glucose as its primary energy
source. This is independent of insulin.
– Glucose is taken by the muscle to produce
energy (insulin required).
– Glucose is stored in the liver as glycogen
and in adipose tissues as fat.
– Insulin is produced and stored by the β-
cells of the pancreas
5
 Carbohydrate Metabolism
– Postprandial glucose metabolism in normal
individuals:
– After food is ingested, blood glucose concs
rise and stimulate insulin release.

– Insulin action:
– glucose uptake by the tissues
– liver glycogen formation and glycogen
breakdown
– lipid synthesis and inhibits fatty acid
breakdown to ketone bodies
– Promotes protein synthesis
6
 Carbohydrate Metabolism

• Fasting glucose metabolism in normal

individuals:
– In the fasting state, insulin release is inhibited.

– Hormones that promote an increase in blood

glucose are released:
• Glucagon, epinephrine, growth hormone,
glucocorticoids, and thyroid hormones.

– Glycogenolysis

– Gluconeogenesis: AA are transported from muscle

to liver and converted to glucose.

– TG are broken down into free FFAs as an alternative

fuel source.
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 Classification of DM
1. Type 1 DM

• It is due to insulin deficiency and is formerly known as.

• Type I
• Juvenile onset DM

2. Type 2 DM

• It is a combined insulin resistance and relative deficiency in

insulin secretion and is frequently known as.
• Type II
• Adult onset DM

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3. Gestational Diabetes Mellitus (GDM):

➢ Gestational Diabetes Mellitus (GDM) developing during some

cases of pregnancy but usually disappears after pregnancy.

4. Other types:

➢ Secondary DM

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 Etiology

1. Etiology of Type 1 Diabetes

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2. Etiology of Type 2 Diabetes

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 Epidemiology
Characteristics Type 1 Type 2
% of DM 5-10% 90%
population
Age of onset Usually < 30 yr + some Usually > 40 + some obese
adults children
Pancreatic Usually none Insulin is low, normal or high
Function
Pathogenesis Autoimmune process Defect in insulin secretion,
tissue resistance to insulin,
increased Hepatic Glucose
Output
Family History Generally not strong Strong
Obesity Uncommon Common
History of Often Present Rare except in stress
Ketoacidosis
Clinical moderate to severe Mild symptoms: Polyuria and
Presentation symptoms: 3Ps, fatigue, fatigue. Diagnosed on routine
wt loss and physical examination
ketoacidosis
Treatment Insulin, Diet, Diet, Exercise 17
Exercise Oral antidiabetics, Insulin
 Risk Factors

• Type 1 DM
– Genetic predisposition
• In an individual with a genetic
predisposition, an event such as
virus or toxin triggers autoimmune
destruction of b-cells probably over
a period of several years.

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 Risk Factors

• Type 2 DM

– Family History
– Obesity
– Habitual physical inactivity
– Previously identified impaired glucose
tolerance (IGT) or impaired fasting
glucose (IFG)
– Hypertension
– Hyperlipidemia

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 Pathophysiology

• Type 1 DM

– Type 1 DM is characterized by an absolute

deficiency of insulin due to immune-
mediated destruction of the pancreatic b-
cells

– In rare cases the b-cell destruction is not

due to immune mediated reaction
(idiopathic type 1 DM)

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 Pathophysiology

• Type 1 DM
▪ There are four stages in the development of
Type 1 DM:

1. Preclinical period with positive b-cell antibodies

2. Hyperglycemia when 80-90% of the

β- cells are destroyed.

3. Transient remission (honeymoon phase).

3. Establishment of the disease

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 Pathophysiology

Birth 24
Time (years)
 Pathophysiology

• Type 2 DM

– Type 2 DM is characterized by the presence

of both insulin resistance (tissue
insensitivity) and some degree of insulin
deficiency or b- cell dysfunction

– Type 2 DM occurs when a diabetogenic

lifestyle (excessive calories, inadequate
caloric expenditure and obesity) is
superimposed upon a susceptible genotype
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 Laboratory Tests

1. Glucosuria

– To detect glucose in urine by a paper strip

• Semi-quantitative
• Normal kidney threshold for glucose is
essential
2. Ketonuria

– To detect keton bodies in urine by a

paper strip
• Semi-quantitative
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 Laboratory Tests

3. Fasting blood glucose

– Glucose blood concentration in samples

obtained after at least 8 hours of the last
meal

4. Random Blood glucose

– Glucose blood concentration in samples
obtained at any time regardless the time of
the last meal

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 Laboratory Tests

5. Glucose tolerance test

– 75 gm of glucose are given to the patient

with 300 ml of water after an overnight fast

– Blood samples are drawn 1, 2, and 3 hours

after taking the glucose

– This is a more accurate test for glucose

utilization if the fasting glucose is
borderline
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 Laboratory Tests

6. Glycosylated hemoglobin (HbA1C)

– HbA1C is formed by condensation of glucose

with free amino groups of the globin component
of hemoglobin

– Normally it comprises 4-6% of the total

hemoglobin.

– Increase in the glucose blood concentration

increases the glycated hemoglobin fraction.

– HbA1C reflects the glycemic state during the

preceding 8-12 weeks.
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 Laboratory Test

7. Serum Fructosamine

– Formed by glycosylation of serum protein (mainly

albumin)

– Since serum albumin has shorter half life than

hemoglobin, serum fructosamine reflects the
glycemic state in the preceding 2 weeks

– Normal is 1.5 - 2.4 mmole/L when serum albumin

is 5 gm/dL.

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 Diagnostic Criteria

• Any one test should be confirmed with a second test, most

often fasting plasma glucose (FPG).

• This criteria for diagnosis should be confirmed by

repeating the test on a different day.

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 Clinical Presentation

• Type 1 DM • Type 2 DM

- Polyuria - Patients can be asymptomatic

- Polydipsia - Polyuria
- Polydipsia
- Polyphagia
- Polyphagia
- Weight loss - Fatigue
- Weakness - Weight loss
- Dry skin - Most patients are discovered
- Ketoacidosis while performing urine glucose
screening
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 Treatment
Desired outcome
- Relieve symptoms
- Reduce mortality
- Improve quality of life
- Reduce the risk of microvascular and macrovascular
disease complications
- Macrovascular complications:
Coronary heart disease, stroke and peripheral vascular disease
- Microvascular Complications:
Retinopathy, nephropathy and neuropathy
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 Treatment

How to achieve the goals ?

- Near normal glycemic control reduce the risk

of developing microvascular disease
complications

- Control of the traditional CV risk factors such

as smoking, management of dyslipidemia,
intensive BP control and antiplatelet therapy.

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 Treatment

General approaches

- Medications
- Dietary and exercise modification
- Regular complication monitoring
- Self monitoring of blood glucose
- Control of BP and lipid level

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Treatment Glycemic goals

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 Treatment
Complication monitoring

- Annual eye examination

- Annual microalbuminuria
- Feet examination
- BP monitoring
- Lipid profile

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 Treatment
Self-monitoring of blood glucose

- Frequent self monitoring of blood

glucose to achieve near normal level

- More intense insulin regimen require

more frequent monitoring

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 Treatment
Nonpharmacological therapy

Diet
- Type 1 DM the goal is to regulate insulin
administration with a balanced diet

- In most cases, high carbohydrate, low fat, and low

cholesterol diet is appropriate

- Type 2 DM patients need caloric restriction

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 Treatment
Nonpharmacological therapy

Diet
- Artificial sweeteners:
- e.g. Aspartame, saccharin, sucralose, and acesulfame
- Safe for use by all people with diabetes
- Nutritive sweeteners:
- e.g. fructose and sorbitol
- Their use is increasing except for acute diarrhea in
some patients
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 Treatment
Nonpharmacological therapy

Activity

- Exercise improves insulin resistance and achieving glycemic

control.
- Exercise should start slowly for patients with limited activity.
- Patients with CV diseases should be evaluated before
starting any exercise

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 Treatment
Pharmacological therapy

- Insulin (Type 1 and Type 2 DM)

- Sulfonylurea (Type 2 DM)
- Biguanides (Type 2 DM)
- Meglitinides (Type 2 DM)
- Thiazolidinediones Glitazones (Type 2 DM)
 a-Glucosidase inhibitors (Type 2 DM)

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 Pharmacological Treatment of Type 2 DM
Strategy for Controlling Hyperglycemia
Absorption from Diet Biosynthesis in Liver

a-Glucosidase Biguanides
Inhibitors

Cellular Uptake
Serum Sugar
Biguanides;
thiazolidinediones

Pancreas
Insulin

Sulfonylureas
Meglitinide
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1. Sulfonylureas
Pharmacological effect

• Stimulate the pancreatic secretion of insulin

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Sulfonylureas
Classification
• First generation
• e.g. tolbutamide, chlorpropamide, and acetohexamide
• Lower potency, more potential for drug interactions
and side effects
• Second generation
• e.g. glimepiride, glipizide, and glyburide
• higher potency, less potential for drug interactions and
side effects
• All sulfonylurea drugs are equally effective in reducing the
blood glucose when given in equipotent doses. 47
 Major Pharmacokinetic Properties of Sulfonyl Ureas

Eqv. Dose Duration Active metabolites

(mg) (h)

First Generation
Tolbutamide 1000-1500 12-24 Yes (p-OH derivative)

Chlorpropamide 250-375 24-60 Yes (2’-OH and 3’OH groups)

Tolazamide 250-375 12-24 No (4-COOH derivative)

Second
generation
Glipizide 10 10-24 No (cleavage of pyrazine ring)

Glyburide 5 16-24 Some (trans + cis 4’-OH groups)

(glibenclamide)

Third generation
Glimepiride 1-2 24 Yes (-OH on CH3 of R’ group)
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Sulfonylureas
Efficacy
– HbA1c: 1.5 – 1.7% reduction.
– FPG: 50 – 70 mg/dL reduction.
– PPG: 92 mg/dL reduction.

Adverse effects
– Hypoglycemia
– Hyponatremia (with tolbutamide and chlorpropamide)
– Weight gain

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Sulfonylureas
Drug interactions

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2. Short-acting Secretogogues/Meglitinide
– Repaglinide
– Nateglinide

Pharmacological effect
– Stimulation of the pancreatic secretion of insulin
– The insulin release is glucose dependent and is decreased
at low blood glucose
– With lower potential for hypoglycemia (incidence 0.3%)
– Should be given before meal or with the first bite of each
meal. If you skip a meal don’t take the dose!
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 2. Short-acting Secretogogues/Meglitinide

Adverse effect
– Incidence of hypoglycemia is very low about 0.3 %

Drug Interactions

– Inducers or inhibitors of CYP3A4 affect the action of repaglinide

– Nateglinide is an inhibitor of CYP2C9

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3. Biguanides Metformin (Glucophage)
Pharmacological effect
– Reduces hepatic glucose production
– Increases peripheral glucose utilization

Adverse effects
– Nausea, vomiting, diarrhea, and anorexia

– Phenformin: another biguanide, was taken off the market

because it causes lactic acidosis in almost 50% of patients

– As a precaution metformin should not be used in patients

with renal insufficiency, CHF, conditions that lead to hypoxia
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4. Thiazolidinediones/Glitazones (TZDs)
- Rosiglitazone - Pioglitazone

Pharmacological effect

– Reduces insulin resistance in the periphery (Sensitize muscle and

fat to the action of insulin) and possibly in the liver
– The onset of action is slow taking 2-3 months to see the full effect
– Edema and weight gain are the most common side effects (no
hepatotoxicity).

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5. a-Glucosidase Inhibitors
- Acarbose - Miglitol

Pharmacological effect
• Prevent the breakdown of sucrose and complex
carbohydrates
– The net effect is to reduce postprandial blood glucose rise
– The effect is limited to the luminal side of the intestine with
limited systemic absorption. Majority eliminated in the feces.
– Postprandial glucose conc is reduced.
– FPG relatively unchanged.
– Average reduction in HbA1c: 0.3-1.0%
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Oral Hypoglycemic Medications

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 Pharmacotherapy :Type 2 DM

General considerations:
- Consider therapeutic life style changes (TLC) for
all patients with Type 2 DM
- Initiation of therapy may depend on the level of HbA1C
- HbA1C < 7% may benefit from TLC

- HbA1C 8-9% may require one oral agent

- HbA1C > 9-10% my require more than one oral agent

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 Pharmacotherapy :Type 2 DM

Obese Patients >120% LBW:

Metformin or TZDs

Add SU or short-acting insulin

secretagogue/Meglitinide

Add Insulin or TZDs

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 Pharmacotherapy :Type 2 DM

Non-obese Patients <120% LBW:

SU or short-acting insulin
secretagogue/Meglitinide

Add Metformin or TZDs

Add Insulin
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Pharmacotherapy :Type 2 DM
Elderly Patients with newly diagnosed
DM :
SU or short-acting insulin
secretagogue or a-glucosidase
inhibitor or insulin

Add or substitute insulin

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Pharmacotherapy :Type 2 DM
Early insulin resistance :
Metformin or TZDs

Add TZDs or metformin

Add SU or short-acting insulin

secretagogue or insulin
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 Combination Oral Agents

Combination oral agents is indicated in:

• Newly diagnosed symptomatic patients with

HbA1c >10

• Patients who are not reaching targets after 3

months on monotherapy

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 Combination Oral Agents and Insulin
 If targets have not been reached after optimal dose of
combination therapy for 3 months, consider adding
intermediate-acting/long-acting insulin.
 Combining insulin and the following oral anti-diabetic
agents has been shown to be effective in people with type
2 diabetes:
◦ Biguanide (metformin)
◦ Insulin secretagogues (sulphonylureas)
◦ Insulin sensitizers (TZDs)(the combination of a TZD
plus insulin is not an approved indication)
◦ α-glucosidase inhibitor (acarbose)
 Insulin dose can be increased until target FPG is
achieved.
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 Insulin
Pharmacological effect:

Anabolic Anticatabolic

- Glucose uptake - Inhibits gluconeogenesis

- Glycogen synthesis- Inhibits glycogenolysis
- Lipogenesis - Inhibits lipolysis
- Protein synthesis - Inhibits proteolysis
- Triglyceride uptake - Inhibits fatty acid
oxidation
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Insulin
Strength

- The number of units/ml

e.g. U-100 , U-20, U-10

Source
- Pork: Differs by one a.a.
- Beef-Pork
- Human (recombinant DNA technology)
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 Insulin
Onset and duration of effect

Changing the properties of insulin preparation can

alter the onset and duration of action
- Lispro: absorbed to the circulation very rapidly
- Aspart: absorbed to the circulation very rapidly
- Regular: absorbed rapidly but slower than lispro
and aspart

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 Insulin
Onset and duration of effect
- Lente insulin: Amorphous precipitate of insulin and
zinc and insoluble crystals of insulin and zinc.
Releases insulin slowly to the circulation
- NPH: R-insulin + Protamine zinc insulin. Releases
insulin slowly to the systemic circulation
- Insulin glargine: Prepared by modification of the
insulin structure. Precipitate after S.C. injection to
form microcrystals that slowly release insulin to the
systemic circulation (N.B. cannot be mixed with other
insulins)
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 Insulin
Onset and duration of effect
- Rapid-acting insulin
- e.g. Insulin lispro and insulin aspart
- Short-acting insulin
- e.g. Regular insulin
- Intermediate-acting insulin
- e.g. NPH and Lente insulin
- Long-acting insulin
- e.g. Insulin Glargine
- Mixture of insulin can provide glycemic control over
extended period of time
- e.g. Humulin 70/30 (NPH + regular)
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 Insulin
Adverse effects
- Hypoglycemia
- Treatment:
- Patients should be aware of symptoms of hypoglycemia
- Oral administration of 10-15 gm glucose
- IV dextrose in patients with lost consciousness
- 1 gm glucagon IM if IV access is not available

- Skin rash at injection site

- Treatment: Use more purified insulin preparation

- Lipodystrophies (increase in fat mass) at injection site

- Treatment: rotate the site of injection

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 Diabetes Mellitus
Drug Therapy: Insulin
• Problems with insulin therapy
– Somogyi effect
• Due to too much insulin
• Early morning hypoglycemia followed by
hyperglycemia
– Dawn Phenomenon
• Hyperglycemia secondary to night time release of
growth hormone (a counter-regulatory hormone)
that cause  BS in early am (5 – 6 am).
• Rx with insulin that will peak at that time
(intermediate at 10 pm)

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 Insulin
Drugs interfering with glucose tolerance
• The most significant interactions are with drugs that alter
the blood glucose level:

- Diazoxide
- Thiazide diuretics
- Corticosteroids
- Oral contraceptives
- Streptazocine
- Phenytoin
• All these drugs increase the blood glucose concentration.
• Monitoring of BG is required.

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 Insulin
Methods of Insulin Administration

• Insulin syringes and needles

• Pen-sized injectors

• Insulin Pumps

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 Diabetes Mellitus
Drug Therapy: Insulin

• Insulin
– Cannot be taken orally
– Self-administered by SQ injection

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Injection Sites

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Pharmacotherapy :Type 1 DM

The choice of therapy is simple

All patients need Insulin

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 Pharmacotherapy :Type 1 DM

The goal is:

To balance the caloric intake with the

glucose lowering processes (insulin and
exercise), and allowing the patient to live
as normal a life as possible

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 Pharmacotherapy :Type 1 DM
Breakfast Lunch Supper
Concentration
Insulin

Time of day

Normal insulin secretion during he day

- Constant background level (basal)
- Spikes of insulin secretion after eating
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 Pharmacotherapy :Type 1 DM

- -The insulin regimen has to mimic the physiological

secretion of insulin

- With the availability of the SMBG and HbA1C

tests adequacy of the insulin regimen can be
assessed

- More intense insulin regimen require more intense

monitoring

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 Pharmacotherapy :Type 1 DM

Example:

1- Morning dose (before breakfast):

Regular + NPH or Lente
2- Before evening meal:
Regular + NPH or Lente
Require strict adherence to the timing of meal and
injections
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 Pharmacotherapy :Type 1 DM

Modification
- NPH evening dose can be moved to bedtime
- Three injections of regular or rapid acting insulin
before each meal + long acting insulin at bedtime (4
injections)
- The choice of the regimen will depend on the patient

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 Pharmacotherapy :Type 1 DM

How much insulin ?

- A good starting dose is 0.6 U/kg/day
- The total dose should be divided to:
- 45% for basal insulin
- 55% for prandial insulin
The prandial dose is divided to
- 25% pre-breakfast
- 15% pre-lunch
- 15% pre-supper 83
 Pharmacotherapy :Type 1 DM

Example: For a 50 kg patient

- The total dose = 0.6X50 = 30 U/day
- 13.5 U for basal insulin (45% of dose)
- Administered in one or two doses
- 16.5 U for prandial insulin (55% of dose)
The 16.5 U are divided to:
- 7.5 U pre-breakfast (25%)
- 4.5 U pre-lunch (15%)
- 4.5 U pre-supper (15%)
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 Pharmacotherapy :Type 1 DM

Monitoring
- Most Type 1 patients require
0.5-1.0 U/kg/d
- The initial regimen should be modified
based on:
- Symptoms
- SMBG
- HbA1C
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 Pharmacotherapy :Type 1 DM
Monitoring

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 Pharmacotherapy :Type 1 DM
Insulin Pump Therapy
- This involves continuous SC administration of
short-acting insulin using a small pump
- The pump can be programmed to deliver basal
insulin and spikes of insulin at the time of the
meals
- Requires intense SMBG
- Requires highly motivated patients because
failure to deliver insulin will have serious
consequences 87
Pharmacotherapy :Type 1 DM
Insulin Pump

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 II. Surgery

• Islet transplantation has been investigated as a

treatment for type 1 diabetes mellitus in selected
patients with inadequate glucose control despite
insulin therapy.

• Observations in patients with type 1 diabetes

indicate that islet transplantation can result in
insulin independence with excellent metabolic
control

Ref. Shapiro A.M. J., et al. N Engl J Med 2000; 343:230-238, Jul 27, 2000
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 Complications of Diabetes
• Short term:
– Symptoms of diabetes
– Dehydration
– Diabetic Coma
– Infections
• Long term:
– Kidney
– Eye
– Heart
– Circulation
– Amputation
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Diabetes Mellitus Complications
1. Hypoglycemia

- Cause: Missing meals or excessive exercise or too

much insulin
- Symptoms: Tachycardia, palpitation, sweating,
nausea, and vomiting. Progress to mental confusion,
bizarre behavior and coma
- Treatment: Candy or sugar
IV glucose
Glucagon 1 gm IM

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 Diabetes Mellitus Complications
2. Diabetes retinopathy

- Microaneurysm
- Hemorrhage
- Exudates
- Retinal edema

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 Diabetes Mellitus Complications

3. Diabetes nephropathy
- 30-40 % of all type 1 DM patients develop
nephropathy in 20 years
- 15-20 % of type 2 DM patients develop nephropathy

- Manifested as:
- Microalbuminuria
- Progressive diabetic nephropathy leading to end-
stage renal disease

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 Diabetes Mellitus Complications
Diabetes nephropathy
- All diabetic patients should be screened annually for
microalbuminurea to detect patients at high risk of
developing progressive diabetic nephropathy

- Tight glycemic control and management of the blood

pressure can significantly decrease the risk of
developing diabetic nephropathy.

- ACE-inhibitors are recommended to decrease the

progression of nephropathy
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Diabetes Mellitus Complications
4. Diabetes neuropathy

Autonomic neuropathy:
- Manifested by orthostatic hypotension, diabetic
diarrhea, erectile dysfunction, and difficulty in
urination. 95
 Diabetes Mellitus Complications
5. Peripheral vascular disease and foot ulcer
Incidence of gangrene
of the feet in DM is 20
fold higher than control
group due to:
- Ischemia
- Peripheral neuropathy
- Secondary infection

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 Special Patient Population

1. Adolescent Type 2 DM
- Type 2 DM is increasing in adolescent
- Lifestyle modification is essential in these patients
- If lifestyle modification alone is not effective,
metformin the only labeled oral agent for use in
children (10-16 years)

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 Special Patient Population
2. Gestational DM
- Dietary control
- If blood glucose is not controlled by dietary control,
insulin therapy is initiated

- One dose of NPH or NPH + regular insulin (2:1) given

before breakfast. Adjust regimen according to SMBG.
- Sulfonylureas: Effective, but require further studies to
demonstrate safety.

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 Special Situations
3. Diabetic ketoacidosis
- It is a true emergency

- Usually results from omitting insulin in type 1 DM or

increase insulin requirements in other illness (e.g.
infection, trauma) in type 1 DM and type 2 DM

- Signs and symptoms:

- Fatigue, nausea, vomiting, evidence of
dehydration, rapid deep breathing, fruity breath
odor, hypotension and tachycardia 99
 Special Situations
Diabetic ketoacidosis
- Diagnosis
- Hyperglycemia, acidosis, low serum
bicarbonate, and positive serum ketones
- Abnormalities:
- Dehydration, acidosis, sodium and
potassium deficit
- Patient education is important

100
 Special Situations
Diabetic ketoacidosis
Management:
- Fluid administration: Rapid fluid administration to
restore the vascular volume,
- IV infusion of insulin to restore the metabolic
abnormalities. Titrate the dose according to the blood
glucose level.
- Potassium and phosphate can be added to the fluid if
needed.
Follow up:
- Metabolic improvement is manifested by an increase in
serum bicarbonate or pH.
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