Diabetes mellitus

Lestari Rahayu
 Diabetes- What is it?
• Body is not producing or has lost sensitivity to
insulin.
• Insulin is a hormone that is needed to convert
sugar, starches and other food into energy.
• Insulin is produced in the body by the
pancreas.
 Types of Diabetes
There are several types of diabetes:

• Type I - body does not produce any insulin.

• Type II- body is not making enough or is losing
sensitivity to insulin made.
 Types of Diabetes
• Secondary - a consequence from another
disease. For example, pancreatitis.
• Gestational Diabetes- diabetes during
pregnancy.
• Impaired Glucose Tolerance- an intermediate
between normal and diabetes.
 Type I
• Usually diagnosed in children and young
adults.
• Must take daily insulin shots to stay alive.
• Type I accounts for 5-10% of the population
with diabetes.
 Type II
• The most common form of the disease.
• Approximately 50% of men and 70% of
women are obese at the time of diagnosis.
 Characteristic Type 1 ( 10% ) Type 2
Onset (Age) Usually < 30 Usually > 40
Type of onset Abrupt Gradual
Nutritional status Usually thin Usually obese
Clinical symptoms Polydipsia, polyphagia, Often asymptomatic
polyurea, Wt loss
Ketosis Frequent Usually absent
Endogenous insulin Absent Present, but relatively
ineffective
Related lipid Hypercholesterolemia Cholesterol & triglycerides
abnormalities frequent, all lipid fractions often elevated;
elevated in ketosis carbohydrate- induced
hypertriglyceridemia
Insulin therapy Required common
Required in only 20 - 30%
of patients
Hypoglycemic drugs Should not be used Clinically indicated
Diet Mandatory with insulin Mandatory with or without
drug
 Gestational Diabetes
• Pregnant women have a higher insulin level.
• If woman has hyperglycemia, her blood
glucose crosses the placenta but her insulin
does not.
• This can cause a high birth weight for baby.
 What are the Symptoms?
• Polyphasia- excessive eating
• Polyurea- excessive urination
• Polydypsia-excessive fluid intake
• Blurred vision
• Poor wound healing
• Irritability
 Diagnosis DM
• In order to be diagnosed with diabetes:
• Person must have symptoms of diabetes
• Fasting blood glucose of >126 mg/dl
• 2-hour post prandial plasma glucose >200
mg/dl
 Who’s at risk?
ADA now recommends that screening for
diabetes should be considered for all patients
at age 45. If the results are normal it should be
repeated every 3 years.
Screening should be considered at a younger
age if patient meets following risk factors:
 Who’s at risk?
• Obesity
• First degree relative with diabetes
• Belongs to a high-risk ethnic group
• Was diagnosed with gestational diabetes or
delivered a baby whose birth weight >9 lbs.
• Hypertension
• HDL level<35 or triglycerides >250
• Found to have impaired glucose tolerance
or impaired fasting on a previous test.
 I’ve got Diabetes, now what?
• After diagnosis, there is a great need for
education.
• A diabetic diet is no different from anyone
else’s but they must keep track of what they
eat.
• Serving sizes must be emphasized.
• Carbohydrates are the component of food that
causes an increase in blood sugar.
 Blood Glucose Monitoring
• All diabetics must keep track of blood glucose levels.
• This is the only way to know if the treatment is
effective.
• Gives the diabetic a good indication of what affects
their blood sugar level.
• Must check at least 2 times a day and four times a
day for at least 3 days a week.
 Dietary Guidelines
• Eat a diet low in saturated and total fat.
• Eat a diet moderate in sodium and sugar.
• Eat 5 or more fruits and vegetables a day.
• Choose a diet rich in whole grains.
• Moderate use of alcohol
• Eat at the same time everyday , at least
within 1 hour of regular time.
• Eat about the same amount of
carbohydrate with each meal.
 Other Treatments
• Type I and sometimes Type II patients need to
be treated with insulin.
• There are more than 20 types.
• They differ in how they are made, how they
work in the body and their cost.
 TYPES OF INSULIN PREPARATIONS

1. Ultra-short-acting

2. Short-acting (Regular)

3. Intermediate-acting

4. Long-acting
 Short-acting (regular) insulins
e.g. Humulin R, Novolin R
Uses Designed to control
postprandial hyperglycemia &
to treat emergency diabetic
ketoacidosis
Physical Clear solution at neutral pH
characteristics
Chemical Hexameric analogue
structure
Route & time of S.C. 30 – 45 min before meal
administration
I.V. in emergency
(e.g. diabetic ketoacidosis)
Ultra-Short acting insulins
e.g. Lispro, aspart, glulisine
Similar to regular insulin but
designed to overcome the
limitations of regular insulin
Clear solution at neutral pH
Monomeric analogue
S.C. 5 min (no more than 15
min) before meal
I.V. in emergency
(e.g. diabetic ketoacidosis)

Onset of action 30 – 45 min ( S.C ) 0 – 15 min ( S.C )

Peak serum 2 – 4 hr 30 – 90 min

levels

Duration of 6 – 8 hr 3 – 4 hr
action

Usual 2 – 3 times/day or more 2 – 3 times / day or more

 3. Intermediate - acting insulins

e.g. isophane (NPH)

Turbid suspension
Injected S.C.(Only)
Onset of action 1 - 2 hr
Peak serum level 5 - 7 hr
Duration of action 13 - 18 hr
Insulin mixtures
75/25 70/30 50/50 ( NPH / Regular )
3. Intermediate - acting insulins (contd)
Lente insulin

Turbid suspension
Mixture of 30% semilente insulin
70% ultralente insulin
Injected S.C. (only)
Onset of action 1 - 3 hr
Peak serum level 4 - 8 hr
Duration of action 13 - 20 hr
 4. Long – acting insulins
e.g.Insulin glargine
Onset of action 2 hr
Absorbed less rapidly than NPH&Lente insulins.
Duration of action upto 24 hr
Designed to overcome the deficiencies of intermediate
acting insulins
Advantages over intermediate-acting insulins:
Constant circulating insulin over 24hr with no pronounced
peak.
More safe than NPH&Lente insulins due to reduced risk of
hypoglycemia(esp.nocturnal hypoglycemia).
Clear solution that does not require resuspention before
administration.
Glargine
 Efek Samping Insulin
1. Hipoglikemia, biasanya terjadi karena over dosis
insulin atau pasien lupa makan sesudah mendapat
insulin
2. Rx hipersensitifitas, biasanya disebabkan
pembentukan antibodi terhadap protein asing
terutama bila diberi insulin sapi.
3. Lipoatrofia (susutnya lemak subkutan ditempat
injeksi) biasanya disebabkan karena salah teknik
injeksi atau kurang sering mengganti tempat injeksi
4. Gangguan akomodasi akibat terlalu berfluktuasinya
kadar glukosa darah yang biasanya terjadi pada 6
minggu pertama terapi
 Oral Medications
Used to treat Type II diabetics. There are four
basic types:
• Sulfonylurea-stimulates the body to make
more insulin.
Meglitinides
• Biguanides-lowers blood sugar by helping
the insulin work better
• Thiazolidinediones- increases muscle
sensitivity to insulin.
• Alpha-glucosidase inhibitors- slow the
process of carbohydrate digestion.
 Primary Sites of Action of Oral
Antihyperglycemic Agents
Stomach -glucosidase inhibitors

Carbohydrate
Gut
I
Insulin Glucose (G)
G
secretagogues I Adipose tissue
G I
Insulin

G
G
PancreasG I

G
I
G
I
I G
G
I
Muscle
G

G
I
I
G

Liver Thiazolidinediones
Biguanides

Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.

Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
 Oral Anti-Diabetic Agents

Sulfonylureas Drugs other than

Sulfonylurea
 Sulfonylureas (Oral Hypoglycemic drugs)

First generation Second generation

Short Intermediate Long Short Long

acting acting acting acting acting

Glyburide
Tolbutamide Acetohexamide Chlorpropamide Glipizide
(Glibenclamide
Tolazamide
Glimepiride
 FIRST GENERATION SULPHONYLUREA COMPOUNDS

Tolbutamid Acetohexamide Tolazamide Chlorpropamide

short-acting intermediate- intermediate- long- acting
acting acting

Absorption Well Well Slow Well

Metabolism Yes Yes Yes Yes
Metabolites Inactive* Active +++ ** Active ++ ** Inactive **
Half-life 4 - 5 hrs 6 – 8 hrs 7 hrs 24 – 40 hrs
Duration of Short Intermediate Intermediate Long
action (6 – 8 hrs) (12 – 20 hrs) (12 – 18 hrs) ( 20 – 60 hrs)
Excretion Urine Urine Urine Urine

* Good for pts with renal impairment

** Pts with renal impairment can expect long t1/2
 SECOND GENERATION SULPHONYLUREA
COMPOUNDS

Glipizide Glibenclamide Glimepiride

Short- (Glyburide) Long-
acting Long-acting acting
Absorption Well Well Well
Metabolism Yes Yes Yes
Metabolites Inactive Inactive Inactive
Half-life 3 – 4 hrs Less than 3 hrs 5 - 9 hrs
Duration of 10–16 12 – 24 hrs 12 – 24 hrs
action hrs
Excretion Urine Urine Urine
 MECHANISM OF ACTION OF
SULPHONYLUREAS

1) Release of insulin from β-cells

2) Reduction of serum glucagon
concentration
3) Potentiation of insulin action on
target tissues
 SIDE EFFECTS OF
SULPHONYLUREAS

1) Nausea, vomiting, abdominal pain, diarrhea

2) Hypoglycaemia
3) Dilutional hyponatraemia & water intoxication
(Chlorpropamide)
4) Disulfiram-like reaction with alcohol
(Chlorpropamide)
5) Weight gain
 SIDE EFFECTS OF SULPHONYLUREAS (contd)

6) Blood dyscrasias
(not common; less than 1% of patients)
- Agranulocytosis
- Haemolytic anaemia
- Thrombocytopenia
7) Cholestatic obstructive jaundice (uncommon)
8) Dermatitis (Mild)
9) Muscle weakness, headache, vertigo
(not common)
10) Increased cardio-vascular mortality with
longterm use ??
 CONTRAINDICATIONS OF
SULPHONYLUREAS

1) Type 1 DM ( insulin dependent)

2) Parenchymal disease of the liver or kidney

3) Pregnancy, lactation

4) Major stress
 DRUGS THAT AUGMENT THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS

WARFARIN
SULFONAMIDES
SALICYLATES
PHENYLBUTAZONE
PROPRANOLOL
CHLORAMPHENICOL
FLUCONAZOLE
DRUGS THAT ANTAGONIZE THE
HYPOGLYCEMIC ACTION OF
SULPHONYLUREAS

DIURETICS (THIAZIDE, FUROSEMIDE)

DIAZOXIDE
CORTICOSTEROIDS
ORAL CONTRACEPTIVES
PHENYTOIN, PHENOBARB., RIFAMPIN
ALCOHOL
Efek yang berbahaya terjadi NSH (Nocturnal Symptomless
Hypoglicaemia) yaitu Hipoglikemia yang terjadi pada
malam hari saat pasien tidur sehingga tanpa gejala
Untuk mengatasi NSH tubuh akan mengatasi dengan
mengeluarkan katekolamin dan glukokortikoid
Apabila terjadi terus-menerus akan mengakibatkan
ANGIOPATI (kerusakan pembuluh darah)
efek yang timbul - impotensi
- gagal ginjal
- penglihatan berkurang
 Drugs other than Sulfonylurea

Meglitinides Biguanides α-Glucosidase Thiazolidinediones

Inhibitors

Repaglinide Metformin Acarbose Rosiglitazone

Nateglinide Pioglitazone
 MEGLITINIDES
e.g. Repaglinide, Nateglinide
PHARMACOKINETICS
Taken orally
Rapidly absorbed ( Peak approx. 1hr )
Metabolized by liver
t1/2 = 1 hr
Duration of action 4-5 hr

MECHANISM OF ACTION
Bind to the same KATP Channel
as do Sulfonylureas,
to cause insulin release from β-cells.
 MEGLITINIDES (Contd.)

CLINICAL USE
Approved as monotherapy and in combination with metformin
in type 2 diabetes
Taken before each meal, 3 times / day
Does not offer any advantage over sulfonylureas;
Advantage: Pts. allergic to sulfur or sulfonylurea

SIDE EFFECTS:
Hypoglycemia
Wt gain ( less than SUs )
Caution in pts with renal & hepatic impairement.
 BIGUANIDES
e.g. Metformin
PHARMACOKINETICS
Given orally
Not bind to plasma proteins
Not metabolized
Excreted unchanged in urine
t 1/2 2 hr

MECHANISM OF ACTION
1. Increase peripheral glucose utilization
2. Inhibits gluconeogenesis
3. Impaired absorption of glucose from the gut
 BIGUANIDES (Contd)

SIDE EFFECTS
1. Metallic taste in the mouth

2. Gastrointestinal (anorexia, nausea, vomiting, diarrhea,

abdominal discomfort)

3. Vitamin B 12 deficiency (prolonged use)

4. Lactic acidosis ( rare – 01/ 30,000-exclusive in renal &

hepatic failure)
 BIGUANIDES
CONTRAINDICATIONS

1. Hepatic impairment

2. Renal impairment

3. Alcoholism

4. Heart failure

INDICATIONS
1. Obese patients with type 11 diabetes
2. Alone or in combination with sulfonylureas
 α-GLUCOSIDASE INHIBITORS
e.g. Acarbose

PHARMACOKINETICS
• Given orally
• Not absorbed from intestine except small amount

- t1/2 3 - 7 hr

- Excreted with stool

MECHANISM OF ACTION
• Inhibits intestinal alpha-glucosidases
• delays carbohydrate absorption,
• reducing postprandial increase in blood glucose
 α-GLUCOSIDASE INHIBITORS

MECHANISM OF ACTION

Acarbose

Acarbose

Acarbose
 α-GLUCOSIDASE INHIBITORS

MECHANISM OF ACTION
 α-GLUCOSIDASE INHIBITORS
SIDE EFFECTS
• Flatulence
• Loose stool or diarrhea
• Abdominal pain
• Alone does not cause hypoglycemia

INDICATIONS
• Patients with Type 11 inadequately controlled by
diet with or without other agents( SU, Metformin)
• Can be combined with insulin may be helpful in
obese Type 11 patients
(similar to metformin)
THIAZOLIDINEDIONE DERIVATIVES
New class of oral antidiabetics
e.g.: Rosiglitazone
Pioglitazone
PHARMACOKINETICS
• 99% absorbed
• Metabolized by liver
• 99% of drug binds to plasma proteins
• Half-life 3 – 4 h
• Eliminated via the urine 64% and feces 23%
INDICATIONS
Type 11 diabetes alone or in combination with metformin or
sulfonylurea or insulin in patients resistant to insulin
treatment.
THIAZOLIDINEDIONE DERIVATIVES

MECHANISM OF ACTION
Increase target tissue sensitivity to insulin by:
reducing hepatic glucose output
increase glucose uptake
increase oxidation in muscles & adipose tissues.
They do not cause hypoglycemia
(similar to metformin and acarbose )

ADVERSE EFFECTS
Mild to moderate edema, Wt gain, Headache, Myalgia
Hepatotoxicity ?
 Diabetes Complications
Diabetes complications are the seventh
leading cause of death. They include:
• Blindness- caused by diabetic retinopathy.
• Kidney Disease- diabetic nephropathy
• Heart Disease and Stroke
• Nerve disease and amputations
• Impotence
 How to Avoid Complications
• Control weight
• Eat a healthy well-balanced diet.
• Get regular exercise
• Have regular checkups
• Check feet everyday for cuts and blisters
• Do not smoke!
• Keep blood sugars normal
• Avoid the 2 common diabetic problems,
hypoglycemia and hyperglycemia
 Hypoglycemia
• Hypoglycemia- low blood sugar
• Happens to everyone with diabetes
• Symptoms include shakiness, dizziness,
sweating, hunger, headache, pale skin, sudden
moodiness, clumsy or jerky movements,
difficulty paying attention, and tingling
sensations around mouth.
 Hypoglycemia
How to treat Hypoglycemia:
• Quickest way to raise blood glucose is with
some form of sugar.
• 3 glucose tablets, 1/2 cup of fruit juice, 5-6
pieces of candy.
• Wait 15-20 minutes and test blood sugar
again. If still low retreat.
• If hypoglycemia goes untreated, patient
could get worse and pass out!
• Stress the importance of a night time snack
in older patients.
 How to treat Hyperglycemia
• Usually can lower it by exercising, or injecting
more insulin, be careful of the somogyi effect.
The somogyi effect is the condition of
hypoglycemia resulting from the treatment of
hyperglycemia.