Transcript Facts and Treatment of Diabetes Mellitus

Definition
 Diabetes Mellitus is a group of Metabolic Diseases
characterized by Hyperglycemia resulting from
defects in insulin secretion, insulin action, or both.
American Diabetes Association
Diabetes: Clinical Features

Symptoms:




Polyuria
Polydipsia=
thirst
Polyphagia=
appetite
Asthenia & Loss of weight

Signs:
No specific signs may be
signs of complications
“Leonard Thompson (14 year
old boy) & Elizabeth Hughes
(aged 14 years), were the first
patients to be treated with
insulin in 1922.
“Fredrick Banting (1921),
successfully, extracted
insulin, gaining the Nobel
prize for this great
discovery”.
“Claude Bernard and
Von Mering (1889),
discovered in the same
year that pancreatectomy
causes diabetes”
“Mathew Dobson (1776),
identified glycosuria.
“ Thomas Willis (1621 1679), discovered the
sweetness of urine, hence,
the name Diabetes Mellitus
arised”
“ Diabetes was long thought
to be a kidney disease
(Greek & Arabic
Methodology).
Predisposing Factors
IDDM





Heredity.
Histocomptability.
Virus infection.
Seasonality.
Cell-mediated immunity.
Insulin Synthesis
PrePro
Insulin
Split at position
61/62
Pro Insulin
Insulin
C peptide
Insulin Secretion Curve
Biphasic insulin response to a constant glucose stimulation
(IVGTT - hyperglycemic Clamp)
Insulin rate
Basal
Time (min)
4
60
Fate of Absorbed Glucose
Glycogenesis
G
G
Glycolysis
Muscle Cells 50 %
Glycogenesis
Liver Cells 30 %
Glycolysis
Lipogenesis
G
Glycolysis
Fat Cells 5 %
Hormonal Regulation
Blood Glucose Level
< 110 mg/L
Insulin
Hypoglycaemic Hormone
Glucagons
Growth Hormone
Adrenaline
Cortisol
Counter regulatory Hormones
Diabetes Estimates and
Projection
1994
2000
2010
Type 1 11.5 million 18.1million 23.7 million
Type 2 98.9 miilion 157.3
million
215.6
million
Total
239.3
million
110.4
million
175.4
million
Classification of Diabetes
Mellitus

Primary Diabetes

Type 1
insulin dependent
diabetes

Type 2
non insulin
dependent diabetes
Classification of Diabetes
Mellitus

Secondary Diabetes
 Gestational diabetes
 Malnutrition related diabetes
 Diabetes resulting from:




Pancreatic disease
Hormonal diseases
Drug/chemical
induced
Genetic syndromes
Key Organs of Diabetes
Pancreas
insulin secretion disorder
Liver
Muscle
in hepatic glucose production
in glucose storage
Hyperglycemia
Peripheral Abnormalities
Liver
Fat tissues
Gluconeogenesis
Glycogenogenosis
Glycolysis
Gluconeogenesis
Muscles
Lipogenesis
Lipolysis
Glycolysis
Glycogenogenesis
FFA
Glucose production
Glucose Storage
Hyperglycaemia
Pathogenesis of diabetes:
metabolic features
Genetic
predisposition
Insulin
resistance
Defective
insulin secretion
Hyperglycemia
Causes of Impaired Insulin
Secretion

Decrease in number of Beta cells by 40-50 %
{In Insulin resistance states,
the number is either normal or increased}
Causes of Impaired Insulin
Secretion
Amyloid deposits
Amylin : amyloid material
secreted by B cells
Interferes with the
recognition of
the glucose signal
Causes of Impaired Insulin
Secretion

Reduced activity of the glucokinase

ATP production reduced inside B cells

Closure of K channel decreases

Entry of Calcium reduced

release of Insulin reduced
Types of Insulin Resistance
Receptor defect


Post Receptor defect
Types of Insulin
Resistance
Receptor defect

Decrease in the affinity

Decrease in number (rare)
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Types of Insulin Resistance

Post receptor defect
Glucose Transporters
Intra cellular utilization
Enzymatic activity
Gluco-toxicity
Insulin secretion
disorder
Chronic
Hyperglycemia
Insulin
resistance
Vascular complications

Micro-vascular complications

Macro-vascular complications
Micro-vascular complications

Retinopathy

Nephropathy

Neuropathy
Macro-vascular complications

CHD

CVD

PAD
10 years accelerated
Treatment of diabetes:

Life style modification

Insulin

Oral hypoglycemic agents
Life style modification

Diet control

Exercise

Smoking cessation
DIET CONTROL

All diabetic patients should be on diet
control.
Diet control is a must either the
patient is taking insulin or oral
therapy.

Over weight should be reduced .
DIET CONTROL

Diet control should be tried at first
before the next step [insulin or
tablets]
especially
in
obese
patients, When diet fails drugs are
indicated.
DIET CONTROL

The diet for a diabetic patient is not
so different from the healthy diets for
the whole population.

Simple sugars Carbohydrate [as
sucrose], should be limited for the
diet of diabetic patients.
DIET CONTROL

Carbohydrate content should be in a
fiber-rich diet [for example fruits
containing fibers as apples].
….. because the fiber content of diet
delays absorption of carbohydrates
avoiding the rapid elevation of blood
glucose levels.
DIET CONTROL
Calories :
Calories should be tailored to the
need of the patient.
•
Diet should contain:
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Carbohydrates → 50 - 55%

Fat→ 30-35%

Protein →10 - 15%
Indication of Insulin

Type 1 diabetes

Unstable diabetes

Type 2 diabetes failed on SUs.
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Pregnant diabetic patients
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Surgery (all diabetic patients)

Diabetic coma
Oral hypoglycemic agents

Biguanides
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Sulfonylureas

α- glucosidase inhibitors
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Thiazolidinediones

Prandial glucose regulator
Biguanides

Biguanides are derivatives of the
antimalarial agent Chloroguanide.
Which is found to have hypoglycemic
action.

The most commonly used member of
biguanides is Metformin [Cidophage].
Biguanides

Indication:

Type 2 diabetes failed on diet

Metformin can be given alone or in
combination with sulfonylureas or
Insulin
Biguanides

Mode of action
Biguanides [Metformin] is an
Antihyperglycemic and not Hypoglycemic
agent.

It does not stimulate pancreas to secrete
insulin and does not cause hypoglycemia (as
a side effect) even in large doses.

Also it has no effect on secretion of Glucagon
or Somatostatin.
Biguanides

Mode of action:

Decreases the intestinal absorption of
CHO

Increases glucose uptake (GLUT 4)

Increases glucose utilization
(glycogensynthase)

Increases glycolysis via anaerobic
pathway (lactic acidosis)
Biguanides
Pharmacokinetics:
Metformin is well absorbed from
small intestine, stable, does not
bind to plasma proteins, excreted
unchanged in urine.
 Half life of Metformin is 1.5 4.5 hours, taken in three doses
with meals

Biguanides
Side effects:

occur in 20-25 % of patients.

include.. Diarrhea, abdominal
discomfort, nausea, metallic taste
and decreased absorption of
vitamin B12.
Biguanides
Contraindications
Patients with renal or hepatic
impairment.
 Past history of lactic acidosis.
 Heart failure, Chronic lung disease.
.. These conditions predispose to
increased lactate production which
causes lactic acidosis which is fatal.

SULFONYLUREAS

SUs., have been discovered during
the 2nd. World war (sulfonamide).

SUs are drugs that used orally to
control blood glucose levels of
type 2 diabetes.
SULFONYLUREAS

Types:

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First generation,
 Chlorpropamide (Pamidin)
 Tolbutamide (Diamol)
Second generation,
 Gliclazide (Diamicron)
 Glibenclamide (Daonil)
 Glipizide (Minidiab)
Third generation,
 Glimepiride (Diabride) (Amaryl)
SULFONYLUREAS

Mechanism of action:

Pancreatic effect

Extra-pancreatic effect
SULFONYLUREAS
Pancreatic effect:
• Increase insulin release from
pancreas
• Suppress secretions of Glucagons
SULFONYLUREAS

Extra pancreatic effect:
Increases the number of insulin
receptors
 Increases post-receptor insulin
sensitivity
 Increases glucolysis
 Increases glycogen storage in muscle
and liver
 Decreases the hepatic output of
glucose

SULFONYLUREAS
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Pharmacokinetics:
 They are effectively absorbed from
gastrointestinal tract.
 Food can reduce the absorption of
sulfonylurea.
 Sulfonylureas are more effective
when given 30 minutes before
eating.
 Plasma protein binding is high 90 –
99 % .. mainly bind to albumen.
SULFONYLUREAS

Pharmacokinetics:
 1st generation members have short
half lives.

2nd generation is administered once,
twice or several times daily.

3rd generation is administered once
daily.
SULFONYLUREAS

Pharmacokinetics:

All sulfonylurea are metabolized by
liver and their metabolites are excreted
in urine with about 20 % excreted
unchanged.

Sulfonylurea should be administered
with caution to patients with either
renal or hepatic insufficiency.
SULFONYLUREAS
Adverse Reactions :

Very few adverse reactions [4 %] in the
first generation and rare in the 2nd and 3rd
generation.

SUs may induce hypoglycemia especially
in elderly patients with impaired hepatic
or renal functions-These cases of
hypoglycemia are treated by I/V glucose
infusion.
SULFONYLUREAS
Adverse Reactions :
First generation may induce other
side effects as …nausea and
vomiting & dermatological
reactions
…These side effects are fewer in the
2nd generation and rare in the 3rd
generation.

SULFONYLUREAS
Drug interactions:

Some drugs may enhance or
suppress the actions of
sulfonylureas Either by affecting:
Their metabolism and excretion
 The concentration of free
sulfonylureas in plasma through
competing them on plasma proteins.

SULFONYLUREAS

Contraindications :

Type 1 DM

Pregnancy and Lactation.

Significant hepatic or renal failure.
Drug – Drug interaction
NSAIDs
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Salicylates
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Sulfonamide
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ß-blockers
Chloramphenicol
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Barbiturates
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Thiazide and loop
diuretics
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Sympathomimetics
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Corticosteroids
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Oestrogen /
Progesterone
combinations
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Diazepam
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MAOI
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α Glycosidase Inhibititor
Acarbose (Glucobay)
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Indicated for type 2 diabetes
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In addition with diet

In addition with other anti-diabetic
therapies
Acarbose (Glucobay)

Mode of action:
Poorly absorbed 1% (act locally in
G.I.T.)
 Inhibits α glucosidase, so inhibits
CHO degradation


Dose:

50mg to 100mg 3 times daily before
meals
Acarbose (Glucobay)

Side effects:
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Flatulence (77%)

Diarrhea

Abdominal pain (21%)

Decreased iron absorption
Thiazolidenedione
Rosiglitazone (Avandia)
Pioglitazone (Actos)
Thiazolidenedione

Mode of action:

Insulin sensitizer (increase insulin sensitivity
in muscle, adipose tissue & liver)

They are not insulin secretagogues (Not
insulin releasers)
Thiazolidenedione

Drawbacks:

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They are not effective alone in case of
severe insulin deficiency and should be
combined with sulfonylurea or metformin
or both
Side effects:
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Hepatotoxicity
weight gain
Dyslipidaemia (increases LDL)
Prandial glucose regulators
(Meglitinide)

Example:


Repaglinide, Novonorm (NovoNordisk)
Rational:
Fast acting, short duration non-sulfonylurea
 Designed to minimize mealtime blood
glucose peaks

Repaglinide, Novonorm

Mechanism of action:
Stimulation of pancreatic insulin
release by closing ß-cells KATP
channels
 Very rapid onset of action and short
duration (TMAX = 1 hour,
metabolized by liver T1/2 = 70
minutes)
 No hypoglycemic metabolites

Repaglinide, Novonorm

Clinical efficacy:

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
Improves postprandial glycemia
Less effective in decreasing fasting blood
glucose levels and HbA1C
drawbacks:


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Fails to provides a stable 24 hours blood
glucose control
Complicated dosage style (3-8
tablets/daily)
How to adapt the dosage to the meal
volume?
SEDICO
Pharmaceuticals