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Diabetes Mellitus

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Definition Diabetes: Clinical Features Symptoms: Polyuria Polydipsia = thirst Polyphagia= appetite Asthenia & Loss of weight Leonard Thompson (14 year old boy ... – PowerPoint PPT presentation

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Title: Diabetes Mellitus


1
Diabetes Mellitus
2
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
3
Diabetes Clinical Features
  • Symptoms
  • Polyuria
  • Polydipsia thirst
  • Polyphagia appetite
  • Asthenia Loss of weight
  • Signs
  • No specific signs may be signs of
    complications

4
Leonard Thompson (14 year old boy) Elizabeth
Hughes (aged 14 years), were the first patients
to be treated with insulin in 1922.
5
Fredrick Banting (1921), successfully, extracted
insulin, gaining the Nobel prize for this great
discovery.
6
Claude Bernard and Von Mering (1889), discovered
in the same year that pancreatectomy causes
diabetes
7
Mathew Dobson (1776), identified glycosuria.
8
Thomas Willis (1621 - 1679), discovered the
sweetness of urine, hence, the name Diabetes
Mellitus arised
9
Diabetes was long thought to be a kidney
disease (Greek Arabic Methodology).
10
Predisposing FactorsIDDM
  • Heredity.
  • Histocomptability.
  • Virus infection.
  • Seasonality.
  • Cell-mediated immunity.

11
Insulin Synthesis
PrePro Insulin
Split at position 61/62
Pro Insulin
C peptide
Insulin
12
Insulin Secretion Curve
Biphasic insulin response to a constant glucose
stimulation (IVGTT - hyperglycemic Clamp)
Insulin rate
Basal
Time (min)
4
60
13
Fate of Absorbed Glucose
Glycogenesis
G
Muscle Cells 50
Glycolysis
Liver Cells 30
Glycogenesis
G
Glycolysis
Lipogenesis
G
Fat Cells 5
Glycolysis
14
Hormonal Regulation
Blood Glucose Level
lt 110 mg/L
Glucagons Growth Hormone Adrenaline Cortisol
Insulin
Hypoglycaemic Hormone
Counter regulatory Hormones
15
Diabetes Estimates and Projection
16
Classification of Diabetes Mellitus
  • Primary Diabetes
  • Type 1 insulin dependent diabetes
  • Type 2 non insulin dependent diabetes

17
Classification of Diabetes Mellitus
  • Secondary Diabetes
  • Gestational diabetes
  • Malnutrition related diabetes
  • Diabetes resulting from
  • Pancreatic disease
  • Hormonal diseases
  • Drug/chemical induced
  • Genetic syndromes

18
METABOLIC ASPECTS
19
Key Organs of Diabetes
Pancreas
insulin secretion disorder
Muscle
Liver
in hepatic glucose production
in glucose storage
Hyperglycemia
20
Peripheral Abnormalities
Muscles
Liver
Fat tissues
Gluconeogenesis
Glycogenogenosis
Glycolysis
Glycolysis
Lipogenesis Lipolysis
Gluconeogenesis
Glycogenogenesis
FFA
Glucose Storage
Glucose production
Hyperglycaemia
21
Pathogenesis of diabetes metabolic features
Genetic predisposition
Insulin resistance
Defective insulin secretion
Hyperglycemia
22
Impaired Insulin Secretion
23
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

24
Causes of Impaired Insulin Secretion
  • Amyloid deposits
  • Amylin amyloid material secreted by B cells
    Interferes with the recognition of
  • the glucose signal

25
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

26
Insulin Resistance
27
Types of Insulin Resistance
  • Receptor defect
  • Post Receptor defect

28
Types of Insulin Resistance
  • Receptor defect
  • Decrease in the affinity
  • Decrease in number (rare)

29
Types of Insulin Resistance
  • Post receptor defect Glucose Transporters
  • Intra cellular utilization
  • Enzymatic activity

30
Gluco-toxicity

Insulin secretion disorder
Chronic Hyperglycemia
Insulin resistance
31
Vascular Complications
32
Vascular complications
  • Micro-vascular complications
  • Macro-vascular complications

33
Micro-vascular complications
  • Retinopathy
  • Nephropathy
  • Neuropathy

34
Macro-vascular complications
  • CHD
  • CVD
  • PAD
  • 10 years accelerated

35
Treatment Of Diabetes
36
Treatment of diabetes
  • Life style modification
  • Insulin
  • Oral hypoglycemic agents

37
Life style modification
  • Diet control
  • Exercise
  • Smoking cessation

38
Diet Control
39
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 .

40
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.

41
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.

42
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.

43
DIET CONTROL
  • Calories
  • Calories should be tailored to the need of the
    patient.
  • Diet should contain
  • Carbohydrates ? 50 - 55
  • Fat? 30-35
  • Protein ?10 - 15

44
INSULIN
45
Indication of Insulin
  • Type 1 diabetes
  • Unstable diabetes
  • Type 2 diabetes failed on SUs.
  • Pregnant diabetic patients
  • Surgery (all diabetic patients)
  • Diabetic coma

46
Oral Hypoglycemic agents
47
Oral hypoglycemic agents
  • Biguanides
  • Sulfonylureas
  • a- glucosidase inhibitors
  • Thiazolidinediones
  • Prandial glucose regulator

48
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.

49
Biguanides
  • Indication
  • Type 2 diabetes failed on diet
  • Metformin can be given alone or in combination
    with sulfonylureas or Insulin

50
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.

51
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)

52
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

53
Biguanides
  • Side effects
  • occur in 20-25 of patients.
  • include.. Diarrhea, abdominaldiscomfort, nausea,
    metallic taste and decreased absorption of
    vitamin B12.

54
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.

55
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.

56
SULFONYLUREAS
  • Types
  • First generation,
  • Chlorpropamide (Pamidin)
  • Tolbutamide (Diamol)
  • Second generation,
  • Gliclazide (Diamicron)
  • Glibenclamide (Daonil)
  • Glipizide (Minidiab)
  • Third generation,
  • Glimepiride (Diabride) (Amaryl)

57
SULFONYLUREAS
  • Mechanism of action
  • Pancreatic effect
  • Extra-pancreatic effect

58
SULFONYLUREAS
  • Pancreatic effect
  • Increase insulin release from pancreas
  • Suppress secretions of Glucagons

59
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

60
SULFONYLUREAS
  • 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.

61
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.

62
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.

63
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.

64
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.

65
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.

66
SULFONYLUREAS
  • Contraindications
  • Type 1 DM
  • Pregnancy and Lactation.
  • Significant hepatic or renal failure.

67
Drug Drug interaction
  • NSAIDs
  • Salicylates
  • Sulfonamide
  • ß-blockers
  • Chloramphenicol
  • Diazepam
  • MAOI
  • Barbiturates
  • Thiazide and loop diuretics
  • Sympathomimetics
  • Corticosteroids
  • Oestrogen / Progesterone combinations

68
a Glycosidase Inhibititor
  • Acarbose (Glucobay)
  • Indicated for type 2 diabetes
  • In addition with diet
  • In addition with other anti-diabetic therapies

69
Acarbose (Glucobay)
  • Mode of action
  • Poorly absorbed 1 (act locally in G.I.T.)
  • Inhibits a glucosidase, so inhibits CHO
    degradation
  • Dose
  • 50mg to 100mg 3 times daily before meals

70
Acarbose (Glucobay)
  • Side effects
  • Flatulence (77)
  • Diarrhea
  • Abdominal pain (21)
  • Decreased iron absorption

71
Thiazolidenedione
  • Rosiglitazone (Avandia)
  • Pioglitazone (Actos)

72
Thiazolidenedione
  • Mode of action
  • Insulin sensitizer (increase insulin sensitivity
    in muscle, adipose tissue liver)
  • They are not insulin secretagogues (Not insulin
    releasers)

73
Thiazolidenedione
  • Drawbacks
  • They are not effective alone in case of severe
    insulin deficiency and should be combined with
    sulfonylurea or metformin or both
  • Side effects
  • Hepatotoxicity
  • weight gain
  • Dyslipidaemia (increases LDL)

74
Prandial glucose regulators (Meglitinide)
  • Example
  • Repaglinide, Novonorm (NovoNordisk)
  • Rational
  • Fast acting, short duration non-sulfonylurea
  • Designed to minimize mealtime blood glucose peaks

75
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

76
Repaglinide, Novonorm
  • Clinical efficacy
  • Improves postprandial glycemia
  • Less effective in decreasing fasting blood
    glucose levels and HbA1C
  • drawbacks
  • 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?

77
SEDICOPharmaceuticals
The End
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