1. Diabetes Mellitus

2. American Diabetes Association
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 ( ), 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 Factors IDDM
Heredity.
Histocomptability.
Virus infection.
Seasonality.
Cell-mediated immunity.

11. Insulin Synthesis PrePro Insulin Split at position 61/62 Pro Insulin
C peptide

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
Glycogenesis
Liver Cells 30 % G
Glycolysis
Lipogenesis G
Fat Cells 5 %
Glycolysis

14. Hypoglycaemic Hormone Counter regulatory Hormones
Hormonal Regulation
Blood Glucose Level
< 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. insulin secretion disorder in hepatic glucose production
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
Glycogenogenosis
Gluconeogenesis
Glycolysis
Glycolysis
Gluconeogenesis
Lipogenesis
Lipolysis
Glycogenogenesis
FFA
Glucose production
Glucose Storage
Hyperglycaemia

21. Pathogenesis of diabetes: metabolic features
Genetic predisposition
Insulin
resistance
Defective
insulin secretion
Hyperglycemia 7

22. Impaired
Insulin
Secretion

23. Causes of Impaired Insulin Secretion
Decrease in number of Beta cells by %
{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
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 → %
Fat→ 30-35%
Protein → %

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
α- 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 hours, taken in three doses with meals

53. Biguanides Side effects: occur in 20-25 % of patients.
include.. Diarrhea, abdominal discomfort, 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. α 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: Dose:
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

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

71. Rosiglitazone (Avandia)
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: Side effects:
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: drawbacks:
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. SEDICO Pharmaceuticals
The End