INSULIN REKEASE,SYNTHESIS,MECHANISM OF ACTION , PHARMACOLOGICAL ACTION, ETIOLOGY,EPIDEMIOLOGY,PHARMACOLOGY OF ORAL HYPOGLYCEMICS.

2. PHARMACOTHERAPY OF DIABETES
Definition:
It is defined as heterogenous metabolic syndrome
characterised by chronic Hyperglycemia,
Glycosuria, Negative nitrogen balance,
Hyperlipaemia & Ketonaemia.
Most common endocrinal disorder which affects
almost each &every cell of human body.
It results either due to :
• Insufficient Insulin production;
• Inability of the body to utilise Insulin ;
• Increased glucose syntheis in body.

3. History of Diabetes
term diabetes is the shortened
version of the full name diabetes
mellitus.
Diabetes mellitus --Greek
word diabetes meaning siphon -
to pass through.
Latin word mellitus meaning
honeyed or sweet.
This is because in diabetes excess
sugar is found in blood as well as
the urine.
It was known in the 17th century as
the “pissing evil”.
Diabetes word coined by
Apollonius of Memphis

4. Sushruta, Arataeus, and Thomas
Willis were the early pioneers
of the treatment of diabetes.
Matthew Dobson confirmed---
sweet taste of urine of
diabetics was due to excess of
sugar in the urine and blood
of people with diabetes.
In Persia Avicenna (980–1037)
provided a detailed account on
diabetes mellitus in “'The
Canon of Medicine” & also
described diabetes insipidus
very precisely.
Avicenna

5. TYPES OF DIABETES:

6. Features TYPE 1 DM TYPE 2 DM
Also known as IDDM NIDDM
Etiology Occurs due to complete deficiency
of insuulin secretion / Autoimmune
destruction of b-cells of
pancreas,lacking insulin hormone.
Total lack of insulin leads to
Ketoacidosis.
Here, body becomes resistant to Insulin.
Inadequate insulin secretion n response to
demand.
Genetic factors, Obesity, High calorie intake,
Insulin abnormaliities, Increased glucose
production in liver, Increased fat breakdown ,
Defective hormonal secretions in intestine.
Characteristic
feature
Decreased insulin secretion . Icreased Glucagon secretion.
Symptoms &
Complcations
Polyuria
Polyphagia
Polydipsia
Fatigue, Weight loss, Weakness
Ketonaemia, Ketonuria, Azoturia
Impaired growth
Poor wound healing
Infection
Hyperglycemia, Glycosuria
Hyperlipaemia
Polyuria
Polyphagia
Polydipsia
Weight loss
Dry, itchy skin
Tingling /Numbness in had
Blurred vision
Poor wound healing

7. TYPE-I
Causes – EXACT cause is UNKNOWN.
Risk factors: Family history, Genetics, Gepgraphy, Age.
Complications:
Heart & B.V disease —DM increases risk of CV disorders with Chest
pain, Heart attack, Stroke, Atherosclerosis, Hypertension .
Neuropathy – Xcess sugar can injure the capillary walls that nourish
your nerves esp. in legs causing Tingling, Numbness, Burning ,pain
that spreads upwards.
Nerve damage in GIT causes N,V,D/Constipation.
Nephropathy – Kidney damage, Kidney failure.
Eye damage: Retina b.v gets damaged causing Retinopathy, Glaucoma,
Blindness,Cataract,.
Foot damage-- If cuts & blisters left untreated becomes serious
infections leading to Toe/Foot/leg Amputation.
Skin & Mouth -- Xerostomia

9. INSULIN
Insulin is a hormone made in your pancreas, a gland located behind your stomach. It
allows your body to use glucose for energy. Glucose is a type of sugar found in many
carbohydrates.
Sir Frederick Banting, a physician and scientist, was the co-discoverer of insulin, a
hormone of critical importance in regulating blood sugar levels.
STRUCTURE OF INSULIN:
It’s a polypeptide with a molecular weight of 6000 daltons.
It has 2 Amino acid chains A & B connected by 2 sulphide bridges
Chain A possess 21 Amino acids ; Chain B --30 Amino acids.

12. Biosynthesis & Mechanism of Insulin

13. Insulin is biosynthesised in beta cells of pancreas from Pre-proinsulin(A single chain precursor
& is the primary translation product of Insulin gene [mRNA])composed of 110 amino acid
residues & is inactive.
Pre-proinsulin undergoes translocation through RER & after loosing 24 amino acid residues
from N-terminal give rise to Proinsulin (Single polypeptide of 86 amino acid residues with
3 portions as Chain A—Carboxy terminal =21 AA
Chain B--Amino terminal =30 AA
Chain C—Connecting peptide =35 AA )
Pro-insulin when exposed to ER Endopeptidases remove chain C peptides & generate
bioactive form of Insulin.

14. Basically, Insulin receptor comprises 2 subunits Alpha (α) & Beta(β) linked via 2
sulphide bonds .
Insulin binding on binding site of α subunits (+)Tyrosine kinase activity of β
subunits.
Due to this,adjacent β subunits undergo Autophosphorylation along with
Phosphorylation of residues of Insulin receptor substrate proteins (IRS-1 & IRS-2)
IRS-1 Phosphorylation results in generation of 2O messengers lyk PIP3 & DAG &
various Protein kinases .
Insulin also causes tranlocation of GLUT-4 from cytoplasm to cell membrane with the
help of ATP. The transporter helps in glucose intake by skeletal muscles & fat cells.
Insulin action gets terminated when insulin receptor complex is internalised by
Endocytosis. Insulin degraded & receptor s recycled& translocated to cell surface.

18. Pharmacological Action:
1)Carbohydrate Metabolism: Glycogenolysis ;
Glycogenesis .
Muscles: Glycolysis ; Glycogenesis.
Adipose Tissue : Increase Triglycerde synthesis.
2)Protein Metabolism: Proteolysis & oxidation of
A.A.
Muscles: Protein synthesis.
3)Fat Metabolism: Lipogenesis. Exert Vasodilation.
Adipose tissue : lipolysis & release FFA & glycerol.
4)Other Actions: Decrease Fibrinolysis;
Cell Proliferation; Differentiation & growth
+
-
+
-
+
+
-
+

19. Adverse Effects
Neuroglycopenic Symptoms:
Headache, Dizziness, Confusion, Visual
& Behavioural disturbances, Hypotension, Seizures, Coma.
Sympathetic Symptoms: Anxiety, Hunger,
Palpitation,Tremors,Sweating,Hypothermia.
Erythema,
Swelling,
Stinging,
Allergy,
Lipdostrophy,
Presbyopia,
Obesity &
Hepatomegaly.

20. Pathophysiology

21. NON-PHARMACOLOGICAL TREATMENT

22. ORAL HYPOGLYCEMICS
Sulfonylureas: 1 generation: Tolbutamide,
Chlorpropamide.
2 generation: Glibenclamide,
Gliclazide,Glipizide,
Glimeperide.
Biguanides: Metformin,Phenformin.
Metaglinides/Phenyalanine: Repaglinde, Nateglinide.
Thiazoldinediones: Rosiglitazone, Pioglitazone.
A-glucosidase inhibitors: Acarbose,Miglitol.

23. Sulfonylureas & Metaglinides
1) SU bind to SUR-
1 on ATP-
sensitive K+
channel----
Depolarisaton
occurs.
2) Ca+2 channes
open –influx
ca+2
3) Stimulate
release of
stored insulin.

24. Adverse Effects:
Hypoglycemia,
Weight gain,
Hypersensitivity,
Nausea, Vomiting ,
Headache,
Cholestatic jaundice,
Drug Interactions:
1) Salicylates,
Phenylbutazone,
Sulfinpyrazone,
Sulphonamides displace SU from binding
sites.
2) Cimetidine, Chronic alcoholism,
Sulfonamides, Warfarin,
Chloramphenicol, inhibit SU metabolism.
3) Phenytoin, Phenobarbitone,Rifampicin
induce SU metabolism.
4) Thiazides, corticosterides ,oral
contraceptives suppress insulin release.
Pulmonary eosinophilia.

25. BIGUANIDES

26. 1) Inhibit Gluconeogenesis & Decrease Renal glucose output.
2) Increase Glucose Uptake & decrease Insulin resistance.
3) Promote insulin mediated glucose disposal in muscles & adipose
tissue.
4) Inhibit glucose absorption .
5) Promote insulin binding to receptors.

27. Adverse effects:
Anorexia,
Nausea ,
Metallic taste,
Mild diarrhoea,
Abdominal pain,
Tiredness,
Lactic acidosis,
Lethargy,
Excess weight loss,
Muscle weakness.
USES:
IN PCOS
In SU failure
In Type-2 Diabetes.

28. Thiazolidinediones

29. Adverse Effects:
Weight gain,
Headache,
Myalgia,
Mild Anaemia,
CHF.
USES:
In PCOS,
In Diabetes,
In NON-ALCOHOLIC STEATOHEPATITIS,
DI:
Ketoconazole inhibits Pioglitazone
metabolism.
Pioglitazone increases the metabolism of
Oral contraceptives & decreases their
action.

30. TH9K U