INSULIN and

ORAL ANTI DIABETICS

Hernita Taurustya, MD

Atas izin: Vivian Soetikno, MD., Sp.FK

Department of Pharmacology and Therapeutic

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 DIABETES MELLITUS

• A disorder of CHO metabolism associated with

insulin deficiency or resistance

• Characterized by hyperglycemia:

• > 126 mg/dl after > 8 hrs fasting, or

• > 200 mg/dl, 2 hour after 75 g oral glucose,

or

• Random blood glucose > 200 mg/dl

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 Type I DM (IDDM)
• Absolut deficiency of insulin

• Destruction of pancreatic islets

 Type II DM (NIDDM)
• Insulin deficiency/insulin exhaustion

• Insulin resistance

 Type III (other type)

• Drugs (corticosteroid), endocrinopathy,
 Gestational DM

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 Pancreas

Pancreatic Approximate Products

cell types percent mass
A cell (alpha) 20 Glucagon
B cell (beta) 75 Insulin
D cell (delta) 3-5 Somatostatin
F cell (PP cell) <2 Pancreatic polypeptide

Pancreas contains up to 8 mg of insulin (200 Unit)

Basal secretion: 5-15 mUnit/ml
After meal : 60-90 mUnit/ml

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 Regulation of insulin secretion
• Stimulants of insulin release:

– Glucose, mannose, secretin, gastrin

– Leucine, arginine, fatty acids, amino acids, keton

bodies

– Vagal stimulation, b2-agonist

– Sulfonylureas

• Inhibitors of insulin release:

– Neural: a-adrenergic agonist

– Humoral: somatostatin, glucagon

– Drugs: diazoxide, phenytoin, colchicin, vinblastine

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• Diet
• Physical exercise
• Drugs:
– Oral anti diabetics

– Insulin

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• Proinsulin:
– A chain, B chain, and C peptide:
– Proteolytic enzyme cleaves proinsulin  insulin
• Insulin: 51 amino acids
– A chain: 21 AA
– B chain: 30 AA
– Linked by 2 disulphide bridges (A7-B7 and A20-B19)
– and another disulphide bridge (A6-A11)
• C peptide:
– No clear physiological function
– Used as a marker of insulin secretion
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 Regulation of Glucose Transport by
Insulin
• Glucose enter cells by diffusion through
glucose transporter (GLUT)

• Without insulin, the GLUT are retained in

vesicles within the cytosol

• Insulin facilitates translocation of GLUT to cell

membrane, thus allowing the passage of
glucose into the cells

• Disturbance of glucose transport may lead to

type II diabetes. 10
Preparations

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•Rapid-acting – aspart, glulisine, lispro, human
insulin recombinant inhaled

•Short-acting insulin – regular

•Intermediate-acting – NPH [neutral protamine

Hagedorn] & lente insulin

•Long-acting – glargine, detemir

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 Indications of insulin therapy
 All T1DM
T2DM uncontrolled by diet and/or
hypoglycemic agents
 Postpancreatectomy diabetes
 Gestational diabetes
 Diabetic ketoacidosis & hyperglycemic
nonketotic

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 Goals of insulin therapy
 fasting blood glucose conc. 90-120 mg/dL
 two-hour postprandial < 150 mg/dL
 HbA1c < 7%
Factors that determine insulin SC absorption:
1. Site of injection – abdominal wall >>
2. Subcutaneous blood flow – to ↑: massage, hot baths,
exercise
3. Volume & concentration of the injected insulin
4. Depth of injection (IM more rapid onset of action)
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Adverse reactions
 Hypoglycemia – counter-regulatory hormones
(epinephrine, norepinephrine, cortisol, growth
hormone, GLUCAGON)
 Insulin allergy
 Lipoatrophy & lipohypertrophy

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Drugs that cause Drugs that cause
hyperglycemia
hypoglycemia
 Epinephrine
 Ethanol  Glucocorticoids

 Beta blockers – mask  Atypical antipsychotic

 Phenytoin
effect  Calcium channel
 Salicylates blockers
 Diuretics

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1. Insulin secretagogues
a. Sufonylurea
b. Meglitinide:
c. D-phenylalanine derivatives

2. Biguanide – decrease hepatic glucose production

3. Thiazolidinediones – reduce insulin resistance

4. α-glucosidase inhibitor – slow digestion & absorption of

starch & disaccharides

5. Increatin-based therapies –control post-meal glucose

excursions by ↑ insulin release & ↓ glucagon secretion

6. Amylin analog – control post-meal glucose levels & reduces

appetite 17
 First generation
• Chlorpropamide
• Tolbutamide
• Tolazamide
• Acetoheximide
 Second generation
• Glybenclamide (glyburide)
• Glypizide
• Glyclazide
• Glymepiride
• Gliquidone

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• ↑ insulin release from the
pancreas
• Reduction of serum
glucagon levels by
stimulate release of
somatostatin
• Closure of potassium
channels in extrahepatic
tissues

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• ADVERSE EFFECTS
– Hypoglycemia

– Allergic reaction

– GI disturbances

– Cholestatic jaudice

• INTERACTION
– Sulfonamides, clofibrate, dicumarol, salicylates displace
the SU from protein binding  increase hypoglycemic
effect

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 • INDICATION
– Type 2 DM which fail with diet therapy

• Contraindications:
– Type 1 DM,

– Type 2 DM with metabolic complication

– pregnancy, lactation,

– Severe hepatic or renal insufficiency

Secondary failure –failure to maintain a good

response over the long-term  additional oral agents
or insulin
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 Meglitinides
Repaglinide
• Mechanism of action  SU

• Metabolism: liver & kidney  used cautiously in

hepatic & renal insuff.

• Absorbed rapidly from GIT Allow for multiple

• Half-life 1 hour preprandial use

• To be taken just before meal

• Major SE: hypoglycemia

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 Meglitinides
Nateglinide – D-phenylalanine derivative
• stimulate very rapid & transient release of insulin from β-cell
pancreas & restores initial insulin release in response to GTT IV
• major therapeutic effect – reduce post-prandial glycemic
elevations in T2DM
• take 1-10 min. before meals
• metabolized in liver (CYP2C9 & CYP3A4)  used cautiously in
hepatic insuff.
• excreted unchanged in urine  dosage adjustment in renal
insuff. Unnecessasry
• fewer episodes of hypoglycemia

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 BIGUANIDES
 metformin, phenformin, buformin
 metformin alone or in combination with a SU  improves
glycemic control & lipid conc.
 EUGLYCEMIC
 Reduce glucose levels by:
1. ↓ hepatic glucose production
2. ↑ insulin action in muscle & fat (AMPK)
3. slowing glucose absorption from GIT; ↑ glucoselactate
4. reduction of plasma glucagon levels

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 BIGUANIDES

• Contraindications – renal disease, alcoholism,

hepatic disese, chronic cardiopulmonary
dysfunction, past history of lactic acidosis

• Preparation: Tablet 500 and 850 mg to be taken 2-3

times daily; maximum daily dose: 2.5 g

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 THIAZOLIDINEDIONES

• Increase sensitivity to insulin in peripheral tissue

– Increase glucose transport into muscle & adipose

tissue by enhancing the synthesis & translocation of
glucose transporters

– Can activate genes that regulate fatty acid

metabolism

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 THIAZOLIDINEDIONES

PREPARATIONS

– Pioglitazone (Actos®)

• Tablet: 15, 30, 45 mg

• Dose: 15-45 mg once daily

– Rosiglitazone (Avandia®)

• Tablet 2, 4, 8 mg

• Dose 2-8 mg once daily

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 THIAZOLIDINEDIONES
• Might be benefit to prevent development of type 2 DM

• EUGLYCEMIC

• Slow onset and offset of action (over weeks – months)

• Long-term use - decrease of triglyceride and increase

of HDL (piogllitazone > rosiglitazone)

• ADR: fluid retention [presents as a mild anemia &

peripheral edema), weight gain

• Contraindications:

• pregnancy, liver disease (ALT > 2.5x ULN), heart

failure 28
 Amylin analog
• Pramlintide – synthetic analog of amylin
• suppresses glucagon release, delays gastric emptying, has
CNS- mediated anorectic effects
• Pharmacokinetics:
- rapidly absorbed after SC, peak 20 min., duration of action
150 min.
- metabolized & excreted in renal
• injected immediately before eating
• dose: 15 mcg-120 mcg  titrated upward
• SE: hypoglycemia & GI symptoms
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 Secreted by a pancreatic cells
• Derived from a precursor of 69 AA (called glycentin)
• Proteolytic enzyme  Glucagon with 29 AA
 Mechanism of Action
• Activates protein Gs in the receptors  adenylyl
cyclase  cAMP 
 Matabolic effects
• Increases blood glucose by facilitating
gluconeogenesis and glycogenolysis in the liver (No
effect on muscle glycogen)
• Increases insulin secretion from the pancreas

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 Cardiac effects:
• Inotropic and chronotropic effects (similar to b-
agonist)
 Other effects:
• relaxation of intestine
 Clinical uses
• Severe hypoglycemia
• Endocrine diagnosis
• Beta blocker poisoning
 Rapid degradation in the liver, kidney, plasma, and
tissues
 Plasma T1/2: 3-6 minutes  need continous iv infusion.

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 An antihypertensive agent
 Potent hyperglycemic action when given
orally
 Mechanism:
• Potassium channel opener (opposite to SU)
• Inhibits insulin secretion
• Modest capacity to inhibit peripheral glucose
utilization

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 Indications
• Treatment of hypoglycemia due to hyper insulinemia
(such as in insulinoma), and other form of
hypoglycemia
• Hypertension
 Side effects
• Nausea, vomiting
• Hypertrichosis
• Na and fluid retention, hyperuricemia,
thrombocytopenia, and leukopenia

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 American Diabetes Association
Standards of Medical Care in Diabetes-
2014
 Pharmakology Katzung
 Phatofisiology Sylvia

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