Pharmacotherapy of Diabetes Mellitus Insulin 15 June 2010

THE ENDOCRINE PANCREAS
1 million islets of Langerhans 4 hormone-producing cells

Cell type Alpha [A] cells

Hormone Glucagon

Function Hyperglycemic factor

Beta [B] Cells

Insulin, Pro insulin, Amylin Somatostatin

Anabolic hormone

Delta[D] Cells

Universal inhibitor of secretion Stim.Gastric secretion

G Cells

Gastrin

F cell[PP cell]

Panc.Polypeptide

Digestion

What is DM?

Diabetes mellitus Elevated blood glucose
Associated with absent or inadequate pancreatic insulin secretion With or without concurrent impairment of insulin action.

Expert Committee, 2003

Type 4

Type 3

Diabetes mellitus -TYPES
TYPE 1 TYPE 2

‡ IDDM ‡ Loss of beta cells deficiency of insulin ³Juvenile diabetes´ majority cases in children.

‡ NIDDM
‡ Due to insulin resistance ‡ [or reduced insulin sensitivity] ‡ Combined with reduced insulin secretion ‡ TYPE 3 ‡ Drug induced or other causes ‡ TYPE 4 ‡ Gestational diabetes mellitus

INSULIN

Proinsulin

Two peptide chains A & B of 21 and 30 amino acids linked by disulfide bridges

Insulin Biosynthesis
[110AA] Preproinsulin (in RER) [110-24AA] Proinsulin (Golgi Apparatus) [51AA] Insulin + C Peptide[-35AA] Stored in granules of F cells Basal rate: 1U/h, o during meals

Control:Insulin Release
‡ Chemical Glucose Incretins ‡ Hormonal GH Corticosteroids, Thyroxine Glucagon Somatostatin ‡ Neural Adrenergic-a2 Adrenergic-b2 Muscarinic [Vagal]

Counter regulatory

Insulin release from the pancreatic Beta cell by Glucose

First phase- Within 2 minutes Delayed phase

Role of ATP sensitive K+ channels (KATP)
Hyperglycemia o Intracellular ATP Blockade of KATP q Outflow of K+ Depolarization of Ca2+ influx Insulin Release cells

Degradation of Insulin
‡ Endogenous:
± Liver ± 60%, Kidney: 35-40%

‡ Exogenous:
± Liver ± 40%, Kidney- 60%

‡ Plasma half-life: 5-6 min.

Insulin receptor
2 covalently linked heterodimers

The binding of an insulin molecule Mutual phosphorylation of tyrosin recidues

Activated Tyrosin kinases Further phosphorylates down stream proteins [IRS]

Insulin receptor substrate

‡Translocation of glucose transporters (especially GLUT 4) to the cell membrane with increase in glucose uptake; ‡Increased glycogen synthase activity and increased glycogen formation; ‡Multiple effects on protein synthesis, lipolysis, and lipogenesis; and ‡Activation of transcription factors that enhance DNA synthesis and cell growth and division.

Insulin receptors
‡ Glucocorticoids lower the affinity of insulin receptors for insulin; ‡ Growth hormone in excess increases this affinity slightly. ‡ Aberrant serine and threonine phosphorylation of the insulin receptor subunits or IRS molecules may result in insulin resistance

Glucose transporters [GLUT]

Absorption

Gluconeogenesis IN LIVER Glycogenolysis Insulin

[-] [-]

Processes add glucose [Hyperglycemia]

Blood

Processes utilize glucose [Hypoglycemia]

[+]
Insulin [+]

Peripheral utilization Lipogenesis

Protein Synth. In Muscles

Endocrine effects of Insulin

Endocrine effects of Insulin«.

Endocrine effects of Insulin«.

Over view of Insulin action

Source and insulin preperations
Species 8th AA Human Pork Beef Analogs
1. ‡ Highly purified pork Insulins Monocomponent insulins

A Chain 10th AA ILEU ILEU VAL THR THR ALA

B Chain 30th AA THR ALA ALA
Conventional prep. ‡Impurities ‡Antigenic ‡Less expensive ‡Replaced by 1. Highly purified pork Insulins 2. Human insulins 3. Insulin analogues

2. Human insulins ‡ Recombninant DNA Technology[E.Coli, Yeast] 3. Insulin analogues Changing or replacing AA sequences 1. Lispro 2. Aspart 3. Glulisine 4. Glargine 5. Detemir

Genetic engineering to produce human insulin

Insulin preparations
‡ Rapid acting insulins:
± Insulin lispro ± Insulin aspart ± Insulin glulisine ± Regular insulin
Analogues

*Long-acting insulins:
± ± ± ± Ultralente insulin Protamine Zinc Insulin (PZI) Insulin Glargine Analogues Insulin detemir

‡ *Short acting insulins: ‡ *Intermediate acting insulins:
± Lente insulin[Insulin Zinc suspension ± NPH insulin [Isophane Insulin suspension]

*Premixed insulins:
± 70% NPH + 30% Regular ± 50% NPH + 50% Regular ± 75% NPH + 25% Lispro

*Animal or human

Insulin preparations Rapid acting
‡ More physiologic prandial insulin replacement - their rapid onset and early peak action - closely mimic normal endogenous prandial insulin secretion than does regular insulin, ‡ Can be taken immediately before the meal without sacrificing glucose control. ‡ Their duration of action is rarely more than 4±5 hours, which decreases the risk of late postmeal hypoglycemia. ‡ Lowest variability of absorption [Monomers] ‡ Preferred insulins for use in continuous subcutaneous insulin infusion [CSII] devices.

Insulin preparations Rapid acting

Lispro

Insulin preparations Rapid acting

Aspart

Insulin preparations Rapid acting

Glulysine

Insulin preparations Short acting
‡ Recombinant DNA techniques, purified porcine ‡ Effect appears within 30 minutes - peaks between 2 and 3 hours after s.c injection -lasts 5±8 hours. ‡ Prandial hyperglycemia and risk of late hypoglycemia [30-45 mts before meals] ‡ Only preperation for i.v.use.

Insulin preparations Intermediate acting
Lente insulin[Insulin Zinc suspension] NPH insulin [Isophane Insulin suspension]

±Onset-1-2 h ±Peak-6-12h ±Duration-18-24 ±Dose related action profile ±Long acting analogs are preferred

Long actingInsulin preparations
±Onset-1-2 h ±Peak less ±Duration-18-24
THRThriiii

Detemir

Glargine

THR Myristic acid

Type Rapid/Short Regular soluble Lispro Aspart Glulisine Intermediate NPH (isophane) Lente Long Ultralente Protamine zinc Glargine Detemir

Appearance Clear Clear Clear Clear Cloudy Cloudy Cloudy Clear Clear Clear

Onset 0.5±0.7 0.25 0.25 --1±2 1±2

Peak 1.5±4 0.5±1.5 0.6±0.8 0.5±1.5 6±12 6±12

Duration 5±8 2±5 3±5 1±2.5 18±24 18±24 20±36 24±36 18±24 6±24

4±6 4±6 2±5 1±2

16±18 14±20 5±24 4±14

Adverse Effects of Insulin: Hypoglycemia
‡ Results from:
± Delay in taking a meal ± Inadequate carbohydrate intake ± Unusual physical exertion ± Too large insulin doses Symptoms

‡ Autonomic hyperactivity
± Sympathetic
‡ Tachycardia, palpitations, sweating, tremulousness

± Parasympathetic:
‡ Nausea, hunger

± Convulsions / Coma

Adverse Effects of Insulin: Hypoglycemia
‡ Hypoglycemia unawareness ‡ Treatment:
± Glucose administration:
‡ Fruit juice / Glucose gel / Sugar containing beverage/food to eat at first sign ‡ If severe: 50% dextrose i.v. Carry identity card

Adverse Effects of Insulin
Insulin Allergy:
‡ Noninsulin protein contaminants ‡ Less with purified insulin preparations ‡ ? Anaphylaxis

Insulin Resistance
[Requirement of > 200U/day] ‡ Acute:
± Causes: Infections, trauma, surgery, stress (in stress corticosteroids oppose insulin action) ± Treated by regular insulin

‡ Chronic:
± Common in type II ± Cause: Antibodies to contaminating proteins which also bind insulin ± Treatment- change to human insulin

‡ Reversible
± Pregnancy

Adverse Effects of Insulin
Insulin Lipodystrophy
‡ Older insulin preparations Repeated injections at the same site Atrophy / Hypertrophy of subcutaneous fat ‡ Atrophy not seen with newer human insulin preparations, hypertrophy still a problem ‡ ? Injection of newer insulin into atrophic area Restoration of normal contours ‡ Sites of injection: Abdomen best, Keep changing

Insulin Edema
‡ Na+ retention, Weight gain

Unitage of Insulin
‡ 1 U = Amount required to reduce blood glucose by 45 mg% in a fasting rabbit ‡ 1mg=28units

Insulin Delivery Systems
‡ ‡ ‡ ‡ Disposable needles and syringes: 27 G Portable Pen Injectors Jet injectors Continuous Subcutaneous Insulin Infusion: CSII
± Most physiologic insulin replacement ± Insulin reservoir/ Program chip/ Keypad/ Display screen ± Excellent glycemic control eg, pregnancy

‡ Inhaled Insulin
± Absorbed through alveolar walls ± Rapid onset of action / Short duration ± ? Pulmonary fibrosis/Pulmonary hypertension

‡ Oral insulin: Liposome encapsulated

Clinical Uses of Insulin
‡ Type 1 diabetes mellitus ‡ Type 2 diabetes mellitus Not controlled by oral agents  Complications: Diabetic ketoacidosis, Gangrene,  To tide over: Infection, Trauma  Pregnancy [Gestational diabetes not controlled by diet alone]
‡ Emergency treatment of hyperkalemia: Insulin + glucose

Indications of Human Insulin
1. Insulin resistance 2. Allergy to conventional preparations 3. Injection site lipodystrophy 4. Short term use- surgery, trauma 5. During pregnancy

Insulin regimens
‡ Intensive Insulin therapy-Based on formulaeCSII ‡ Conventional- For type 2 ‡ Spl circumstances ‡ Principle: ‡ Supply postprandial needs ‡ Provide basal control

Glargine + 3 Analogs

2Long acting+2 Rapid or Short acting

CSII

Diabetic Ketoacidocis [Diabetic coma]
‡ Precipitated by infection, trauma, stress in insulin dependent patients ‡ Serious ‡ Hypotension, shock, tachycardia, dehydration, hyperventilation, vomiting, coma

Treatment: 1. Regular insulin-I.V. 2. Bolus followed by infusion 3. i.v fluids. 4. Kcl ??? 5. NaHco3 6. Phosphate 7. Antibiotics

Drug interactions
Beta blockersInhibit comp mechanisms Warning signs of hypoglycemia are masked Thiazides, Furosemide, Corticosteroids, OCPs, reduce the effect of insulin ‡ Salicylates, Li, increase insulin secretion ‡ ‡ ‡ ‡

Insulin Delivery Systems

Disposable needles and syringes: 27 G

Portable Pen Injectors

Insulin Delivery Systems

A device that uses high pressure instead of a needle to propel insulin through the skin and into the body.

Inhaled Insulin

Insulin Delivery Systems

Continuous Subcutaneous Insulin Infusion: CSII

Insulin Delivery Systems
1 - Continuous glucose sensor monitors blood sugar level 2 - Data transmitted for the computer program to work out insulin dose 3 - Insulin pump delivers the dose

µArtificial pancreas¶ Sensor activated pump

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