Insulin and its Analogues.pptx

Insulin and its analogues : History, Insulin Molecule, DNA Recombinant Technology, Pharmacology of Insulin, Types of Insulin, Indications of Insulin. A complete comprehensive overlook of Insulin, its types and the pharmacology.

1. Insulin & its Analogues in DM By Mohammed Muneebullah PharmD VI th Year 16111T0014 Shadan College of Pharmacy

2. Outline History Insulin Molecule DNA recombinant Technology Types & Indications of Insulin Pharmacology

3. W h at is Insulin? Insulin is a P eptide H ormone  secreted by the β cells of the pancreatic islets of Langerhans and maintains normal blood glucose levels by facilitating cellular glucose uptake, regulating carbohydrate, lipid and protein metabolism and promoting cell division and growth through its mitogenic effects . Insulin is usually injected into the fatty tissue just under the skin. This is also called subcutaneous tissue.

4. History Of Insulin

5. Eli Lilly began producing insulin from animal pancreas but fell short of the demand, and the potency varied up to 25% per lot . The development of an Isoelectric precipitation method led to a purer and more potent animal insulin, decreasing the variation between lots to 10 %. Because the insulin preparation required several injections daily, investigators worked to find ways to prolong its duration of action. In the 1930s, H.C. Hagedorn , a chemist in Denmark, prolonged the action of insulin by adding Protamine. In Toronto, Scott and Fisher prolonged insulin action further by adding zinc. These discoveries led to the introduction of longer-acting animal insulins in the market. Protamine zinc insulin lasted 24–36 hours. Isophane neutral protamine Hagedorn lasted 24 hours and could be mixed with regular insulin. The pharmacokinetics and effects of such insulin depended on the proportion of zinc . Insulin from cattle and pigs was used for many years to treat diabetes and saved millions of lives, but it wasn’t perfect, as it caused allergic reactions in many patients.  In 1978, the first recombinant DNA human insulin was prepared by David Goeddel and his colleagues (of Genentech) by utilizing and combining the insulin A- and B- chains expressed in  Escherichia coli . Thereafter, Genentech and Lilly signed an agreement to commercialize rDNA insulin. In 1982, the first insulin utilizing rDNA technology, Humulin  R (rapid) and N (NPH, intermediate-acting), were marketed.

6. Insulin is a two chain polypeptide having 51 amino acids and MW about 6000D. The A-chain has 21 while B-chain has 30 amino acids. The A and B chains are held together by two disulfide bonds. Insulin is synthesized in the β cells of pancreatic islets as a single chain peptide Preproinsulin (110 AA) from which 24 AAs are first removed to produce Proinsulin . The Connecting or ‘C’ peptide (35 AA) is split off by Proteolysis in Golgi apparatus; both Insulin and C peptide are stored in granules within the cell. The C peptide is secreted in the blood along with insulin . Structure of Insulin

7. Categorization of Insulin Insulins are categorized by differences in: Onset (how quickly they act) Peak (how long it takes to achieve maximum impact) Duration (how long they last before they wear off) Concentration (Insulins sold in the U.S. have a concentration of 100 units per ml or U100. In other countries, additional concentrations are available). Route of delivery  (whether they are injected under the skin or given intravenously)

8. MOA of Insulin Binding of Insulin to Insulin α receptor & stimulation of β subunit Adjacent β subunit auto-phosphorylation and phosphorylation of Insulin Receptor Substrate proteins (IRS-1 and IRS-2) Cascade of Phosphorylation and Dephosphorylation reactions. Activation of Protein Kinases which induce multiplication and differentiation of several specific cells Generation of secondary messengers like Diacyl Glycerol (DAG) and Phophatidyl Inositol Phosphate(PIP 3 ) Insulin action on specific metabolizing enzymes Long term effects of Insulin Insulin also causes translocation of Glucose transporter 4 (GLUT4) from Cytoplasm to Cell-membrane with the help of ATP and thus GLUT4 intakes glucose in skeletal muscles and fat cells

9. I n sulin Action in Carbohydrate Metabolism

10. Insulin Types / Ultra Short acting (analogues ) (analogues) Rapid acting : Also called Meal-time Insulin. As dose is increased, Onset and Peak time remain same, but duration increases. Short acting : As dose in increased, Onset is faster, Duration of the effect is long but it takes more time to attain Peak. Intermediate acting : Very small doses have earlier peak effect and shorter DOA, while higher doses take higher time to peak and have prolonged duration of action. Long acting : are absorbed slowly and have large duration of action. Ultra Long acting (Degludec) : true 24hrs, can be taken thrice a week, lower risk of Hypoglycemia.

11. Insulin analogues are molecules produced by genetic engineering wherein the amino acid sequence in human insulin is changed to alter its pharmacokinetics. They bind to insulin receptor in the same way as human insulin and produce similar effects. They are also called as: Designer Insulins, Insulin receptor Ligands, Democratic Insulins. Insulin Analogues were developed to overcome the limitations of available Insulins: Ultrashort acting Analogues were to overcome limitation of short acting Insulins. Long acting Analogues to overcome limitations of Long/Intermediate acting Insulins(NPH) Need for Insulin Analogues

12. Regular Insulins Form Hexamers which dissociate slowly into Monomers thus delaying Absorption. Delayed Onset of action (0.5-1hr). ( PPH ) Prolonged time of peak action (2-3hrs) and Duration of action (5-8hrs) ( Late PPh ) Hence, DOES NOT MIMIC physiological Insulin secretion. Should be taken 35-40mins prior to meal . Dose of Insulin can not be adjusted with size of meal . Analogues of Insulin Less tendency to form Hexamers, dissociate rapidly into monomers and are rapidly absorbed. Rapid Onset of action (10-20mins). ( control of PPH ) Peak action (1-2 hrs ) and Duration of action (4-5hrs) ( Decreased risk of late PPh ) MIMICS physiological Insulin secretion. Can be taken just before or after meals . Allows adjustment of Insulin dose with size of meal .

13. Insulin Indications

14. Contraindications Diarrhea, fever, infection, surgery, thyroid disease, trauma, vomiting Hepatic disease, renal failure, renal impairment Hypoglycemia Hypokalemia H ypersensitivity Pregnancy Breast-feeding Tobacco smoking