| Primary information |
|---|
| ThPP ID | Th1040 |
| Therapeutic Peptide/Protein Name | Insulin Lispro |
| Sequence | A chain:GIVEQCCTSICSLYQLENYCN;B chain:FVNQHLCGSHLV view full sequnce in fasta |
| Functional Classification | Ia |
| Molecular Weight | 5808 |
| Chemical Formula | C257H387N65O76S6 |
| Isoelectric Point | 5.39 |
| Hydrophobicity | 0.218 |
| Melting Point (℃) | 81 |
| Half Life | On subcutaneous administration = 1 hour |
| Description | Insulin lispro is a recombinant human insulin analogue produced in a specialized laboratory strain of Escherischia coli. Plasmid DNA transfected into the bacteria encodes for an analogue of human insulin that has a lysine at residuce B28 and proline at B29; these residues are reversed in endogenous human insulin. Reversal of these amino acid residues produces a rapid-acting insulin analogue. FDA approved on 1996. |
| Indication/Disease | To treat type 1 or 2 diabetes mellitus. To be used in conjunction with an intermediate or long-acting insulin except when used in a continuous insulin infusion pump. |
| Pharmacodynamics | Insulin is a natural hormone produced by beta cells of the pancreas. In non-diabetic individuals, a basal level of insulin is supplemented with insulin spikes following meals. Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to absorptive state. Insulin promotes cellular uptake of glucose, particularly in muscle and adipose tissues, promotes energy storage via glycogenesis, opposes catabolism of energy stores, increases DNA replication and protein synthesis by stimulating amino acid uptake by liver, muscle and adipose tissue, and modifies the activity of numerous enzymes involved in glycogen synthesis and glycolysis. Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis). Insulin lispro is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin lispro is 10-15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 4-5 hours. Compared to regular human insulin, insulin lispro has a more rapid onset of action and a shorter duration of action. Insulin lispro is also shown to be equipotent to human insulin on a molar basis. |
| Mechanism of Action | Insulin lispro binds to the insulin receptor(IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. Activation of these proteins leads to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism. In humans, insulin is stored in the form of hexamers; however, only insulin monomers are able to interact with IR. Reversal of the proline and lysine residues at positions B28 and B29 of native insulin eliminates hydrophobic interactions and weakens some of the hydrogen bonds that contribute to the stability of the insulin dimers that comprise insulin hexamers. Hexamers of insulin lispro are produced in the presence of zinc and -cresol. These weakly associated hexamers quickly dissociate upon subcutaneous injection and are absorbed as monomers through vascular endothelial cells. These properties give insulin lispro its fast-acting properties. |
| Toxicity | Inappropriately high dosages relative to food intake and/or energy expenditure may result in severe and sometimes prolonged and life-threatening hypoglycemia. Neurogenic (autonomic) signs and symptoms of hypoglycemia include trembling, palpitations, sweat |
| Metabolism | Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process. |
| Absorption | Rapidly absorbed following subcutaneous administration. It is also absorbed more quickly than regular human insulin. Peak serum levels occur 30-90 minutes after injection in healthy subjects. Absorption also differs depending on the site of injection. Aft |
| Volume of Distribution | When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of insulin lispro appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively). |
| Clearance | Clearance is dose dependent. When a dose of 0.1 unit/kg and 0.2 unit/kg were administered intravenously, the mean clearance was 21.0 mL/min/kg and 9.6 mL/min/kg respectively. |
| Categories | Hypoglycemic Agents |
| Patents Number | US5474978 |
| Date of Issue | 16/06/94 |
| Date of Expiry | 16/06/14 |
| Drug Interaction | The beta-blocker, acebutolol, atenolol, bisoprolol, carvedilol, may decrease symptoms of hypoglycemia. |
| Target | Insulin receptor,Insulin-like growth factor 1 receptor |
| Information of corresponding available drug in the market |
|---|
| Brand Name | Humalog |
| Company | Eli Lilly |
| Brand Discription | HUMALOG (insulin lispro injection, USP [rDNA origin]) is a rapid-acting human insulin analog used to lower blood glucose. Insulin lispro is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. Insulin li |
| Prescribed for | Humalog is used to treat type 1 diabetes in adults. It is usually given together with another long-acting insulin. Humalog is also used together with oral medications to treat type 2 diabetes in adults. |
| Chemical Name | N.A. |
| Formulation | Each milliliter of HUMALOG contains insulin lispro 100 units, 16 mg glycerin, 1.88 mg dibasic sodium phosphate, 3.15 mg Metacresol, zinc oxide content adjusted to provide 0.0197 mg zinc ion, trace amounts of phenol, and Water for Injection. Insulin lispro |
| Physcial Appearnce | Sterile, aqueous, clear, and colorless solution |
| Route of Administration | Subcutaneous and Intravenous infusion |
| Recommended Dosage | The total daily insulin requirement may vary and is usually between 0.5 to 1 unit/kg/day. Insulin requirements may be altered during stress, major illness, or with changes in exercise, meal patterns, or coadministered drugs. Usual maintenance range is 0.5-1 unit/kg/day in divided doses; nonobese may require 0.4-0.6 unit/kg/day; obese may require 0.8-1.2 units/kg/day. |
| Contraindication | During episodes of hypoglycemia in patients who are hypersensitive to HUMALOG or to any of its excipients. |
| Side Effects | Low blood sugar--headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery. |
| Useful Link | http://pi.lilly.com/us/humalog-pen-pi.pdf |
| PubMed ID | 18454569, 20424816, 19496630, 18076215, 17764465, 17703632, 16706558, 11118018 |
| 3-D Structure | Th1040 (View) or (Download) |