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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	Antidiabetic Agents
Patents Number	US5514646
Date of Issue	07/05/93
Date of Expiry	07/05/13
Drug Interaction	Concomitant therapy with drugs like Dextropropoxyphene, Pentoxifylline, Pramlintide, Fluoxetine, Fenofibrate and Disopyramide that may increase the blood-glucose-lowering effect of insulin lispro
Target	N.A.
Information of corresponding available drug in the market
Brand Name	N.A.
Company	N.A.
Brand Discription	N.A.
Prescribed for	N.A.
Chemical Name	N.A.
Formulation	N.A.
Physcial Appearnce	N.A.
Route of Administration	N.A.
Recommended Dosage	N.A.
Contraindication	N.A.
Side Effects	N.A.
Useful Link	http://www.rxlist.com/humalog-drug.htm
PubMed ID	18454569, 20424816, 19496630, 18076215, 17764465, 17703632, 16706558, 11118018
3-D Structure	Th1040 (View) or (Download)