1. Insulin Glargine Drugbank ID: DB00047
Protein chemical formula : C267H404N72O78S6
Protein average weight : 6063 Daltons
Half-life : Not reported in humans; 30 hours; in vitro in mammalian reticulocytes.
Chemical name : Chemically, insulin glargine is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin

2. Description : Indication
Insulin glargine is produced by recombinant DNA technology using a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. It is an analogue of human insulin made by replacing the asparagine residue at position A21 of the A-chain with glycine and adding two arginines to the C-terminus (positions B31 and 32) of the B-chain. The resulting protein is soluble at pH 4 and forms microprecipitates at physiological pH 7.4. Small amounts of insulin glargine are slowly released from microprecipitates giving the drug a long duration of action (up to 24 hours) and no pronounced peak concentration.
Indication
For the treatment of Type 1 or 2 diabetes mellitus in patients over 17 years old who require a long-acting (basal) insulin for the control of hyperglycemia. May be used in pediatric patients with Type 1 diabetes mellitus who require a long-acting (basal) insulin for glycemic control.

3. 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 glargine is a long-acting insulin analogue with a flat and predictable action profile. It is used to mimic the basal levels of insulin in diabetic individuals. The onset of action of insulin glargine is approximately 90 minutes and its duration of action is up to 24 hours. The action profile of insulin glargine is peakless. The significance of this finding is that insulin glargine has a lower chance of nocturnal hypoglycemia.

4. Mechanism Of Action
Insulin glargine 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. Insulin glargine is completely soluble at pH 4, the pH of administered solution, and has low solubility at physiological pH 7.4. Upon subcuteous injection, the solution is neutralized resulting in the formation of microprecipitates. Small amounts of insulin glargine are released from microprecipitates giving the drug a relatively constant concentration over time profile over 24 hours with no pronounced peak. This release mechanism allows the drug to mimic basal insulin levels within the body.

5. 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, sweating, anxiety, hunger, nausea and tingling. Neuroglycopenic signs and symptoms of hypoglycemia include difficulty concentrating, lethargy/weakness, confusion, drowsiness, vision changes, difficulty speaking, headache, and dizziness. Mild hypoglycemia is characterized by the presence of autonomic symptoms. Moderate hypoglycemia is characterized by the presence of autonomic and neuroglycopenic symptoms. Individuals may become unconscious in severe cases of hypoglycemia. Other adverse events that may occur include allergic reaction, injection site reaction, lipodystrophy, pruritis, and rash.

6. Metabolism Absorption Categories Affected Organism
Partly metabolized to two active metabolites with similar in vitro activity to insulin: A21-Gly-insulin and A21-Gly-des-B30-Thr-insulin.
Absorption
Because of the modifications to the A and B chain, the isoelectric point shifts towards a neutral pH and insulin glargine is more stable in acidic conditions than regular insulin. As insulin glargine is less soluble at neutral pH, once injected, forms microprecipitates. Slow release of insulin glargine from microprecipitates provides a relatively constant concentration of insulin over 24 hours. Onset of action is approximately 1.1 hours.
Categories
Hypoglycemic Agents and Antidiabetic Agents
Affected Organism
Humans and other mammals

7. Patents Drug interaction
Country Patent Number Approved Expires (estimated)
Canada
United States
United States
Drug interaction
Acebutolol : The beta-blocker, acebutolol, may decrease symptoms of hypoglycemia.
Atenolol : The beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
Betaxolol : The beta-blocker, betaxolol, may decrease symptoms of hypoglycemia.
Bevantolol : The beta-blocker, bevantolol, may decrease symptoms of hypoglycemia.
Bisoprolol : The beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
Carteolol : The beta-blocker, carteolol, may decrease symptoms of hypoglycemia.
Carvedilol : The beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
Esmolol : The beta-blocker, esmolol, may decrease symptoms of hypoglycemia.

8. Labetalol : The beta-blocker, labetolol, may decrease symptoms of hypoglycemia. Metoprolol : The beta-blocker, metoprolol, may decrease symptoms of hypoglycemia. Nadolol : The beta-blocker, nadolol, may decrease symptoms of hypoglycemia. OxprenololThe beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia. Penbutolol : The beta-blocker, penbutolol, may decrease symptoms of hypoglycemia. Pindolol : The beta-blocker, pindolol, may decrease symptoms of hypoglycemia. Practolol : The beta-blocker, practolol, may decrease symptoms of hypoglycemia .Propranolol : The beta-blocker, propranolol, may decrease symptoms of hypoglycemia. Somatropin recombinant : Somatropin may antagonize the hypoglycemic effect of insulin glargine. Monitor for changes in fasting and postprandial blood sugars. Sotalol : The beta-blocker, sotalol, may decrease symptoms of hypoglycemia. Timolol : The beta-blocker, timolol, may decrease symptoms of hypoglycemia.

9. Sequence Targets A chain GIVEQCCTSICSLYQLENYCG B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR
Targets
Insulin receptor,Insulin-like growth factor 1 receptor

10. Genral References
# Chatterjee S, Tringham JR, Davies MJ: Insulin glargine and its place in the treatment of Types 1 and 2 diabetes mellitus. Expert Opin Pharmacother Jul;7(10): "Pubmed":
# Dunn CJ, Plosker GL, Keating GM, McKeage K, Scott LJ: Insulin glargine: an updated review of its use in the management of diabetes mellitus. Drugs. 2003;63(16): "Pubmed":
# Home PD, Ashwell SG: An overview of insulin glargine. Diabetes Metab Res Rev Sep-Oct;18 Suppl 3:S "Pubmed":
# Jones R: Insulin glargine (Aventis Pharma). IDrugs Sep;3(9): "Pubmed":
# Wang F, Carabino JM, Vergara CM: Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther Jun;25(6): , discussion "Pubmed":
# Warren E, Weatherley-Jones E, Chilcott J, Beverley C: Systematic review and economic evaluation of a long-acting insulin analogue, insulin glargine. Health Technol Assess Nov;8(45):iii, "Pubmed":
# Owens DR, Bolli GB: Beyond the era of NPH insulin--long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther Oct;10(5): doi: /dia "Pubmed":

11. Brands : Lantus Company : Sanofi-Aventis Description : Lantus is a recombinant human insulin analog that is a long-acting (up to 24-hour duration of action), parenteral blood-glucose-lowering agent. LANTUS is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Lantus is a long-acting form of insulin that is slightly different from other forms of insulin that are not man-made. Used For/Prescribed for : It is used to improve glycemic control in adults and children with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Chemical name : Chemically, insulin glargine is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin

12. Formulation : LANTUS consists of insulin glargine dissolved in a clear aqueous fluid. Each milliliter of LANTUS (insulin glargine injection) contains 100 Units ( mg) insulin glargine. The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection. The 3 mL cartridge presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection. Form : solution Route of administration : subcutaneous injection Dosage : LANTUS may be administered at any time during the day. LANTUS should be administered subcutaneously once a day at the same time every day. The dose of LANTUS must be individualized based on clinical response. Contraindication : hypersensitivity

13. Side effects : Common Lantus side effects may include: low blood sugar (headache, hunger, weakness, sweating, confusion, irritability, dizziness, fast heart rate, or feeling jittery). Sign of insulin allergy include itching skin rash over the entire body, wheezing, trouble breathing, fast heart rate, sweating, or feeling like you might pass out. Drug Interaction : total of 800 drugs (5324 brand and generic names) are known to interact with Humalog (insulin lispro) major drug interactions (3 brand and generic names) moderate drug interactions (4727 brand and generic names) minor drug interactions (594 brand and generic names)

14. Refrence : http://www. lantus. com/ http://www. drugs. com/lantus