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Identification
Name Insulin Glargine
Accession Number DB00047 (BIOD00045, BTD00045, DB01308)
Type biotech
Groups approved
Description

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 and no pronounced peak concentration.
Protein structure Db00047
Display: 3D Structure
Protein chemical formula C267H408N72O77S6
Protein average weight 6063.0000
Sequences 
>A chain
GIVEQCCTSICSLYQLENYCG

>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR

FASTA
Synonyms
  • Insulin Glargine (rDNA origin)
Synonyms
Insulin Glargine (rDNA origin)
Salts Not Available
Brand names
Name Company
Lantus Sanofi-Aventis
Lantus SoloStar
Brand mixtures Not Available
Categories
  • Hypoglycemic Agents
  • Antidiabetic
CAS number 160337-95-1
Taxonomy
Kingdom Not Available
Classes Not Available
Substructures Not Available
Pharmacology
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.
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.
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.
Absorption Forms microprecipitates following subcutaneous injection. 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.
Volume of distribution Not Available
Protein binding Not Available
Metabolism Partly metabolized to two active metabolites with similar in vitro activity to insulin: A21-Gly-insulin and A21-Gly-des-B30-Thr-insulin.
Route of elimination Not Available
Half life Not reported in humans; 30 hours in vitro in mammalian reticulocytes.
Clearance Not Available
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.
Affected organisms
  • Humans and other mammals
Pathways Not Available
Pharmacoeconomics
Manufacturers
  • Sanofi aventis us llc
Packagers
Dosage forms
Form Route Strength
Injection, solution Subcutaneous 100 units/ml
Prices
Unit description Cost Unit
Lantus SoloStar 100 unit/ml Solution 1 Box = Five 3ml Syringes 223.89 USD box
Lantus 100 unit/ml Solution 10ml Vial 111.88 USD vial
Lantus for OptiClik 100 unit/ml Solution 3ml Cartridge 44.78 USD cartridge
Lantus 100 unit/ml cartridge 14.35 USD ml
Lantus solostar 100 unit/ml 14.35 USD ml
Patents
Country Patent Number Approved Expires (estimated)
United States 7476652 2004-01-23 2024-01-23
United States 6100376 1992-11-06 2009-11-06
Canada 1339044 1997-04-01 2014-04-01
Properties
State liquid
Melting point 81 oC (Khachidze, D.G. et al., J. Biol. Phys. Chem. 1:64-67 (2001))
Experimental Properties
Property Value Source
hydrophobicity 0.098 PhysProp
isoelectric point 6.88 Various sources
References
Synthesis Reference Not Available
General Reference
  1. Chatterjee S, Tringham JR, Davies MJ: Insulin glargine and its place in the treatment of Types 1 and 2 diabetes mellitus. Expert Opin Pharmacother. 2006 Jul;7(10):1357-71. Pubmed
  2. 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):1743-78. Pubmed
  3. Home PD, Ashwell SG: An overview of insulin glargine. Diabetes Metab Res Rev. 2002 Sep-Oct;18 Suppl 3:S57-63. Pubmed
  4. Jones R: Insulin glargine (Aventis Pharma). IDrugs. 2000 Sep;3(9):1081-7. Pubmed
  5. Wang F, Carabino JM, Vergara CM: Insulin glargine: a systematic review of a long-acting insulin analogue. Clin Ther. 2003 Jun;25(6):1541-77, discussion 1539-40. Pubmed
  6. 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. 2004 Nov;8(45):iii, 1-57. Pubmed
External Links
Resource Link
PharmGKB PA449994 Link_out
Drug Product Database 2245689 Link_out
RxList http://www.rxlist.com/cgi/generic2/lantus.htm Link_out
Drugs.com http://www.drugs.com/cdi/insulin-glargine-cartridge-systems.html Link_out
Wikipedia http://en.wikipedia.org/wiki/Insulin_glargine Link_out
ATC Codes
  • A10AE04
AHFS Codes
  • 68:20.08
PDB Entries
FDA label show (51.2 KB)
MSDS Not Available
Interactions
Drug Interactions
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.
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.
Oxprenolol The 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.
Food Interactions Not Available
Targets

1. Insulin receptor

Pharmacological action: yes
Actions: agonist

This receptor binds insulin and has a tyrosine-protein kinase activity. Isoform Short has a higher affinity for insulin. Mediates the metabolic functions of insulin. Binding to insulin stimulates association of the receptor with downstream mediators including IRS1 and phosphatidylinositol 3'-kinase (PI3K). Can activate PI3K either directly by binding to the p85 regulatory subunit, or indirectly via IRS1

Organism class: human
UniProt ID: P06213 Link_out
Gene: INSR Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
  2. Le Roith D: Insulin glargine and receptor-mediated signalling: clinical implications in treating type 2 diabetes. Diabetes Metab Res Rev. 2007 Nov;23(8):593-9. Pubmed
  3. Sciacca L, Cassarino MF, Genua M, Pandini G, Le Moli R, Squatrito S, Vigneri R: Insulin analogues differently activate insulin receptor isoforms and post-receptor signalling. Diabetologia. 2010 Apr 28. Pubmed
  4. Wada T, Azegami M, Sugiyama M, Tsuneki H, Sasaoka T: Characteristics of signalling properties mediated by long-acting insulin analogue glargine and detemir in target cells of insulin. Diabetes Res Clin Pract. 2008 Sep;81(3):269-77. Epub 2008 Jun 27. Pubmed

2. Insulin-like growth factor 1 receptor

Pharmacological action: unknown
Actions: agonist

This receptor binds insulin-like growth factor 1 (IGF1) with a high affinity and IGF2 with a lower affinity. It has a tyrosine-protein kinase activity, which is necessary for the activation of the IGF1-stimulated downstream signaling cascade

Organism class: human
UniProt ID: P08069 Link_out
Gene: IGF1R Link_out
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Smith TJ: Insulin-like growth factor-I regulation of immune function: a potential therapeutic target in autoimmune diseases? Pharmacol Rev. 2010 Jun;62(2):199-236. Epub 2010 Apr 14. Pubmed
Enzymes

1. Cytochrome P450 1A2

Actions: inducer

Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally unrelated compounds, including steroids, fatty acids, and xenobiotics. Most active in catalyzing 2-hydroxylation. Caffeine is metabolized primarily by cytochrome CYP1A2 in the liver through an initial N3-demethylation. Also acts in the metabolism of aflatoxin B1 and acetaminophen

UniProt ID: P05177 Link_out
Gene: CYP1A2
Protein Sequence: FASTA
Gene Sequence: FASTA
SNPs: SNPJam Report Link_out

References:
  1. Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). Accessed May 28, 2010.
Comments
Drug created on June 13, 2005 07:24 / Updated on October 16, 2010 15:58