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Identification
NameInsulin Glargine
Accession NumberDB00047  (BIOD00045, BTD00045, DB01308)
Typebiotech
Groupsapproved
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 (up to 24 hours) and no pronounced peak concentration.

Protein structureDb00047
Protein chemical formulaC267H404N72O78S6
Protein average weight6063 Daltons
Sequences
>A chain
GIVEQCCTSICSLYQLENYCG
>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR
Download FASTA Format
Synonyms
SynonymLanguageCode
Insulin Glargine (rDNA origin)Not AvailableNot Available
SaltsNot Available
Brand names
NameCompany
LantusSanofi-Aventis
Lantus OptiSet Not Available
Lantus SoloStarNot Available
Brand mixturesNot Available
Categories
CAS number160337-95-1
Taxonomy
KingdomOrganic Compounds
SuperclassOrganic Acids
ClassCarboxylic Acids and Derivatives
SubclassAmino Acids, Peptides, and Analogues
Direct parentPeptides
Alternative parentsNot Available
SubstituentsNot Available
Classification descriptionNot Available
Pharmacology
IndicationFor 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.
PharmacodynamicsInsulin 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.
Mechanism of actionInsulin 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.
AbsorptionBecause 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.
Volume of distributionNot Available
Protein bindingNot Available
Metabolism

Partly metabolized to two active metabolites with similar <i>in vitro</i> activity to insulin: A21-Gly-insulin and A21-Gly-des-B30-Thr-insulin.

SubstrateEnzymesProduct
Insulin Glargine
    A21-Gly-des-B30-Thr-insulinDetails
    Insulin Glargine
      A21-Gly-insulinDetails
      Route of eliminationNot Available
      Half lifeNot reported in humans; 30 hours in vitro in mammalian reticulocytes.
      ClearanceNot Available
      ToxicityInappropriately 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
      PathwaysNot Available
      SNP Mediated EffectsNot Available
      SNP Mediated Adverse Drug ReactionsNot Available
      ADMET
      Predicted ADMET features
      Property Value Probability
      Human Intestinal Absorption Not Available Not Available
      Blood Brain Barrier Not Available Not Available
      Caco-2 permeable Not Available Not Available
      P-glycoprotein substrate Not Available Not Available
      P-glycoprotein inhibitor I Not Available Not Available
      P-glycoprotein inhibitor II Not Available Not Available
      Renal organic cation transporter Not Available Not Available
      CYP450 2C9 substrate Not Available Not Available
      CYP450 2D6 substrate Not Available Not Available
      CYP450 3A4 substrate Not Available Not Available
      CYP450 1A2 substrate Not Available Not Available
      CYP450 2C9 substrate Not Available Not Available
      CYP450 2D6 substrate Not Available Not Available
      CYP450 2C19 substrate Not Available Not Available
      CYP450 3A4 substrate Not Available Not Available
      CYP450 inhibitory promiscuity Not Available Not Available
      Ames test Not Available Not Available
      Carcinogenicity Not Available Not Available
      Biodegradation Not Available Not Available
      Rat acute toxicity Not Available Not applicable
      hERG inhibition (predictor I) Not Available Not Available
      hERG inhibition (predictor II) Not Available Not Available
      Pharmacoeconomics
      Manufacturers
      • Sanofi aventis us llc
      Packagers
      Dosage forms
      FormRouteStrength
      Injection, solutionSubcutaneous100 units/ml
      Prices
      Unit descriptionCostUnit
      Lantus SoloStar 100 unit/ml Solution 1 Box = Five 3ml Syringes223.89USDbox
      Lantus 100 unit/ml Solution 10ml Vial111.88USDvial
      Lantus for OptiClik 100 unit/ml Solution 3ml Cartridge44.78USDcartridge
      Lantus 100 unit/ml cartridge14.35USDml
      Lantus solostar 100 unit/ml14.35USDml
      DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
      Patents
      CountryPatent NumberApprovedExpires (estimated)
      United States74766522004-01-232024-01-23
      United States61003761992-11-062009-11-06
      Canada13390441997-04-012014-04-01
      Properties
      Stateliquid
      Experimental Properties
      PropertyValueSource
      melting point81 °CKhachidze, D.G. et al., J. Biol. Phys. Chem. 1:64-67 (2001)
      hydrophobicity0.098Not Available
      isoelectric point6.88Not Available
      Spectra
      SpectraNot Available
      References
      Synthesis ReferenceNot 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
      7. Owens DR, Bolli GB: Beyond the era of NPH insulin—long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther. 2008 Oct;10(5):333-49. doi: 10.1089/dia.2008.0023. Pubmed
      External Links
      ResourceLink
      PharmGKBPA449992
      Drug Product Database2245689
      RxListhttp://www.rxlist.com/cgi/generic2/lantus.htm
      Drugs.comhttp://www.drugs.com/cdi/insulin-glargine-cartridge-systems.html
      WikipediaInsulin_glargine
      ATC CodesNot Available
      AHFS Codes
      • 68:20.08
      PDB Entries
      FDA labelshow(51.2 KB)
      MSDSNot Available
      Interactions
      Drug Interactions
      Drug
      AcebutololThe beta-blocker, acebutolol, may decrease symptoms of hypoglycemia.
      AtenololThe beta-blocker, atenolol, may decrease symptoms of hypoglycemia.
      BetaxololThe beta-blocker, betaxolol, may decrease symptoms of hypoglycemia.
      BevantololThe beta-blocker, bevantolol, may decrease symptoms of hypoglycemia.
      BisoprololThe beta-blocker, bisoprolol, may decrease symptoms of hypoglycemia.
      CarteololThe beta-blocker, carteolol, may decrease symptoms of hypoglycemia.
      CarvedilolThe beta-blocker, carvedilol, may decrease symptoms of hypoglycemia.
      EsmololThe beta-blocker, esmolol, may decrease symptoms of hypoglycemia.
      LabetalolThe beta-blocker, labetolol, may decrease symptoms of hypoglycemia.
      MetoprololThe beta-blocker, metoprolol, may decrease symptoms of hypoglycemia.
      NadololThe beta-blocker, nadolol, may decrease symptoms of hypoglycemia.
      OxprenololThe beta-blocker, oxprenolol, may decrease symptoms of hypoglycemia.
      PenbutololThe beta-blocker, penbutolol, may decrease symptoms of hypoglycemia.
      PindololThe beta-blocker, pindolol, may decrease symptoms of hypoglycemia.
      PractololThe beta-blocker, practolol, may decrease symptoms of hypoglycemia.
      PropranololThe beta-blocker, propranolol, may decrease symptoms of hypoglycemia.
      Somatropin recombinantSomatropin may antagonize the hypoglycemic effect of insulin glargine. Monitor for changes in fasting and postprandial blood sugars.
      SotalolThe beta-blocker, sotalol, may decrease symptoms of hypoglycemia.
      TimololThe beta-blocker, timolol, may decrease symptoms of hypoglycemia.
      Food InteractionsNot Available

      1. Insulin receptor

      Kind: protein

      Organism: Human

      Pharmacological action: yes

      Actions: agonist

      Components

      Name UniProt ID Details
      Insulin receptor P06213 Details

      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

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: agonist

      Components

      Name UniProt ID Details
      Insulin-like growth factor 1 receptor P08069 Details

      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

      1. Cytochrome P450 1A2

      Kind: protein

      Organism: Human

      Pharmacological action: unknown

      Actions: inducer

      Components

      Name UniProt ID Details
      Cytochrome P450 1A2 P05177 Details

      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 June 27, 2013 16:53