Insulin glulisine

Identification

Name
Insulin glulisine
Accession Number
DB01309
Description

Insulin glulisine is a short-acting form of insulin used for the treatment of hyperglycemia caused by Type 1 and Type 2 Diabetes. Insulin is typically prescribed for the management of diabetes mellitus to mimic the activity of endogenously produced human insulin, a peptide hormone produced by beta cells of the pancreas that promotes glucose metabolism. Insulin is released from the pancreas following a meal to promote the uptake of glucose from the blood into internal organs and tissues such as the liver, fat cells, and skeletal muscle. Absorption of glucose into cells allows for its transformation into glycogen or fat for storage. Insulin also inhibits hepatic glucose production, enhances protein synthesis, and inhibits lipolysis and proteolysis among many other functions.

Insulin is an important treatment in the management of Type 1 Diabetes (T1D) which is caused by an autoimmune reaction that destroys the beta cells of the pancreas, resulting in the body not being able to produce or synthesize the insulin needed to manage circulating blood sugar levels. As a result, people with T1D rely primarily on exogenous forms of insulin, such as insulin glulisine, to lower glucose levels in the blood. Insulin is also used in the treatment of Type 2 Diabetes (T2D), another form of diabetes mellitus that is a slowly progressing metabolic disorder caused by a combination of genetic and lifestyle factors that promote chronically elevated blood sugar levels. Without treatment or improvement in non-pharmacological measures such as diet and exercise to lower blood glucose, high blood sugar eventually causes cellular resistance to endogenous insulin, and in the long term, damage to pancreatic islet cells. Insulin is typically prescribed later in the course of T2D, after trying several oral medications such as Metformin, Gliclazide, or Sitagliptin have been tried, when sufficient damage has been caused to pancreatic cells that the body is no longer able to produce insulin on its own.

Marketed as the brand name product Apidra, insulin glulisine begins to exert its effects within 15 minutes of subcutaneous administration, while peak levels occur 30 to 90 minutes after administration. Due to its duration of action of around 5 hours, Apidra is considered "bolus insulin" as it provides high levels of insulin in a short period of time to mimic the release of endogenous insulin from the pancreas after meals. Bolus insulin is often combined with once daily, long-acting "basal insulin" such as Insulin detemir, Insulin degludec, and Insulin glargine to provide low concentrations of background insulin that can keep blood sugar stable between meals or overnight. Use of basal and bolus insulin together is intended to mimic the pancreas' production of endogenous insulin, with a goal of avoiding any periods of hypoglycemia.

Insulin glulisine is a biosynthetic, rapid-acting human insulin analogue produced in a non-pathogenic laboratory strain of Escherichia coli (K12). This recombinant hormone differs from native human insulin in that the amino acid arginine at position B3 is replaced by lysine and the lysine at position B29 is replaced by glutamic acid. These structural modifications decrease hexamer formation, stabilize insulin glulisine monomers and increase the rate of absorption and onset of action compared to human insulin.

Without an adequate supply of insulin to promote absorption of glucose from the bloodstream, blood sugar levels can climb to dangerously high levels and can result in symptoms such as fatigue, headache, blurred vision, and increased thirst. If left untreated, the body starts to break down fat, instead of glucose, for energy which results in a build-up of ketone acids in the blood and a syndrome called ketoacidosis, which is a life-threatening medical emergency. In the long term, elevated blood sugar levels increase the risk of heart attack, stroke, and diabetic neuropathy.

Type
Biotech
Groups
Approved
Biologic Classification
Protein Based Therapies
Hormones / Insulins
Protein Chemical Formula
C258H384N64O78S6
Protein Average Weight
5823.0 Da
Sequences
>A chain
GIVEQCCTSICSLYQLENYCN
>B chain
FVKQHLCGSHLVEALYLVCGERGFFYTPET
Download FASTA Format
Synonyms
  • Insulin Glulisine (recombinant DNA origin)
  • Insulin glulisine recombinant
  • Insulina glulisina

Pharmacology

Indication

Insulin glulisine is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus.

Associated Conditions
Contraindications & Blackbox Warnings
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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. Postprandial insulin spikes are 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 glulisine is a rapid-acting insulin analogue used to mimic postprandial insulin spikes in diabetic individuals. The onset of action of insulin glulisine is approximately 15 minutes. Its activity peaks 60 minutes following subcutaneous injection and its duration of action is 2-4 hours.

Mechanism of action

Insulin glulisine 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. Substitution of the arginine at position B3 for lysine and replacement of the B29 lysine with glutamic acid decreases the propensity to form hexamers, stabilizes the hormone in monomeric form and results in a rapid rate of absorption and short duration of action.

TargetActionsOrganism
AInsulin receptor
agonist
Humans
UInsulin-like growth factor 1 receptorNot AvailableHumans
Absorption

In a study in patients with type 1 diabetes (n=20) after subcutaneous administration of 0.15 units/kg, the median time to maximum concentration (Tmax) was 60 minutes (range 40 to 120 minutes) and the peak concentration (Cmax) was 83 microunits/mL (range 40 to 131 microunits/mL) for insulin glulisine compared to a median Tmax of 120 minutes (range 60 to 239 minutes) and a Cmax of 50 microunits/mL (range 35 to 71 microunits/mL) for regular human insulin. When insulin glulisine was injected subcutaneously into different areas of the body, the time-concentration profiles were similar. The absolute bioavailability of insulin glulisine after subcutaneous administration is approximately 70%, regardless of injection area (abdomen 73%, deltoid 71%, thigh 68%).

Volume of distribution

13 L

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half-life

Elimination half life= 42 minutes (following subcutaneous injection)

Clearance
Not Available
Adverse Effects
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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.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Insulin glulisine.
AcebutololThe therapeutic efficacy of Insulin glulisine can be increased when used in combination with Acebutolol.
AcenocoumarolThe metabolism of Acenocoumarol can be increased when combined with Insulin glulisine.
AcetaminophenThe metabolism of Acetaminophen can be increased when combined with Insulin glulisine.
AcetazolamideThe therapeutic efficacy of Insulin glulisine can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Insulin glulisine.
Acetyl sulfisoxazoleThe therapeutic efficacy of Insulin glulisine can be increased when used in combination with Acetyl sulfisoxazole.
Acetylsalicylic acidThe risk or severity of hypoglycemia can be increased when Acetylsalicylic acid is combined with Insulin glulisine.
AcyclovirThe metabolism of Acyclovir can be increased when combined with Insulin glulisine.
AgomelatineThe metabolism of Agomelatine can be increased when combined with Insulin glulisine.
Additional Data Available
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  • Severity
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  • Evidence Level
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  • Action
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Food Interactions
  • Avoid alcohol. Alcohol may impair blood glucose control.

Products

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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
ApidraInjection, solution100 Units/mlIntravenous; SubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 [iU]/1mLSubcutaneoussanofi-aventis U.S. LLC2009-02-24Not applicableUS flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
ApidraInjection, solution100 Units/mlSubcutaneousSanofi Aventis Deutschland Gmb H2004-09-27Not applicableEU flag
Additional Data Available
  • Application Number
    Application Number
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    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
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    A governmentally-recognized ID which uniquely identifies the product within its regulatory market.

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Categories

ATC Codes
A10AB06 — Insulin glulisine
Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Chemical Identifiers

UNII
7XIY785AZD
CAS number
207748-29-6

References

General References
  1. Arnolds S, Rave K, Hovelmann U, Fischer A, Sert-Langeron C, Heise T: Insulin glulisine has a faster onset of action compared with insulin aspart in healthy volunteers. Exp Clin Endocrinol Diabetes. 2010 Oct;118(9):662-4. doi: 10.1055/s-0030-1252067. Epub 2010 Apr 28. [PubMed:20429049]
  2. Becker RH: Insulin glulisine complementing basal insulins: a review of structure and activity. Diabetes Technol Ther. 2007 Feb;9(1):109-21. [PubMed:17316105]
  3. Becker RH, Frick AD: Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47(1):7-20. [PubMed:18076215]
  4. Cox SL: Insulin glulisine. Drugs Today (Barc). 2005 Jul;41(7):433-40. [PubMed:16193096]
  5. Garnock-Jones KP, Plosker GL: Insulin glulisine: a review of its use in the management of diabetes mellitus. Drugs. 2009 May 29;69(8):1035-57. doi: 10.2165/00003495-200969080-00006. [PubMed:19496630]
  6. Horvath K, Bock G, Regittnig W, Bodenlenz M, Wutte A, Plank J, Magnes C, Sinner F, Furst-Recktenwald S, Theobald K, Pieber TR: Insulin glulisine, insulin lispro and regular human insulin show comparable end-organ metabolic effects: an exploratory study. Diabetes Obes Metab. 2008 Jun;10(6):484-91. Epub 2007 Aug 30. [PubMed:17764465]
  7. Authors unspecified: Insuline glusine (Apidra): a new rapid-acting insulin. Med Lett Drugs Ther. 2006 Apr 24;48(1233):33-4. [PubMed:16625142]
  8. Robinson DM, Wellington K: Insulin glulisine. Drugs. 2006;66(6):861-9. [PubMed:16706558]
  9. Ulrich H, Snyder B, Garg SK: Combining insulins for optimal blood glucose control in type I and 2 diabetes: focus on insulin glulisine. Vasc Health Risk Manag. 2007;3(3):245-54. [PubMed:17703632]
  10. FDA Approved Drug Products: Apidra (insulin glulisine) [Link]
KEGG Drug
D04540
PubChem Substance
46504450
RxNav
400008
ChEMBL
CHEMBL1201613
Therapeutic Targets Database
DAP001093
PharmGKB
PA164760859
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Insulin_glulisine
AHFS Codes
  • 68:20.08 — Insulins
FDA label
Download (1.67 MB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedTreatmentDiabetes Mellitus1
4CompletedTreatmentDiabetes Mellitus / Diabetic Kidney Disease / Glucagon-Like Peptide 1 / Nephropathy, Diabetic1
4CompletedTreatmentDiabetes / Hyperglycemia2
4CompletedTreatmentDiabetic Ketoacidosis1
4CompletedTreatmentHyperglycemia / Type 2 Diabetes Mellitus1
4CompletedTreatmentImpaired kidney function / Type 2 Diabetes Mellitus1
4CompletedTreatmentInpatient Hyperglycemia / Type 2 Diabetes Mellitus1
4CompletedTreatmentLipoatrophy / Type 1 Diabetes Mellitus1
4CompletedTreatmentType 1 Diabetes Mellitus10
4CompletedTreatmentType 2 Diabetes Mellitus14

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Sanofi-Aventis Inc.
Dosage Forms
FormRouteStrength
Injection, solutionCutaneous; Parenteral100 U/ML
Injection, solutionIntravenous; Subcutaneous100 Units/ml
Injection, solutionSubcutaneous100 [iU]/1mL
Injection, solutionSubcutaneous100 Units/ml
SolutionSubcutaneous100 unit
SolutionSubcutaneous100 IU
InjectionSubcutaneous100 U/ml
Injection, solutionSubcutaneous100 iu/1mL
Prices
Unit descriptionCostUnit
Apidra 100 unit/ml cartridge13.3USD ml
Apidra 100 unit/ml Cartridge3.56USD cartridge
Apidra 100 unit/ml Syringe3.56USD syringe
Apidra 100 unit/ml2.67USD cartridge
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9011391No2015-04-212024-03-26US flag
US9233211No2016-01-122024-03-02US flag
US8603044No2013-12-102024-03-02US flag
US8512297No2013-08-202024-09-15US flag
US8679069No2014-03-252025-04-12US flag
US8992486No2015-03-312024-06-05US flag
US8556864No2013-10-152024-03-03US flag
US7918833Yes2011-04-052028-03-23US flag
US6221633No2001-04-242018-06-18US flag
US6960561No2005-11-012023-01-25US flag
US7696162No2010-04-132022-03-22US flag
US7452860No2008-11-182022-03-22US flag
US9561331No2017-02-072024-08-28US flag
US9623189No2017-04-182024-08-19US flag
US9610409No2017-04-042024-03-02US flag
US9526844No2016-12-272024-03-02US flag
US9604008No2017-03-282024-03-02US flag
US9533105No2017-01-032024-08-17US flag
US9408979No2016-08-092024-03-02US flag
US9604009No2017-03-282024-08-16US flag
US9775954No2017-10-032024-03-02US flag
US9827379No2017-11-282024-03-02US flag
US9717852No2017-08-012033-04-08US flag
Additional Data Available
  • Filed On
    Filed On
    Available for Purchase

    The date on which a patent was filed with the relevant government.

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Properties

State
Liquid
Experimental Properties
Not Available

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Receptor signaling protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates the pleiotropic actions of insulin. Binding of insulin leads to phosphorylation of several intracellular substrates, including, insulin receptor substrates (...
Gene Name
INSR
Uniprot ID
P06213
Uniprot Name
Insulin receptor
Molecular Weight
156331.465 Da
References
  1. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
  2. 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 Aug;53(8):1743-53. doi: 10.1007/s00125-010-1760-6. Epub 2010 Apr 28. [PubMed:20424816]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Protein tyrosine kinase activity
Specific Function
Receptor tyrosine kinase which mediates actions of insulin-like growth factor 1 (IGF1). Binds IGF1 with high affinity and IGF2 and insulin (INS) with a lower affinity. The activated IGF1R is involv...
Gene Name
IGF1R
Uniprot ID
P08069
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da
References
  1. Varewijck AJ, Janssen JA: Insulin and its analogues and their affinities for the IGF1 receptor. Endocr Relat Cancer. 2012 Sep 5;19(5):F63-75. doi: 10.1530/ERC-12-0026. Print 2012 Oct. [PubMed:22420005]

Enzymes

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Inducer
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
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 un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Barnett CR, Wilson J, Wolf CR, Flatt PR, Ioannides C: Hyperinsulinaemia causes a preferential increase in hepatic P4501A2 activity. Biochem Pharmacol. 1992 Mar 17;43(6):1255-61. doi: 10.1016/0006-2952(92)90500-i. [PubMed:1562279]
  2. Pass GJ, Becker W, Kluge R, Linnartz K, Plum L, Giesen K, Joost HG: Effect of hyperinsulinemia and type 2 diabetes-like hyperglycemia on expression of hepatic cytochrome p450 and glutathione s-transferase isoforms in a New Zealand obese-derived mouse backcross population. J Pharmacol Exp Ther. 2002 Aug;302(2):442-50. doi: 10.1124/jpet.102.033553. [PubMed:12130701]

Drug created on June 30, 2007 08:46 / Updated on October 29, 2020 19:26

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