Insulin glulisine

Identification

Summary

Insulin glulisine is a short-acting form of insulin used for glycemic control in type 1 and type 2 diabetes mellitus.

Brand Names

Apidra

Generic Name

Insulin glulisine

DrugBank Accession Number

DB01309

Background

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 asparagine at position B3 is replaced by lysine and the lysine at position B29 is replaced by glutamic acid.¹⁰ 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
Insulin Glulisine (recombinant DNA origin)
Insulin glulisine recombinant
Insulina glulisina

External IDs

HMR 1964
HMR-1964

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Pharmacology

Indication

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

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Associated Conditions

Indication Type	Indication	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Diabetes mellitus	••• •••	•••••		•••••••••
Management of	Diabetes mellitus	••••••••••••	•••••• ••••••••		•••••••••• ••••••••
Management of	Type 1 insulin-dependent diabetes mellitus	••• •••	••••••••	••••••• •••••••••••• ••••••• ••• ••• •••••••••• •• •••••••••••••	•••••••••
Management of	Hyperglycemia during critical illness	••• •••••

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.

Target	Actions	Organism
AInsulin receptor	agonist	Humans
UInsulin-like growth factor 1 receptor	activator	Humans

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.

Pathways

Not Available

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Not Available

Interactions

Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">

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.

Drug	Interaction
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Acarbose	The risk or severity of hypoglycemia can be increased when Acarbose is combined with Insulin glulisine.
Acebutolol	The therapeutic efficacy of Insulin glulisine can be increased when used in combination with Acebutolol.
Acetazolamide	The risk or severity of hypoglycemia can be increased when Acetazolamide is combined with Insulin glulisine.
Acetohexamide	The risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Insulin glulisine.
Acetophenazine	The therapeutic efficacy of Insulin glulisine can be decreased when used in combination with Acetophenazine.

Food Interactions

Avoid alcohol. Alcohol may impair blood glucose control.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Apidra	Injection, solution	100 Units/ml	Subcutaneous	Sanofi Aventis Deutschland Gmb H	2016-09-08	Not applicable
Apidra	Injection, solution	100 Units/ml	Subcutaneous	Sanofi Aventis Deutschland Gmb H	2016-09-08	2017-03-03
Apidra	Injection, solution	100 Units/ml	Subcutaneous	Sanofi Aventis Deutschland Gmb H	2016-09-08	2017-03-03
Apidra	Injection, solution	100 Units/ml	Subcutaneous	Sanofi Aventis Deutschland Gmb H	2016-09-08	2017-03-03
Apidra	Solution	100 unit / mL	Subcutaneous	Sanofi Aventis	2008-09-22	Not applicable

Chemical Identifiers

UNII: 7XIY785AZD
CAS number: 207748-29-6

References

General References

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. [Article]
Becker RH: Insulin glulisine complementing basal insulins: a review of structure and activity. Diabetes Technol Ther. 2007 Feb;9(1):109-21. [Article]
Becker RH, Frick AD: Clinical pharmacokinetics and pharmacodynamics of insulin glulisine. Clin Pharmacokinet. 2008;47(1):7-20. [Article]
Cox SL: Insulin glulisine. Drugs Today (Barc). 2005 Jul;41(7):433-40. [Article]
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. [Article]
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. [Article]
Authors unspecified: Insuline glusine (Apidra): a new rapid-acting insulin. Med Lett Drugs Ther. 2006 Apr 24;48(1233):33-4. [Article]
Robinson DM, Wellington K: Insulin glulisine. Drugs. 2006;66(6):861-9. [Article]
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. [Article]
FDA Approved Drug Products: Apidra (insulin glulisine) [Link]

External Links

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

FDA label

Download (1.67 MB)

Clinical Trials

Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">

Phase	Status	Purpose	Conditions	Count
4	Completed	Treatment	Diabetes Mellitus	1
4	Completed	Treatment	Diabetes Mellitus / Diabetic Kidney Disease (DKD) / Diabetic Nephropathy / Glucagon-Like Peptide 1	1
4	Completed	Treatment	Diabetes / Hyperglycemia	2
4	Completed	Treatment	Diabetic Ketoacidosis	1
4	Completed	Treatment	Hyperglycemia / Type 2 Diabetes Mellitus	1

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Sanofi-Aventis Inc.

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous; Subcutaneous	100 [iU]/1mL
Injection, solution	Intravenous; Subcutaneous	100 Units/ml
Injection, solution	Parenteral; Subcutaneous	100 U/ML
Solution	Subcutaneous	100 unit / mL
Solution	Intravenous; Subcutaneous	100 IU
Solution	Subcutaneous	100 IU
Injection, solution	Subcutaneous	100 U/ML
Injection, solution	Subcutaneous	3.49 mg
Injection	Subcutaneous	100 U/ml
Injection, solution	Subcutaneous	100 [iU]/1mL
Injection, solution	Subcutaneous	100 Units/mL
Injection, solution	Subcutaneous
Solution	Subcutaneous	100 iu/1ml
Solution	Parenteral	100.000 UI

Prices

Unit description	Cost	Unit
Apidra 100 unit/ml cartridge	13.3USD	ml
Apidra 100 unit/ml Cartridge	3.56USD	cartridge
Apidra 100 unit/ml Syringe	3.56USD	syringe
Apidra 100 unit/ml	2.67USD	cartridge

DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)
US9011391	No	2015-04-21	2024-03-26
US9233211	No	2016-01-12	2024-03-02
US8603044	No	2013-12-10	2024-03-02
US8512297	No	2013-08-20	2024-09-15
US8679069	No	2014-03-25	2025-04-12
US8992486	No	2015-03-31	2024-06-05
US8556864	No	2013-10-15	2024-03-03
US7918833	Yes	2011-04-05	2028-03-23
US6221633	No	2001-04-24	2018-06-18
US6960561	No	2005-11-01	2023-01-25
US7696162	No	2010-04-13	2022-03-22
US7452860	No	2008-11-18	2022-03-22
US9561331	No	2017-02-07	2024-08-28
US9623189	No	2017-04-18	2024-08-19
US9610409	No	2017-04-04	2024-03-02
US9526844	No	2016-12-27	2024-03-02
US9604008	No	2017-03-28	2024-03-02
US9533105	No	2017-01-03	2024-08-17
US9408979	No	2016-08-09	2024-03-02
US9604009	No	2017-03-28	2024-08-16
US9775954	No	2017-10-03	2024-03-02
US9827379	No	2017-11-28	2024-03-02
US9717852	No	2017-08-01	2033-04-08

Properties

State: Liquid
Experimental Properties: Not Available

Targets

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Details1. Insulin receptor

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

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. [Article]
De Meyts P: The Insulin Receptor and Its Signal Transduction Network . [Article]

Details2. Insulin-like growth factor 1 receptor

Kind: Protein
Organism: Humans
Pharmacological action: Unknown
Actions: Activator

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

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. [Article]

Enzymes

Details1. Cytochrome P450 1A2

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

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. [Article]
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. [Article]
Flockhart Table of Drug Interactions [Link]

Drug created at June 30, 2007 14:46 / Updated at February 20, 2024 23:55

Insulin glulisine

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References

References

Enzymes

References