Identification

Name
Insulin detemir
Accession Number
DB01307
Description

Insulin detemir is a long-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 detemir, 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 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 Levemir, insulin detemir has a duration of action of 16-24 hours allowing for once-daily dosing, typically at bedtime. Due to its duration of action, Levemir is considered "basal insulin" as it provides low concentrations of background insulin that can keep blood sugar stable between meals or overnight. Basal insulin is often combined with short-acting "bolus insulin" such as Insulin lispro, Insulin glulisine, and Insulin aspart to provide higher doses of insulin required following meals. 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 detemir is produced using recombinant DNA technology in yeast cells. This insulin analogue has a 14-C fatty acid, myristic acid, bound to the lysine amino acid at position B29. The myristoyl side chain increases self-association and albumin binding. This along with slow systemic absorption from the injection site prolongs distribution of the hormone into tissues and results in a long duration of action.

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
Insulins
Protein Structure
Db01307
Protein Chemical Formula
C267H402N64O76S6
Protein Average Weight
5916.9 Da
Sequences
>Protein sequence for A chain
GIVEQCCTSICSLYQLENYCN
>Protein sequence for B chain 
FVNQHLCGSHLVEALYLVCGERGFFYTPK
Download FASTA Format
Synonyms
  • Detemir
  • Insulin detemir recombinant
  • Insulin,detemir,human
  • Insulina detemir
External IDs
  • NN-304

Pharmacology

Indication

Insulin detemir is indicated to improve glycemic control in adults and children 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, the pancreas produces a continuous supply of low levels of basal insulin along with spikes of insulin 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 the 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 detemir 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 detemir is 1 to 2 hours and its duration of action is up to 24 hours. Interestingly, it has a lower affinity (30%) for the insulin receptor than human insulin.

Mechanism of action

Insulin detemir 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 signalling 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. Insulin detemir’s long duration of action appears to be a result of slow systemic absorption from the injection site and delayed distribution to target tissues. The myristic acid side chain on insulin detemir increases self-association and gives it a high binding affinity to serum albumin. These features slow its distribution into target tissues and prolong its duration of action.

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

Maximum serum concentrations are reached 6 to 8 hours following subcutaneous injection. The duration of action of insulin detemir is mediated by slowed systemic absorption of insulin detemir molecules from the injection site due to self-association of the drug molecule. When single dose of 0.5 units/kg of insulin detemir was given to adult type 1 diabetes patients, the maximum serum concentration (Cmax) was 4,641 ± 2,299 pmol/L. Insulin detemir has a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak. The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The absolute bioavailability of insulin detemir is approximately 60%.

Volume of distribution

Insulin detemir has an apparent volume of distribution of approximately 0.1 L/kg.

Protein binding

More than 98% of insulin detemir in the bloodstream is bound to albumin. The results of in vitro and in vivo protein binding studies demonstrate that there is no clinically relevant interaction between insulin detemir and fatty acids or other protein-bound drugs.

Metabolism
Not Available
Route of elimination
Not Available
Half-life

After subcutaneous administration in patients with type 1 diabetes, insulin detemir has a terminal half-life of 5 to 7 hours depending on dose.

Clearance

Apparent clearance (CL/F), type 1 diabetes adult patients = 3.41 ± 1.00 L/min·kg

Adverse Effects
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Toxicity

Hypoglycemia may occur with inappropriately high doses. 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. Injection site reactions may also occur. Symptoms include: redness, inflammation, bruising, swelling and itching at the injection site.

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 detemir.
AcebutololThe therapeutic efficacy of Insulin detemir can be increased when used in combination with Acebutolol.
AcetazolamideThe therapeutic efficacy of Insulin detemir can be increased when used in combination with Acetazolamide.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Insulin detemir.
Acetyl sulfisoxazoleThe therapeutic efficacy of Insulin detemir 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 detemir.
AlbiglutideAlbiglutide may increase the hypoglycemic activities of Insulin detemir.
AlclometasoneThe risk or severity of hyperglycemia can be increased when Alclometasone is combined with Insulin detemir.
AlogliptinAlogliptin may increase the hypoglycemic activities of Insulin detemir.
AmcinonideThe risk or severity of hyperglycemia can be increased when Amcinonide is combined with Insulin detemir.
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
  • Take with food. Once daily administration should be given with the evening meal or prior to bedtime.

Products

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International/Other Brands
Levemir FlexPen (Novo Nordisk)
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
LevemirInjection, solution100 U/mlSubcutaneousNovo Nordisk2004-06-01Not applicableEU flag
LevemirInjection, solution100 [iU]/1mLSubcutaneousA-S Medication Solutions2006-03-27Not applicableUS flag
LevemirInjection14.2 mg/1mLSubcutaneousNovo Nordisk Inc.2007-08-172007-08-17US flag
LevemirInjection, solution100 U/mlSubcutaneousNovo Nordisk2004-06-01Not applicableEU flag
LevemirInjection14.2 mg/1mLSubcutaneousNovo Nordisk Inc.2007-08-172007-08-17US flag
LevemirInjection, solution100 U/mlSubcutaneousNovo Nordisk2004-06-01Not applicableEU flag
LevemirInjection, solution100 U/mlSubcutaneousNovo Nordisk2004-06-01Not applicableEU flag
LevemirInjection, solution100 [iU]/1mLSubcutaneousNovo Nordisk2006-03-27Not applicableUS flag
LevemirInjection, solution100 U/mlSubcutaneousNovo Nordisk2004-06-01Not applicableEU flag
LevemirInjection, solution100 [iU]/1mLSubcutaneousA-S Medication Solutions2013-10-31Not applicableUS flag
Additional Data Available
  • Application Number
    Application Number
    Available for Purchase

    A unique ID assigned by the FDA when a product is submitted for approval by the labeller.

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  • Product Code
    Product Code
    Available for Purchase

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

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Categories

ATC Codes
A10AE05 — Insulin detemir
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
4FT78T86XV
CAS number
169148-63-4

References

General References
  1. Kurtzhals P: Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007 Aug;36 Suppl 1:14-20. [PubMed:17881328]
  2. Morales J: Defining the role of insulin detemir in Basal insulin therapy. Drugs. 2007;67(17):2557-84. [PubMed:18034591]
  3. Tibaldi J: Actions of insulin beyond glycemic control: a perspective on insulin detemir. Adv Ther. 2007 Jul-Aug;24(4):868-82. [PubMed:17901036]
  4. Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA: Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care. 2003 Nov;26(11):3087-92. [PubMed:14578244]
  5. 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:18715209]
  6. FDA Approved Drug Products: Levemir (insulin detemir) for subcutaneous injection [Link]
KEGG Drug
D04539
PubChem Substance
46508877
RxNav
139825
ChEMBL
CHEMBL2104391
Therapeutic Targets Database
DAP001090
PharmGKB
PA164746470
RxList
RxList Drug Page
Drugs.com
Drugs.com Drug Page
PDRhealth
PDRhealth Drug Page
Wikipedia
Insulin_detemir
AHFS Codes
  • 68:20.08 — Insulins
FDA label
Download (911 KB)
MSDS
Download (504 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4CompletedBasic ScienceType 2 Diabetes Mellitus / Weight Gain1
4CompletedDiagnosticDiabetes Mellitus1
4CompletedPreventionHyperglycemia1
4CompletedTreatmentArteriosclerosis / Atherosclerosis / Type 2 Diabetes Mellitus1
4CompletedTreatmentCardiovascular Heart Disease / Endothelial Dysfunction / Type 2 Diabetes Mellitus1
4CompletedTreatmentDiabetes2
4CompletedTreatmentDiabetes Mellitus2
4CompletedTreatmentDiabetes / Type 1 Diabetes Mellitus3
4CompletedTreatmentDiabetes / Type 2 Diabetes Mellitus13
4CompletedTreatmentEvidence of Liver Transplantation / Hyperglycemia / Rejection1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
  • Novo Nordisk Inc.
Dosage Forms
FormRouteStrength
ImplantSoft tissue14.2 mg/1mL
InjectionSubcutaneous14.2 mg/1mL
Injection, solutionCutaneous; Parenteral100 U/ML
Injection, solutionSubcutaneous100 U/ml
Injection, solutionSubcutaneous100 [iU]/1mL
Injection, solutionSubcutaneous14.2 mg/1mL
SolutionSubcutaneous14.2 mg
InjectionSubcutaneous100 IU/ML
Injection, solution100 iu/1mL
Injection, solutionSubcutaneous100 units/mL
SolutionSubcutaneous100 U/ML
SolutionSubcutaneous
Prices
Unit descriptionCostUnit
Levemir flexpen 100 unit/ml14.28USD ml
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US6011007No2000-01-042014-02-02US flag
CA2171424No2002-06-042014-09-16Canada flag
US8672898Yes2014-03-182022-07-02US flag
US8684969Yes2014-04-012026-04-20US flag
US9132239Yes2015-09-152032-08-01US flag
US8920383Yes2014-12-302027-01-17US flag
US7686786No2010-03-302026-08-03US flag
US6899699Yes2005-05-312022-07-01US flag
US5866538Yes1999-02-022017-12-20US flag
US9108002Yes2015-08-182026-07-26US flag
USRE41956Yes2010-11-232021-07-21US flag
US9265893Yes2016-02-232033-03-23US flag
US6004297Yes1999-12-212019-07-28US flag
USRE43834No2012-11-272019-01-28US flag
US5750497No1998-05-122019-06-16US flag
US9486588Yes2016-11-082022-07-02US flag
US9457154Yes2016-10-042028-03-27US flag
USRE46363Yes2017-04-112027-02-03US flag
US9687611Yes2017-06-272027-08-27US flag
US9775953Yes2017-10-032027-01-17US flag
US8579869Yes2013-11-122023-12-30US flag
US7762994Yes2010-07-272024-11-23US flag
US9861757Yes2018-01-092026-07-20US flag
US9616180Yes2017-04-112026-07-20US flag
US10220155Yes2019-03-052027-01-17US flag
US10357616No2019-07-232026-01-20US flag
US10376652No2019-08-132026-01-20US 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. Hennige AM, Sartorius T, Tschritter O, Preissl H, Fritsche A, Ruth P, Haring HU: Tissue selectivity of insulin detemir action in vivo. Diabetologia. 2006 Jun;49(6):1274-82. Epub 2006 Mar 29. [PubMed:16570163]
  2. Kurtzhals P, Schaffer L, Sorensen A, Kristensen C, Jonassen I, Schmid C, Trub T: Correlations of receptor binding and metabolic and mitogenic potencies of insulin analogs designed for clinical use. Diabetes. 2000 Jun;49(6):999-1005. [PubMed:10866053]
  3. Sorensen AR, Stidsen CE, Ribel U, Nishimura E, Sturis J, Jonassen I, Bouman SD, Kurtzhals P, Brand CL: Insulin detemir is a fully efficacious, low affinity agonist at the insulin receptor. Diabetes Obes Metab. 2010 Aug;12(8):665-73. doi: 10.1111/j.1463-1326.2010.01206.x. [PubMed:20590743]
  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. doi: 10.1016/j.diabres.2008.05.007. Epub 2008 Jun 27. [PubMed:18585815]
  5. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [PubMed:11752352]
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]

Carriers

Kind
Protein
Organism
Humans
Pharmacological action
No
Actions
Other/unknown
General Function
Toxic substance binding
Specific Function
Serum albumin, the main protein of plasma, has a good binding capacity for water, Ca(2+), Na(+), K(+), fatty acids, hormones, bilirubin and drugs. Its main function is the regulation of the colloid...
Gene Name
ALB
Uniprot ID
P02768
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
References
  1. Klein O, Lynge J, Endahl L, Damholt B, Nosek L, Heise T: Albumin-bound basal insulin analogues (insulin detemir and NN344): comparable time-action profiles but less variability than insulin glargine in type 2 diabetes. Diabetes Obes Metab. 2007 May;9(3):290-9. [PubMed:17391154]
  2. Kurtzhals P: Pharmacology of insulin detemir. Endocrinol Metab Clin North Am. 2007 Aug;36 Suppl 1:14-20. [PubMed:17881328]

Drug created on June 30, 2007 08:45 / Updated on November 23, 2020 09:08

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