Insulin degludec



Insulin degludec is a long acting insulin used to treat hyperglycemia caused by type 1 and 2 diabetes mellitus.

Brand Names
Ryzodeg, Tresiba, Xultophy
Generic Name
Insulin degludec
DrugBank Accession Number

Insulin degludec is an ultra-long-acting form of insulin used for the treatment of hyperglycemia caused by Type 1 and Type 2 Diabetes.1,2,3,4,5 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.1,2,3,4,5 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.1,2,3,4,5 Absorption of glucose into cells allows for its transformation into glycogen or fat for storage.1,2,3,4,5 Insulin also inhibits hepatic glucose production, enhances protein synthesis, and inhibits lipolysis and proteolysis among many other functions.1,2,3,4,5

Insulin is an essential 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.1,2,3,4,5 As a result, people with T1D rely primarily on exogenous forms of insulin, such as insulin degludec, to lower glucose levels in the blood.1,2,3,4,5 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.1,2,3,4,5 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.1,2,3,4,5 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.1,2,3,4,5

Marketed as the brand name product Tresiba, insulin degludec has a duration of action up to 42 hours allowing for once-daily dosing, typically at bedtime.1,2,3,4,5 Due to its duration of action, Tresiba is considered "basal insulin" as it provides low concentrations of background insulin that can keep blood sugar stable between meals or overnight.1,2,3,4,5 Basal insulin is often combined with short-acting "bolus insulin" such as Insulin lispro, Insulin glulisine, or 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 the goal of avoiding any periods of hypoglycemia.1,2,3,4,5

Compared to endogenous insulin, insulin degludec has an added hexadecanedioic acid on lysine at the B29 position, allowing for the formation of multi-hexamers.1,2,3,4,5 When injected subcutaneously, these multi-hexamers form a drug depot store from which monomers are slowly and continuously absorbed into circulation.1,2,3,4,5 As a result, Insulin Degludec has a protracted time action profile due to the delayed absorption from subcutaneous tissue depots into the systemic circulation.1,2,3,4,5 Compared to available long-acting analogs such as Insulin glargine and Insulin detemir, which have a duration of action of 20-24 hours, insulin degludec provides a consistent level of basal insulin over 42 hours with a low peak: trough ratio.1,2,3,4,5 Limitations of shorter-acting analogs include more frequent dosing and less stable pharmacokinetics, which may negatively impact patient adherence and glucose control, particularly nocturnal control.1,2,3,4,5

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.1,2,3,4,5 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.1,2,3,4,5

Insulin Degludec was approved by the FDA in September 2015 as the product Tresiba, for use in providing glycemic control to adults with diabetes mellitus.

Biologic Classification
Protein Based Therapies
Hormones / Insulins
Protein Structure
Protein Chemical Formula
Protein Average Weight
6103.97 Da
>A Chain
>B Chain
  1. FDA Approved Drug Products: Tresiba (insulin degludec) for subcutaneous injection [Link]
Download FASTA Format
  • Insulin degludec
  • Insulina degludec
External IDs
  • NN-1250
  • NN1250



Insulin degludec is indicated to improve glycemic control in patients 1 year of age and older with diabetes mellitus.10

Reduce drug development failure rates
Build, train, & validate machine-learning models
with evidence-based and structured datasets.
See how
Build, train, & validate predictive machine-learning models with structured datasets.
See how
Associated Conditions
Indication TypeIndicationCombined Product DetailsApproval LevelAge GroupPatient CharacteristicsDose Form
Used in combination to manageDiabetes mellitusCombination Product in combination with: Insulin aspart (DB01306)••••••••••••••••••••••• •••••• •••••••••••••••••• ••••••••
Management ofDiabetes mellitus••••••••••••••••••••••••••• ••••••••
Management ofDiabetes mellitus•••••••••••••••••• •••••••••••••••••• ••••••••
Management ofDiabetes mellitus type 1••••••••••••••••••••••••••••••• ••••••••
Used as adjunct in combination to manageType 2 diabetes mellitusCombination Product in combination with: Liraglutide (DB06655)••••••••••••••••••••••••••••• •••• •••• •• ••••• ••••••••••••••••••••• ••••••••
Contraindications & Blackbox Warnings
Prevent Adverse Drug Events Today
Tap into our Clinical API for life-saving information on contraindications & blackbox warnings, population restrictions, harmful risks, & more.
Learn more
Avoid life-threatening adverse drug events with our Clinical API
Learn more

Insulin is a natural hormone produced by beta cells of the pancreas. In nondiabetic individuals, the pancreas produces a continuous supply of low basal insulin levels and spikes of insulin following meals.1,2,3,4,5 Increased insulin secretion following meals is responsible for the metabolic changes that occur as the body transitions from a postabsorptive to an absorptive state.1,2,3,4,5 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.1,2,3,4,5 Insulin also promotes growth and is required for the actions of growth hormone (e.g. protein synthesis, cell division, DNA synthesis).1,2,3,4,5 Insulin detemir is a long-acting insulin analogue with a flat and predictable action profile.1,2,3,4,5 It mimics the basal insulin levels 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.1,2,3,4,5

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.8 The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor.8 The bound receptor autophosphorylates and phosphorylates numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc, and Gab 1.8 Activation of these proteins leads to activation of downstream signaling molecules including PI3 kinase and Akt.8 Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC), both of which play critical roles in metabolism and catabolism.8

AInsulin receptor
UInsulin-like growth factor 1 receptor

In patients with type 1 diabetes, after 8 days of once-daily subcutaneous dosing with 0.4 U/kg, maximum insulin degludec concentrations of 4472 pmol/L were attained at a median of 9 hours (tmax).10 After the first dose, the median onset of appearance was around one hour. The glucose-lowering effect lasted at least 42 hours after the last of 8 once-daily injections. Insulin degludec concentration reaches steady-state levels after 3-4 days.10

Volume of distribution

Using a one-compartment pharmacokinetics model, the apparent volume of distribution was estimated to be 10.6 L for the pediatric population and 13.9 L for the adult population.14

Protein binding

The affinity of insulin degludec to serum albumin corresponds to a plasma protein binding of >99% in human plasma.10 The results of the in vitro protein binding studies demonstrate that there is no clinically relevant interaction between insulin degludec and other protein-bound drugs.10


All insulin degludec metabolites are inactive.10 The liver and kidney play the major role in metabolizing insulin.7However, while the liver predominantly metabolizes endogenous insulin, exogenous insulin is primarily metabolized due to the kidney since it is not directly delivered into the portal system.7

Route of elimination

30 to 80% of circulating insulin is removed by the kidney.6


The half-life after subcutaneous administration is determined primarily by the rate of absorption from the subcutaneous tissue. On average, the half-life at a steady state is approximately 25 hours independent of dose.10


The mean apparent clearance of insulin degludec is 0.03 L/kg (2.1 L/h in 70 kg individuals) after a single subcutaneous dose of 0.4 units/kg.10

Adverse Effects
Improve decision support & research outcomes
With structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!
See the data
Improve decision support & research outcomes with our structured adverse effects data.
See a data sample

An excess of insulin relative to food intake, energy expenditure, or both may lead to severe and sometimes prolonged and life-threatening hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral glucose. Lowering the insulin dosage and adjusting meal patterns or exercise may be needed. More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with glucagon for emergency use or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid the reoccurrence of hypoglycemia. Hypokalemia must be corrected appropriately.10

Insulin degludec was investigated in studies covering fertility, embryo-fetal development, and pre and post-natal development in rats and during the period of embryo-fetal development in rabbits. Human insulin (NPH insulin) was included as a comparator. In these studies, insulin degludec caused pre and post-implantation losses and visceral/skeletal abnormalities when given subcutaneously at up to 21 U/kg/day in rats and 3.3 U/kg/day in rabbits, resulting in 5 times (rat) and 10 times (rabbit) the human exposure (AUC) at a human subcutaneous dose of 0.75 U/kg/day. Overall, the effects of insulin degludec were similar to those observed with human insulin, which was probably secondary to maternal hypoglycemia.10

Not Available
Pharmacogenomic Effects/ADRs
Not Available


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.
AcarboseThe risk or severity of hypoglycemia can be increased when Acarbose is combined with Insulin degludec.
AcebutololThe therapeutic efficacy of Insulin degludec can be increased when used in combination with Acebutolol.
AcetazolamideThe risk or severity of hypoglycemia can be increased when Acetazolamide is combined with Insulin degludec.
AcetohexamideThe risk or severity of hypoglycemia can be increased when Acetohexamide is combined with Insulin degludec.
AcetophenazineThe therapeutic efficacy of Insulin degludec can be decreased when used in combination with Acetophenazine.
Food Interactions
  • Avoid alcohol. Alcohol may impair blood glucose control.


Drug product information from 10+ global regions
Our datasets provide approved product information including:
dosage, form, labeller, route of administration, and marketing period.
Access now
Access drug product information from over 10 global regions.
Access now
Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
Insulin DegludecInjection, solution100 U/1mLSubcutaneousA-S Medication Solutions2022-07-01Not applicableUS flag
Insulin DegludecInjection, solution100 U/1mLSubcutaneousNovo Nordisk Pharma, Inc.2022-07-01Not applicableUS flag
Insulin DegludecInjection, solution200 U/1mLSubcutaneousA-S Medication Solutions2022-07-01Not applicableUS flag
Insulin DegludecInjection, solution100 U/1mLSubcutaneousNovo Nordisk Pharma, Inc.2022-07-01Not applicableUS flag
Insulin DegludecInjection, solution200 U/1mLSubcutaneousNovo Nordisk Pharma, Inc.2022-07-01Not applicableUS flag
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing EndRegionImage
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RyzodegInsulin degludec (2.56 mg/ml) + Insulin aspart (1.05 mg/ml)Injection, solutionSubcutaneousNovo Nordisk2016-09-08Not applicableEU flag
RYZODEGInsulin degludec (70 U/ML) + Insulin aspart (30 U/mL)Injection, solutionSubcutaneousNovo Nordisk2014-07-08Not applicableItaly flag
RYZODEGInsulin degludec (70 U/ML) + Insulin aspart (30 U/mL)Injection, solutionSubcutaneousNovo Nordisk2014-07-08Not applicableItaly flag
RYZODEGInsulin degludec (70 U/ML) + Insulin aspart (30 U/mL)Injection, solutionSubcutaneousNovo Nordisk2014-10-06Not applicableItaly flag


ATC Codes
A10AD06 — Insulin degludec and insulin aspartA10AE56 — Insulin degludec and liraglutideA10AE06 — Insulin degludec
Drug Categories
Chemical TaxonomyProvided by Classyfire
Not Available
Organic Compounds
Super Class
Organic Acids
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Alternative Parents
Not Available
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available
Affected organisms
Not Available

Chemical Identifiers

CAS number


General References
  1. Garber AJ, King AB, Del Prato S, Sreenan S, Balci MK, Munoz-Torres M, Rosenstock J, Endahl LA, Francisco AM, Hollander P: Insulin degludec, an ultra-longacting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN Basal-Bolus Type 2): a phase 3, randomised, open-label, treat-to-target non-inferiority trial. Lancet. 2012 Apr 21;379(9825):1498-507. doi: 10.1016/S0140-6736(12)60205-0. [Article]
  2. Wang F, Surh J, Kaur M: Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191-204. doi: 10.2147/DMSO.S21979. Epub 2012 Jul 5. [Article]
  3. Haahr H, Heise T: A review of the pharmacological properties of insulin degludec and their clinical relevance. Clin Pharmacokinet. 2014 Sep;53(9):787-800. doi: 10.1007/s40262-014-0165-y. [Article]
  4. Jonassen I, Havelund S, Hoeg-Jensen T, Steensgaard DB, Wahlund PO, Ribel U: Design of the novel protraction mechanism of insulin degludec, an ultra-long-acting basal insulin. Pharm Res. 2012 Aug;29(8):2104-14. doi: 10.1007/s11095-012-0739-z. Epub 2012 Apr 7. [Article]
  5. Thuillier P, Alavi Z, Kerlan V: Long-term safety and efficacy of insulin degludec in the management of type 2 diabetes. Diabetes Metab Syndr Obes. 2015 Oct 1;8:483-93. doi: 10.2147/DMSO.S54953. eCollection 2015. [Article]
  6. Morello CM: Pharmacokinetics and pharmacodynamics of insulin analogs in special populations with type 2 diabetes mellitus. Int J Gen Med. 2011;4:827-35. doi: 10.2147/IJGM.S26889. Epub 2011 Dec 12. [Article]
  7. Donner T, Sarkar S: Insulin - Pharmacology, Therapeutic Regimens, and Principles of Intensive Insulin Therapy . [Article]
  8. De Meyts P: The Insulin Receptor and Its Signal Transduction Network . [Article]
  9. FDA Approved Drug Products: Tresiba (insulin degludec) for subcutaneous injection [Link]
  10. FDA Approved Drug Products: Tresiba (insulin degludec) for subcutaneous injection 2022 [Link]
  11. FDA Approved Drug Products: XULTOPHY® 100/3.6 (insulin degludec and liraglutide) injection, for subcutaneous use [Link]
  12. EMA Approved Drug Proucts: RYZODEG® 70/30 (insulin degludec and insulin aspart injection), for 7 subcutaneous use [Link]
  13. Health Canada Approved Drug Proucts: Tresiba (insulin degludec) for subcutaneous injection [Link]
  14. Clinical Pharmacology Review: Tresiba [Link]
PubChem Substance
RxList Drug Page Drug Page
FDA label
Download (7.77 MB)

Clinical Trials

Clinical Trials
4Active Not RecruitingTreatmentType 1 Diabetes Mellitus1
4CompletedTreatmentNocturnal Hypoglycemia / Recurrent Severe Hypoglycaemia / Type 1 Diabetes Mellitus1
4CompletedTreatmentType 1 Diabetes Mellitus7
4CompletedTreatmentType 2 Diabetes Mellitus8
4RecruitingTreatmentDiabetes Mellitus / Diabetic Kidney Disease (DKD)1


Not Available
Not Available
Dosage Forms
Injection, solutionSubcutaneous
Injection, solutionSubcutaneous100 U/1mL
Injection, solutionSubcutaneous200 U/1mL
SolutionSubcutaneous100 U
SolutionSubcutaneous100 unit / mL
SolutionSubcutaneous200 unit / mL
Injection, solutionSubcutaneous
SolutionSubcutaneous100 IU
SolutionSubcutaneous10000000 IU
Injection, solutionSubcutaneous100 U/ml
Injection, solutionSubcutaneous200 U/ml
SolutionSubcutaneous200 IU
InjectionSubcutaneous100 IU/ml
Injection, solutionParenteral; Subcutaneous
Injection, solution
Injection, solutionSubcutaneous100 iu/1ml
Not Available
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
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
US6458924No2002-10-012017-08-22US flag
US6268343Yes2001-07-312023-02-22US flag
US8846618Yes2014-09-302022-12-27US flag
US7235627No2007-06-262017-08-22US flag
US7615532Yes2009-11-102029-12-28US flag
US9486588Yes2016-11-082022-07-02US flag
US9457154Yes2016-10-042028-03-27US flag
USRE46363Yes2017-04-112027-02-03US flag
US8937042Yes2015-01-202029-11-05US 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
US9884094No2018-02-062033-05-01US 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


Experimental Properties
Not Available


Build, predict & validate machine-learning models
Use our structured and evidence-based datasets to unlock new
insights and accelerate drug research.
Learn more
Use our structured and evidence-based datasets to unlock new insights and accelerate drug research.
Learn more
Pharmacological action
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
Uniprot ID
Uniprot Name
Insulin receptor
Molecular Weight
156331.465 Da
  1. De Meyts P: The Insulin Receptor and Its Signal Transduction Network . [Article]
Pharmacological action
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
Uniprot ID
Uniprot Name
Insulin-like growth factor 1 receptor
Molecular Weight
154791.73 Da
  1. Wang F, Surh J, Kaur M: Insulin degludec as an ultralong-acting basal insulin once a day: a systematic review. Diabetes Metab Syndr Obes. 2012;5:191-204. doi: 10.2147/DMSO.S21979. Epub 2012 Jul 5. [Article]
  2. 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]


Pharmacological action
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
Uniprot ID
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
  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. [Article]
  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. [Article]
  3. Flockhart Table of Drug Interactions [Link]
Pharmacological action
General Function
Zinc ion binding
Specific Function
Plays a role in the cellular breakdown of insulin, IAPP, glucagon, bradykinin, kallidin and other peptides, and thereby plays a role in intercellular peptide signaling. Degrades amyloid formed by A...
Gene Name
Uniprot ID
Uniprot Name
Insulin-degrading enzyme
Molecular Weight
117967.49 Da
  1. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP, Eckman CB, Tanzi RE, Selkoe DJ, Guenette S: Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci U S A. 2003 Apr 1;100(7):4162-7. doi: 10.1073/pnas.0230450100. Epub 2003 Mar 12. [Article]


Pharmacological action
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
Uniprot ID
Uniprot Name
Serum albumin
Molecular Weight
69365.94 Da
  1. Ryberg LA, Sonderby P, Barrientos F, Bukrinski JT, Peters GHJ, Harris P: Solution structures of long-acting insulin analogues and their complexes with albumin. Acta Crystallogr D Struct Biol. 2019 Mar 1;75(Pt 3):272-282. doi: 10.1107/S2059798318017552. Epub 2019 Feb 26. [Article]

Drug created at November 30, 2015 19:10 / Updated at September 05, 2022 12:50