Insulin human

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Overview

Description

A medication used to control blood sugar in diabetes.

Structure

Description

A medication used to control blood sugar in diabetes.

DrugBank ID

DB00030

Type

Biotech

US Approved

YES

Other Approved

YES

Patents

49

Indicated Conditions

2

Clinical Trials

Phase 0

24

Phase 1

194

Phase 2

234

Phase 3

318

Phase 4

375

Therapeutic Categories

• Insulin

Mechanism of Action

• Insulin receptor
  Agonist

Identification

Summary

Insulin human is a recombinant form of human insulin used to control hyperglycemia in diabetes mellitus.

Brand Names

Actraphane, Actrapid, Afrezza, Entuzity, Exubera, Humulin, Humulin N, Humulin R, Insulatard, Insuman, Myxredlin, Novolin, Novolin N, Novolin R

Generic Name

Insulin human

DrugBank Accession Number

DB00030

Background

Human Insulin, also known as Regular Insulin, is a short-acting form of insulin used for the treatment of hyperglycemia caused by Type 1 and Type 2 Diabetes. Human insulin is produced by recombinant DNA technology and is identical to endogenously produced insulin. Typically prescribed for the management of diabetes mellitus, insulin is 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 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 Humulin R or Novolin R, human insulin begins to exert its effects within 30 minutes of subcutaneous administration, while peak levels occur 3-4 hours after administration. Due to its quick onset of action, human insulin 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.

Human insulin is also available in an inhalable form, intended to be used as a bolus meal-time insulin. Exubera was the first inhaled insulin available on the market and was developed by Inhale Therapeutics (later named Nektar Therapeutics). Unfortunately, limited uptake by physicians and patients, poor sales, bulky packaging, and concerns over the possible impact on lung cancer development resulted in Exubera products being withdrawn from the US markets ⁶. Exubera was followed by Afrezza, a monomeric inhaled insulin developed by Mannkind Corporation, which received FDA approval in 2016. While still available in the US, Afrezza has had similar concerns associated with its use, and had an FDA "black box" warning added to it to warn about use in patients with chronic lung disease. Afrezza does not currently have Health Canada or European Medicines Agency approval for marketing in Canada or the EU.

Human Insulin is a 51 residue peptide hormone produced by recombinant DNA technology by inserting the human insulin gene into Escherichia coli bacteria or Saccharomyces cerevisiae. The structure is identical to native human insulin, with two amino acid chains covalently linked by disulfide bonds.

Human insulin is also available in an intermediate-acting form as NPH (Neutral Protamine Hagedorn) as the marketed products Novolin N and Humulin N. NPH insulin is provided as a crystalline suspension of insulin with protamine and zinc, resulting in an onset of action in 1 to 3 hours, duration of action up to 24 hours, and peak action from 6 to 8 hours. Due to the added crystals, NPH insulin is typically cloudy when compared to other forms of insulin and has a neutral pH.

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, Investigational

Biologic Classification

Protein Based Therapies
Hormones / Insulins

Protein Structure

Protein Chemical Formula

C₂₅₇H₃₈₃N₆₅O₇₇S₆

Protein Average Weight

5808.0 Da

Sequences

>A chain
GIVEQCCTSICSLYQLENYCN

>B chain
FVNQHLCGSHLVEALYLVCGERGFFYTPKT

Download FASTA Format

Synonyms

• High molecular weight insulin human
• Human insulin
• human insulin (rDNA)
• Insulin (human)
• Insulin human
• Insulin human [rDNA origin]
• Insulin Human Regular
• Insulin human regular (rDNA)
• Insulin human, rDNA origin
• Insulin recombinant human
• Insulin recombinant purified human
• Insulin regular
• Insulin, human
• Insulina regular
• Neutral insulin
• Regular Insulin, human
• Soluble insulin

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Pharmacology

Indication

Human insulin is indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus.

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Diabetes mellitus		••• •••	•••••• ••••••••	•••••••••••••••••	•••••••••
Management of	Diabetes mellitus		••• •••	•••••• ••••••••		•••••••••
Management of	Diabetes mellitus		••• •••	•••••• ••••••••		•••••••••• ••••••••
Management of	Diabetes mellitus		••• •••	•••••• ••••••••		•••••••••• ••••••••
Management of	Diabetes mellitus		••••••••••••	•••••		•••••••• ••••••

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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).

Mechanism of action

The primary activity of insulin is the regulation of glucose metabolism. Insulin promotes glucose and amino acid uptake into muscle and adipose tissues, and other tissues except brain and liver. It also has an anabolic role in stimulating glycogen, fatty acid, and protein synthesis. Insulin inhibits gluconeogenesis in the liver. Insulin 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 is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead 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) which play a critical role in metabolism and catabolism.

Target	Actions	Organism
AInsulin receptor	agonist	Humans
UInsulin-like growth factor 1 receptor	activator	Humans
UCarboxypeptidase E	modulator product of	Humans
UCCN family member 3	downregulator	Humans
ULow-density lipoprotein receptor-related protein 2	substrate	Humans
UInsulin-like growth factor-binding protein 7	inhibitor binder	Humans

Absorption

When injected subcutaneously, the glucose-lowering effect of human insulin begins approximately 30 minutes post-dose. After a single subcutaneous administration of 0.1 unit/kg of human insulin to healthy subjects, peak insulin concentrations occurred between 1.5 to 2.5 hours post-dose.

When administered in an inhaled form (as the product Afrezza), the time to maximum serum insulin concentration ranges from 10-20 minutes after oral inhalation of 4 to 48 units of human insulin. Serum insulin concentrations declined to baseline by approximately 60-240 minutes for these dose levels. Intrapatient variability in insulin exposure measured by AUC and Cmax is approximately 16% (95% CI 12-23%) and 21% (95% CI 16-30%), respectively.

Volume of distribution

Not Available

Protein binding

Not Available

Metabolism

The metabolism and elimination of orally inhaled human insulin are comparable to regular human insulin.

Route of elimination

Following oral inhalation of human insulin, a mean of 39% of the inhaled dose of carrier particles was distributed to the lungs and a mean of 7% of the dose was swallowed. The swallowed fraction was not absorbed from the GI tract and was eliminated unchanged in the feces.

Half-life

Systemic insulin disposition (apparent terminal half-life) following oral inhalation of 4 to 48 units of human insulin was 120-206 minutes.

Clearance

Not Available

Adverse Effects

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Toxicity

Not Available

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

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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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

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

Food Interactions

• Avoid alcohol. Alcohol may impair blood glucose control.

Products

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Product Ingredients

Ingredient	UNII	CAS	InChI Key
Insulin human zinc suspension	Not Available	Not Available	Not applicable
NPH insulin	Not Available	53027-39-7	Not applicable

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Actraphane 30	Injection, suspension	100 iu/ml	Subcutaneous	Novo Nordisk	2016-09-07	Not applicable
Actraphane 30	Injection, suspension	40 iu/ml	Subcutaneous	Novo Nordisk	2016-09-07	Not applicable
Actraphane 30	Injection, suspension	100 iu/ml	Subcutaneous	Novo Nordisk	2016-09-07	Not applicable
Actraphane 30	Injection, suspension	100 iu/ml	Subcutaneous	Novo Nordisk	2016-09-07	Not applicable
Actraphane 30	Injection, suspension	40 iu/ml	Subcutaneous	Novo Nordisk	2016-09-07	Not applicable

Over the Counter Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
ACTRAPID INJECTION 100 IU/ml	Injection	100 IU/ml	Intramuscular; Intravenous; Subcutaneous	NOVO NORDISK PHARMA (MALAYSIA) SDN. BHD.	1988-11-24	Not applicable
ACTRAPID PENFILL INJECTION 100 IU/ml	Injection	100 iu/ml	Subcutaneous	NOVO NORDISK PHARMA (MALAYSIA) SDN. BHD.	1988-11-24	Not applicable
Humalog 70/30	Injection, suspension	100 [iU]/1mL	Subcutaneous	Physicians Total Care, Inc.	1994-12-28	Not applicable
Humulin 50/50	Injection, suspension	100 [iU]/1mL	Subcutaneous	Eli Lilly & Co. Ltd.	1992-05-18	2010-05-31
Humulin 70/30	Injection, suspension	100 [iU]/1mL	Subcutaneous	A-S Medication Solutions	1989-06-26	Not applicable

Mixture Products

Name	Ingredients	Dosage	Route	Labeller	Marketing Start	Marketing End	Region	Image
ACTRAPHANE 30 FLEXPEN	Insulin human (30 IU/mL) + NPH insulin (70 IU/ml)	Injection, suspension	Parenteral		2015-04-01	Not applicable
ACTRAPHANE 30 FLEXPEN	Insulin human (30 IU/mL) + NPH insulin (70 IU/ml)	Injection, suspension	Parenteral		2015-04-01	Not applicable
ACTRAPHANE 30 FLEXPEN	Insulin human (30 IU/mL) + NPH insulin (70 IU/ml)	Injection, suspension	Parenteral		2015-04-01	Not applicable
ACTRAPHANE 30 FLEXPEN	Insulin human (30 IU/mL) + NPH insulin (70 IU/ml)	Injection, suspension	Parenteral		2015-04-01	Not applicable
ACTRAPHANE 30 INNOLET FER	Insulin human (30 IU/mL) + NPH insulin (70 IU/ml)	Injection, suspension	Parenteral		2015-04-01	Not applicable

Categories

ATC Codes

A10AC01 — Insulin (human)

• A10AC — Insulins and analogues for injection, intermediate-acting
• A10A — INSULINS AND ANALOGUES
• A10 — DRUGS USED IN DIABETES
• A — ALIMENTARY TRACT AND METABOLISM

A10AE01 — Insulin (human)

• A10AE — Insulins and analogues for injection, long-acting
• A10A — INSULINS AND ANALOGUES
• A10 — DRUGS USED IN DIABETES
• A — ALIMENTARY TRACT AND METABOLISM

A10AB01 — Insulin (human)

• A10AB — Insulins and analogues for injection, fast-acting
• A10A — INSULINS AND ANALOGUES
• A10 — DRUGS USED IN DIABETES
• A — ALIMENTARY TRACT AND METABOLISM

A10AD01 — Insulin (human)

• A10AD — Insulins and analogues for injection, intermediate- or long-acting combined with fast-acting
• A10A — INSULINS AND ANALOGUES
• A10 — DRUGS USED IN DIABETES
• A — ALIMENTARY TRACT AND METABOLISM

A10AF01 — Insulin (human)

• A10AF — Insulins and analogues for inhalation
• A10A — INSULINS AND ANALOGUES
• A10 — DRUGS USED IN DIABETES
• A — ALIMENTARY TRACT AND METABOLISM

Drug Categories

• Alimentary Tract and Metabolism
• Amino Acids, Peptides, and Proteins
• Blood Glucose Lowering Agents
• Cytochrome P-450 CYP1A2 Inducers
• Cytochrome P-450 CYP1A2 Inducers (strength unknown)
• Cytochrome P-450 Enzyme Inducers
• Drugs Used in Diabetes
• Hormones
• Hormones, Hormone Substitutes, and Hormone Antagonists
• Hypoglycemia-Associated Agents
• Insulin
• Insulin, metabolism
• Insulin, Short-Acting
• Insulins and Analogues for Injection, Fast-Acting
• Pancreatic Hormones
• Peptide Hormones
• Peptides

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

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

1Y17CTI5SR

CAS number

11061-68-0

References

Synthesis Reference

Humulin is synthesized in a special non-disease-producing laboratory strain of Escherichia coli bacteria that has been genetically altered to produce human insulin.

General References

1. Herrmann BL, Kasser C, Keuthage W, Huptas M, Dette H, Klute A: Comparison of insulin aspart vs. regular human insulin with or without insulin detemir concerning adipozytokines and metabolic effects in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2013 Apr;121(4):210-3. doi: 10.1055/s-0033-1334905. Epub 2013 Mar 19. [Article]
2. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes. 2000 Dec;49(12):2142-8. [Article]
3. Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R: Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care. 2000 Jun;23(6):813-9. [Article]
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. [Article]
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. [Article]
6. Oleck J, Kassam S, Goldman JD: Commentary: Why Was Inhaled Insulin a Failure in the Market? Diabetes Spectr. 2016 Aug;29(3):180-4. doi: 10.2337/diaspect.29.3.180. [Article]
7. FDA Approved Drug Products: Humulin R (insulin human) [Link]
8. FDA Approved Drug Products: AFREZZA® (insulin human) inhalation powder, for oral inhalation use (February 2023) [Link]
9. FDA Approved Drug Products: AFREZZA (insulin human) Inhalation Powder [Link]

External Links

UniProt

Q8HXV2

Genbank

AY137503

KEGG Drug

D03230

KEGG Compound

C00723

PubChem Substance

46506231

RxNav

253182

ChEBI

5931

Therapeutic Targets Database

DAP000802

PharmGKB

PA164744571

RxList

RxList Drug Page

Drugs.com

Drugs.com Drug Page

Wikipedia

Insulin

FDA label

Download (828 KB)

MSDS

Download (47 KB)

Clinical Trials

Clinical Trials

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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Not Available	Active Not Recruiting	Basic Science	Type 1 Diabetes Mellitus	1	somestatus	stop reason	just information to hide
Not Available	Active Not Recruiting	Other	Type 2 Diabetes Mellitus	1	somestatus	stop reason	just information to hide
Not Available	Active Not Recruiting	Prevention	Type 1 Diabetes Mellitus	1	somestatus	stop reason	just information to hide
Not Available	Active Not Recruiting	Treatment	Insulin Resistance, Diabetes / Wound Complications	1	somestatus	stop reason	just information to hide
Not Available	Completed	Not Available	Anesthetics Adverse Reaction / Delirium	1	somestatus	stop reason	just information to hide

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Pharmacoeconomics

Manufacturers

• Novo nordisk inc

Packagers

• A-S Medication Solutions LLC
• DispenseXpress Inc.
• Eli Lilly & Co.
• Hospira Inc.
• Intervet International
• Novo Nordisk Inc.
• Pfizer Inc.
• Physicians Total Care Inc.

Dosage Forms

Form	Route	Strength
Injection, suspension	Cutaneous; Parenteral	100 IU/ml
Injection, suspension	Cutaneous; Parenteral	40 IU/ml
Injection, suspension	Parenteral; Subcutaneous	100 UI/ML
Injection, suspension	Parenteral; Subcutaneous	100 IU/ml
Injection, suspension	Parenteral; Subcutaneous	40 UI/ML
Injection, suspension	Parenteral
Injection, solution	Intravenous; Parenteral	100 IU/ML
Injection, solution	Intravenous; Parenteral	40 IU/ML
Injection, solution	Intravenous; Subcutaneous	100 IU/ML
Injection, solution	Intravenous; Subcutaneous	40 iu/ml
Injection, solution	Parenteral; Subcutaneous	100 IU/ML
Solution	Subcutaneous
Injection, solution	Parenteral	100 IU/mL
Injection
Injection	Intramuscular; Intravenous; Subcutaneous	100 IU/ml
Injection, solution	Parenteral	100 IE
Injection, solution	Parenteral	100 IE/ML
Injection, solution	Parenteral	100 I.E./ML
Solution	Subcutaneous	100 IU/ml
Solution		100 IU/ml
Kit	Respiratory (inhalation)
Powder, metered	Respiratory (inhalation)	12 [arb'U]/1
Powder, metered	Respiratory (inhalation)	4 [arb'U]/1
Powder, metered	Respiratory (inhalation)	4 1/1
Powder, metered	Respiratory (inhalation)	8 [arb'U]/1
Powder, metered	Respiratory (inhalation)	8 1/1
Injection, suspension	Parenteral	3 ML
Injection, solution	Parenteral	3 ML
Injection, suspension	Subcutaneous
Injection, suspension		100 iu/1ml
Solution	Subcutaneous	500 unit / mL
Aerosol, powder	Respiratory (inhalation)	1 mg/1
Aerosol, powder	Respiratory (inhalation)	3 mg/1
Injection	Parenteral
Injection, solution	Subcutaneous
Injection, solution
Injection, suspension	Parenteral	100 IU
Injection, suspension	Parenteral	1000 IU
Injection, solution	Parenteral	100 IU
Injection, solution	Intravenous	100 IU/ML
Injection, solution	Subcutaneous	100 IU/ML
Injection, suspension	Subcutaneous	100 units/mL
Injection, suspension	Subcutaneous	40 units/mL
Suspension	Subcutaneous
Injection	Subcutaneous	100 U/ML
Injection	Intramuscular; Subcutaneous
Injection, suspension		100 IU
Injection, suspension	Subcutaneous	100 [iU]/1mL
Injection, suspension	Subcutaneous	100
Injection, suspension	Parenteral	300 IU
Injection	Subcutaneous
Suspension	Subcutaneous	100 unit/mL
Suspension	Subcutaneous	100 unit / mL
Injection	Intramuscular; Subcutaneous	100 iu/ml
Injection, solution	Parenteral	300 IU
Injection, solution		100 IU
Injection, solution	Parenteral	100 [iU]/1mL
Injection, solution	Subcutaneous	100 [iU]/1mL
Solution	Intramuscular; Intravenous; Subcutaneous	100 unit/mL
Solution	Subcutaneous	100 UI
Solution	Intramuscular; Subcutaneous	100 unit/mL
Injection, solution	Subcutaneous	500 [iU]/1mL
Solution	Intravenous; Subcutaneous	100 IU
Injection, solution	Intravenous	1 IU/ml
Injection, solution	Intravenous	1 UI/mL
Injection, suspension	Subcutaneous	100 IU/mL
Suspension	Subcutaneous
Injection		100 iu/ml
Injection, suspension	Parenteral	100 IE/ML
Injection	Subcutaneous	100 IU/ml
Injection, suspension	Subcutaneous	30 iu/1mL
Suspension	Intramuscular; Subcutaneous	100 IU
Solution	Subcutaneous	100 IU
Solution	Parenteral	100.000 UI
Injection, solution	Intramuscular; Parenteral	100 IU/ML
Injection, solution	Intravenous; Parenteral	100 UI/ML
Injection, solution	Parenteral; Subcutaneous	100 UI/ML
Injection, solution	Parenteral; Subcutaneous	40 UI/ML
Injection, suspension	Intramuscular	100 IU/ml
Injection, suspension	Intramuscular	40 IU/ml
Injection, suspension	Intramuscular; Subcutaneous	100 IU/ml
Injection, suspension	Subcutaneous	100 UI/ML
Injection, suspension	Subcutaneous	40 UI/ML
Injection, suspension	Subcutaneous	40 IU/ml
Solution	Subcutaneous	100 UI/ML
Solution	Subcutaneous	40 UI/ML
Suspension		100 IU/ML
Injection, suspension	Parenteral	100 I.E./ML
Injection, suspension	Parenteral	40 IE/ML
Injection, suspension	Parenteral	100 IE
Suspension	Subcutaneous	100 IU/ml
Injection, solution	Intraperitoneal	400 IU/ml
Injection, solution	Parenteral	40 IE/ML
Injection, solution		100 iu/ml
Injection; injection, solution		100 IU/ml
Injection		300 IU/ml
Injection	Subcutaneous
Injection	Subcutaneous	70 IU/ml
Injection, suspension	Parenteral	100 IU/ml
Injection, suspension	Subcutaneous
Injection, solution	Intravenous	1.00 [iU]/1mL
Solution	Intravenous	1 unit / mL
Injection, suspension	Subcutaneous	100 [USP'U]/1mL
Solution	Intramuscular; Intravenous; Subcutaneous	100 unit / mL
Solution	Other	100 UI
Liquid	Intramuscular; Intravenous; Subcutaneous	100 unit / mL
Injection, suspension	Parenteral; Subcutaneous	40 IU/ML
Injection, suspension	Parenteral	100 UI/ml
Injection		100 IU
Suspension
Solution	Intramuscular; Intravenous; Subcutaneous	100 IU
Suspension	Subcutaneous	100 IU
Solution	Parenteral	100 UI
Suspension	Parenteral	100 UI
Injection, suspension
Suspension
Suspension		100 iu/1ml
Injection, solution		100 iu/1ml
Solution		100 iu/1ml

Prices

Unit description	Cost	Unit
NovoLIN R PenFill 100 unit/ml Solution Five 3ml Cartridges Per Box = 15ml	162.26USD	cartridge
NovoLIN R 100 unit/ml Solution 10ml Vial	73.19USD	vial
Novolin r 100 unit/ml cartridg	33.33USD	ml
NovoLIN R InnoLet 100 unit/ml Solution 3ml Cartridge	24.17USD	cartridge
Humulin N Cartridge 100 unit/ml Cartridge	2.99USD	cartridge
Humulin R Cartridge 100 unit/ml Cartridge	2.99USD	cartridge
Novolin Ge Toronto Penfill 100 unit/ml Cartridge	2.8USD	cartridge
Novolin Ge Nph Penfill 100 unit/ml Cartridge	2.78USD	cartridge
Humulin N 100 unit/ml	2.29USD	cartridge
Humulin R 100 unit/ml	2.29USD	cartridge
Novolin Ge Nph 100 unit/ml	2.14USD	cartridge
Novolin Ge Toronto 100 unit/ml	2.14USD	cartridge

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Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
USRE37872	No	2002-10-08	2010-02-12
CA2183577	No	2007-10-30	2015-02-07
CA2253393	No	2007-10-09	2017-05-07
US7291132	No	2007-11-06	2024-08-09
US6257233	No	2001-07-10	2019-05-14
US6546929	No	2003-04-15	2019-05-14
US6685967	No	2004-02-03	2018-09-11
US6582728	No	2003-06-24	2020-06-24
US8912193	No	2014-12-16	2029-06-12
US7648960	No	2010-01-19	2020-06-29
US6652885	No	2003-11-25	2020-06-29
US8258095	No	2012-09-04	2029-08-11
US8778403	No	2014-07-15	2030-06-11
US6444226	No	2002-09-03	2020-06-29
US7943572	No	2011-05-17	2026-08-10
US8119593	No	2012-02-21	2029-08-11
US7943178	No	2011-05-17	2020-06-29
US8889099	No	2014-11-18	2020-06-29
US8623817	No	2014-01-07	2029-09-18
US8389470	No	2013-03-05	2020-06-29
US9192675	No	2015-11-24	2029-06-12
US8215300	No	2012-07-10	2022-11-24
US8146588	No	2012-04-03	2023-04-24
US8950397	No	2015-02-10	2021-07-20
US8485180	No	2013-07-16	2030-03-25
US9283193	No	2016-03-15	2026-09-14
US8636001	No	2014-01-28	2032-07-12
US8424518	No	2013-04-23	2031-10-17
US8551528	No	2013-10-08	2030-06-11
US7464706	No	2008-12-16	2023-03-02
US8729019	No	2014-05-20	2028-12-26
US7305986	No	2007-12-11	2023-01-16
US8499757	No	2013-08-06	2032-02-19
US8156936	No	2012-04-17	2023-01-16
US8734845	No	2014-05-27	2030-06-11
US8227409	No	2012-07-24	2031-03-08
US9393372	No	2016-07-19	2029-07-04
US9339615	No	2016-05-17	2029-10-20
US9511198	No	2016-12-06	2030-02-16
US9597374	No	2017-03-21	2031-10-08
US9358352	No	2016-06-07	2031-02-15
US9446133	No	2016-09-20	2029-06-12
US9662461	No	2017-05-30	2029-06-12
US9717689	No	2017-08-01	2026-09-14
US9943571	No	2018-04-17	2029-08-11
US10046031	No	2018-08-14	2029-08-11
US10201672	No	2019-02-12	2030-08-02
US10342938	No	2019-07-09	2029-06-12
US10500159	No	2019-12-10	2030-11-02

Properties

State

Liquid

Experimental Properties

Property	Value	Source
melting point (°C)	81 °C	Khachidze, D.G. et al., J. Biol. Phys. Chem. 1:64-67 (2001)

Targets

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Details1. Insulin receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

General 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 (IRS1, 2, 3, 4), SHC, GAB1, CBL and other signaling intermediates. Each of these phosphorylated proteins serve as docking proteins for other signaling proteins that contain Src-homology-2 domains (SH2 domain) that specifically recognize different phosphotyrosine residues, including the p85 regulatory subunit of PI3K and SHP2. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway, which is responsible for most of the metabolic actions of insulin, and the Ras-MAPK pathway, which regulates expression of some genes and cooperates with the PI3K pathway to control cell growth and differentiation. Binding of the SH2 domains of PI3K to phosphotyrosines on IRS1 leads to the activation of PI3K and the generation of phosphatidylinositol-(3, 4, 5)-triphosphate (PIP3), a lipid second messenger, which activates several PIP3-dependent serine/threonine kinases, such as PDPK1 and subsequently AKT/PKB. The net effect of this pathway is to produce a translocation of the glucose transporter SLC2A4/GLUT4 from cytoplasmic vesicles to the cell membrane to facilitate glucose transport. Moreover, upon insulin stimulation, activated AKT/PKB is responsible for: anti-apoptotic effect of insulin by inducing phosphorylation of BAD; regulates the expression of gluconeogenic and lipogenic enzymes by controlling the activity of the winged helix or forkhead (FOX) class of transcription factors. Another pathway regulated by PI3K-AKT/PKB activation is mTORC1 signaling pathway which regulates cell growth and metabolism and integrates signals from insulin. AKT mediates insulin-stimulated protein synthesis by phosphorylating TSC2 thereby activating mTORC1 pathway. The Ras/RAF/MAP2K/MAPK pathway is mainly involved in mediating cell growth, survival and cellular differentiation of insulin. Phosphorylated IRS1 recruits GRB2/SOS complex, which triggers the activation of the Ras/RAF/MAP2K/MAPK pathway. In addition to binding insulin, the insulin receptor can bind insulin-like growth factors (IGFI and IGFII). Isoform Short has a higher affinity for IGFII binding. When present in a hybrid receptor with IGF1R, binds IGF1. PubMed:12138094 shows that hybrid receptors composed of IGF1R and INSR isoform Long are activated with a high affinity by IGF1, with low affinity by IGF2 and not significantly activated by insulin, and that hybrid receptors composed of IGF1R and INSR isoform Short are activated by IGF1, IGF2 and insulin. In contrast, PubMed:16831875 shows that hybrid receptors composed of IGF1R and INSR isoform Long and hybrid receptors composed of IGF1R and INSR isoform Short have similar binding characteristics, both bind IGF1 and have a low affinity for insulin. In adipocytes, inhibits lipolysis (By similarity)

Specific Function

amyloid-beta binding

Gene Name

INSR

Uniprot ID

P06213

Uniprot Name

Insulin receptor

Molecular Weight

156331.465 Da

References

1. Desbuquois B, Chauvet G, Kouach M, Authier F: Cell itinerary and metabolic fate of proinsulin in rat liver: in vivo and in vitro studies. Endocrinology. 2003 Dec;144(12):5308-21. Epub 2003 Sep 11. [Article]
2. Chen LM, Yang XW, Tang JG: Acidic residues on the N-terminus of proinsulin C-Peptide are important for the folding of insulin precursor. J Biochem. 2002 Jun;131(6):855-9. [Article]
3. Bell DS: Insulin therapy in diabetes mellitus: how can the currently available injectable insulins be most prudently and efficaciously utilised? Drugs. 2007;67(13):1813-27. [Article]
4. Tanti JF, Jager J: Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Curr Opin Pharmacol. 2009 Dec;9(6):753-62. doi: 10.1016/j.coph.2009.07.004. Epub 2009 Aug 13. [Article]
5. Chiu SL, Cline HT: Insulin receptor signaling in the development of neuronal structure and function. Neural Dev. 2010 Mar 15;5:7. doi: 10.1186/1749-8104-5-7. [Article]
6. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [Article]
7. 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

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 involved in cell growth and survival control. IGF1R is crucial for tumor transformation and survival of malignant cell. Ligand binding activates the receptor kinase, leading to receptor autophosphorylation, and tyrosines phosphorylation of multiple substrates, that function as signaling adapter proteins including, the insulin-receptor substrates (IRS1/2), Shc and 14-3-3 proteins. Phosphorylation of IRSs proteins lead to the activation of two main signaling pathways: the PI3K-AKT/PKB pathway and the Ras-MAPK pathway. The result of activating the MAPK pathway is increased cellular proliferation, whereas activating the PI3K pathway inhibits apoptosis and stimulates protein synthesis. Phosphorylated IRS1 can activate the 85 kDa regulatory subunit of PI3K (PIK3R1), leading to activation of several downstream substrates, including protein AKT/PKB. AKT phosphorylation, in turn, enhances protein synthesis through mTOR activation and triggers the antiapoptotic effects of IGFIR through phosphorylation and inactivation of BAD. In parallel to PI3K-driven signaling, recruitment of Grb2/SOS by phosphorylated IRS1 or Shc leads to recruitment of Ras and activation of the ras-MAPK pathway. In addition to these two main signaling pathways IGF1R signals also through the Janus kinase/signal transducer and activator of transcription pathway (JAK/STAT). Phosphorylation of JAK proteins can lead to phosphorylation/activation of signal transducers and activators of transcription (STAT) proteins. In particular activation of STAT3, may be essential for the transforming activity of IGF1R. The JAK/STAT pathway activates gene transcription and may be responsible for the transforming activity. JNK kinases can also be activated by the IGF1R. IGF1 exerts inhibiting activities on JNK activation via phosphorylation and inhibition of MAP3K5/ASK1, which is able to directly associate with the IGF1R

Specific Function

ATP binding

Gene Name

IGF1R

Uniprot ID

P08069

Uniprot Name

Insulin-like growth factor 1 receptor

Molecular Weight

154791.73 Da

References

1. Weinstein D, Simon M, Yehezkel E, Laron Z, Werner H: Insulin analogues display IGF-I-like mitogenic and anti-apoptotic activities in cultured cancer cells. Diabetes Metab Res Rev. 2009 Jan;25(1):41-9. doi: 10.1002/dmrr.912. [Article]
2. Werner H, Weinstein D, Yehezkel E, Laron Z: Controversies in the use of insulin analogues. Expert Opin Biol Ther. 2011 Feb;11(2):199-209. doi: 10.1517/14712598.2011.540233. [Article]
3. 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]
4. Sarfstein R, Nagaraj K, LeRoith D, Werner H: Differential Effects of Insulin and IGF1 Receptors on ERK and AKT Subcellular Distribution in Breast Cancer Cells. Cells. 2019 Nov 23;8(12). pii: cells8121499. doi: 10.3390/cells8121499. [Article]
5. Donner T, Sarkar S: Insulin - Pharmacology, Therapeutic Regimens, and Principles of Intensive Insulin Therapy . [Article]

Details3. Carboxypeptidase E

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Modulator

Product of

General Function

Sorting receptor that directs prohormones to the regulated secretory pathway. Acts also as a prohormone processing enzyme in neuro/endocrine cells, removing dibasic residues from the C-terminal end of peptide hormone precursors after initial endoprotease cleavage

Specific Function

carboxypeptidase activity

Gene Name

CPE

Uniprot ID

P16870

Uniprot Name

Carboxypeptidase E

Molecular Weight

53150.185 Da

References

1. Liew CW, Assmann A, Templin AT, Raum JC, Lipson KL, Rajan S, Qiang G, Hu J, Kawamori D, Lindberg I, Philipson LH, Sonenberg N, Goldfine AB, Stoffers DA, Mirmira RG, Urano F, Kulkarni RN: Insulin regulates carboxypeptidase E by modulating translation initiation scaffolding protein eIF4G1 in pancreatic beta cells. Proc Natl Acad Sci U S A. 2014 Jun 3;111(22):E2319-28. doi: 10.1073/pnas.1323066111. Epub 2014 May 19. [Article]

Details4. CCN family member 3

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Downregulator

General Function

Immediate-early protein playing a role in various cellular processes including proliferation, adhesion, migration, differentiation and survival (PubMed:12050162, PubMed:12695522, PubMed:15181016, PubMed:15611078, PubMed:21344378). Acts by binding to integrins or membrane receptors such as NOTCH1 (PubMed:12695522, PubMed:15611078, PubMed:21344378). Essential regulator of hematopoietic stem and progenitor cell function (PubMed:17463287). Inhibits myogenic differentiation through the activation of Notch-signaling pathway (PubMed:12050162). Inhibits vascular smooth muscle cells proliferation by increasing expression of cell-cycle regulators such as CDKN2B or CDKN1A independently of TGFB1 signaling (PubMed:20139355). Ligand of integrins ITGAV:ITGB3 and ITGA5:ITGB1, acts directly upon endothelial cells to stimulate pro-angiogenic activities and induces angiogenesis. In endothelial cells, supports cell adhesion, induces directed cell migration (chemotaxis) and promotes cell survival (PubMed:12695522). Also plays a role in cutaneous wound healing acting as integrin receptor ligand. Supports skin fibroblast adhesion through ITGA5:ITGB1 and ITGA6:ITGB1 and induces fibroblast chemotaxis through ITGAV:ITGB5. Seems to enhance bFGF-induced DNA synthesis in fibroblasts (PubMed:15611078). Involved in bone regeneration as a negative regulator (By similarity). Enhances the articular chondrocytic phenotype, whereas it repressed the one representing endochondral ossification (PubMed:21871891). Impairs pancreatic beta-cell function, inhibits beta-cell proliferation and insulin secretion (By similarity). Plays a role as negative regulator of endothelial pro-inflammatory activation reducing monocyte adhesion, its anti-inflammatory effects occur secondary to the inhibition of NF-kappaB signaling pathway (PubMed:21063504). Contributes to the control and coordination of inflammatory processes in atherosclerosis (By similarity). Attenuates inflammatory pain through regulation of IL1B- and TNF-induced MMP9, MMP2 and CCL2 expression. Inhibits MMP9 expression through ITGB1 engagement (PubMed:21871891)

Specific Function

growth factor activity

Gene Name

CCN3

Uniprot ID

P48745

Uniprot Name

CCN family member 3

Molecular Weight

39161.82 Da

References

1. Paradis R, Lazar N, Antinozzi P, Perbal B, Buteau J: Nov/Ccn3, a novel transcriptional target of FoxO1, impairs pancreatic beta-cell function. PLoS One. 2013 May 21;8(5):e64957. doi: 10.1371/journal.pone.0064957. Print 2013. [Article]

Details5. Low-density lipoprotein receptor-related protein 2

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Substrate

General Function

Multiligand endocytic receptor (By similarity). Acts together with CUBN to mediate endocytosis of high-density lipoproteins (By similarity). Mediates receptor-mediated uptake of polybasic drugs such as aprotinin, aminoglycosides and polymyxin B (By similarity). In the kidney, mediates the tubular uptake and clearance of leptin (By similarity). Also mediates transport of leptin across the blood-brain barrier through endocytosis at the choroid plexus epithelium (By similarity). Endocytosis of leptin in neuronal cells is required for hypothalamic leptin signaling and leptin-mediated regulation of feeding and body weight (By similarity). Mediates endocytosis and subsequent lysosomal degradation of CST3 in kidney proximal tubule cells (By similarity). Mediates renal uptake of 25-hydroxyvitamin D3 in complex with the vitamin D3 transporter GC/DBP (By similarity). Mediates renal uptake of metallothionein-bound heavy metals (PubMed:15126248). Together with CUBN, mediates renal reabsorption of myoglobin (By similarity). Mediates renal uptake and subsequent lysosomal degradation of APOM (By similarity). Plays a role in kidney selenium homeostasis by mediating renal endocytosis of selenoprotein SEPP1 (By similarity). Mediates renal uptake of the antiapoptotic protein BIRC5/survivin which may be important for functional integrity of the kidney (PubMed:23825075). Mediates renal uptake of matrix metalloproteinase MMP2 in complex with metalloproteinase inhibitor TIMP1 (By similarity). Mediates endocytosis of Sonic hedgehog protein N-product (ShhN), the active product of SHH (By similarity). Also mediates ShhN transcytosis (By similarity). In the embryonic neuroepithelium, mediates endocytic uptake and degradation of BMP4, is required for correct SHH localization in the ventral neural tube and plays a role in patterning of the ventral telencephalon (By similarity). Required at the onset of neurulation to sequester SHH on the apical surface of neuroepithelial cells of the rostral diencephalon ventral midline and to control PTCH1-dependent uptake and intracellular trafficking of SHH (By similarity). During neurulation, required in neuroepithelial cells for uptake of folate bound to the folate receptor FOLR1 which is necessary for neural tube closure (By similarity). In the adult brain, negatively regulates BMP signaling in the subependymal zone which enables neurogenesis to proceed (By similarity). In astrocytes, mediates endocytosis of ALB which is required for the synthesis of the neurotrophic factor oleic acid (By similarity). Involved in neurite branching (By similarity). During optic nerve development, required for SHH-mediated migration and proliferation of oligodendrocyte precursor cells (By similarity). Mediates endocytic uptake and clearance of SHH in the retinal margin which protects retinal progenitor cells from mitogenic stimuli and keeps them quiescent (By similarity). Plays a role in reproductive organ development by mediating uptake in reproductive tissues of androgen and estrogen bound to the sex hormone binding protein SHBG (By similarity). Mediates endocytosis of angiotensin-2 (By similarity). Also mediates endocytosis of angiotensis 1-7 (By similarity). Binds to the complex composed of beta-amyloid protein 40 and CLU/APOJ and mediates its endocytosis and lysosomal degradation (By similarity). Required for embryonic heart development (By similarity). Required for normal hearing, possibly through interaction with estrogen in the inner ear (By similarity)

Specific Function

calcium ion binding

Gene Name

LRP2

Uniprot ID

P98164

Uniprot Name

Low-density lipoprotein receptor-related protein 2

Molecular Weight

521952.77 Da

References

1. Orlando RA, Rader K, Authier F, Yamazaki H, Posner BI, Bergeron JJ, Farquhar MG: Megalin is an endocytic receptor for insulin. J Am Soc Nephrol. 1998 Oct;9(10):1759-66. [Article]

Details6. Insulin-like growth factor-binding protein 7

Kind

Protein

Organism

Humans

Pharmacological action

Unknown

Actions

Inhibitor

Binder

General Function

Binds IGF-I and IGF-II with a relatively low affinity. Stimulates prostacyclin (PGI2) production. Stimulates cell adhesion. Acts as a ligand for CD93 to play a role in angiogenesis (PubMed:38218180)

Specific Function

insulin-like growth factor binding

Gene Name

IGFBP7

Uniprot ID

Q16270

Uniprot Name

Insulin-like growth factor-binding protein 7

Molecular Weight

29130.055 Da

References

1. Radulescu RT: One for all and all for one: RB defends the cell while IDE, PTEN and IGFBP-7 antagonize insulin and IGFs to protect RB. Med Hypotheses. 2007;69(5):1018-20. Epub 2007 May 1. [Article]

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Drug created at June 13, 2005 13:24 / Updated at November 05, 2024 02:22