Insulin Glargine Structure

Glargine And Degludec: Solution Behaviour Of Higher Dose Synthetic Insulins

Glargine and degludec: Solution behaviour of higher dose synthetic insulins Scientific Reportsvolume7, Articlenumber:7287 (2017) Single, double and triple doses of the synthetic insulins glargine and degludec currently used in patient therapy are characterised using macromolecular hydrodynamic techniques (dynamic light scattering and analytical ultracentrifugation) in an attempt to provide the basis for improved personalised insulin profiling in patients with diabetes. Using dynamic light scattering and sedimentation velocity in the analytical ultracentrifuge glargine was shown to be primarily dimeric under solvent conditions used in current formulations whereas degludec behaved as a dihexamer with evidence of further association of the hexamers (multi-hexamerisation). Further analysis by sedimentation equilibrium showed that degludec exhibited reversible interaction between mono- and-di-hexamer forms. Unlike glargine, degludec showed strong thermodynamic non-ideality, but this was suppressed by the addition of salt. With such large injectable doses of synthetic insulins remaining in the physiological system for extended periods of time, in some case 2440 hours, double and triple dose insulins may impact adversely on personalised insulin profiling in patients with diabetes. The ideal insulin profile for any individual with diabetes will fluctuate due to lifestyle variations and metabolic influences for example hypoglycaemia - so the physiological importance of insulin is vital for glycaemic homeostasis 1 . The biologically active, circulating form of insulin is monomeric in structure and consists of two chains, an A chain of 21 amino acids and a B chain of 30 amino acids (human), linked by two disulfide bridges, A7B7 and A20B19. The A chain contains an intra-chain disu Continue reading >>

Insulin And Its Analogues And Their Affinities For The Igf1 Receptor

Abstract Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the IGF1 receptor (IGF1R). As a consequence, insulin analogues may theoretically have an increased mitogenic action compared to human insulin. In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. This hypothesis has been evaluated extensively in vitro and also in vivo by using animal models. In vitro, all at present commercially available insulin analogues have lower affinities for the insulin receptor (IR). Although it has been suggested that especially insulin analogues with an increased affinity for the IGF1R (such as insulin glargine) are more mitogenic when tested in vitro in cells expressing a high proportion of IGF1R, the question remains whether this has any clinical consequences. At present, there are several uncertainties which make it very difficult to answer this question decisively. In addition, recent data suggest that insulin (or insulin analogues)-mediated stimulation of IRs may play a key role in the progression of human cancer. More detailed information is required to elucidate the exact mechanisms as to how insulin analogues may activate the IR and IGF1R and how this activation may be linked to mitogenesis. The introduction of insulin analogues in the treatment of diabetes The discovery of insulin by Banting and Best in 1922 represented a milestone in cl Continue reading >>

What Are The Possible Side Effects Of Insulin Glargine (lantus, Lantus Opticlik Cartridge, Lantus Solostar Pen)?

LANTUS® (insulin glargine) Injection DESCRIPTION LANTUS (insulin glargine injection) is a sterile solution of insulin glargine for subcutaneous use. Insulin glargine is a recombinant human insulin analog that is a long-acting, parenteral blood-glucose-lowering agent [see CLINICAL PHARMACOLOGY]. Insulin glargine has low aqueous solubility at neutral pH. At pH 4 insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows oncedaily dosing as a basal insulin. LANTUS is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, insulin glargine is 21A-Gly-30Ba-L-Arg-3030b-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and a molecular weight of 6063. Insulin glargine has the following structural formula: LANTUS consists of insulin glargine dissolved in a clear aqueous fluid. Each milliliter of LANTUS (insulin glargine injection) contains 100 Units (3.6378 mg) insulin glargine. The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection. The 3 mL prefilled pen presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for inje Continue reading >>

Insulin Glargine - Australian Prescriber

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source. 100 IU/mL in 3 mL cartridges, and 5 mL and 10 mL vials Australian Medicines Handbook section 10.1.1 Insulin glargine is a recombinant insulin. Its chemical structure differs from human insulin by three amino acids. The molecule is completely soluble at pH4, but after injection it becomes less soluble. Microprecipitates form, and these allow a slow continuous release of insulin. These properties make a daily injection of insulin glargine suitable for providing a patient's basal insulin requirements. In clinical trials insulin glargine had similar effects to NPH human insulin, but in some studies fewer patients experienced symptomatic hypoglycaemia. These trials were relatively short, so the long-term effectiveness of insulin glargine is currently unknown. Patients may find insulin glargine more painful to inject because of its acidity. It should not be mixed with other insulins. An analysis by the National Institute for Clinical Excellence in the UK concluded that while insulin glargine is an option for type 1 diabetes, it is not recommended for routine use in people with type 2 diabetes who require insulin. 1 Continue reading >>

Insulin Glargine - Proteopedia, Life In 3d

Insulin glargine is made up of two subunits, denoted A and B (PDB code 4iyd ) is made by recombinant DNA technology with Escherichia coli. [1] Insulin glargine was originally created by Aventis Pharmaceuticals and was accepted for use in 2000 in the USA and the EU. [2] Insulin glargine is created through the manipulation of amino acids. [2] A glycine is added to the C-terminal A-chain asparagine and two arginines are added to the C-terminal B-chain threonine. [2] The final drug product forms at a pH of 4 through the expression of E. coli and the generation of the precursor proinsulin. [3] Insulin glargine is a hormone protein consisting of 52 amino acids in an asymmetric unit. It has two unique chains, chain A and B. The structure was determined by X-ray diffraction and was measured at a resolution of 1.66 Angstroms. Chain A is 21 amino acids long and consists of two alpha helices and one beta sheet. It is modified from normal insulin by the at the twenty first amino acid of the chain. It also has an L-cystine protein modification at amino acids C6 and C11 of the chain. [4] This modification consists of a disulfide bond formed between the side chains of two cysteine residues within the amino acid chain; this occurs via an oxidation reaction. [5] Chain B is 31 amino acids long and consists of two alpha helices and one beta sheet. [4] [6] It is modified from normal insulin by the addition of to the C-terminus of the chain. [6] These modifications raise the isoelectric point (pI) from 5.4 to 6.7, improving solubility under mildly acidic conditions. [7] These two chains are held together by formed between cysteine side chains on opposing chains. One disulfide bond is formed between the cysteine residues at amino acid seven of chain A and amino acid seven of chain B. Anothe Continue reading >>

Insulin Glargine

What is Insulin Glargine (Lantus)? Insulin Glargine is recombinant human insulin analogue that act as blood-glucose-lowering agent. What is the generic and brand name of the drug? The drug is available under generic name Insulin Glargine and brand names Lantus , Toujeo,Abasaglar, and Basaglar What is the source of the drug (natural or synthetic)? Insulin Glargine is a synthetic bioengineered (man-made) injectable form of long-acting insulin. Why is this medication prescribed? Insulin Glargine acts as a long lasting (upto 24 hour duration) insulin, which reduces the amount of sugar in the blood and urine. The drug is used to treat patients with type 1diabetes or diabetes mellitus type 1. In type 1diabetes the insulin-producing beta cells in the pancreas were non functional and unable to produce insulin. The drug is also used to treat type 2 diabetes or noninsulin-dependent diabetes mellitus, (condition in which insulin is not produced in sufficient amount or not effective due to insulin resistance) to control the blood sugar level. Insulin Glargine is recommended in combination with other short acting insulin in case of type 1 diabetes, while in case of type 2 diabetes, insulin Glargine may be used with short acting insulin or with oral drugs used to treat diabetes. Pharmacophore structure: Information about the chemical structure of the drug Insulin Glargine chemically belongs to the class of organic compounds which are known as s Amino Acids, Peptides, and Analogues. The drug is prepared by recombinant DNA technology in non pathogenic bacteria coli. The detailed chemical classification of Insulin Glargine is described below: Kingdom Organic compounds Super Class Organic Acids Class Carboxylic Acids and Derivatives Sub Class Amino Acids, Peptides, and Analogues Direct P Continue reading >>

Supramolecular Protein Engineering

From the Departments of Biochemistry and Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106 2 To whom correspondence should be addressed. E-mail: michael.weiss{at}case.edu. 1 Both authors contributed equally to this work. Bottom-up control of supramolecular protein assembly can provide a therapeutic nanobiotechnology. We demonstrate that the pharmacological properties of insulin can be enhanced by design of zinc staples between hexamers. Paired (i, i+4) His substitutions were introduced at an -helical surface. The crystal structure contains both classical axial zinc ions and novel zinc ions at hexamer-hexamer interfaces. Although soluble at pH 4, the combined electrostatic effects of the substitutions and bridging zinc ions cause isoelectric precipitation at neutral pH. Following subcutaneous injection in a diabetic rat, the analog effected glycemic control with a time course similar to that of long acting formulation Lantus. Relative to Lantus, however, the analog discriminates at least 30-fold more stringently between the insulin receptor and mitogenic insulin-like growth factor receptor. Because aberrant mitogenic signaling may be associated with elevated cancer risk, such enhanced specificity may improve safety. Zinc stapling provides a general strategy to modify the pharmacokinetic and biological properties of a subcutaneous protein depot. Supramolecular chemistry envisages the construction of novel materials and nanoscale devices ranging from molecular sensors to stimulus-responsive polymers ( 1 , 2 ). Spatial organization may be achieved either by templating (design from the top down) or through self-assembly of molecular components (bottom up). Connective tissue provides an example of the bottom-up design of a biomaterial based Continue reading >>

Interactive Dosing Calculator

Lantus® is a long-acting insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Lantus® should be administered once a day at the same time every day. Limitations of Use: Lantus® is not recommended for the treatment of diabetic ketoacidosis. Contraindications Lantus® is contraindicated during episodes of hypoglycemia and in patients hypersensitive to insulin glargine or one of its excipients. Warnings and Precautions Insulin pens, needles, or syringes must never be shared between patients. Do NOT reuse needles. Monitor blood glucose in all patients treated with insulin. Modify insulin regimen cautiously and only under medical supervision. Changes in insulin strength, manufacturer, type, or method of administration may result in the need for a change in insulin dose or an adjustment in concomitant oral antidiabetic treatment. Do not dilute or mix Lantus® with any other insulin or solution. If mixed or diluted, the solution may become cloudy, and the onset of action/time to peak effect may be altered in an unpredictable manner. Do not administer Lantus® via an insulin pump or intravenously because severe hypoglycemia can occur. Hypoglycemia is the most common adverse reaction of insulin therapy, including Lantus®, and may be life-threatening. Medication errors, such as accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, have been reported. Patients should be instructed to always verify the insulin label before each injection. Severe life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Lantus®, treat and monitor until symptoms resolve. A reduction in the Lantus® dose may be re Continue reading >>

Lantus (insulin Glargine [rdna Origin] Injection)

The following drug information is obtained from various newswires, published medical journal articles, and medical conference presentations. Specific Treatments: For adults and children w/Type 1 diabetes, or adults w/Type 2 diabetes requiring basal insulin to control hyperglycemia Lantus is the first FDA approved long-acting (basal) recombinant human insulin analog with a once-daily administration and a 24-hour glucose-lowering effect. This biosynthetic insulin, injected subcutaneously and designed to mimic NPH human insulin, is indicated for both adult and pediatric patients with Type 1 diabetes. It may also be used for the treatment of adults with Type 2 diabetes who require basal insulin for the control of hyperglycemia. The chemical structure of Lantus allows for regulated release of the insulin into the circulation with a glucose-lowering effect over a 24-hour period. In clinical studies, no specific pronounced peak was detected over this period. In clinical studies, the efficacy of Lantus, measured by metabolic control, was comparable to NPH human insulin. In addition, Lantus had a slower absorption rate than NPH human insulin. This absorption allowed for a relatively constant concentration/time profile over 24-hours. The glucose-lowering effect was detected over the entire 24-hour period. As with other insulin therapies, Lantus can cause the following side effects (with hypoglycemia being the most common adverse effect): Hypoglycemia Worsening of diabetic retinopathy Lipodystrophy Skin reactions (such as injection-site reaction, pruritus, and rash)* Allergic reactions Sodium retention Edema *In clinical trials, patients treated with Lantus had a higher incidence of injection-site pain (2.7%) than did patients receiving NPH human insulin (0.7%). In general, the re Continue reading >>

Drug: Insulin Glargine

Brite Anatomical Therapeutic Chemical (ATC) classification [BR:br08303] A ALIMENTARY TRACT AND METABOLISM A10 DRUGS USED IN DIABETES A10A INSULINS AND ANALOGUES A10AE Insulins and analogues for injection, long-acting A10AE04 Insulin glargine D03250 Insulin glargine (USAN/INN) USP drug classification [BR:br08302] Blood Glucose Regulators Insulins Insulin glargine D03250 Insulin glargine (USAN/INN) Therapeutic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones 249 Miscellaneous 2492 Pancreatic hormones D03250 Insulin glargine (USAN/INN); Insulin glargine (genetical recombination) (JP17); Insulin glargine (genetical recombination) injection (JP17); Insulin glargine (genetical recombination [Insulin glargin biosimilar 1] (JAN); Insulin glargine (genetical recombination) [Insulin glargin biosimilar 2] (JAN) Target-based classification of drugs [BR:br08310] Cytokine receptors Receptor tyrosine kinase RTK class II (Insulin receptor family) insulin receptor Insulin glargine D03250 Insulin glargine (USAN/INN) Cytochrome P450 interactions [BR:br08309] CYP inducers CYP1A2 Insulin glargine D03250 Insulin glargine (USAN/INN) Drugs listed in the Japanese Pharmacopoeia [BR:br08311] Chemicals D03250 Insulin glargine (genetical recombination) D03250 Insulin glargine (genetical recombination) injection Antidiabetics [br08361.html] D03250 New drug approvals in the USA [br08319.html] New Molecular Entity and New Therapeutic Biological Product Approvals D03250 New drug approvals in Europe [br08329.html] European public assessment reports (EPAR) authorised medicine D03250 New drug approvals in Japan [br08318.html] Drugs with new active ingredients D03250 New drug approvals in the USA, Europe and Japan [br08328.html] Approval dates by FDA, EMA and PMDA D0 Continue reading >>

Fda Approves New Insulin Glargine Basaglar – The First “biosimilar” Insulin In The Us

Twitter Summary: 1st ever “biosimilar” insulin approved in US – potential to come cheaper than other insulins, with launch in December 2016 Lilly/BI recently announced the FDA approval of its long-awaited biosimilar insulin glargine, Basaglar, for type 1 and type 2 diabetes. Basaglar is biologically similar to Sanofi’s basal insulin Lantus (insulin glargine), including the same protein sequence and a similar glucose-lowering effect. While the FDA does not call it a “biosimilar” drug for regulatory reasons, it can essentially be thought of as an alternative form of Lantus. Pricing for Basaglar is unknown at this time (more on this below), and the drug will not be launching in the US until after December 15, 2016. Why are “biosimilar” insulin options exciting? Most notably, they could potentially be offered at lower costs than brand name insulins. Basaglar has already launched in several international countries (under the brand name Abasaglar) and is typically priced at a 15%-20% discount relative to Lantus in those markets. It’s not clear yet how the discounts for Basaglar will compare in the US, and how much less patients with insurance might pay. “Generic” versions of drugs in the US typically come at a 50-80% discount to the original product. But unlike most generic drugs, biosimilar insulins are much more expensive to manufacture, so it’s unlikely they’ll see that same level of discount in the US. Indeed, Novartis launched the first “biosimilar” drug approved in the US last September (not in diabetes), which came at a 15% discount. Still, we’ve heard great optimism that biosimilar insulin glargine will help patients facing higher insulin costs. At the IDF conference in December, Dr. Matthew Riddle suggested that of all the insulins new Continue reading >>

Insulin Glargine

Insulin glargine, marketed under the names Lantus, among others, is a long-acting basal insulin analogue, given once daily to help control the blood sugar level of those with diabetes. It consists of microcrystals that slowly release insulin, giving a long duration of action of 18 to 26 hours, with a "peakless" profile (according to the insulin glargine package insert). Pharmacokinetically, it resembles basal insulin secretion of non-diabetic pancreatic beta cells. Sometimes, in type 2 diabetes and in combination with a short acting sulfonylurea (drugs which stimulate the pancreas to make more insulin), it can offer moderate control of serum glucose levels. In the absence of endogenous insulin—type 1 diabetes, depleted type 2 (in some cases) or latent autoimmune diabetes of adults in late stage—insulin glargine needs the support of fast acting insulin taken with food to reduce the effect of prandially derived glucose. Medical uses[edit] The long-acting insulin class, which includes insulin glargine, do not appear much better than neutral protamine Hagedorn (NPH) insulin but have a significantly greater cost making them, as of 2010, not cost effective.[1] It is unclear if there is a difference in hypoglycemia and not enough data to determine any differences with respect to long term outcomes.[2] Mixing with other insulins[edit] Unlike some other longer-acting insulins, glargine must not be diluted or mixed with other insulin or solution in the same syringe.[3] However, this restriction has been questioned.[4] Adverse effects[edit] Cancer[edit] As of 2012 tentative evidence shows no association between insulin glargine and cancer.[5] Previous studies had raised concerns.[6] Pharmacology[edit] Mechanism of action[edit] Insulin glargine has a substitution of glycine for Continue reading >>

1. Indications And Usage

Generic Name: insulin glargine Dosage Form: injection, solution Lantus is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Limitations of Use Lantus is not recommended for the treatment of diabetic ketoacidosis. 2. DOSAGE AND ADMINISTRATION Important Administration Instructions Administer Lantus subcutaneously once daily at any time of day but at the same time every day. Prior to initiation of Lantus, train patients on proper use and injection technique. Patient should follow the Instructions for Use to correctly administer Lantus. Administer Lantus subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)]. Visually inspect Lantus vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles. Refrigerate unused (unopened) Lantus vials and SoloStar® prefilled pens. Do not administer intravenously or via an insulin pump. Do not dilute or mix Lantus with any other insulin or solution. General Dosing Instructions Individualize and adjust the dosage of Lantus based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)]. Initiation of Lantu Continue reading >>

Insulin Analogs: What Are The Clinical Implications Of Structural Differences?

US Pharm. 2010;35(5)(Diabetes suppl):3-7. In healthy adults, basal insulin concentrations of 5 to 15 µU/mL help to maintain fasting plasma glucose concentrations (FIGURE 1).1 Immediately following a meal, insulin concentration peaks at 60 to 80 µU/mL, returning to basal levels 1 to 3 hours later. In type 2 diabetes mellitus, progressive loss of beta cells results in the disruption of endogenous insulin secretion, in turn leading to requirement for insulin therapy. Considering that the daily pattern of normal insulin secretion is complex, close replication of this pattern is needed to address both fasting and prandial glucose control. In human insulin preparations, such as regular human insulin (RHI), insulin molecules typically self-aggregate to form dimers, which in turn stabilize around zinc ions to form hexamers.2 Following injection, the subcutaneous insulin depot is diluted by the interstitial fluid, causing hexamers to break down into dimers and biologically active monomers. The dissociation of hexamers into dimers and monomers is a rate-limiting step in absorption for all insulins and contributes to the delay in the effect of RHI. Because insulin hexamers are too bulky to be transported across the vascular endothelium, there is a 30- to 60-minute lag phase between injection and onset of action, which requires careful dose administration and food consumption. In addition to slow onset, a slow clearance can result in prolonged periods of elevated insulin and “delayed” hypoglycemia. Exogenous basal insulin delivery has traditionally involved single or twice-daily injections of neutral protamine Hagedorn (NPH) insulin, which is a formulation of protamine insulin in a zinc suspension. Protamine prolongs the absorption of NPH insulin, causing an intermediate dura Continue reading >>

In Vitro Metabolic And Mitogenic Signaling Of Insulin Glargine And Its Metabolites

In Vitro Metabolic and Mitogenic Signaling of Insulin Glargine and Its Metabolites Affiliation: Research and Development TD Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Research and Development TD Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Research and Development TD Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Process Development Biotechnology, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Process Development Biotechnology, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Research and Development TD Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Affiliation: Research and Development TD Metabolism, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany Insulin glargine (Lantus) is a long-acting basal insulin analog that demonstrates effective day-long glycemic control and a lower incidence of hypoglycemia than NPH insulin. After subcutaneous injection insulin glargine is partly converted into the two main metabolites M1 ([GlyA21]insulin) and M2 ([GlyA21,des-ThrB30]insulin). The aim of this study was to characterize the glargine metabolites in vitro with regard to their insulin receptor (IR) and IGF-1 receptor (IGF1R) binding and signaling properties as well as their metabolic and mitogenic activities. The affinity of human insulin, insulin glargine and its metabolites to the IR isoforms A and B or IGF1R was analyzed in a competitive binding assay using SPA technology. Receptor autophosphorylation activities were studied via In-Cell Western in CHO and MEF cells overexpressing human IR-A and IR-B or IGF1R, respectively. The metabolic response of the insulins was studied a Continue reading >>