Figure 1 - available via license: Creative Commons Attribution-NonCommercial 4.0 International
Content may be subject to copyright.
Source publication
Diabetes mellitus is a growing public health concern in the US and worldwide. Insulin therapy is the cornerstone of diabetes therapy, and the use of basal insulins will increase as clinicians strive to help their patients reach glycemic goals. Basal insulins have been continually improved upon over the years, and the long-acting basal insulin analo...
Contexts in source publication
Context 1
... glargine (Gly A21 Arg B21 Arg B32 human insulin) is synthesized via recombinant DNA technology using Escherichia coli K12. 13 The amino acid asparagine at posi- tion A21 in human insulin is replaced with glycine, and two arginines are added to the C-terminus of the β-chain (Figure 1a). 13 These modifications cause a shift in the isoelectric point towards neutrality. At a pH of 4 in acidic solution, glargine is not soluble at physiologic neutral pH and forms a microprecipitate upon injection into subcuta- neous tissue. 13 Insulin detemir [Lys B29 (N-tetradecanoyl)des(B30)human insulin] is also synthesized via recombinant technology, using the yeast Saccharomyces cerevisiae. 14 It differs from human insulin in that the amino acid threonine in position B30 is omitted and a carbon 14 fatty acid chain is attached to lysine at B29 (Figure 1b). 14 Detemir has a pH of 7.4 and is therefore soluble at physiologic pH. 14 It is reversibly bound to albumin. 14 Both glargine and detemir are clear solutions 13,14 that unlike NPH do not require resuspension prior to ...
Context 2
... glargine (Gly A21 Arg B21 Arg B32 human insulin) is synthesized via recombinant DNA technology using Escherichia coli K12. 13 The amino acid asparagine at posi- tion A21 in human insulin is replaced with glycine, and two arginines are added to the C-terminus of the β-chain (Figure 1a). 13 These modifications cause a shift in the isoelectric point towards neutrality. At a pH of 4 in acidic solution, glargine is not soluble at physiologic neutral pH and forms a microprecipitate upon injection into subcuta- neous tissue. 13 Insulin detemir [Lys B29 (N-tetradecanoyl)des(B30)human insulin] is also synthesized via recombinant technology, using the yeast Saccharomyces cerevisiae. 14 It differs from human insulin in that the amino acid threonine in position B30 is omitted and a carbon 14 fatty acid chain is attached to lysine at B29 (Figure 1b). 14 Detemir has a pH of 7.4 and is therefore soluble at physiologic pH. 14 It is reversibly bound to albumin. 14 Both glargine and detemir are clear solutions 13,14 that unlike NPH do not require resuspension prior to ...
Similar publications
BACKGROUND: Few studies have evaluated the perioperative management of diabetes mellitus. A retrospective chart review was therefore conducted to evaluate the efficacy and safety of an intravenous (IV) insulin protocol. METHOD: The charts of 50 patients with diabetes who were admitted to the hospital for surgery and who received perioperative IV in...
Introduction
Although individualized target glycated hemoglobin (HbA 1c ) levels are recommended in older people with type 2 diabetes, studies report high levels of potential overtreatment. We aimed to investigate the proportion of older patients (aged ≥65 years) who potentially received an inappropriately intensive treatment (HbA 1c level <7.0% (5...
CHOICE (CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy; NCT00635492) assessed, as its primary objective, the time to a 'significant treatment change' (defined within this paper) after patients with type 2 diabetes mellitus initiated their first injectable, glucose-lowering therapy [exenatide twice d...
Citations
... These changes result in chemical stability in its low pH solution (formulated at pH 4) and precipitation of glargine at physiological pH after subcutaneous injection, and are responsible for its slow absorption and controlled release of about 24 hours with no peak of action. [37][38][39][40] Detemir insulin, marketed as Levemir (Novo Nordisk), is another long-acting insulin, which is produced through bioengineering by the yeast Saccharomyces cerevisiae, and lacks the threonine at position B30 and has a fatty acid chain attached to lysine at B29. 41 Detemir forms dihexamers and binds to subcutaneous albumin after injection as well as in the bloodstream, resulting in slower release and distribution to peripheral tissues. It has no pronounced peak and lasts up to 24 hours. ...
... Some studies indicate that because NPH crystallizes and requires proper resuspension, it has variable absorption rates that are detrimental to the patient, therefore detemir or glargine is favored. 41,47 However, other studies indicate that the long-acting insulin analogs, which can cost much more than NPH, are not superior and that NPH may provide better glycemic control and result in fewer severe hypoglycemic episodes than the long-acting insulin analogs. [48][49][50] ...
The clinical use of insulin to treat diabetes started just over 100 years ago. The past century has witnessed remarkable innovations in insulin therapy, evolving from animal organ extracts to bioengineered human insulins with ultra-rapid onset or prolonged action. Insulin delivery systems have also progressed to current automated insulin delivery systems. In this review, we discuss the history of insulin and the pharmacology and therapeutic indications for a variety of available insulins, especially newer analog insulins. We highlight recent advances in insulin pump therapy and review evidence on the therapeutic benefits of automated insulin delivery. As with any form of progress, there have been setbacks, and insulin has recently faced an affordability crisis. We address the challenges of insulin accessibility, along with recent progress to improve insulin affordability. Finally, we mention research on glucose-responsive insulins and hepato-preferential insulins that are likely to shape the future of insulin therapy.
... Die Entwicklung langwirksamer Insulinanaloga (Insulin Glargin U 100, Insulin Detemir) hatte zum Ziel, eine gegenüber NPH-Insulin flachere Wirkkurve und längere Wirkdauer zu erzielen. Langwirksame Insulinanaloga zeigten in klinischen Studien gegenüber NPH-Insulin eine Reduktion vor allem nächtlicher Hypoglykämien [27][28][29]. Von Vorteil in der klinischen Praxis und Handhabung ist auch das Vorliegen der langwirksamen Insulinanaloga in Form einer klaren Lösung, während bei Applikation von NPH-Insulin eine vorausgehende Suspension des Insulins erforderlich ist. S100 Diagnostik und Therapie des Typ 1 Diabetes mellitus (Update 2023 ) K leitlinien für die praxis Zu den sogenannten ultralangwirksamen Insulinanaloga zählen Insulin Glargin U 300 und Insulin Degludec [30,31]. ...
Zusammenfassung
Die Leitlinie nimmt Bezug auf die Diagnostik, einschließlich begleitender Autoimmunerkrankungen, bei Typ 1 Diabetes mellitus, die Insulintherapie und die glykämischen Zielwerte.
... Thus, the assembly of subunits interacting through the covalent and noncovalent bonds defines their structure-function correlations [21]. Ideally, phenolic ligands and zinc atoms retain the hexameric form of insulin [22]. The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [22]. ...
... Ideally, phenolic ligands and zinc atoms retain the hexameric form of insulin [22]. The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [22]. Thus, after injection of the detemir subcutaneously, phenolic ligands and fatty acid groups attached to insulin rapidly diffuse into the subcutaneous area, establishing the hexamer:dihexamer equilibrium [22]. ...
... The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [22]. Thus, after injection of the detemir subcutaneously, phenolic ligands and fatty acid groups attached to insulin rapidly diffuse into the subcutaneous area, establishing the hexamer:dihexamer equilibrium [22]. The accumulated forms slowly dissociate into dimers and monomers, after which the myristic acid groups on insulin permit self-assembly, prolonging its action [11,22] ( Figure S2). ...
The treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with type 1 diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here, we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 Å resolution at cryogenic temperature. We computationally further investigated our crystal structure’s monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ), obtained at elevated pH, provides electrostatically triggered minor movements in the equilibrium between alternate conformational substates compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Supplemented with orientational cross-correlation analysis by a Gaussian network model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions originated by loose coupling of distant conformational substates of a protracted insulin analog that has not been previously observed.
... J B Collip produced a successful, contaminant-free extract of insulin from chilled beef pancreas 3 . Patients responded positively to this new series of injections-their glycosuria, ketonuria disappeared, and blood glucose levels dropped to normal 3 .The year 2021 marked 100 years of insulin discovery and many modifications came along the way, by the 1990's Insulin analogs came to the market and were preferred because of the duration of action according to the need, consistent effect, Pharmacoeconomic advantage, and many other factors 4 . Analog were divided into 3 parts according to the duration: Long-acting, rapid-acting, and intermediate, "sweet would not always be served, sometimes Bitter things would always be there", Insulin analogs also possess side effect and some may be there for a long-term; the theory that it can cause Cancer is not proved and is still controversial, but people sensitive about their weight would prefer Insulin analogs over Human Insulin since there is no significant gain 5 . ...
Chronic metabolic illnesses, like diabetes mellitus, have become diseases that harm human health and are now one of the most critical public health problems in almost half a century, as a result of societal development and lifestyle changes. For decades, conventional insulin therapy has been playing a significant role while treating millions of patients around the globe. Unfortunately, despite breakthroughs in DNA recombinant technology and pharmacotherapy, these therapeutic goals are rarely met, and results have not improved significantly. The low effectiveness rate of insulin treatment is becoming recognized as a result of intra-individual and inter-individual differences in insulin needs. Thus, our review focuses on finding superior insulin derivatives to treat diabetes more effectively and efficiently. Insulin analogs hold the potential to overcome the limitations of conventional insulin. We have taken a deep dive into rapid acting and long-acting analogs by discussing their pharmacokinetics, pharmacodynamics, dosage and therapeutic efficacy. But their safety profile has been questioned several times and therefore we have thrown some light on the current innovation trends that are being scrutinized.
... Thus, the assembly of subunits interacting through the covalent and noncovalent bonds defines their structure-function correlations [28]. Ideally, phenolic ligands and zinc atoms retain the hexameric form of insulin [29]. The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [29]. ...
... Ideally, phenolic ligands and zinc atoms retain the hexameric form of insulin [29]. The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [29]. Thus, after injection of the detemir subcutaneously, phenolic ligands and fatty acid groups attached to insulin rapidly diffuse into the subcutaneous area, establishing the hexamer:dihexamer equilibrium [29]. ...
... The rationale for the long-acting form of the insulin detemir is characterized by keeping the molecule in the dimer form of hexamers compared to other protracted insulins [29]. Thus, after injection of the detemir subcutaneously, phenolic ligands and fatty acid groups attached to insulin rapidly diffuse into the subcutaneous area, establishing the hexamer:dihexamer equilibrium [29]. The accumulated forms slowly dissociate into dimers and monomers, after which the myristic acid groups on insulin permit self-assembly, prolonging its action [11,29] (Figure S2). ...
The treatment of insulin-dependent diabetes mellitus is characterized by artificial supplementation of pancreatic β-cell ability to regulate sugar levels in the blood. Even though various insulin analogs are crucial for reasonable glycemic control, understanding the dynamic mechanism of the insulin analogs may help to improve the best-protracted insulin analog to assist people with Type 1 Diabetes (T1D) to live comfortably while maintaining tight glycemic control. Here we present the high-resolution crystal structure of NN304, known as insulin detemir, to 1.7 A resolution at cryogenic temperature. We computationally further investigated our crystal structure's monomeric-dimeric conformation and dynamic profile by comparing it with a previously available detemir structure (PDB ID: 1XDA). Our structure (PDB ID: 8HGZ) obtained at elevated pH provides a distinct alternative dimeric conformation compared to the previous structure, suggesting it might induce an intermediate state in the dissociation pathway of the insulin detemir’s hexamer:dihexamer equilibrium. Combined with orientational cross-correlation analysis by Gaussian Network Model (GNM), this alternate oligomeric conformation offers the distinct cooperative motions of a protracted insulin analog that has not been previously observed.
... Herein, basal insulin analogues were created by the A21G mutation and addition of two R residues at the C-terminus to incorporate additional positive charges and improve its solubility at physiological conditions. 57,58 Alternative mutations were also adopted to create a soluble insulin detemir, 59 while ester tags were used by Nadendla and Friedman to block acidic group exposures in the native insulin with a photocleavable linker. 60 Mathematically, pI is the average of pK a values for functional groups within an amino acid, and is calculated from the acid dissociation constant K a , which is an equilibrium constant for dissociation. ...
Water solubility and structural stability are key merits for proteins defined by the primary sequence and 3D-conformation. Their manipulation represents important aspects of the protein design field that relies on the accurate placement of amino acids and molecular interactions, guided by underlying physiochemical principles. Emulated designer proteins with well-defined properties both fuel the knowledge-base for more precise computational design models and are used in various biomedical and nanotechnological applications. The continuous developments in protein science, increasing computing power, new algorithms, and characterization techniques provide sophisticated toolkits for solubility design beyond guess work. In this review, we summarize recent advances in the protein design field with respect to water solubility and structural stability. After introducing fundamental design rules, we discuss the transmembrane protein solubilization and de novo transmembrane protein design. Traditional strategies to enhance protein solubility and structural stability are introduced. The designs of stable protein complexes and high-order assemblies are covered. Computational methodologies behind these endeavors, including structure prediction programs, machine learning algorithms, and specialty software dedicated to the evaluation of protein solubility and aggregation, are discussed. The findings and opportunities for Cryo-EM are presented. This review provides an overview of significant progress and prospects in accurate protein design for solubility and stability.
... Long-acting insulin analogs have a slow onset of action, longer duration of action, and longer half-life. The long-acting insulin analogs provide a relatively peakless profile for approximately 24 hours, and as a result, only one dose is given daily [19]. The long-acting insulin analogs provide the opportunity for more physiological action profiles, which yield better reproducibility and improved predictability and are associated with reduced risk for hypoglycaemia [20]. ...
Since the discovery of insulin, continuous developments of this peptide have led to better management of diabetes mellitus, thus leading to a decrease in diabetes-related mortality. Despite these developments, we have seen an increase in diabetes cases, which has further necessitated for more innovative methods of diabetes management. The subcutaneous administration of insulin remains the mainstay therapy for type 1 diabetes mellitus. However, despite the availability of insulin analogues with improved pharmacokinetics, challenges with the conventional administration exists. The challenges associated with insulin injections include hypoglycaemic episodes, needle phobia, and injection-site inflammation which all have been reported to reduce patient compliance. Ongoing research on diabetes management strives to develop therapies that provide improved glycaemic control with minimal side effects. It is, in part, for these reasons that we have seen an increase in the search and development of alternative insulin delivery systems that are envisaged to circumvent the shortfalls associated with the conventional administration route. In the last century, several alternative drug delivery systems such as oral, pulmonary, buccal, nasal and transdermal have been explored. These efforts have not been without victory, as we have seen the emergence of pulmonary (Exubera and Afrezza) and buccal insulin delivery systems licenced for therapeutic use. Despite the success seen in these two systems, their marketability and popularity have been severely compromised due to reported safety concerns. Although oral insulin delivery has always shown promise in the past decades, however it was only limited to preclinical trials. The main challenge associated this with delivery route is poor bioavaialabiltiy which necessitates high insulin concentration to be administered. Recent developments have however seen oral insulin reaching phase 3 clinical trials. It is believed that patients would welcome oral insulin as their preference is often observed for oral antidiabetics over injected ones. In the last decade, transdermal insulin has also gained interest, where delivery of insulin with concomitant reducation in blood glucose concentration have been demonstrated in vivo. However, at present, there are no clinical studies that have reported the efficacy of transdermal insulin administration With technological advancement, there is a potential to develop yet another insulin delivery system which would likely enter the markets. Although these novel delivery systems are welcome, however, emerging competing products should be welcome and appreciated
... Kombinasi insulin novorapid dengan levemir dan novorapid dengan lantus memberikan onset dan durasi kerja yang sama yakni onset kerja yang cepat dengan durasi kerja yang lebih panjang sehingga lebih dapat meniru profil insulin normal tubuh (Kartika, Lestari and Swastini, 2013). Apabila dibandingkan levemir (insulin detemir) memiliki keuntungan mengurangi risiko hipoglikemia berat dan nokturnal, dibandingkan dengan lantus (insulin glargine) selain itu kenaikan berat badan rata-rata lebih rendah dengan kelompok detemir, yaitu 2,8 kg berbanding 3,8 kg dari pada kelompok glargine (Poon and King, 2010 Persentase jumlah subjek berdasarkan efek samping pada pasien DM tipe 2 rawat jalan di RS X di Kota Denpasar dapat dilihat pada tabel 7. Jumlah pasien DM tipe 2 yang mengalami keluhan berupa pusing sebesar 38,5%, pasien dengan keluhan lemas sebesar 32,3%, pasien dengan keluhan berdebar sebesar 12,4%, pasien dengan keluhan gemetar dan hipoglikemia masing masing sebesar 6,1%, serta pasien dengan keluhan berkeringat sebesar 4,6%. Keluhan yang dirasakan oleh pasien dapat disebabkan oleh timbulnya gejala serta tanda dari hipoglikemia. ...
Diabetes Melitus (DM) merupakan salah satu penyakit metabolik yang meningkat secara signifikan setiap tahun di Indonesia. Banyaknya kasus DM di Indonesia serta penggunaan obat anti diabetes yang mengalami peningkatan dapat berpengaruh pada prevalensi terjadinya efek samping. Penelitian ini bertujuan untuk mengetahui efek samping pemberian kombinasi insulin pada pasien DM tipe 2 rawat jalan di salah satu Rumah Sakit di Denpasar. Penelitian ini merupakan jenis penelitian deskriptif dengan desain cross sectional secara retrospektif pada pasien DM tipe 2 yang menjalani rawat jalan di salah satu Rumah Sakit di Denpasar. Pengambilan data dilakukan dengan penelusuran data rekam medik. Jumlah subjek yang diperoleh dalam penelitian ini adalah 65 orang yang memenuhi kriteria inklusi. Hasil penelitian menujukkan bahwa jumlah laki-laki (58,5%) lebih banyak menderita DM tipe 2 dibandingkan perempuan (41,5%). Usia terbanyak yang menderita DM tipe 2, yaitu pada rentang 55-65 tahun (40%). Persentase tertinggi penderita DM tipe 2 pada tingkat pendidikan menengah (SMA) (38,5%). Efek samping yang diperoleh pada pemberian kombinasi insulin pada pasien DM tipe 2 di salah satu Rumah Sakit di Denpasar yaitu pusing (38,5%), lemas (32,3%), berdebar (12,4%), berkeringat (4,6%), gemetar dan hipoglikemia masing-masing (6,15%). Dari data tersebut dapat disimpulkan bahwa keluhan yang dialami disebabkan oleh timbulnya gejala serta tanda dari adanya efek samping penggunaan insulin yaitu hipoglikemia.
... Both insulin detemir (detemir) and insulin glargine (glargine) are long-acting insulin analogues, administered subcutaneously via injection, with a duration of action of up to, or over, 24 h depending on the product and dose [4,5]. Both insulins are a pharmacological advance compared to human insulins, but differ in their pharmacokinetic/pharmacodynamic profiles, resulting in differing propensity for causing weight gain, hypoglycaemia and periods of hyperglycaemia or variability in blood glucose levels [6,7]. As these factors may all contribute to cardiovascular risk, it is possible that different basal insulins may affect prognosis differently. ...
IntroductionUncontrolled type 2 diabetes (T2D) is associated with an increased risk of micro- and macrovascular complications and mortality. The impact of basal insulins on the risks of mortality and cardiovascular mortality in people with T2D has not been thoroughly investigated in real-world settings. The aim of the present real-word study was to investigate differences in mortality among insulin-naïve people with T2D who initiated insulin detemir (detemir) and insulin glargine (glargine).Methods
We assessed all-cause and cardiovascular mortality in people with T2D, aged ≥ 40 years and insulin-naïve at treatment initiation. People were identified from the United Kingdom Clinical Practice Research Datalink GOLD national database (2004–2019). Database information included prescribed medications, demographic and clinical variables and mortality. Cause of death was obtained from the Office for National Statistics (ONS). For mortality, 24 clinically relevant confounders were considered and adjusted for using Cox regression analyses.ResultsThe total cohort included 12,847 people with T2D, including 3031 who commenced detemir and 9816 who commenced glargine. Median age was 66.8 years and median diabetes duration was 7.6 years. From the total cohort, 3231 deaths occurred during follow-up and 6897 people were eligible for linkage to the ONS for cardiovascular mortality data (528 cardiovascular deaths). The adjusted hazard ratio (HR) (95% confidence interval [CI]) was 0.86 (0.79; 0.95) for all-cause mortality and 0.83 (0.67; 1.03) for cardiovascular mortality, in favour of detemir versus glargine. These associations were more pronounced among people with obesity (body mass index ≥ 30 kg/m2), with HRs (95% CI) of 0.79 (0.69; 0.91) and 0.69 (0.50; 0.96) for all-cause and cardiovascular mortality, respectively.Conclusion
In this real-world observational study, there was an association between all-cause mortality and basal insulin choice in insulin-naïve people with T2D; the mortality risk was lower with detemir versus glargine after adjustment for potential confounders.
... The underlying pathophysiology of type 1 diabetes mellitus (T1D) results in absolute insulinopenia 1,2 and a tendency towards ketosis. 3 As such, insulin analogues (including the animal insulins) have been the mainstay of therapy in T1D for most of the past 90 years. Previous studies have demonstrated that intensified insulin therapy causes weight gain, increased insulin doses, and an increased frequency of hypoglycemia. ...
... 27 This could be due to insulin glargine's molecular structure and pharmacokinetic properties, where subcutaneous micro-precipitates are formed that dissolve slowly, thus prolonging its duration of action upon injection into neutral pH subcutaneous tissues reducing the risk of hypoglycemia and its attendant food ingestion. 3 On the contrary, a study by Rosenstock et al., 28 described a 52 week multinational, randomized, open label, parallel group study in which there were modest reductions in weight gain among patients who received insulin detemir as compared to those who received insulin glargine in patients with type 2 diabetes. 28 Further research needs to be done to provide more evidence regarding the mechanisms of differences in body composition following treatment with different long acting insulins, as well as their effects on hunger and satiety. ...
Background: Insulin detemir is long-acting insulin analog that is weight-neutral compared with other long-acting insulins in patients with type 1 diabetes. One mechanism for this may be an effect of insulin detemir to enhance satiety. We hypothesized that type 1 diabetes patients on insulin detemir will eat fewer calories when presented with a standardized buffet meal following a 24-hour fast as compared to those on insulin glargine. Methods: Ten subjects with C-peptide negative type 1 diabetes participated in a randomized, double-blind crossover study in which they received equivalent doses of either insulin detemir or insulin glargine twice daily for at least 3 weeks. They were subsequently admitted to the UNM Clinical Research Unit for a 24-hour fast, after which they were allowed to eat to satiety from a standardized buffet. Caloric consumption, hunger score and body compositions were measured. Leptin, Ghrelin and Peptide YY were assessed at baseline, after 24-hour fast, and after ingestion of the meal. Results: Subjects were aged 35±11 years, had diabetes for 18±11 years, had A1c levels of 8±1% and BMI of 30±8 kg/m2. Short acting insulin doses were higher for subjects receiving insulin detemir versus insulin glargine (p<0.001). Hunger scores, total energy ingested following the 24-hour fast, and Resting Energy Expenditure did not significant differ between the two study conditions. Conclusion: The weight-neutrality of insulin detemir in type 1 diabetes is not attributable to reduced caloric intake following a fast, or to serum satiety factors.
