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Insulin analogues

Insulin analogues

Inshlin Insulin analogues to Insulin analogues hide. Kurtzhals P. Issue Section:. Khedkar ALebovitz HFleming Aet al. Insulin stimulates the liver to store glucose in the form of glycogen.

George Grunberger; Analogjes Analogs—Are They Worth It? Diabetes Analoguess 1 June ; 37 6 : — The availability of insulin analogs has offered insulin replacement strategies that are analogufs to more closely mimic normal human physiology. Analogkes, there are a considerable number of reports demonstrating that prandial insulin analogs lispro, aspart, Insulin analogues Insylin pharmacokinetic Insuulin pharmacodynamic profiles closer to normal, with resulting faster onset and offset of insulin effect when aanlogues with regular human insulin.

In addition, basal insulin analogs glargine, detemir have been Active recovery techniques to offer analogue duration of action, Insuiln variability, more predictability, less hypoglycemia especially nocturnal Nitric oxide and erectile dysfunction, and a favorable effect on weight.

However, analoguess argument analogkes use anaalogues analog insulins as compared with use of regular or NPH insulin is one that states that the effectiveness and risk of hypoglycemia are analofues only two valid Ineulin outcomes Innsulin should be used Obesity and community support compare Insuiln analog and human insulins.

Thus, there remains a debate in some circles that analog insulins Isulin no more analoguues than human insulins, Insulin analogues at a much higher financial cost. To provide an in-depth understanding of both sides of the argument, we provide a discussion of this analgues as part of this two-part point-counterpoint narrative.

In the nIsulin narrative, Dr. Insulin analogues provides analkgues argument and defends Insulin analogues opinion that outside of a few exceptions, analog insulins anlaogues no clinical benefit compared with human insulins but cost anwlogues more.

In the point narrative presented here, Inaulin. These insulin preparations started becoming available on the U. market Insulin analogues the approval of lispro in Sports nutrition bars for athletes Hundreds of Insilin trials and postmarketing studies have been conducted and representative results for each analog are listed in references 1 — Specifically, prandial insulin analogs lispro, aspart, anaoogues have pharmacokinetic and pharmacodynamic anaalogues closer to normal; i.

Basal analotues analogs aanlogues, detemir offer anxlogues duration of action, less Insulin analogues, more predictability, less hypoglycemia especially nocturnaland, in case of detemir, more Detoxification through sauna therapy weight profile 4 — Balanced plate for athletic success Thus, fewer injections are necessary to achieve their purpose which is anlogues of glucose production Insulin analogues meals and overnight.

The clinical advantages of analog insulin use are apparent from results of Insullin numerous analoguess. As the registration trials were designed to Inslin equivalent Insulin analogues lowering in the subjects treated with human versus anlaogues analog insulin, Insklin advantages could be summarized as decreased incidence of hypoglycemia and weight gain, the two major Insulih both patients and physicians xnalogues when intensifying diabetes therapy.

The Cochrane review of data abalogues rapid-acting analogs concluded there was likewise a analotues reduction Binge eating disorder severe hypoglycemic reactions The analpgues advantage of insulin detemir versus NPH has been analoguea in every study, in both type 1 and Dance nutrition for endurance 2 diabetes range 1—2 kg over 16—week duration of studiesexemplified Insklin Raslová et Fat burn abs. Analog insulins have several Insulin analogues advantages over human insulins: Their Insilin has been shown to Indulin treatment adherence and treatment satisfaction Insu,in to fewer injections, flexibility of timing of basal analogs, less fear of dose adjustments, mealtime administration of prandial analogs, as well as user-friendly injection devices.

In spite of analogue opinion sthere is also evidence Holistic cancer prevention methods a pharmacoeconomic advantage with insulin anlogues mainly due to reduction in analotues claims and analoguues inpatient hospital costs.

For a patient on an intensive insulin injection regimen, these are the choices in Insulin analogues inject a basal insulin once a day regardless of Insulin analogues time of the day Inaulin inject prandial insulin just analoyues or even immediately after each meal based on the carbohydrate or calorie content of the meal or 2 inject an intermediate-acting insulin at least twice a day and regular insulin 30—45 min before a meal, while constantly fearing late postprandial and nocturnal hypoglycemia and having to eat a bedtime snack to prevent the latter not exactly physiologic and not helpful with the ongoing obesity epidemic.

One would think this would represent an easy choice. How does one truly evaluate the question? We are dealing with the cost to individuals, their families, employers, insurance companies, and society as a whole over a lifetime as one can safely assume most of these patients will need insulin for the rest of their lives.

Thus, one has to focus not on the grossly inflated retail cost of the next insulin prescription in the local pharmacy, but on the big picture.

That picture, of necessity, needs to include the overall cost of medical care, rate of absenteeism, loss of productivity, as well as adherence, treatment satisfaction, and satisfaction with lifestyle imposed on an individual by demands of this complex disease.

Clearly, patients are paying for the gamesmanship between the government regulatory bodies and big pharma politics. Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen IQWiG considered only seven small randomized controlled trials In five of the studies, lispro insulin was compared with human insulin; in the other two, the comparison was with glulisine insulin.

In all cases, short-acting insulin was added to basal long-acting insulin. All the clinical trials that met the inclusion criteria were over a short period 5. The analysis was limited to assessments of hypoglycemic rate and stability of the blood glucose level.

There were only limited measurements of illness-related quality of life and none of patient satisfaction. Not surprisingly, no differences were found. Manufacturers reacted by offering large rebates to the sickness funds, while keeping the retail prices above the threshold. When G-BA issued an edict to similarly exclude insulin analogs from treatment of type 1 diabetes, a worldwide storm of protest ensued in This decision was eventually withdrawn but the situation demonstrated the difficulty in objectively assessing the cost of the analog versus human insulin therapy.

When more educated attempts were made to assess these costs, a different picture emerged. Palmer et al. Brixner et al. In their retrospective cost analysis using computerized databases from the Veterans Health Administration, Medicaid, Medi-Cal, and a variety of U.

health plans and regional U. managed care plansthe cost-effectiveness of analogs was shown, predominantly due to the lower costs of treating hypoglycemia and in several instances to lower inpatient costs.

Meece 20 similarly concluded a pharmacoeconomic advantage of insulin analogs due to improved glycemic control, improved adherence to therapy less fear of hypoglycemia and weight gainand lower rates of hypoglycemia.

The complexity of dealing with overall cost issues was shown in an analysis that found only 6 studies out of publications between and offered data on both the acquisition costs of glargine versus NPH in patients with type 1 diabetes but also on clinical effects, diabetes complications, quality of life, fear of hypoglycemia, etc.

The slightly higher cost of the analog insulin was more than offset by smaller use of test strips. Detemir-based regimens cost more, mainly due to higher cost of the bolus component. That survey was based on the IMS LRx database a longitudinal history of de-identified but unique patients collected by IMS Health worldwide of virtually all dispensed prescriptions; it accesses nationwide pharmacy data centers processing prescription data ofpatients between and With the reported reduction of anywhere between 14 and 43 such episodes per patients per year among those on lispro versus regular insulin, Reviriego et al.

In a different take on the issue, Chen et al. Due to fewer hospitalizations for lispro users and thus less expensive nondiabetes-related medical costs, total costs were similar for the human and analog insulin users. There are few studies of adherence, but in two examples the lower perceived fear of nocturnal hypoglycemia was less with glargine than with NPH insulin and patients were more willing to adjust insulin to titrate their fasting glucose levels 27 Treatment satisfaction was increased while being treated with insulin analogs among teens and adults on lispro who found coping with diabetes less difficult than on regular insulin.

Less negative effect on quality of life and fewer worries about diabetes were reported with lispro than with regular insulin 29 — The same observation was reported among Japanese children and adolescents with type 1 diabetes where rapid-acting analog therapy was associated with more flexibility and improved quality of life Health-related quality-of-life scores increased significantly in patients administering any insulin analog regimen whether starting or switching to in a week prospective study among 66, patients across India Duality of Interest.

No other potential conflicts of interest relevant to this article were reported. See accompanying article, p. Sign In or Create an Account. Search Dropdown Menu. header search search input Search input auto suggest.

filter your search All Content All Journals Diabetes Care. Advanced Search. User Tools Dropdown. Sign In. Skip Nav Destination Close navigation menu Article navigation. Volume 37, Issue 6. Previous Article Next Article.

Article Information. Article Navigation. Point-Counterpoint May 10 Insulin Analogs—Are They Worth It? George Grunberger George Grunberger.

Grunberger Diabetes Institute, Bloomfield Hills, MI; Internal Medicine and Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI; and Oakland University William Beaumont School of Medicine, Rochester, MI.

Corresponding author: George Grunberger, grunberger comcast. This Site. Google Scholar. Diabetes Care ;37 6 — Connected Content.

A companion article has been published: Insulin Analogs—Is There a Compelling Case to Use Them? Get Permissions. toolbar search Search Dropdown Menu. toolbar search search input Search input auto suggest. Cefalu Editor in Chief, Diabetes Care.

Search ADS. Time-action profile of the long-acting insulin analog insulin glargine HOE in comparison with those of NPH insulin and placebo. A double-blind, randomized, dose-response study investigating the pharmacodynamic and pharmacokinetic properties of the long-acting insulin analog detemir.

Lower within-subject variability of insulin detemir in comparison to NPH insulin and insulin glargine in people with type 1 diabetes.

Long-acting insulin analogues versus NPH insulin human isophane insulin for type 2 diabetes mellitus. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients.

Insulin detemir and insulin aspart: a promising basal-bolus regimen for type 2 diabetes. A week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes.

Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on basal-bolus regimen with pre meal insulin aspart. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus.

Health Action International.

: Insulin analogues

In this section, you will find information about: Cochrane Abstract Background. Here are some do's and don'ts to pay attention to as you learn how to effectively manage your diabetes with…. Moving toward the ideal insulin for insulin pumps. PubMed Google Scholar Fonte, P. Diabetes Metab Syndr Obes. For example, potential organospecific insulin analogues may circumvent a current feature of SQ delivery, relative overinsulinization of the periphery and underinsulinization of the liver No studies were found that compared regular insulin with short-acting analogues in terms of their effects on the long-term complications of diabetes.
Human Insulin vs. Insulin Analogs, Pros, Cons, More

KU Leuven has received research support for C. from Abbott, Eli Lilly and Company, Intrexon, Merck Sharp and Dohme Ltd. serves or has served on the speakers bureau for AstraZeneca, Boehringer Ingelheim, Eli Lilly and Company, Merck Sharp and Dohme, Novartis, Novo Nordisk and Sanofi.

has served on the advisory panel for AstraZeneca, Lilly, Merck Sharp and Dohme Ltd. has served on the speakers bureau for AstraZeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novartis, Novo Nordisk and Sanofi.

has served on the advisory panel for AstraZeneca, Merck Sharp and Dohme Ltd. and Novo Nordisk. has served on the speakers bureau for AstraZeneca, Bristol-Meyers Squibb, Boehringer Ingelheim, Janssen Pharmaceuticals, Lilly, Novartis and Novo Nordisk.

KU Leuven has received research grants for K. from AstraZeneca, Janssen Pharmaceuticals, Merck Sharp and Dohme Ltd. Reprints and permissions.

Insulin analogues in type 1 diabetes mellitus: getting better all the time. Nat Rev Endocrinol 13 , — Download citation. Published : 21 April Issue Date : July Anyone you share the following link with will be able to read this content:.

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Skip to main content Thank you for visiting nature. nature nature reviews endocrinology review articles article. Subjects Drug development Drug therapy Type 1 diabetes. Key Points Established rapid-acting and long-acting insulin analogues have enabled more patients with type 1 diabetes mellitus to reach better glucose targets, with lower hypoglycaemia rates and a better quality of life than was possible with short-acting and long-acting human insulin In patients who are prone to severe hypoglycaemia, using a full analogue regimen is rapidly cost saving and should therefore be the standard of care in all patients with type 1 diabetes mellitus The new long-acting insulin analogues insulin glargine U and insulin degludec have shown increased stability, which translates to a reduced risk of nocturnal hypoglycaemia and increased flexibility in timing of administration Faster and shorter acting insulin analogues are needed for use in insulin pumps and future 'artificial pancreas' systems; fast-acting insulin aspart, a new formulation of aspart, is well advanced in clinical development.

Abstract The treatment of type 1 diabetes mellitus consists of external replacement of the functions of β cells in an attempt to achieve blood levels of glucose as close to the normal range as possible. Access through your institution. Buy or subscribe. Change institution.

Learn more. Figure 1: Different determinants of absorption and duration of action of human and analogue insulins. Figure 2: Pharmacokinetic action profiles of rapid-acting insulins.

Figure 3: Pharmacodynamic action profiles of long-acting insulins. Figure 4: Amino acid structure of short-acting and long-acting insulins. References Atkinson, M. PubMed Google Scholar Donner, T. CAS PubMed Google Scholar Home, P. CAS PubMed Google Scholar de la Pena, A. CAS PubMed PubMed Central Google Scholar Heise, T.

CAS PubMed Google Scholar Heise, T. CAS PubMed Google Scholar Lucidi, P. CAS PubMed PubMed Central Google Scholar Brange, J. CAS PubMed Google Scholar Heinemann, L. CAS PubMed Google Scholar ter Braak, E.

CAS PubMed Google Scholar Tamas, G. CAS PubMed Google Scholar Valle, D. CAS PubMed Google Scholar Lindholm, A. CAS PubMed Google Scholar Plank, J. PubMed Google Scholar Homko, C. CAS PubMed Google Scholar Bartolo, P. PubMed Google Scholar Bode, B. CAS PubMed Google Scholar Dreyer, M.

CAS PubMed Google Scholar Raskin, P. CAS PubMed Google Scholar Becker, R. CAS PubMed Google Scholar Kerr, D. PubMed PubMed Central Google Scholar Heise, T.

CAS PubMed Google Scholar Arnolds, S. CAS PubMed Google Scholar Luzio, S. CAS PubMed Google Scholar Bolli, G. CAS PubMed PubMed Central Google Scholar Garg, S. PubMed Google Scholar Fullerton, B. Google Scholar Russell-Jones, D. CAS PubMed Google Scholar Shafie, A.

PubMed Google Scholar Pedersen-Bjergaard, U. CAS PubMed Google Scholar American Diabetes Association. PubMed Google Scholar Mathiesen, E. CAS PubMed Google Scholar Pozzilli, P. PubMed PubMed Central Google Scholar Brunner, G.

CAS PubMed Google Scholar Porcellati, F. PubMed Google Scholar Rosenstock, J. CAS PubMed Google Scholar Albright, E.

PubMed Google Scholar Ratner, R. CAS PubMed Google Scholar Dornhorst, A. CAS PubMed Google Scholar Hermansen, K. CAS PubMed Google Scholar [No authors listed. CAS PubMed Google Scholar Hilgenfeld, R.

Google Scholar Klein, O. CAS PubMed Google Scholar Ashwell, S. CAS PubMed Google Scholar Havelund, S. CAS PubMed Google Scholar Pieber, T. Google Scholar Pieber, T. CAS PubMed Google Scholar Heller, S.

CAS PubMed Google Scholar Koehler, G. CAS PubMed Google Scholar Danne, T. CAS PubMed Google Scholar De Leeuw, I. CAS PubMed Google Scholar Tricco, A. PubMed PubMed Central Google Scholar Frier, B. CAS PubMed Google Scholar Rosenstock, J. CAS PubMed PubMed Central Google Scholar Hordern, S. CAS PubMed Google Scholar Herring, R.

CAS PubMed Google Scholar Pollex, E. CAS PubMed Google Scholar Blumer, I. CAS PubMed Google Scholar Mathiesen, E. CAS PubMed PubMed Central Google Scholar Tan, C. PubMed Google Scholar Thalange, N. CAS PubMed Google Scholar National Institute for Health and Care Excellence. CAS PubMed Google Scholar Pedersen-Bjergaard, U.

CAS PubMed Google Scholar Taki, K. CAS PubMed Google Scholar Maia, F. CAS PubMed Google Scholar European Medicines Agency. CAS PubMed Google Scholar Linnebjerg, H. CAS PubMed PubMed Central Google Scholar Ilag, L. CAS PubMed PubMed Central Google Scholar Hadjiyianni, I.

CAS PubMed PubMed Central Google Scholar Linnebjerg, H. PubMed PubMed Central Google Scholar Sindelka, G. CAS PubMed PubMed Central Google Scholar Becker, R. CAS PubMed Google Scholar Bergenstal, R. CAS PubMed Google Scholar Matsuhisa, M. CAS PubMed Google Scholar Mathieu, C.

CAS PubMed PubMed Central Google Scholar Ratner, R. PubMed Google Scholar Heller, S. CAS PubMed Google Scholar Lane, W. CAS PubMed Google Scholar Korsatko, S. CAS PubMed Google Scholar Jonassen, I.

CAS PubMed PubMed Central Google Scholar Haahr, H. CAS PubMed PubMed Central Google Scholar Thalange, N. CAS PubMed PubMed Central Google Scholar Evans, M. CAS PubMed Google Scholar Sinha, V.

CAS PubMed Google Scholar Caparrotta, T. CAS PubMed Google Scholar Buse, J. CAS PubMed Google Scholar Garg, S. Google Scholar Bergenstal, R.

CAS PubMed PubMed Central Google Scholar Cusi, K. CAS PubMed Google Scholar Munoz-Garach, A. CAS PubMed Google Scholar Atkin, S. CAS PubMed PubMed Central Google Scholar Hirsch, I. CAS PubMed PubMed Central Google Scholar de la Pena, A. CAS PubMed Google Scholar Muchmore, D.

PubMed PubMed Central Google Scholar Muchmore, D. PubMed PubMed Central Google Scholar Krasner, A. PubMed PubMed Central Google Scholar Pandyarajan, V.

CAS PubMed Google Scholar Fath, M. CAS PubMed Google Scholar Bode, B. CAS PubMed PubMed Central Google Scholar European Medicines Agency. CAS PubMed Google Scholar Zaykov, A. CAS PubMed Google Scholar Wang, Y. CAS PubMed PubMed Central Google Scholar Phillips, N.

PubMed PubMed Central Google Scholar Chou, D. CAS PubMed Google Scholar Baeshen, N. PubMed PubMed Central Google Scholar Santos Cavaiola, T. PubMed Google Scholar Fonte, P. PubMed PubMed Central Google Scholar Download references.

View author publications. Ethics declarations Competing interests C. PowerPoint slides. PowerPoint slide for Fig. Rights and permissions Reprints and permissions. About this article. Cite this article Mathieu, C. Copy to clipboard. This article is cited by Safety and glycemic control with insulin degludec use in clinical practice: results from a 3-year Japanese post-marketing surveillance study Takashi Murata Lise Lotte N.

Husemoen Munehide Matsuhisa Diabetology International Enhanced hexamerization of insulin via assembly pathway rerouting revealed by single particle studies Freja Bohr Søren S. Bohr Nikos S.

Hatzakis Communications Biology Development and Characterization of Guinea Pig Anti-Insulin Polyclonal Antibody Sathiya Varadarajan Arumugam Muruganandam V. Ramesh Kumar Applied Biochemistry and Biotechnology Diagnostik und Therapie des Typ 1 Diabetes mellitus Update Monika Lechleitner Susanne Kaser Martin Clodi Wiener klinische Wochenschrift Diabetes mellitus und Straßenverkehr — ein Positionspapier der Österreichischen Diabetesgesellschaft Update Heidemarie Abrahamian Birgit Salamon Martin Clodi Wiener klinische Wochenschrift Publish with us For Authors For Referees Submit manuscript.

Search Search articles by subject, keyword or author. Show results from All journals This journal. However, the growing number of patients who require very high insulin doses created a market for more concentrated insulin prod­ucts like U or U [24].

The pharmacokinetics of inhaled and injectable insulins are comparable, apart from an appreciably faster absorption of the former, and both show the same intra-individual variability.

The total bioavailability is definitely lower with the inhaled route but is notably increased in smokers. These characteristics can vary according to the inhalation system used. A frequent induced cough, the increase in circulating anti-insulin antibodies, and a potentially higher cost are not really determining obstacles [25].

Expiration of patent protection for recombinant insulins provides the opportunity to introduce biosimilars, onto the market [26]. Since they differ by few amino acids in chain B, production of one biosimilar for all three drug products is not feasible.

However, from clinical data, rapid-acting insulin analogues seem to have similar therapeutic efficacy [26]. Although the majority of patients with diabetes now use biosynthetic human insulin, there are a small number of patients who cannot manage their disease with these biosynthetic human insulins.

They need animal sourced insulin to manage their diabetes and they are concerned about the uninterrupted availability of animal-sourced insulin for the future [27].

Unlike antiretroviral drugs or most other medicines, insulin is a biological product and thus creating a biosimilar is more difficult than creating a copy of a chemical entity [28]. Biosimilars face a more stringent regulatory assessment than generics, including the need for clinical trials, which significantly increases costs and timelines to market entry of biosimilars.

This approval provided the first example of a company other than one of the multinational producers that was able to gain approval in a highly regulated market [28].

PK parameters determine the concentration of drug and metabolites that are achieved in blood, plasma, or other tissues, whereas PD parameters examine how a drug affects the body.

However, the relationship between PK and PD is less direct with insulins that exert pharmacologic effects through binding to cell surface receptors [30].

In patients with diabetes, altered insulin sensitivity can result in altered PD activity for the same PK concentration in different individuals. The most common adverse drug reactions for both groups were sim­ilar and included infection, central nervous system disorders, gastroin­testinal events, hypoglycemia, injection site reactions and musculoskeletal complaints [24].

The major clinical studies on insulin showed that the safety and effectiveness of human biosynthetic insulin and animal-sourced insulin are comparable. In addition, the number and types of adverse reactions reported with both types of insulins were similar.

In fact, adverse reactions such as hypoglycemia low blood glucose , may occur while taking either type of insulin without any major difference [27].

Hypoglycemia can occur regardless of what type of insulin you take and can cause fatigue, sweating, heart palpitations, disturbed behaviour, hunger, loss of consciousness, or in extreme circumstances even death and can occur without recognizable symptoms.

Several types of hypersensitivity reactions to insulin preparations have been described. These reactions may be caused by the insulin itself or by additives within the preparation.

Hypersensitivity reactions to insulin are rare with human insulins and insulin analogues. However, some types of reactions are serious and even life-threatening and may have a significant detrimental impact on the patient's diabetic management [31].

Local reactions may present as erythema , swelling, heat, or subcutaneous nodules [32]. They usually occur within the first two weeks of therapy, then disappear [32]. Immunologic responses to insulin, particularly animal insulin formulations, include the formation of anti-insulin antibodies. An unusual ocular disturbance during the beginning of therapy is bilateral presyopia blurry vision.

Dermatologic reactions to insulin can result in lipohypertrophy or lipoatrophy [32]. Adverse effect reports of malignancies have caused concern regarding the long-term use of these therapies. Recently published studies investigating a possible relationship between insulin analogues, in particular insulin glargine, and the risk of cancer are currently under review of the European Medicines Association EMA [33].

There are no conclusions that can be drawn from the studies about the long-term effects of the interventions on the risk of diabetes-related complications and overall mortality [34]. Diabetes and cardiovascular outcomes are closely linked.

Many studies have implicated insulin resistance and hyperinsulinemia as a major factor for poor cardiovascular outcomes. Additional studies link the anabolic effects of therapeutic insulin to weight gain, along with hypoglycemia, which may further aggravate cardiovascular risk in this population.

Though good glycemic control has been shown to improve microvascular risks in type 1 and type 2 diabetes, what are the known cardiovascular effects of insulin therapy? The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes.

Recent studies have demonstrated that ultra-long-acting insulin analogs like insulin degludec are non-inferior to insulin glargine with regard to cardiovascular outcomes [34]. A randomized crossover study in healthy male subjects revealed a hepato-preferential effect and relatively decreased peripheral action of polyethyleneglicol PEG lispro on glucose homeostasis that might better recreate the physiological actions of endogenous insulin, which is secreted into the portal vein [35].

In the open-label IMAGINE 1 trial, patients receiving PEGlispro reported a statistically significant higher rate of severe hypoglycaemic events; however, in the larger, blinded IMAGINE 3 trial the rate of severe hypoglycaemic events for PEGlispro treatment was numerically lower than for IGlar U, but not statistically significant [36,37].

PEGlispro was associated with less weight gain versus U in patients with type 2 diabetes not previously using insulin IMAGINE-2 , [39] those using basal insulin with mealtime insulin IMAGINE-4 [40] and similar weight gain versus U in patients currently using a basal insulin IMAGINE-5 [38].

Collectively, the trials demonstrated an improved balance between glycaemic control and tolerability for both analogues compared to NPH, regardless of regimen and diabetes type. Established rapid-acting and long-acting insulin analogues have enabled more patients with type 1 diabetes mellitus to reach better glucose targets, with lower hypoglycaemia rates and a better quality of life than was possible with short-acting and long-acting human insulin [41].

Compliance with the insulin therapy is important in preventing the adverse clinical effects of the disease [42]. In human beings the β-cells of pancreatic islets of Lang rhans synthesize insulin from a single-chain precursor of amino acids termed preproinsulin. Insulin was purifi ed and crystallized by Abel within a few years of its discovery.

Sanger established the amino acid sequence of insulin in and it was synthesized in The second-generation basal insulin analogues provide physicians with new treatment options for achieving targeted glycaemic control.

While providing similar efficacy in lowering HbA1c to first-generation insulin analogues, the newer insulin treatment options provide additional clinical benefits, including a more stable, ultra-long duration of action that enables once-daily administration with flexibility in daily injection time, together with a lower risk of hypoglycaemia [45].

The results of another study found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. The certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse [46].

The need of insulin analogues arises from the fact that the human insulin injections have a lag period of around 30 minutes between administration and onset of action.

As a result, regular human insulin is not able to mimic the human physiology. Endogenous insulin, after secretion from the pancreas, enters the portal circulation, after which it reaches the systemic circulation.

Thus, the portal and systemic gradient of insulin is inverted in the case of exogenous insulin. The limitations of the relatively short duration of the clinical development programs to study long-term safety e.

the potential effects of long-term treatment on the initiation or promotion of malignancy. Identification of risk factors for developing malignancy in patients treated with insulin of insulin analogues e.

indication for treatment, age, sex, disease including severity , body mass index BMI , menopausal status, parity, socioeconomic status, prior and during treatment. Biphasic insulin analogues can target both fasting and postprandial hyperglycaemia. A practical and feasible option is to initiate insulin with one or more biphasic preparations at mealtimes.

Individual titration of dose and frequency of daily injections with biphasic insulin preparations has the potential for improving glycaemic control with a high degree of patient acceptance. Drawbacks include a more rigid regimen, a relative lack of flexibility, and a somewhat higher degree of glycaemic variability and hypoglycaemia when compared to multiple daily basal-bolus injections.

Human regular U insulin is efficacious and safe for patients with type 2 diabetes who require a high dosage of insulin to control hyperglycemia.

Evidence concerning the efficacy and safety of glucose-lowering agents for treating pre-existing and new-onset diabetes in kidney transplant recipients is limited [50]. Long diabetes duration, obesity, insulin resistance and female sex indicate a need for further treatment intensification [51].

Older adults are at an increased risk of developing type 2 diabetes mellitus T2DM. Although oral agents i.

Long-acting insulin analogues are the preferred insulin products for older adults with T2DM. Insulin degludec and insulin glargine U are both new generations long-acting insulins [52]. There is a pharmacoeconomic advantage of insulin analogs due to improved glycemic control, improved adherence to therapy less fear of hypoglycemia and weight gain , and lower rates of hypoglycemia [53].

In patients who are prone to severe hypoglycaemia, using a full analogue regimen is rapidly cost saving and should therefore be the standard of care in all patients with type 1 diabetes mellitus [54].

The cost-effectiveness of insulin analogues depends on the type of insulin analogue and whether the patient receiving the treatment has type 1 or type 2 diabetes. With the exception of rapid-acting insulin analogues in type 1 diabetes, routine use of insulin analogues, especially long-acting analogues in type 2 diabetes, is unlikely to represent an efficient use of finite health care resources [55].

Studies of incremental cost-effectiveness ratio per quality adjusted life year gained generally demonstrated that insulin analogues could be cost-effective compared with conventional human insulin. The drug costs were higher in the insulin analogues group than the conventional human insulin, but this was partly offset by reduced complication costs [56].

Compared with human insulin, insulin detemir was likely to be cost-effective for type 1 diabetes mellitus based on the willingness to pay threshold in Sweden SEK , per QALY gained , U. The benefit of insulin aspart compared with human insulin in adult patients is unclear due to a lack of data or poor-quality data; an additional benefit is therefore not proven.

In patients without a higher than usual risk of hypoglycaemia, overall, the studies show similar results between insulin lispro and human insulin. On the basis of the data available, it is unclear whether insulin lispro has an additional benefit in patients with an increased risk of serious hypoglycaemic events.

Due to a lack of data, there is no evidence of an additional benefit of insulin glulisine versus human insulin. There is an indication of an additional benefit of insulin lispro versus insulin glulisine.

This indication is solely based on a lower rate of serious nocturnal hypoglycaemic events under insulin lispro observed in one study. Exenatide, the gliptins and detemir were all clinically effective. The long-acting insulin analogues glargine and detemir appeared to have only slight clinical advantages over NPH but had much higher costs and did not appear to be cost-effective as first-line insulins for type 2 diabetes.

Neither did exenatide appear to be cost-effective compared with NPH but, when used as third drug after failure of dual oral combination therapy, exenatide appeared cost-effective relative to glargine in this analysis [61].

Current evidence indicates that insulin analogues are cost effective for T1DM; however, evidence for their use in T2DM is not convincing. Additional evidence regarding compliance and efficacy is required to support the broader use of long-acting and biphasic insulin analogues in T2DM.

The value of insulin analogues depends strongly on reductions in hypoglycaemia event rates and its efficacy in lowering glycated haemoglobin HbA 1c [62]. One trial compared Lispro insulin with regular insulin and provided very low-quality evidence for the outcomes.

There were seven episodes of pre-eclampsia in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups. There were five caesarean sections in the Lispro group and nine in the regular insulin group, with no clear difference between the two groups.

There were no cases of fetal anomaly in the Lispro group and one in the regular insulin group, with no clear difference between the groups. Macrosomia, perinatal deaths, episodes of birth trauma including shoulder dystocia, nerve palsy, and fracture, and thecomposite outcome measure of neonatal morbidity were not reported [63].

The use of lispro was associated with lower rates of neonatal jaundice and severe maternal hypoglycemia than regular insulin. Lispro use was also associated with higher birth weight and an increased incidence of large for gestational age births compared with regular insulin.

Rates of cesarean section and macrosomia were similar in pregnant women treated with aspart and regular insulin. Birth weights and rates of severe maternal hypoglycemia, respiratory dysfunction syndrome, and neonatal intensive care unit admission were similar after pregnant women were treated with glargine and NPH insulin [64].

In a retrospective population-based cohort study, the authors found no increase in the risk of congenital anomalies in fetuses exposed to insulin analogues in the first trimester compared with those exposed to human insulin.

Furthermore, a significantly lower risk of congenital heart defects was observed with exposure to insulin analogues [65].

Furthermore, the issues around immunogenicity for biosimilar insulins are becoming clearer. The release of data on the Lilly insulin glargine approval in the EU shows the complexity of biosimilar approval and is for the more general understanding of such assessments for the future [66].

Increasing competition in insulin manufacture could lead to large price reductions, potentially enabling the scale-up of access to treatment [67]. It is important to note that FDA pregnancy categories are not used after [68]. Main article: Insulin glulisine.

Main article: Insulin detemir. Main article: Insulin degludec. Main article: Insulin glargine. Main article: NPH insulin. Further information: Comparative effectiveness research. American Family Physician. PMID Archived from the original on Retrieved Food and Drug Administration FDA Press release.

Retrieved 28 July European Medicines Agency EMA. Diabetes Technol Ther. Oct;10 5 Pharm Res. Diabetes Obes. Nature Aug 21; Arch Physiol Biochem. N Engl J Med. Curr Diab Rep. The Cochrane Database of Systematic Reviews. doi : ISSN X.

PMC Short-acting insulin analogues for diabetes mellitus: meta-analysis of clinical outcomes and assessment of cost-effectiveness Report. Canadian Agency for Drugs and Technologies in Health CADTH.

Technology Report no Archived from the original on 4 November Retrieved 10 September Oral diabetes medication , insulins and insulin analogs , and other drugs used in diabetes A Insulin aspart Insulin glulisine Insulin lispro. Regular insulin. Cagrilintide § Pramlintide. Mitiglinide Nateglinide Repaglinide.

Alogliptin Anagliptin Evogliptin Garvagliptin Gemigliptin Gosogliptin Linagliptin Melogliptin Omarigliptin Saxagliptin Sitagliptin Teneligliptin Trelagliptin Vildagliptin.

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Take a look at the Recent articles For example, potential organospecific insulin analogues may circumvent a current feature of SQ delivery, relative overinsulinization of the periphery and underinsulinization of the liver Randomized clinical trial comparing basal insulin peglispro and insulin glargine in patients with type 2 diabetes previously treated with basal insulin: IMAGINE 5. The ORIGIN trial suggests at least a neutral effect of the basal insulin glargine on cardiovascular outcomes. Insulin fibrillation and protein design: topological resistance of single-chain analogs to thermal degradation with application to a pump reservoir. But the lack of study blinding does increase the risk of bias in these studies.
Insulin Analogs: What Are the Clinical Implications of Structural Differences? Editorial Information Editor-in-Chief Katsunori Nonogaki Tohoku University, Japan Article Type Review Article Publication history Received date: August 16, Accepted date: August 26, Published date: August 29, Copyright © Guney Z. Structure of insulin in 4-zinc insulin. Glycaemic control in type 1 diabetic patients using optimised insulin aspart or human insulin in a randomised multinational study. Figure 4. Chaykin LB. Because such coadministration exploits a physiologic switch in the liver Fig.
Insulin analogues


Insulin Pharm Mnemonic (2/5): Rapid, Intermediate, Long-acting: Diabetes blood sugar management

Insulin analogues -

The bound insulin is shown as a ribbon, A chain in green and B chain in blue. C, Model of His B25 and His B16 at variant interface.

D, WT insulin residues Phe B25 and Tyr B16 at receptor interface. Side chains are shown as sticks and methyl groups as spheres at one-third effective van der Waals radius. Images were generated using PYMOL. Foreshadowing next-generation basal analogues, insulin IDeg was developed as a true hour peakless formulation see Table 1B.

This des -B30 analogue is formulated at neutral pH as a novel dimer of T 3 R f 3 zinc hexamers linked by an acyl modification of Lys B29 hexadecanedioic acid with a γ-L-glutamyl spacer; see Figs. Remarkably, the analogue undergoes multihexamer SQ assembly to achieve protracted action see Fig.

The B29 modification also mediates albumin binding more effectively than the shorter acyl chain of IDet IDeg and IGlar are both known for their near-peakless PD profiles. Open-label studies have provided evidence of reduced day-to-day variability and risks of severe hypoglycemia among patients using IDeg than among those who received IGlar The efficacy and convenience of once-a-week GLP-1 agonists motivated the design of analogous insulin products.

Insulin icodec exhibits time to maximum concentration of 16 hours with a half-life of hours 90 , Its ultralong PK profile is enabled by i strengthening HSA binding and ii weakening its binding to the IR, each delaying clearance. HSA binding was strengthened by further lengthening the dicarboxylic adduct at Lys B29 C diacid linked through a 2xOEG-γ Glu linker; see Fig.

Because intercurrent illnesses can unexpectedly interrupt food consumption, the safety of once-a-week insulin products if not glucose responsive will require careful assessment with respect to hypoglycemia.

Ultrabasal formulations can in principle be engineered by fusion of insulin to other moieties For example, polyethylene-glycol PEG can enhance overall hydrodynamic radii, thus delaying renal clearance to prolong duration of action.

This principle was exemplified by insulin peglispro LY , discontinued after phase 3 trials because of risk of hepatotoxicity An alternative approach involves fusion of proteins or peptides to the immunoglobulin F c domain and provides a general method to prolong plasma half-life , , due in part to Fc-receptor—mediated recycling ; such binding is pH dependent.

Whereas in the bloodstream at neutral pH such binding is weak, within an acidic endocytic vesicle binding is strong, protecting the tethered fusion peptide from degradation and enabling its recycling. Investigational application to single-chain insulin SCI analogues has been described see Fig.

Alternative embodiments of this strategy include LAPS Insulin; see Fig. Abbreviations: IgG, immunoglobulin G; PEG, polyethylene-glycol; SCI, single-chain insulin; T2D, type 2 diabetes.

Premixed insulin formulations have long provided biphasic PD profiles as a simplified regimen , Such products, which provide both mealtime and basal glycemic control, are of widespread use in the developing world , and as a mode of T2D intensification in the developed world It is possible that the latter product may be further modified to contain active excipients as in Fiasp to promote ultrarapid absorption of the aspart component , A further frontier may exploit ultrastable biphasic SCI analogues to simplify distribution, storage, and use Current guidelines recommend avoidance of both hypoglycemia and weight gain as important therapeutic considerations when individualizing regimens Combination therapy with insulin and a glucagon-like peptide-1 receptor agonist GLP-1RA shows promise in T2D by significantly reducing HbA 1c , glycemic variability and body mass in patients otherwise not well controlled 89 , Relative to short-acting GLP-1RAs, these agents exhibit increased effectiveness on overnight and fasting plasma glucose concentration associated with lower HbA1 c.

In a recent meta-analysis use of long-acting GLP-1RAs rather than short-acting agonists in combination therapy with basal insulin therapy demonstrated therapeutic advantages, including lower HbA 1c , fasting plasma glucose concentration, and body mass The pending introduction of once-a-week basal insulin analogue formulations 91 , is likely to further encourage studies of its synchronous coadministration or FRC combination with once-a-week GLP-1RAs.

Combination of insulin analogues with other hormones may also provide clinical benefit. In T1D a favored approach is coadministration of insulin analogues and pramlintide an amylin analogue , which resembles their endogenous cosecretion from β cells. Like coadministered GLP-1, amylin can enhance glycemic control, mitigate weight gain, and reduce the frequency of hypoglycemia , Physiological mechanisms include reduced food intake increased satiety , slower gastric emptying, and inhibition of glucagon secretion Fig.

Such use of pramlintide has been hampered by its formulation incompatibility with insulin, leading to the need for separate injections.

Circumventing this barrier in an investigational dual-hormone pump led to increased TiR with reduced hypoglycemic events A novel polymer-stabilized coformulation of insulin and pramlintide is under investigation Novel frontiers: bi-hormonal delivery and switchable insulin analogues.

A, left, coadministration of basal insulins with glucagon-like peptide-1 GLP-1 agonists at fixed-ratio combinations see Table 1 footnote : right, coadministration of insulin and pramlintide. Fructose-sensor N- fPBA A1 is attached to Gly A1 whereas Lys B28 is modified by aromatic diol, 3,4-dihydroxy benzoic acid labeled K DHBA B C, Model of a complex between open form and insulin receptor IR ectodomain PDB entry 6HN5 on monosaccharide displacement of the switch A long-standing goal is design of a glucose-responsive insulin GRI or deliver system to protect patients from hypoglycemia for reviews, see [ 25 , , ].

Intrinsic or unimolecular GRIs define a novel investigational class of analogues wherein the modified hormone itself confers glucose-dependent activity or bioavailability Initial efforts focused on sequestration of the active insulin hormone within the SQ space or bloodstream as inactive complexes with release or activation enhanced by hyperglycemia.

Recent bioinspired advances exploit specific endogenous features of the SQ space, potential hormone-carrier proteins, or cellular clearance systems The following investigational schemes exploit chemical or protein-based glucose sensing Fig.

i Phenylboronic acid PBA. This diol-binding element senses carbohydrates , and was first exploited in studies of PBA-modified insulin The essential idea envisioned a glucose-responsive polymer-based release system 25 , GRI activity was subsequently described in a murine peritoneal glucose-infusion assay using a PBA-modified IDet analogue see Fig.

Although glucose-dependent HSA binding was hypothesized, this mechanism could not be demonstrated. ii Diboronate sensors. Novo Nordisk prepared diboronate insulin derivatives exhibiting glucose-sensitive HSA binding in the physiologic range K d 0.

A substantial literature pertains to mechanisms of monosaccharide binding and selectivity among such sensors , iii GLUT1 as a GRI carrier. Proteins other than HSA can sequester properly modified insulins 98 , Wang and colleagues exploited glucose transporter GLUT1 as found on the surface of erythrocytes to sequester insulin molecules linked to a GLUT1-specific antagonist , see Fig.

This technology circumvents the need for a chemical glucose sensor , Ambient glucose at high concentration displaces the antagonist to liberate the tethered insulin moiety. iv Glucose-dependent clearance.

A novel GRI scheme exploited glucose-dependent clearance of a saccharide-modified insulin derivative by the ubiquitous mannose receptor Such clearance was more rapid under conditions of hypoglycemia than under conditions of hyperglycemia see Fig. This mechanism differs from the aforementioned albumin-bound circulating depots in that mannose receptor clearance is irreversible.

Clinical trials exhibited only limited efficacy A novel class of unimolecular GRIs operates independently of a carrier protein, transporter, or repurposed clearance receptor.

Proof of principle was recently provided by a fructose-responsive switch inserted between the C terminus of the B chain and N terminus of the A chain in an His A8 -KP framework see Fig. This conformational cycle is in principle reversible depending on metabolic state.

The monosaccharide-opened state is compatible with native insulin-IR binding see Fig. Nuclear magnetic resonance studies documented changes in protein conformation regulated by fructose but not glucose, consistent with the monosaccharide-binding selectivity of the sensor. Beyond translational guidance, the cellular studies validated a structural coupling between hinge opening in the insulin B chain and reorganization of the IR ectodomain leading to transmembrane signaling These findings motivated simultaneous administration of both hormones as an investigational strategy for glycemic control with reduced risk of hypoglycemia Because such coadministration exploits a physiologic switch in the liver Fig.

In the past 2 decades organ-specific knockout of the IR or IRS genes have generated valuable mouse models to probe organ-specific insulin signaling Such insights complement long-standing concerns regarding peripheral administration of insulin vs endogenous portal secretion Next-generation insulin analogue design thus envisions organ-specific targeting.

i Liver. First-pass hepatic metabolism does not occur with SQ insulin, resulting in relative underinsulinization of the liver with suboptimal suppression of hepatic gluconeogenesis and relative overinsulinization of peripheral tissues.

This can increase the risk of insulin resistance, hypoglycemia, and weight gain Peglispro , a PEG-linked analogue, exhibited partial hepatic selectivity , , but its clinical development was abandoned because of signs of hepatic toxicity in clinical trials ii Brain.

Interestingly, peripheral administration of IDet increases brain signaling relative to WT insulin , presumably by enhanced transport through the blood-brain barrier. IDet may thus reduce food intake and mitigate weight gain relative to nonacetylated analogues.

Mechanisms related to HSA binding are under investigation The IR glycoform mass in the brain differs from glycoform masses elsewhere in the body , suggesting that specific targeting may be achievable Such targeting may also be relevant in Alzheimer disease iii Adipocyte.

Insulin signaling in adipose tissue regulates lipid storage and in turn whole-body glucose homeostasis , In mice palmitoleic acid inhibits lipogenesis and increases insulin sensitivity in the liver and skeletal muscle Novel branched fatty acid esters of hydroxyl fatty acids exert antidiabetic and anti-inflammatory effects ; their deficiency can lead to glucose intolerance.

Although insulin-induced adiposity is undesirable, adipocyte-targeted insulins may, as a seeming paradox, reduce insulin resistance , Such bias can reflect subtle conformational differences among receptor-ligand complexes as exemplified by G-protein—coupled receptors Extension of this paradigm to the IR could be transformational in T2D: Brown and Goldstein highlighted selective insulin resistance in the liver as a key unsolved problem related to hepatic steatosis In T2D insulin becomes ineffective at glycemic control and yet can continue to drive excess lipid biosynthesis and mitogenic outputs How might biased agonists of the IR be designed?

Hints are provided by advanced phosphoproteomics approaches Fig. Proof of principle has been obtained using IR-targeted phage-display peptides Fig. The distinct phosphoproteomic signatures of phage-display—derived IR agonists relative to insulin suggest that, as in G-protein—coupled receptors, subtle conformational features of the IR-ligand complex can indeed bias signaling outputs Fig.

Such efforts may exploit yeast-display technology as demonstrated by Chou and colleagues The epidemiological relationship between T2D and increased risk of several common cancers including breast and colon cancer has focused particular attention on the attenuation of mitogenic signaling by insulin analogues Comparison of mitogenic signaling outputs triggered by binding insulin vs insulin-like growth factors IGFs I and II to the type 1 IGF receptor may be regarded as an experiment of nature demonstrating biased agonism in a receptor tyrosine kinase Insulin analogues are routinely characterized for extent of cross-binding to type 1 IGF receptor and ratio of affinities for the IR isoforms IR-A and IR-B.

Insulin receptor IR signal transduction and biased agonism. A, Insulin signaling via IR substrate IRS proteins that interact with downstream target proteins to activate phosphoinositide 3-kinase PI3K and protein kinase B AKT pathways.

B, Schematic phosphoproteomics workflow. Following exposure of cells to a hormone under 2 conditions gold and blue , respective lysates are digested with protease s. Phosphopeptides are identified by liquid chromatography with tandem mass spectrometry. C and D, Biased signaling can be triggered by agonists via subtle differences in ligand-receptor conformations.

C, Left, IR-targeted phage-display—derived peptides purple circle, pentagon, and diamond defined potential IR allosteric control sites , Bidirectional horizontal arrow between the tyrosine kinase TK domains indicates their proximity on receptor activation. D, IR signaling pathways mediate the divergent downstream outputs.

The binding of a ligand can result in unbalanced activation of signaling by enhancing one output and reducing another.

In hepatocytes left the goal is to minimize lipid synthesis relative to control of glucose output; in cancer cells right the goal is to inhibit mitogenicity The discovery of insulin in , a landmark in endocrinology, galvanized broad public support for biomedical research 1.

The ensuring efforts of the late D. Hodgkin extended over 6 decades—inspiring an international network of laboratories—defined the atomic structure of insulin and its conformational repertoire.

The 50th anniversary of the first high-resolution crystal structure of insulin comes at a time of transition from rapid-acting analogues to ultrarapid and from basal to ultrabasal. The frontiers of insulin analogue design extend beyond first-generation mutagenesis to highlight the optimization of protein adducts and formulation excipients Synergies among diverse technologies are of particular clinical promise, as ultrarapid analogue formulations may enhance the performance of algorithm-regulated closed-loop systems as captured by CGM-defined time-in-range metrics and once-a-week ultrabasal analogue formulations may enhance the efficacy of once-a-week GLP-1 agonists 88 , Ultrarapid reformulations of prandial analogues may enhance TiR in closed-loop systems and thereby mitigate glycemic variability, including risk of hypoglycemia 39 , Investigational ultrabasal insulin analogue formulations currently in clinical trials may simplify basal-bolus regimens in T1D and basal-only or basal-bolus regimens in T2D.

Therapeutic considerations in T2D are holistic, integrating glycemia control with management of cardiovascular risk, weight, and the multiple components of metabolic syndrome 12 , 13 , For patients requiring insulin, glycemic targets may be moderated on an individual basis Frontiers of innovation among insulin technologies focus on yet-unmet clinical needs , , such as glucose-responsive strategies to avoid hypoglycemia 25 , , Fundamental features of metabolism in specific organs and cell types may be exploited to mitigate weight gain.

For example, potential organospecific insulin analogues may circumvent a current feature of SQ delivery, relative overinsulinization of the periphery and underinsulinization of the liver Biased control of specific postreceptor signaling pathways in the liver may be of particular benefit to treat or avoid hepatosteatosis , The combination of insulin with other hormones, such as GLP-1R agonists or amylin analogues, promises to exploit physiological synergies 89 , whereas coadministration of insulin and glucagon may buffer hepatic glucose output to reduce hypoglycemic risk , The insulin analogues highlighted in this review, including those under investigation, were designed to meet standards of stability appropriate in the developed world.

Whereas in affluent societies thermal degradation of insulin and insulin analogues is uncommon, the majority of patients in the coming decades will be living in underprivileged regions of the developing world In such regions intertwined medical and societal challenges are posed by the cold chain of insulin delivery in the absence of refrigeration or a reliable electrical grid , Given this growing global health need, we envisage a third-generation of insulin analogues: combining the present desiderata of properties with ultrastability.

Such efforts are likely to require further structural analysis of degradation mechanisms, including metastable partial folds and amyloid. The rugged landscape of protein folding and misfolding, for the present a foundational topic in biophysics, may thus emerge as a new translational frontier in molecular pharmacology.

wild type. Amino acids are designated by standard 3-letter code; residue numbers in insulin are shown by chain in superscript. Names of insulin analogues are italicized in lower case. We thank Prof F. Ismail-Beigi Case Western Reserve University and Prof A.

Cherrington Vanderbilt University for helpful discussion. This article is a contribution from the Center for Diabetes at the Indiana University School of Medicine. Financial Support: This work was supported by the JDRF, the Leon M.

and Harry B. Helmsley Charitable Trust, and the National Institutes of Health grant Nos. R01 DK and DK to M. Disclosures: M. holds shares in and is chief innovation officer of Thermalin Diabetes, LLC.

He has also been a consultant to Eli Lilly and Co; Merck, Inc; and the DEKA Research and Development Corp. The other authors have nothing to disclose. Data sharing is not applicable to this article because no data sets were generated or analyzed during the present study.

Bliss M. The Discovery of Insulin 25th Anniversary Edition. University of Toronto Press ; Google Scholar. Google Preview. Blundell TL , Cutfield JF , Dodson GG , Dodson E , Hodgkin DC , Mercola D. The structure and biology of insulin. Biochem J.

Kurtzhals P , Nishimura E , Haahr H , et al. Trends Pharmacol Sci. Zaykov AN , Mayer JP , DiMarchi RD. Pursuit of a perfect insulin. Nat Rev Drug Discov. American Diabetes Association. Glycemic targets: Standards of Medical Care in Diabetes— Diabetes Care.

Boughton CK , Hovorka R. New closed-loop insulin systems. Hovorka R. Closed-loop insulin delivery: from bench to clinical practice.

Nat Rev Endocrinol. Diabetes technology: Standards of Medical Care in Diabetes— Breyton AE , Lambert-Porcheron S , Laville M , Vinoy S , Nazare JA. CGMS and glycemic variability, relevance in clinical research to evaluate interventions in T2D, a literature review. Front Endocrinol Lausanne.

Agiostratidou G , Anhalt H , Ball D , et al. Standardizing clinically meaningful outcome measures beyond HbA 1c for type 1 diabetes: a consensus report of the American Association of Clinical Endocrinologists, the American Association of Diabetes Educators, the American Diabetes Association, the Endocrine Society, JDRF International, The Leona M.

Helmsley Charitable Trust, the Pediatric Endocrine Society, and the T1D Exchange. Management of hyperglycemia in type 2 diabetes, A consensus report by the American Diabetes Association ADA and the European Association for the Study of Diabetes EASD.

Makin V , Lansang MC. Diabetes management: beyond hemoglobin A 1c. Cleve Clin J Med. Perreault L , Skyler JS , Rosenstock J. Novel therapies with precision mechanisms for type 2 diabetes mellitus. Battelino T , Danne T , Bergenstal RM , et al. Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range.

Chehregosha H , Khamseh ME , Malek M , Hosseinpanah F , Ismail-Beigi F. A view beyond HbA1c: role of continuous glucose monitoring. Diabetes Ther. Ceriello A , Monnier L , Owens D. Glycaemic variability in diabetes: clinical and therapeutic implications. Lancet Diabetes Endocrinol.

Monnier L , Colette C , Owens D. Application of medium-term metrics for assessing glucose homoeostasis: usefulness, strengths and weaknesses. Diabetes Metab. Andreasen CR , Andersen A , Knop FK , Vilsbøll T. Understanding the place for GLP-1RA therapy: translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection.

Diabetes Obes Metab. Schernthaner G , Shehadeh N , Ametov AS , et al. Worldwide inertia to the use of cardiorenal protective glucose-lowering drugs SGLT2i and GLP-1 RA in high-risk patients with type 2 diabetes. Cardiovasc Diabetol. Brown E , Heerspink HJ , Cuthbertson DJ , Wilding JPH.

SGLT2 inhibitors and GLP-1 receptor agonists: established and emerging indications. Brunton S. GLP-1 receptor agonists vs. DPP-4 inhibitors for type 2 diabetes: is one approach more successful or preferable than the other? Int J Clin Pract.

Consoli A , Czupryniak L , Duarte R , et al. Positioning sulphonylureas in a modern treatment algorithm for patients with type 2 diabetes: expert opinion from a European consensus panel.

Reed J , Bain S , Kanamarlapudi V. A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis, treatments and future perspectives. Diabetes Metab Syndr Obes. Xie Y , Bowe B , Gibson AK , McGill JB , Maddukuri G , Al-Aly Z.

Comparative effectiveness of sodium-glucose cotransporter 2 inhibitors vs sulfonylureas in patients with type 2 diabetes. JAMA Intern Med. Bakh NA , Cortinas AB , Weiss MA , et al.

Glucose-responsive insulin by molecular and physical design. Nat Chem. Jarosinski MA , Dhayalan B , Rege N , Chatterjee D , Weiss MA. Steiner DF , James DE. Cellular and molecular biology of the beta cell. Dodson G , Steiner D. Curr Opin Struct Biol. Baker EN , Blundell TL , Cutfield JF , et al.

The structure of 2Zn pig insulin crystals at 1. Philos Trans R Soc Lond B Biol Sci. Lawrence MC. Understanding insulin and its receptor from their three-dimensional structures. Mol Metab. Brange J. Galenics of Insulin: The Physico-Chemical and Pharmaceutical Aspects of Insulin and Insulin Preparations.

Jeitler K , Horvath K , Berghold A , et al. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in patients with diabetes mellitus: systematic review and meta-analysis. Freckmann G , Buck S , Waldenmaier D , et al.

Insulin pump therapy for patients with type 2 diabetes mellitus: evidence, current barriers, and new technologies. J Diabetes Sci Technol.

Boscari F , Avogaro A. Current treatment options and challenges in patients with type 1 diabetes: pharmacological, technical advances and future perspectives. Rev Endocr Metab Disord. Woods RJ , Alarcón J , McVey E , Pettis RJ. Intrinsic fibrillation of fast-acting insulin analogs.

Krasner A , Pohl R , Simms P , Pichotta P , Hauser R , De Souza E. A review of a family of ultra-rapid-acting insulins: formulation development. Owens DR , Bolli GB. The continuing quest for better subcutaneously administered prandial insulins: a review of recent developments and potential clinical implications.

Falk BT , Liang Y , McCoy MA. Profiling insulin oligomeric states by 1 H NMR spectroscopy for formulation development of ultra-rapid-acting insulin. J Pharm Sci. Boughton CK , Hartnell S , Thabit H , et al. Hybrid closed-loop glucose control with faster insulin aspart compared with standard insulin aspart in adults with type 1 diabetes: a double-blind, multicentre, multinational, randomized, crossover study.

Ciszak E , Beals JM , Frank BH , Baker JC , Carter ND , Smith GD. Role of C-terminal B-chain residues in insulin assembly: the structure of hexameric LysB28ProBhuman insulin. Whittingham JL , Edwards DJ , Antson AA , Clarkson JM , Dodson GG. Hua QX , Shoelson SE , Kochoyan M , Weiss MA.

Receptor binding redefined by a structural switch in a mutant human insulin. Mapping the functional surface of insulin by design: structure and function of a novel A-chain analogue.

J Mol Biol. Olsen HB , Ludvigsen S , Kaarsholm NC. Solution structure of an engineered insulin monomer at neutral pH. Jacoby E , Hua QX , Stern AS , Frank BH , Weiss MA. Structure and dynamics of a protein assembly.

Bentley G , Dodson E , Dodson G , Hodgkin D , Mercola D. Structure of insulin in 4-zinc insulin. Derewenda U , Derewenda Z , Dodson EJ , et al. Phenol stabilizes more helix in a new symmetrical zinc insulin hexamer.

Gillis RB , Solomon HV , Govada L , et al. Analysis of insulin glulisine at the molecular level by X-ray crystallography and biophysical techniques. Sci Rep. Warren M , Bode B , Cho JI , et al. Improved postprandial glucose control with ultra rapid lispro versus lispro with continuous subcutaneous insulin infusion in type 1 diabetes: PRONTO-Pump Berenson DF , Weiss AR , Wan ZL , Weiss MA.

Insulin analogs for the treatment of diabetes mellitus: therapeutic applications of protein engineering. Ann N Y Acad Sci. Levin P , Hoogwerf BJ , Snell-Bergeon J , Vigers T , Pyle L , Bromberger L. Ultra rapid-acting inhaled insulin improves glucose control in patients with type 2 diabetes mellitus.

Endocr Pract. Paavola CD , Cox AL , Sperry AE , et al. A stable, hexameric, ultra-rapid insulin formulation containing citrate. Original Investigation. Program to Switch Medicare Beneficiaries With Diabetes From Analogue to Human Insulin. Jing Luo, MD, MPH; Nazleen F.

Khan, MS; Thomas Manetti, MPH; Jim Rose, PharmD; Ani Kaloghlian, PharmD; Balu Gadhe, MD; Sachin H. Jain, MD, MBA; Joshua J. Gagne, PharmD, ScD; Aaron S. Kesselheim, MD, JD, MPH.

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Save Preferences. Privacy Policy Terms of Use. Sanofi- Aventis developed glargine as a longer-lasting insulin analogue, and sells it under the brand name Lantus.

It was created by modifying three amino acids. Two positively charged arginine molecules were added to the C-terminus of the B-chain, and they shift the isoelectric point from 5. Replacing the acid-sensitive asparagine at position 21 in the A-chain by glycine is needed to avoid deamination and dimerization of the arginine residue.

These three structural changes and formulation with zinc result in a prolonged action when compared with biosynthetic human insulin. When the pH 4. A small amount is immediately available for use, and the remainder is sequestered in subcutaneous tissue.

As the glargine is used, small amounts of the precipitated material will move into solution in the bloodstream, and the basal level of insulin will be maintained up to 24 hours. The onset of action of subcutaneous insulin glargine is somewhat slower than NPH human insulin.

It is clear solution as there is no zinc in formula. NPH Neutral Protamine Hagedorn insulin is an intermediate-acting insulin with delayed absorption after subcutaneous injection, used for basal insulin support in diabetes type 1 and type 2. NPH insulins are suspensions that require shaking for reconstitution prior to injection.

Basal insulin analogs were subsequently developed and introduced into clinical practice to achieve more predictable absorption profiles and clinical efficacy. The amino acid sequence of animal insulins in different mammals may be similar to human insulin insulin human INN , there is however considerable viability within vertebrate species.

Both are active on the human receptor with approximately the same strength. Bovine insulin and porcine insulin may be considered as the first clinically used insulin analogs naturally occurring, produced by extraction from animal pancreas , at the time when biosynthetic human insulin insulin human rDNA was not available.

There are extensive reviews on structure-relationship of naturally occurring insulins phylogenic relationship in animals and structural modifications.

Insulin from some species of fish may be also effective in humans. Non-human insulins have caused allergic reactions in some patients related to the extent of purification, formation of non-neutralising antibodies is rarely observed with recombinant human insulin insulin human rDNA but allergy may occur in some patients.

This may be enhanced by the preservatives used in insulin preparations, or occur as a reaction to the preservative. Biosynthetic insulin insulin human rDNA has largely replaced animal insulin. Before biosynthetic human recombinant analogues were available, porcine insulin was chemically converted into human insulin.

Semisynthetic insulins were clinically used for some time based on chemical modification of animal insulins, for example Novo Nordisk enzymatically converted porcine insulin into semisynthetic 'human' insulin by removing the single amino acid that varies from the human variety, and chemically adding the human amino acid.

Normal unmodified insulin is soluble at physiological pH. Analogues have been created that have a shifted isoelectric point so that they exist in a solubility equilibrium in which most precipitates out but slowly dissolves in the bloodstream and is eventually excreted by the kidneys.

These insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours. However, some insulin analogues, such as insulin detemir, bind to albumin rather than fat like earlier insulin varieties, and results from long-term usage e.

more than 10 years are currently not available but required for assessment of clinical benefit. Unmodified human and porcine insulins tend to complex with zinc in the blood, forming hexamers.

Insulin in the form of a hexamer will not bind to its receptors, so the hexamer has to slowly equilibrate back into its monomers to be biologically useful. Hexameric insulin delivered subcutaneously is not readily available for the body when insulin is needed in larger doses, such as after a meal although this is more a function of subcutaneously administered insulin, as intravenously dosed insulin is distributed rapidly to the cell receptors, and therefore, avoids this problem.

Zinc combinations of insulin are used for slow release of basal insulin. Non hexameric insulins monomeric insulins were developed to be faster acting and to replace the injection of normal unmodified insulin before a meal.

There are phylogenetic examples for such monomeric insulins in animals. All insulin analogs must be tested for carcinogenicity , as insulin engages in cross-talk with IGF pathways, which can cause abnormal cell growth and tumorigenesis.

Modifications to insulin always carry the risk of unintentionally enhancing IGF signalling in addition to the desired pharmacological properties. Recent study result of the 6. A meta-analysis completed in and updated in of numerous randomized controlled trials by the international Cochrane Collaboration found that the effects on blood glucose and glycated haemoglobin A1c HbA1c were comparable, treatment with glargine and detemir resulted in fewer cases of hypoglycemia when compared to NPH insulin.

In , Germany's Institute for Quality and Cost Effectiveness in the Health Care Sector IQWiG report , concluded that there is currently "no evidence" available of the superiority of rapid-acting insulin analogs over synthetic human insulins in the treatment of adult patients with type 1 diabetes.

Many of the studies reviewed by IQWiG were either too small to be considered statistically reliable and, perhaps most significantly, none of the studies included in their widespread review were blinded, the gold-standard methodology for conducting clinical research. However, IQWiG's terms of reference explicitly disregard any issues which cannot be tested in double-blind studies, for example a comparison of radically different treatment regimes.

Application of analoguse Insulin analogues tool kit—integrating protein anaolgues, chemical modification, analogeus Insulin analogues thus led to improved prandial and basal formulations Coenzyme Q heart health Insulin analogues treatment Insulin analogues diabetes mellitus. Continuing innovation Insuljn providing Insulin analogues improvements to achieve ultrarapid and ultrabasal analogue formulations in an effort to reduce glycemic analoguess and optimize time in range. Smart insulin analogues and delivery systems promise to mitigate hypoglycemic risk, a critical barrier to glycemic control, whereas biased and organ-targeted insulin analogues may better recapitulate physiologic hormonal regulation. In each therapeutic class considerations of cost and stability will affect use and global distribution. This review highlights structural principles underlying next-generation design efforts, their respective biological rationale, and potential clinical applications. Indeed, unmet clinical needs in the treatment of type 1 and type 2 diabetes T1D and T2D represent continuing sources of therapeutic innovation.

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