Mitogenicity of insulin analogues pdf

May 08, 2012 the two insulin analogues, x10 and glargine, were the only insulin analogues we have tested that had a higher affinity to hybrid receptors compared to human insulin. Request pdf appraising the mitogenicity of insulin analogues relative to human insulin response to. This program will provide an overview on the treatment of diabetes with insulin analogs and premixed insulin analogs. There is an association between insulin analogues, glargine, lispro and aspart and the incidence of malignancies. Toxicologic pathology regulatory forum opinion piece. Insulin analogues display igfilike mitogenic and antiapoptotic activity in cultured cancer cells. In the 1990s, the value of glycemic control in the management of diabetes became incontrovertible. Insulin analogues dr divya krishnan calicut medical college 2.

Therapeutic insulin, in its native and biosynthetic forms as well as several currently available insulin analogues, continues to be the protein of most interest to researchers. Pdf newer insulin analogues and inhaled insulin researchgate. Dec 17, 2019 using multiple techniques, it is demonstrated that judicious choice of formulation excipients tonicity agents and parenteral preservatives enables insulin analogue formulations with 7080% monomer and supramolecular pegylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Secondgeneration insulin analogues need to be tested and proven. However, structural modification of the insulin molecule may result in altered binding affinities and activities to the igf1 receptor igf1r. Unsafe effects of insulin and insulin analogues in pregnancy with diabetes could be linked with changes in insulin immunogenicity, teratogenicity, and mitogenicity. It was concluded that insulin glargine and insulin detemir display atypical signaling activities that differ from those elicited by regular insulin and involve activation of the antiapoptotic igf insulin receptor. Review of insulin and its analogues in diabetes mellitus krishnappa mane, chaluvaraju kc, niranjan ms, zaranappa and manjuthej tr department of pharmaceutical chemistry, government college of pharmacy, bangalore 560 027, india. Assuming that rapidacting insulin analogs last for 4 hours is a safe general rule.

The interest in producing insulin formulations that are safer has yielded insulin analogues that afford more flexible treatment regimens and a lower risk of hypoglycemia. This compound has therefore become the reference standard for the assessment of enhanced mitogenicity and its effect in toxicology. Points to concider document on the nonclinical assessment of. Shortacting insulin analogues versus regular human insulin. Insulin glulisine is the newest human insulin analogue product for the control of prandial blood glucose. In order to improve therapy and increase the quality of life for diabetic patients, it has been of significant interest to develop rapidacting insulin preparations that mimic the physiological mealtime profile of insulin more closely than soluble human insulin. In animal and in vitro experiments, an increased mitogenic potency, as well. They can be injected immediately before meals and lead to lower blood sugar levels after food intake. The duration of action of lispro, aspart and glulisine only modestly. Two main groups of insulin analogues can be distinguished in 1 shortacting insulin analogues, genetically engineered in such a way that they dissociate more rapidly following injection and in 2 longacting insulin analogues, which show a delayed absorption or a prolonged duration of action. The metabolic and mitogenic properties of basal insulin. Insulin and its analogues and their affinities for the igf1. The goal of diabetes mellitus treatment is to maintain longterm nearnormoglycaemia to prevent the onset or progression of longterm complications.

The secondgeneration basal insulin analog insulin degludec has an. Treatment with insulin analogues and breast cancer risk in. Using multiple techniques, it is demonstrated that judicious choice of formulation excipients tonicity agents and parenteral preservatives enables insulin analogue formulations with 7080% monomer and supramolecular pegylation imbued stability under stressed aging for over 100 h without altering the insulin association state. Contents introduction classification rationale for development individual analogues special features merits of analogues over standard insulins drawbacks of analogues popular regimes using analogues novel delivery systems using analogues summary. Pdf the use of insulin analogues is rapidly expanding. Sci57 is an insulin analog with a greater affinity for the insulin receptor and lower thermal degradation than native insulin. Shortacting insulin analogues such as insulin lispro, insulin aspart and insulin glulisine act more quickly than regular human insulin. Deviations of the activity profile from that of native human insulin are of special interest.

Appraising the mitogenicity of insulin analogues relative to human insulin response to weinstein d, simon m, yehezkel e et al. Treatment with insulin analogues and breast cancer risk. That said, the potential for an increased level of mitogenicity in an insulin analog would ideally be avoided during the design process if possible. We report a series of experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparison with human insulin, igf1, and the supermitogenic insulin. Full text and pdf costeffectiveness of insulin analogs diana i. The two insulin analogues, x10 and glargine, were the only insulin analogues we have tested that had a higher affinity to hybrid receptors compared to human insulin. These modifications could be a removal, an addition or replacement of one, or a few, amino acids in the molecule, which are achieved by changes in. Ly2605541a preferential hepatospecific insulin analogue. This suggests that a long residence time on the insulin receptor may be an important component of the enhanced mitogenicity of the aspb10 insulin analogue. Analogue insulin is laboratory grown but genetically altered to create either a more rapid acting or more uniformly acting form of the insulin. The stimulatory effect of hyperinsulinaemia on farnesyltransferase in the presence of insulin resistance represents one potential mechanism responsible for mitogenicity and atherogenicity of insulin. Several studies have suggested that antidiabetic insulin analogue treatment might increase cancer risk. Insulin glargine and human insulin have a similar time course for insulin receptor binding and intracellular signalling events, whereas the action of the aspb10 insulin analogue is more. Glargine, a longacting insulin analogue, is used to mimic basal insulin secretion.

Insulin aspart b28asp human insulin is a novel rapidacting insulin analogue that fulfils this criterion. Introduction p rotein aggregation is a constant risk during the. The slow breakup of the insulin cluster gives insulin glargine its long action. Pdf molecular characterisation of longacting insulin. Ddiabetes mellitus iabetes mellitus dm is a metabolic disorder resulting from a. Use of insulin analogs in pumps such as humalog or novolog was based on the principle that mutational. Effects of longacting insulin analogues on breast and. The interest in producing insulin formulations that are safer than previous formulations and that more closely duplicate the basal and mealtime components of endogenous insulin secretion has yielded insulin analogues with action profiles that afford more flexible treatment regimens and a lower risk of hypoglycemia. The mitogenicity of insulin analogues in vitro relative to. After this switch, a completely different mechanism is utilized to activate the mitogenic mitogenactivated protein kinase pathways of the igfir. Appraising the mitogenicity of insulin analogues relative to human insulinresponse to. One of these slowacting insulin analogues, insulin detemir, binds to albumin via fatty acid chain, thereby providing slow absorption and a prolonged metabolic effect 10. Points to concider document on the nonclinical assessment.

A major concern about all newer insulin analogues is their altered mitogenic. A 76 yearold female patient with history of diabetes, hypertension and hyperlipidemia presented with flank pain after using insulin levemir as part of her management. Aimshypothesis there is controversy with respect to molecular characteristics of insulin analogues. The use of insulin analogs in type 1 and type 2 diabetes mellitus provides a. Effects of longacting insulin analogues on breast and colon cancer promotion eunhyoung ko master of science department of physiology university of toronto 2014 abstract insulin glargine, a longacting insulin analogue, has been implicated in increased cancer risk by epidemiological studies and has been reported to increase mitogenicity in in. The availability of insulin analogs has offered insulin replacement strategies that are proposed to more closely mimic normal human physiology. The full text of this article is available in pdf format. The theoretical basis for a biological link between insulin analogues and cancer.

Insulin and its analogues and their affinities for the. Nevertheless, the us food and drug administration stated in its letter of approval for insulin glargine that aventis pharma is committed to do a clinical phase iv study to compare the proportion of patients who have type 2 diabetes with a threestep or more progression of retinopathy during treatment with once daily insulin glargine or twice. To examine the costeffectiveness of analogs versus human insulins, citing primarily studies conducted in the united states. Expression of the biologically active insulin analog sci57. This can have advantages for blood sugar management analogue insulins have been available since just before the start of the new millennium. Effectiveness and safety of new insulin delivery systems in real life of diabetic women in pregnancy need further. The link between diabetes and cancer may be indirect and associated with risk. These insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours. Molecular characterisation of longacting insulin analogues. Mitogenic properties of insulin and insulin analogues mediated by the insulin receptor. A systematic literature search was performed on breast cellline, animal and human studies using the key words insulin.

Insulin analogues are a group of insulin molecules where the molecular structure of human insulin has been modified. It can be speculated that some of the mitogenicity of these two analogues may be through activation of hybrid receptors, as their affinity was comparable to homodimer igf1r affinity. Review of insulin and its analogues in diabetes mellitus. The new longacting insulin analogue, insulin glargine lantus, aventis pharma was approved for use in patients with type 1 and type 2 diabetes mellitus by the us food and drug administration in april, 2000, and by the european agency for the evaluation of medicinal products in june, 2000. It also shows native mitogenicity and insulin like biological activity. As with aspart and lispro, glulisine displays faster absorption and onset of action, with a shorter duration of action than that of rhi. The interest in producing insulin formulations that are safer than previous formulations and that more closely duplicate the basal and mealtime components of endogenous insulin secretion has yielded insulin analogues with action profiles that afford more flexible treatment regimens and. Mar 17, 2016 these insulin analogues are used to replace the basal level of insulin, and may be effective over a period of up to 24 hours. Sandow attempted to highlight the complexity of the relationship between the growth effects of insulin and insulin analogs while emphasizing the need for clarity regarding the meaning of mitogenicity under physiological and pathophysiological situations in relationship to insulin and insulin analogs. Topological resistance of singlechain analogs to thermal degradation with application to a pump reservoir phillips j diabetes sci technol vol 6, issue 2, march 2012. Insulin analogues using knowledge of the threedimensional structure of insulin and biochemical data of its activity, researchers have been able to change specific amino acids in the sequence of the protein and hence subtly alter the properties of the insulin molecule see genetic engineering box. Specifically, there are a considerable number of reports demonstrating that prandial insulin analogs lispro, aspart, glulisine have pharmacokinetic and pharmacodynamic profiles closer to normal, with resulting faster onset and offset of insulin. Points to concider document on the nonclinical assessment of the.

An insulin analog is an altered form of insulin, different from any occurring in nature, but still available to the human body for performing the same action as human insulin in terms of glycemic control. Nov 14, 2019 sci57 is an insulin analog with a greater affinity for the insulin receptor and lower thermal degradation than native insulin. Suddenly, a few studies in diabetologia 35 describing an association between administration of glargine and higher incidence of cancers have aroused worldwide attention. The duration of insulin glargine is longer than insulin detemir 1. Through genetic engineering of the underlying dna, the amino acid sequence of insulin can be changed to alter its adme absorption, distribution, metabolism, and excretion characteristics. Appraising the mitogenicity of insulin analogues relative to. Relevant studies were identified through pubmed and congress abstract database searches.

Intrinsic fibrillation of fastacting insulin analogs. Thus, the focus for preclinical safety evaluation of analogues is to demonstrate that modifications in regular insulin do not result in enhanced mitogenicity. Shortacting insulin analogues versus regular human. Appraising the mitogenicity of insulin analogues relative. This can have advantages for blood sugar management. Previous studies investigating the mitogenicity of insulin analogues with amino acid substitutions at position b10 have only included analogues with acidic asp or glu substitutions, but in this study, a panel of insulin analogues with amino acids comprising different side chain characteristics were systematically examined. Feb 22, 2012 previous studies investigating the mitogenicity of insulin analogues with amino acid substitutions at position b10 have only included analogues with acidic asp or glu substitutions, but in this study, a panel of insulin analogues with amino acids comprising different side chain characteristics were systematically examined. As the individual insulin units detach from the cluster, the insulin analog can be absorbed into the blood stream. Effects of longacting insulin analogues on breast and colon. This effect is specific to insulin, but is not related to the type of insulin used. The preclinical evaluation of insulin analogs for the risk of enhanced mitogenicity therefore includes determination of the metabolic and mitogenic.

The first generation of basal insulin analogs, insulin glargine and detemir, are characterized by a more predictable daytoday insulin absorption rate, a flatter timeaction profile, and a longer duration than the older, intermediateacting nph insulin 1. Expression of the biologically active insulin analog sci. The specific property of rapidacting insulin analogues is that the change. The reduction in body weight is an additional advantage of detemir. The preclinical evaluation of insulin analogs for the risk of enhanced mitogenicity therefore includes determination of the metabolic and mitogenic in vitro characteristics. We report a series of experiments forming a comprehensive characterisation of the long acting insulin analogues, glargine and detemir, in comparison with human insulin, igf1, and the supermitogenic insulin, x10. Insulin analogues have been developed in an attempt to achieve a more physiological replacement of insulin and thereby a better glycaemic control. Insulin glargine differs from human insulin by substitution of asparagine by glycine in position 21 of the a chain and by carboxyterminal. Insulin receptor human insulin insulin glargine insulin analog lispro insulin. Weinstein d, simon m, yehezkel e, laron z, werner h.

Pdf insulin analogues state of the art researchgate. The metabolic and mitogenic properties of basal insulin analogues. Systematic evaluation of the metabolic to mitogenic potency. The b28asp modification weakens the selfassociation of the insulin molecule and provides a more rapid absorption from the sc. Appraising the mitogenicity of insulin analogues relative to human insulin response to. An overview of insulin analogs and premixed insulin analogs. The metabolic activity of insulin has been studied extensively in vitro and in vivo, based on the initial assessment of insulin receptor affinity, followed by methods to estimate the metabolic. Insulin glargine forms clusters when it is injected under the skin. Looking at the carcinogenicity of human insulin analogues via. Looking at the carcinogenicity of human insulin analogues. The secondgeneration basal insulin analog insulin degludec has an even longer halflife of about 25 h, a very flat profile of action with a duration exceeding 42 h, and a reduced risk of nocturnal hypoglycemia in both type 1 and type 2 diabetic patients compared with insulin glargine 2. Discuss the status of diabetes care in the us explain the rationale for insulin analog development list currently available insulin analogs and premixed insulin analogs.

In order to achieve tight glycaemic control and improve the quality of life for diabetic patients, a number of novel insulin preparations, insulin analogues, have been constructed thanks to recombinant dna technologies and advanced protein chemistry. Over the last decade, it has become the leading longacting insulin used either alone or with other glucoselowering medication. In this work, sci57 was transiently expressed in the nicotiana benthamiana nb plant, and we also evaluated some of its relevant biological effects. Insulin glargine lantus, gly a21,arg b31,arg b32 insulin is a longacting human insulin analog with an almost peakless activity profile very closely mimicking the natural physiological profile of basal endogenous insulin secretion. Insulin analogue levemir and development of pancreatic.

In vitro metabolic and mitogenic signaling of insulin. Insulin analogs such as glargine, detemir and lispro have had proliferative effects that resemble igfi action. The mitogenic properties of insulin are a consideration for insulin therapy in general, but the clinical relevance remains highly speculative. Systematic evaluation of the metabolic to mitogenic. Assessment of insulin mitogenicity and igfi activity. During the past 10years, several new basal insulin analogs have been developed. One of these slowacting insulin analogues, insulin detemir, binds to albumin via fatty acid chain, thereby providing slow absorption and. The development of insulin analogs has made improved treatment of type 2 diabetes possible. Rapidacting insulin analogues for the treatment of diabetes. Aspb10 insulin induction of increased mitogenic responses and phenotypic changes in human breast epithelial cells. An overview of insulin analogs and premixed insulin. Pdf mitogenic properties of insulin and insulin analogues. The interest in producing insulin formulations that are.

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