Insulin X10 revisited: a super-mitogenic insulin analogue

Hansen, Bent; Kurtzhals, Peter; Jensen, Astrid B.; Dejgaard, A.; Russell‐Jones, David

doi:10.1007/s00125-011-2203-8

Cited by 59 publications

(74 citation statements)

References 36 publications

(58 reference statements)

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“…Prolonged binding of an insulin analog to hIR can result in prolonged activation of the tyrosine kinase domain of hIR, leading to extended tyrosine phosphorylation and downstream signaling (Kurtzhals et al, 2000;Hansen et al, 2011). To gain insight into an insulin agonist/hIR interaction or residence time, a time course of hIR dephosphorylation following a washout of maximally efficacious doses of insulin test samples was measured (Fig.…”

Section: Biological Properties Of Basal Insulin Peglispromentioning

confidence: 99%

In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog

Owens¹,

Hansen²,

Kahl³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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The aim of this research was to characterize the in vivo and in vitro properties of basal insulin peglispro (BIL), a new basal insulin, wherein insulin lispro was derivatized through the covalent and site-specific attachment of a 20-kDa polyethylene-glycol (PEG; specifically, methoxy-terminated) moiety to lysine B28. Addition of the PEG moiety increased the hydrodynamic size of the insulin lispro molecule. Studies show there is a prolonged duration of action and a reduction in clearance. Given the different physical properties of BIL, it was also important to assess the metabolic and mitogenic activity of the molecule. Streptozotocin (STZ)-treated diabetic rats were used to study the pharmacokinetic and pharmacodynamic characteristics of BIL. Binding affinity and functional characterization of BIL were compared with those of several therapeutic insulins, insulin AspB10, and insulin-like growth factor 1 (IGF-1). BIL exhibited a markedly longer time to maximum concentration after subcutaneous injection, a greater area under the concentration-time curve, and a longer duration of action in the STZ-treated diabetic rat than insulin lispro. BIL exhibited reduced binding affinity and functional potency as compared with insulin lispro and demonstrated greater selectivity for the human insulin receptor (hIR) as compared with the human insulin-like growth factor 1 receptor. Furthermore, BIL showed a more rapid rate of dephosphorylation following maximal hIR stimulation, and reduced mitogenic potential in an IGF-1 receptordominant cellular model. PEGylation of insulin lispro with a 20-kDa PEG moiety at lysine B28 alters the absorption, clearance, distribution, and activity profile receptor, but does not alter its selectivity and full agonist receptor properties.

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Section: Biological Properties Of Basal Insulin Peglispromentioning

confidence: 99%

In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog

Owens¹,

Hansen²,

Kahl³

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

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“…The first rapid-acting insulin analogue was developed by replacing a histidine residue for the negatively charged aspartic acid at position B10 (insulin X10 or B10Asp; Hansen et al 2011). The applied genetic modification led to disrupting the ability of insulin molecules to self-associate as hexamers.…”

Section: The Common Origin Of Insulin Igfs and Their Receptorsmentioning

confidence: 99%

“…Insulin X10 has been shown to induce enhanced mitogenic effects due to the activation of both the IRs and the IGF1Rs (Milazzo et al 1997). In most studies, its binding affinity for the IR has been found to be 200-400% higher than that of human insulin (Hansen et al 2011). Although it has an identical 'on-rate', it has a much slower 'off-rate' from the IR than human insulin (Drejer et al 1991).…”

Section: The Common Origin Of Insulin Igfs and Their Receptorsmentioning

confidence: 99%

Insulin and its analogues and their affinities for the IGF1 receptor

Varewijck¹,

Janssen²

2012

Endocrine-Related Cancer

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

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“…In clinical pharmacological studies, insulin degludec exerted a long‐lasting action (>42 h)11, with a flat and stable insulin profile in the glucose‐lowering effect for individual patients12.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of insulin degludec in Japanese patients with type 1 and type 2 diabetes: 24‐week results from the observational study in routine clinical practice

Kobuke

Yoneda

Nakanishi

et al. 2015

J of Diabetes Invest

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Aims/IntroductionInsulin degludec, a new long‐acting insulin analog, showed its better glycemic control and reduced risk of hypoglycemia. This is the first prospective observational study that evaluated the efficacy and safety of insulin degludec in routine clinical practice.Materials and MethodsJapanese patients with type 1 or type 2 diabetes mellitus receiving basal–bolus insulin therapy were switched their basal insulin to degludec, and prospectively observed over a 24‐week course. The Diabetes Therapy‐Related Quality of Life questionnaire was administered before and 12 weeks after switching.ResultsThe participants were 80 diabetes patients = (type 1, 44; type 2, 36). In the type 1 group, there was no difference in glycated hemoglobin levels between the pre‐switching and 24‐week measurements (from 62 to 62 mmol/mol, P = 0.768), whereas the daily insulin dose (per kg of bodyweight) decreased significantly (basal, from 0.25 to 0.20 U/kg, P < 0.001; bolus, from 0.40 to 0.37 U/kg, P = 0.001). In the type 2 group, glycated hemoglobin levels decreased after switching (from 60 to 58 mmol/mol, P = 0.028). In the type 1 group, the frequency of hypoglycemia decreased significantly after switching, but not significantly in the type 2 group. Patient satisfaction with the control of hypoglycemia tended to improve in the type 1 group.ConclusionsCompared with existing long‐acting insulin, degludec can maintain glycemic control at a lower insulin dose and frequency of hypoglycemia in type 1 diabetes, while it can improve glycemic control at an equal insulin dose in type 2 diabetes.

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Insulin X10 revisited: a super-mitogenic insulin analogue

Cited by 59 publications

References 36 publications

In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog

In Vivo and In Vitro Characterization of Basal Insulin Peglispro: A Novel Insulin Analog

Insulin and its analogues and their affinities for the IGF1 receptor

Efficacy and safety of insulin degludec in Japanese patients with type 1 and type 2 diabetes: 24‐week results from the observational study in routine clinical practice

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