Smarter Modeling to Enable a Smarter Insulin

Taylor, Simeon I.; DiMarchi, Richard D.

doi:10.2337/dbi20-0011

Cited by 8 publications

(9 citation statements)

References 17 publications

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“…Although animal-based and pilot clinical studies were pursued, this approach is no longer under development. These challenges to create a modified insulin with an improved therapeutic index that enables tighter glycaemic control with a reduced risk for hypoglycaemia, as well as the challenges of translating in vivo animal models and data for application in humans, highlight the importance of developing better in silico GRI modelling in the developmental pipeline [23,[103][104][105].…”

Section: Intrinsic Gri Systemsmentioning

confidence: 99%

“…In addition to the elegance of the associated chemistries and macromolecular structures, ongoing research has a compelling clinical motivation: to enhance the health and quality of life of patients with type 1 diabetes and of patients with type 2 diabetes refractory to oral therapy-and with less burden on patients [136]. To bridge the valley between basic science and clinical applications, in silico simulations of animal physiology and human patients are likely to provide key guidance [23,[103][104][105].…”

Section: Clinical Significance and Conclusionmentioning

confidence: 99%

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‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

et al. 2021

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Insulin replacement therapy for diabetes mellitus seeks to minimise excursions in blood glucose concentration above or below the therapeutic range (hyper-or hypoglycaemia). To mitigate acute and chronic risks of such excursions, glucose-responsive insulindelivery technologies have long been sought for clinical application in type 1 and long-standing type 2 diabetes mellitus. Such 'smart' systems or insulin analogues seek to provide hormonal activity proportional to blood glucose levels without external monitoring. This review highlights three broad strategies to co-optimise mean glycaemic control and time in range: (1) coupling of continuous glucose monitoring (CGM) to delivery devices (algorithm-based 'closed-loop' systems); (2) glucose-responsive polymer encapsulation of insulin; and (3) mechanism-based hormone modifications. Innovations span control algorithms for CGM-based insulin-delivery systems, glucose-responsive polymer matrices, bio-inspired design based on insulin's conformational switch mechanism upon insulin receptor engagement, and glucose-responsive modifications of new insulin analogues. In each case, innovations in insulin chemistry and formulation may enhance clinical outcomes. Prospects are discussed for intrinsic glucose-responsive insulin analogues containing a reversible switch (regulating bioavailability or conformation) that can be activated by glucose at high concentrations.

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Section: Intrinsic Gri Systemsmentioning

confidence: 99%

Section: Clinical Significance and Conclusionmentioning

confidence: 99%

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

et al. 2021

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“…Therefore, the development of MK-2640 was abandoned. As animal studies were only a poor predictor of the clinical outcome, a wider use of compartmental mathematical models has been proposed for the development of future GRIs [48,49].…”

Section: Clinical Data Of Glucose-responsive Insulinsmentioning

confidence: 99%

The future of insulin therapy

Heise

2021

Diabetes Research and Clinical Practice

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“…Which in vitro and in vivo systems should be used for compound evaluations? [ 31 , 32 ] How glucose-responsive must your lead molecule be at high glucose vs normal glucose vs low glucose? In healthy individuals, the circulated insulin concentration increases approximately 5- to 10-fold if blood glucose levels double from 5 mM to approximately 10 mM after a meal, that is, 5- to 10-fold gearing.…”

Section: Challengesmentioning

confidence: 99%

Review: Glucose-sensitive insulin

Høeg-Jensen

2021

Molecular Metabolism

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Background Hypoglycemia, the condition of low blood sugar, is a common occurance in people with diabetes using insulin therapy. Protecting against hypoglycaemia by engineering an insulin preparation that can auto-adjust its biological activity to fluctuating blood glucose levels has been pursued since the 1970s, but despite numerous publications, no system that works well enough for practical use has reached clinical practise. Scope of review This review will summarise and scrutinise known approaches for producing glucose-sensitive insulin therapies. Notably, systems described in patent applications will be extensively covered, which has not been the case for earlier reviews of this area. Major conclusions The vast majority of published systems are not suitable for product development, but a few glucose-sensitive insulin concepts have recently reached clinical trials, and there is hope that glucose-sensitive insulin will become available to people with diabetes in the near future.

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Smarter Modeling to Enable a Smarter Insulin

Cited by 8 publications

References 17 publications

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues

The future of insulin therapy

Review: Glucose-sensitive insulin

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