Browsing by Subject "Glucose-responsive insulin"

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    Rational Design and Efficacy of Glucose-Responsive Insulin Therapeutics and Insulin Delivery Systems by Computation using Connected Human and Rodent Models
    (Wiley, 2023) Yang, Sungyun; Yang, Jing Fan; Gong, Xun; Weiss, Michael A.; Strano, Michael S.; Biochemistry and Molecular Biology, School of Medicine
    Glucose-responsive insulins (GRIs) use plasma glucose levels in a diabetic patient to activate a specifically designed insulin analogue to a more potent state in real time. Alternatively, some GRI concepts use glucose-mediated release or injection of insulin into the bloodstream. GRIs hold promise to exhibit much improved pharmacological control of the plasma glucose concentration, particularly for the problem of therapeutically induced hypoglycemia. Several innovative GRI schemes are introduced into the literature, but there remains a dearth of quantitative analysis to aid the development and optimization of these constructs into effective therapeutics. This work evaluates several classes of GRIs that are proposed using a pharmacokinetic model as previously described, PAMERAH, simulating the glucoregulatory system of humans and rodents. GRI concepts are grouped into three mechanistic classes: 1) intrinsic GRIs, 2) glucose-responsive particles, and 3) glucose-responsive devices. Each class is analyzed for optimal designs that maintain glucose levels within the euglycemic range. These derived GRI parameter spaces are then compared between rodents and humans, providing the differences in clinical translation success for each candidate. This work demonstrates a computational framework to evaluate the potential clinical translatability of existing glucose-responsive systems, providing a useful approach for future GRI development.
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    ‘Smart’ insulin-delivery technologies and intrinsic glucose-responsive insulin analogues
    (SpringerLink, 2021-05) Jarosinski, Mark A.; Dhayalan, Balamurugan; Rege, Nischay; Chatterjee, Deepak; Weiss, Michael A.; Biochemistry and Molecular Biology, School of Medicine
    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 insulin-delivery 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.