A serious danger of insulin treatment in diabetic patients is the high risk of hypoglycemic episodes. Although mild episodes are manageable by sugar ingestion, severe episodes can lead to convulsions, broken bones, brain damage and even death. Repeated chronic occurrence increases the probability of ischemic events, arrhythmias, and cumulative neurological damage.
Delivery devices for therapeutic peptides and proteins (such as patches, pens, and pumps) play critical roles in treating T1D and other diseases. Despite extraordinary advances in engineering in the past decade, device specifications continue to be constrained by the properties of the biomolecules themselves. My project focuses on the design, synthesis and characterization of a novel class of glucose-responsive insulin (GRI) analogs. GRI technologies aim to address an unmet clinical need: the ever-present threat of hypoglycemic episodes. Our strategy envisions ultra-stable proteins containing a glucagon analog “stapled” to an insulin analog.
This proposal exploits a physiological switch in the hormonal responsiveness of the liver depending on blood sugar levels. During incipient hypoglycemia, the glucagon (as a counter regulatory hormone) will prevent further declines in blood-glucose concentration, whereas during incipient hyperglycemia insulin action will predominate. We anticipate that appropriate “tuning” of respective glucagon- and insulin activities in the fusion protein will optimize time in range with decreased risk of severe hypoglycemia. The fusion protein will be resistant to misfolding and therefore can be used in soluble formulations, including in the reservoir of insulin pumps. The glucose-responsive action of the fusion protein would complement closed-loop control algorithms to maximize time in range as measured by continuous glucose monitors.
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