Objective
We will rationally engineer new materials which can bind to insulin and regulate its release more precisely in response to changes in blood glucose. These materials will then be further explored for incorporation of amylin analogues, a natural hormone which is secreted along with insulin in healthy pancreas function but is not usually included in hormone replacement therapy for type-1 diabetes.
Background Rationale
Type-1 diabetes is increasing in incidence in recent years. Current blood glucose management requires rigorous therapy, and yet fails to restore blood glucose control which can lead to a number of short- and long-term health complications. Efforts toward more autonomous therapies have struggled in matching glucose sensing and therapeutic deployment, and often are either too slow to respond to a rise in blood glucose, or fail to rapidly shut off release once blood glucose is corrected which can lead to insulin overdose. There is furthermore increasing evidence that many of the long-term complications which arise following a life of insulin dependence may be circumvented by inclusion of amylin within the therapeutic regimen to more fully restore the hormone function of a healthy beta cell. Yet, due to the present requirements for multiple separate injections of insulin and amylin analogues, few have adopted this dual hormone replacement regimen in spite of its promising short- and long-term benefits.
Description of Project
Type-1 diabetes is increasing in incidence in recent years. Current blood glucose management requires rigorous therapy, and yet fails to fully restore healthy glucose control which can lead to many health complications. Work toward “smart” therapies have struggled in effectively recreating glucose sensing and offering insulin delivered at the exact time of need. As an example where present therapies are insufficient, healthy beta cells sense blood glucose and respond with the precise dose of insulin needed to correct glucose to a normal level. Insulin therapy is intended to replace those beta cells when they are destroyed in the course of type-1 diabetes onset. Yet, the standard in insulin therapy still entails guesswork on the part of the individual, determining approximately how much insulin is needed based on how much their blood glucose is likely to change with ingestion of a meal. The error inherent in this approach can be dangerous and leads to a number of immediate and long-term health complications. Another way in which the present standard of care fails to replicate the function of a healthy pancreas arises from insulin-centered hormone replacement. Type-1 diabetes is presently addressed by insulin replacement, yet in a healthy scenario beta cells secrete both insulin and pramlintide together in response to elevated glucose. Increasingly it is being understood that the amylin signaling which is absent in the present standard of care has a number of important roles in addressing many of the secondary complications that arise in treating diabetes. Yet implementing this in the form of replacement amylin requires separate injections on top of what is already done for insulin and as such has been limited in its application.
We hope to address these present deficiencies in therapy by engineering responsive materials which are up to the task of restoring blood glucose control via glucose-dictated insulin release which is dictated by need and regulated to ensure safety. We will furthermore explore the inclusion of pramlintide within these materials so as to more fully restore the natural hormone signaling of a healthy pancreas in our envisioned therapeutic. Our prior experience in designing glucose-responsive materials and protein formulation tools inspires these research efforts. It is our hope that our approach will yield a therapeutic solution that is responsive, safe, and more effective in managing Type-1 diabetes.
Anticipated Outcome
Through this approach, we hope to achieve a once-daily injectable formulation which contains all of the insulin required for a day of therapy, releasing insulin throughout the day in accordance with basal and meal-time needs. Beyond this, the incorporation of amylin analogues within this material will lead to further improved therapeutic outcomes by synchronizing its release with insulin. The outcomes of this work will be characterization and optimization of lead formulations, testing of these in diabetic models, and ensuring the safety necessary to move on to subsequent development and eventual translation into a commercialized therapy.
Relevance to T1D
People with type-1 diabetes, along with their caregivers, live with constant management of the the disease, perform numerous calculations throughout the day to predict insulin need, and rigorously monitor blood glucose. In spite of this, several complications arise from imperfect control. Furthermore, the fear of hypoglycemia causes many of these people to purposely under-dose insulin. An insulin therapy which had more autonomous function may address many of these issues, as it would require less frequent and less precise dosing and adjust the actual amount of insulin available in response to need. Beyond this, only a small fraction of type-1 diabetics who would benefit from amylin combination therapy are actively being managed in this way. The reasons for this are many, but include the present need for multiple injections due to incompatibility of mixing insulin and amylin analogues. Pairing release of insulin and amylin in response to glucose levels would restore more natural insulin/amylin synergy and expand access to dual-hormone therapy for more people.