(262d) Graduate Student Award Session: Glucose-Fueled Peptide Self-Assembly for Hypoglycemia Rescue

Intensified insulin treatment in diabetics presents risk of acute hypoglycemia (blood glucose level, BGL < 70 mg/dL) leading to life-threatening complications. More than 3 million severe hypoglycemic emergency visits occur in the United States each year. Upon experiencing a severe hypoglycemic episode, the administration of exogenous glucagon, a peptide hormone signaling a rise in glucose levels, may need to be administered. However, consciousness is often impaired upon severe hypoglycemia and when combined with frequent occurrence of hypoglycemia at night the result is a limited capacity for self-administration. These risks are especially concerning diabetic children. Therefore, an autonomous and smart system for a precise glucagon delivery is urgently needed.

The living world offers many examples of materials, such as actin and microtubule cytoskeletal elements, that exist transiently under the continuous presence of a consumable sources of energy such as ATP or GTP. This has inspired recent efforts in the field of supramolecular systems chemistry to achieve transient nonequilibrium materials that exist under direction of a continuous source of energy. Glucose oxidase (GOx), an enzyme that converts glucose to gluconic acid, has been widely used to prepare glucose-responsive materials for insulin delivery by actuating glucose level into a pH change that alters material formation and lifetime. Here, we incorporated GOx to drive peptide self-assembly in order to develop a supramolecular nanofibrillar hydrogel that could encapsulate glucagon in the presence of normal glucose levels but would dissociate to release glucagon if glucose fuel became limited.

The resulting material demonstrated both pH- and glucose-dependent self-assembly and gelation, forming more stable hydrogels at either lower pH or higher glucose concentration. Rheological testing revealed shear-thinning and self-recovery character ideal for injection-based delivery. Additionally, in vitro release studies demonstrated glucose-dependent glucagon release, with accelerated release rate and increased release amount in a manner inversely related to glucose concentrations. Subsequently, these materials were evaluated in a protective capacity in diabetic mice exposed to an insulin overdose. Mice administrated glucose-fueled hydrogels prior to induction of hypoglycemia had limited onset and severity of hypoglycemia and more rapid recovery. Comparatively, control mice treated with buffer or glucagon alone showed more severe hypoglycemia. Accordingly, the supramolecular peptide material prepared here to be under direction of a glucose fuel was demonstrated as a useful strategy for protective delivery of glucagon to combat a subsequent hypoglycemic episode.