Glucagon is a peptide hormone, critical for maintenance of glucose homeostasis. Glucagon acts to increase blood glucose by signaling the liver to release glucose from stored glycogen under hypoglycemic conditions. In this work, we are trying to achieve controlled glucagon delivery using light to incorporate it into a minimally invasive light controlled artificial pancreas. The light activated glucagon material must be sufficiently insoluble to form a depot under skin after injection and release native glucagon hormone upon transdermal irradiation. We designed a glucagon trimer which has a hydrophobic core that can be attached to three glucagon molecules via photocleavable groups. The resultant glucagon trimer has ~175x less solubility than that of the native glucagon, and thus can potentially form an insoluble depot under skin. Soluble glucagon can then be released in varying amounts by irradiating the depot with varying amounts of light using a source placed on the skin above the site of injection. We demonstrated the photorelease of native glucagon from the trimer at pH 7.2 and fitted the release to a first order rate law. Furthermore, we hypothesized and subsequently demonstrated that modified glucagon in the trimer is stable and does not undergo fibrillation unlike native glucagon. On aging, native glucagon in solution fibrillates in approximately 10 hours, while we observed no signs of fibrillation in trimer up to 70 hours. Due to its resistance to fibrillation and its ability to deliver native glucagon in response to light, the trimeric DMNPE-caged glucagon is an ideal material for use in in vivo systems. The ultimate application of the photoactivated glucagon trimer is to complement the photoactivated insulin system. This then can allow tighter bi-hormonal control of blood glucose in diabetics.

Fibrillation resistant, photoactivated glucagon trimer for the light activated artificial pancreas

ACS Fall 2021

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