ABSTRACT
Previously we have demonstrated that light can be used to control the release of insulin in diabetic animals, followed by a reduction in blood glucose. This is accomplished using a photoactivated depot (PAD) of insulin injected into the skin, and irradiated by a small external LED light source. In this work for the first time we demonstrate dose-response, showing that we can vary insulin release and commensurate blood glucose reduction by varying the amount of light administered. In addition to demonstrating dose-response, we have shown multi-day depot response, with insulin being released on two different days from the same depot. The material used in these studies was CD-insulin, a form of insulin that has a highly non-polar cyclododecyl group attached, markedly reducing the solubility of the modified material, and allowing it to form a depot upon injection. Upon photolysis, the cyclododecyl group is removed, releasing fully native, soluble insulin. Variable response and multi-day response as demonstrated strongly support the potential utility of the PAD approach for the variable and extended release of therapeutic peptides.
Subject(s)
Blood Glucose , Insulin , Animals , Skin , Solubility , PhotolysisABSTRACT
In this work, we have brought the release of glucagon under the control of light. The aim of this approach is to allow minimally invasive, two-hormone control of blood glucose. Glucagon has two major challenges associated with its therapeutic application: (1) the required amount and timing of glucagon release is highly variable, and (2) glucagon rapidly fibrillates in solution, forming aggregates that are inactive. We have developed a light activated glucagon trimer, in which we have joined three glucagon molecules via light cleaved linkers. We demonstrated that this material can be stimulated by light to release glucagon in a predictable manner. In addition, we demonstrated that in the absence of light, the trimer does not form fibrils and thus releases normal unfibrillated glucagon upon irradiation. These qualities make this material ideal for incorporation into a two hormone light-activated artificial pancreas system.
Subject(s)
Glucagon , Pancreas, Artificial , Blood Glucose , InsulinABSTRACT
A conceptually new and general strategy has been developed for the construction of a benzimidazole or a benzoxazole ring fused with isoquinolinone affording a diverse and unique class of small molecules as potential and novel inhibitors of PDE4.