Glucose‐Operated Widget (GLOW) for Closed‐Loop Optogenetic Glycemic Control

Abstract

AbstractClosed‐loop control systems for precise control of therapeutic gene expression are promising candidates for personalized treatment of chronic ailments such as diabetes. Pancreatic iβ‐cells are engineered with blue‐light‐inducible melanopsin to drive rapid insulin release by vesicular secretion from intracellular stores. In this work, a glucose‐operated widget (GLOW) is designed as a component of a closed‐loop control system for diabetes treatment by employing a probe that emits blue fluorescence in a glucose‐concentration‐dependent manner as a real‐time glucose sensor to precisely control insulin release from these iβ‐cells. As proof‐of‐concept of the complete control system, the probe is encapsulated together with iβ‐cells in alginate‐poly‐(L‐lysine) hydrogel‐microbeads(400 µm in diameter and containing about 500 cells) called GLOWiβ (GLOW with iβ‐cells), are subcutaneously implanted into type‐1‐diabetic (T1D) mice. Illumination by UV‐A light at 390 nm results in glucose‐concentration‐dependent blue‐light emission from the probe at 445 nm that in turn induces glucose‐concentration‐dependent insulin release from the iβ‐cells in a fully reversible manner. Activation of the injected GLOWiβ at 390 nm for 15 min effectively restores normoglycemia within 60–120 min in a closed‐loop manner in these diabetic mice. The system is robust, as normoglycemia is well maintained by daily activation for at least 7 days.