ESPE Yearbook of Paediatric Endocrinology

Brief summary: In this experimental study, a transdermal polymeric microneedle (MN) patch for glucose-responsive closed-loop insulin and glucagon delivery was developed. In chemically-induced type 1 diabetes (T1D) mouse and minipig models, this glucose-responsive dual-hormone MN patch demonstrated tight regulation in blood glucose.

The interplay between insulin and glucagon is essential for blood glucose regulation in individuals with or without diabetes. Over the last decades several glucose-responsive insulin delivery systems have been developed to improve glucose management in people with diabetes. The available systems are mainly single hormone and based on insulin delivery modulated by sensor glucose levels (1). There is growing interest in the development of dual-hormone (insulin and glucagon) closed loop systems in order to minimize the risk of hypoglycemia, which is still a barrier against the achievement of optimal glycemic targets (1).

In this study, a unique glucose-responsive MN patch, loaded with both insulin and glucagon, was developed and tested in mouse and pig models of diabetes. A key component of the MN patch was the glucose-responsive phenylboronic acid unit, which binds to glucose to reversibly shift the net charge of the entire polymeric matrix within the MN. This allows a modulated release ratio of the negatively charged insulin or the positively charged glucagon from the patch in response to glucose levels. On exposure to hyperglycemia, the increased negative charge density due to the formation of the glucose-borate complex enhances electrostatic repulsion between the negatively charged insulin and the polymeric matrix, leading to insulin release, whereas the positively charged glucagon remains in the MN. Conversely, on exposure to hypoglycemia, the net charge of the polymeric matrix switches from negative to positive due to the disassociation of the glucose-borate complex, thus inhibiting insulin release and facilitating glucagon release. The system was validated in streptozotocin-induced diabetes mouse and minipig models, confirming that the dual hormone MN patches could mimic the function of pancreatic islets to achieve ideal glycemic targets and reduce the risk of hypoglycemia.

This study is an important step towards the development of a dual glucose responsive closed loop system, to be potentially used in people with T1D to allow a tighter regulation of glucose levels and particularly to reduce episodes of hypoglycemia.

Reference: 1. Lakshman R, Boughton C, Hovorka R.The changing landscape of automated insulin delivery in the management of type 1 diabetes. Endocr Connect. 2023;10.1530/ec-23-0132.