UCLA researchers in the Department of Chemistry and Biochemistry have developed a novel glucose-responsive drug delivery system that enables the controlled release of glucagon for the prevention of hypoglycemia.
BACKGROUND: Diabetes is a metabolic disorder in which the body cannot properly regulate blood sugar levels due to the loss of insulin-producing β-cells in Type 1 Diabetes or the development of insulin resistance in Type 2 Diabetes. In healthy individuals, blood glucose is controlled by two key hormones: Insulin lowers blood sugar when levels are high and glucagon raises it when levels are low. In diabetic patients, insulin therapy is commonly used to treat high blood sugar, but it can also lead to hypoglycemia, a dangerous condition characterized by abnormally low blood glucose.
Glucagon is used as an emergency medication to treat insulin-induced hypoglycemia, which can lead to malaise, cognitive impairment, seizure, and coma. A major limitation of glucagon formulations is that they often degrade quickly in aqueous media and exhibit low solubility. Recent efforts have generated more stable and soluble glucagon analogues, but these treatments are reactive and only address hypoglycemia after it occurs. More advanced systems, such as dual-hormone pumps, attempt to balance insulin and glucagon delivery, but they rely on external devices and continuous monitoring, which adds complexity and limits accessibility.
An ideal approach would prevent hypoglycemia before it occurs by automatically releasing glucagon when blood sugar reaches the counterregulatory level. This would combine glucose sensing and drug delivery into a single system and offer a shift from reactive treatment to proactive prevention of hypoglycemia.
INNOVATION: Researchers at UCLA, led by Dr. Heather Maynard, have developed a novel glucose-responsive glucagon delivery platform using phenyl boronic acid (PBA)-engineered responsive micelles. Under normoglycemic conditions, these micelles self-assemble. However, under hypoglycemic conditions, these micelles disassemble, enabling the controlled release of glucagon at the appropriate time to reduce the risk of hypoglycemic episodes. Researchers found that the glucagon–polymer conjugate demonstrated five-fold increased biological activity compared to glucagon alone in vitro. Furthermore, researchers demonstrated that these micelles were safe in vivo, did not accumulate in organs, and successfully regulated glucose levels in a mouse model of insulin-induced hypoglycemia. Importantly, no glucagon was released at moderate hypoglycemia or normoglycemic conditions, further affirming the safety of this technology. Thus, this technology serves as a translational, responsive glucagon delivery platform that can prevent insulin-induced hypoglycemia.
POTENTIAL APPLICATIONS:
ADVANTAGES:
DEVELOPMENT-TO-DATE: This technology has been shown to be both safe and effective in preventing and reversing insulin-induced hypoglycemia in in vivo mouse studies.
Related Papers (from the inventors only):
Vinciguerra D, Rajalakshmi P S, Yang J, Georgiou PG, Snell K, Pesenti T, Collins J, Tamboline M, Xu S, van Dam RM, Messina KMM, Hevener AL, Maynard HD. A Glucose-Responsive Glucagon-Micelle for the Prevention of Hypoglycemia. ACS Cent Sci. 2024 Oct 2;10(11):2036-2047. doi: 10.1021/acscentsci.4c00937. PMID: 39634211; PMCID: PMC11613347.
Keywords: Diabetes, hypoglycemia, cardiometabolic, Type-1 diabetes, Type-2 diabetes, hyperinsulinemia, blood sugar, micelle, platform, glucagon, polymers, phenyl boronic acids, nanomaterials