A new injectable to prevent and treat hypoglycemia

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Prof. Heather Maynard

Professor Heather Maynard is co-leader of a group of UCLA researchers who have developed glucose-responsive micelles that encapsulate and protect glucagon, releasing it only when blood sugar levels drop dangerously low, offering a potential new method to prevent hypoglycemia in people with diabetes.

From the Maynard group, the first two authors are former postdoctoral researcher Dr. Daniele Vinciguerra and current postdoctoral researcher Dr. Rajalakshmi Sivasankaran. Other co-authors include former graduate student Dr. Jane Yang, current graduate student Katie Snell, and former postdoctoral researchers Dr. Panos Georgiou and Dr. Théo Pesenti. Maynard’s collaborator on the work is Professor Andrea L. Hevener (UCLA Department of Medicine, Division of Endocrinology, David Geffen School of Medicine), and additional contributors are from the UCLA Crump Preclinical Imaging Technology Center.

UCLA’s Dr. Myung Ki Hong Endowed Chair in Polymer Science, Maynard is a worldwide leader in the area of protein-polymer conjugates, which are important therapeutics for a variety of diseases. She develops new synthetic methods to make the materials, invents new polymers to improve properties such as stability, and demonstrates preclinical efficacy of her conjugates with an eye towards translation for human health. Maynard also works in the area of smart materials for precision medicine: materials that respond to disease states in the body.

From American Chemical Society,  Discover Chemistry,  Science Releases:

“A Glucose-Responsive Glucagon-Micelle for the Prevention of Hypoglycemia”
ACS Central Science

People with diabetes take insulin to lower high blood sugar. However, if glucose levels plunge too low — from taking too much insulin or not eating enough sugar — people can experience hypoglycemia, which can lead to dizziness, cognitive impairment, seizures or comas. To prevent and treat this condition, researchers in ACS Central Science report encapsulating the hormone glucagon. In mouse trials, the nanocapsules activated when blood sugar levels dropped dangerously low and quickly restored glucose levels.

Encapsulated glucagon for insulin-induced hypoglycemia dissolves when sugar levels get seriously low (less than 60 milligrams per deciliter, mg/dL), releasing the hormone into the bloodstream and triggering the liver to release glucose. At normal sugar levels (more than 100 mg/dL), the micelles remain intact, keeping glucagon inactive. Adapted from ACS Central Science 2024, DOI: 10.1021/acscentsci.4c00937

Glucagon is a hormone that signals the liver to release glucose into the bloodstream. It’s typically given by injection to counteract severe hypoglycemia in people who have diabetes. While an emergency glucagon injection can correct blood sugar levels in about 30 minutes, formulations can be unstable and insoluble in water. In some cases, the hormone quickly breaks down when mixed for injections and clumps together to form toxic fibrils. Additionally, many hypoglycemic episodes occur at night, when people with diabetes aren’t likely to test their blood sugar. To improve commercial glucagon stability and prevent hypoglycemia, Andrea Hevener and Heather Maynard looked to micelles: nanoscale, soap-like bubbles that can be customized to assemble or disassemble in different environments and are used for drug delivery. They developed a glucose-responsive micelle that encapsulates and protects glucagon in the bloodstream when sugar levels are normal but dissolves if levels drop dangerously low. To prevent hypoglycemia, the micelles could be injected ahead of time and circulate in the bloodstream until they are needed.

In lab experiments, the researchers observed that the micelles disassembled only in liquid environments that mimicked hypoglycemic conditions in both human and mice bodies: less than 60 milligrams of glucose per deciliter. Next, when mice experiencing insulin-induced hypoglycemia received an injection of the specialized micelles, they achieved normal blood sugar levels within 40 minutes. The team also determined that glucagon-packed micelles stayed intact in mice and didn’t release the hormone unless blood glucose levels fell below the clinical threshold for severe hypoglycemia. From additional toxicity and biosafety studies in mice, the researchers note that empty micelles didn’t trigger an immune response or induce organ damage.

While more studies are needed, the researchers say their proof-of-concept is a first step toward a new on-demand and effective method for preventing or mitigating extremely low blood sugar levels.

The authors acknowledge funding from the Leona M. and Harry B. Helmsley Charitable Trust; BioPACIFIC Materials Innovation Platform funded by the National Science Foundation; the National Science Foundation Graduate Research Fellowship Program; the National Institutes of Health; and the University of California, Los Angeles Clinical and Translational Science Institute.

A Spanish translation of the ACS press release is available here: Una nueva sustancia inyectable para prevenir | EurekAlert!