Nanoparticles offer an on-demand solution to low blood sugar

People living with type 1 or type 2 diabetes lack or have cells unresponsive to insulin. This vital hormone tamps down levels of blood glucose, and in its absence, symptoms like lethargy, retinopathy, organ damage, and stroke can follow.

People with diabetes keep these symptoms at bay by taking medication that lowers glucose levels or by injecting insulin. But after insulin treatment, some people living with diabetes enter a state called hypoglycemia, where their blood sugar levels crash. Hypoglycemia comes with its own risks. Normally, the body will release the hormone glucagon, which tells the liver to raise blood sugar levels by pumping out glucose. In people with impaired glucagon responses, however, the best solution is a candy bar or another source of glucose.

“Acute hypoglycemia and severe hypoglycemia are really very worrisome complications in diabetes, especially when they're associated with so-called hypoglycemia unawareness — when people lose the capability to sense when their blood glucose is dropping,” said Camillo Ricordi , a diabetes researcher at iTolerance, a biotech company developing new therapies for type 1 diabetes. If people cannot sense their glucose dropping, they could lose consciousness or die, Ricordi added.

While medications that get insulin into the body efficiently are well established, the same cannot be said for glucagon delivery. In a new study, researchers at the University of California, Los Angeles (UCLA) hope to change that. They developed a nanosystem that raises blood sugar levels in mice by delivering glucagon precisely when it’s needed (1).

Heather Maynard, a biochemist at UCLA and coauthor of the study, said that the team’s first foray into diabetes involved stabilizing insulin. “When we talked to some diabetes doctors at UCLA, they were excited about our insulin work, but they kept telling me, ‘If you could stabilize or do something with glucagon, we would be really interested,’” said Maynard.

When we talked to some diabetes doctors at UCLA, they were excited about our insulin work, but they kept telling me, ‘If you could stabilize or do something with glucagon, we would be really interested.’
- Heather Maynard, University of California, Los Angeles

Glucagon is a difficult hormone to work with. It’s insoluble in neutral solutions and can break down into cytotoxic fibrils (2). One previous treatment option for hypoglycemia, Eli Lilly’s Glucagon Emergency Kit, required users to pour a powder into an acidic solution to activate the hormone. The kit was discontinued due to side effects from the low-pH solution, said Maynard. Hypoglycemic events often occur at night, she added, making these events harder to detect with conventional testing.

To engineer a solution, Maynard’s team turned to nanomedicine.

In previous research, scientists at Nankai University encapsulated glucagon inside tiny structures called micelles (3). These are particles with both hydrophobic and hydrophilic components that form bubble-like spheres that can hold drugs or other therapeutic molecules. Depending on the hydrophobicity of their surroundings, micelles can keep a drug encapsulated inside of them or release it into the surroundings.

The Nankai University team’s micelles form when exposed to glucose, which stops the encapsulated glucagon from binding to its target receptors. But when glucose levels drop, the hydrophobicity of the structure changes, and the now-soluble micelles pop, releasing glucagon.

These micelles had a limitation. They only formed when glucose levels were much higher than physiologically possible. Maynard and her team took a similar approach, but they altered the micellar polymers’ length and subunit structure so that they could respond to in vivo glucose levels.

In mice, Maynard’s micelles formed at normal glucose levels and, when these levels fell, restored normal blood sugar levels within 40 minutes. Control injections of glucagon increased blood sugar at a similar rate.

The researchers noted that the micelles didn’t lead to any adverse effects or toxicity. As an eventual therapy in people, the micelles could be injected ahead of a hypoglycemic event and left to circulate in the bloodstream, making them a preventive rather than responsive intervention. Ricordi said the technology was intriguing, highlighting that the micelles’ inactivity under normoglycemic conditions would prevent the risk of hyperglycemia caused by excessive glucagon levels.

Much additional study remains before researchers can test the micelles in humans. Maynard said that her team wants to look at how the mice’s immune systems react to the micelles and the effect of long-term dosing.

“A successful nanotechnology to eliminate the risk of severe hypoglycemia would be very important for patients and their families,” said Ricordi.

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