How an enzyme helps control blood sugar after meals

A recent study published in Life Metabolism has uncovered a surprising new player in the body’s ability to regulate blood sugar after eating. Researchers from Baylor College of Medicine and the University of Namur found that an enzyme called hyaluronidase-1 (HYAL1) plays a crucial role in suppressing excessive glucose production in the liver, particularly after meals. This discovery could open new doors for treating metabolic disorders like type 2 diabetes, where blood sugar control is impaired.

The study focused on hyaluronan (HA), a sugar molecule that naturally surges in the bloodstream after eating. While HA is known for its roles in tissue structure and inflammation, this research reveals its unexpected connection to glucose metabolism. The team discovered that HYAL1, which breaks down HA in the liver, helps shut down gluconeogenesis—the process by which the liver produces glucose from non-carbohydrate sources. Normally, gluconeogenesis is suppressed after meals to prevent blood sugar spikes, but in diabetes, it remains overactive.

Using genetically modified mice, the researchers found that deleting the Hyal1 gene led to higher glucose production, especially in mice fed a high-fat diet. Conversely, boosting HYAL1 levels in the liver improved glucose tolerance and reduced gluconeogenesis, even in insulin-resistant animals.

Digging deeper, the team uncovered the mechanism: HYAL1’s breakdown of HA redirects cellular Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), reducing a key modification (O-GlcNAcylation) on mitochondrial proteins that are key in energy metabolism (Figure 1). This lowers ATP production, making it harder for the liver to sustain glucose synthesis. Importantly, this regulation remains functional even in insulin-resistant conditions, making it an attractive target for therapies.

While more research is needed to quantify the contribution of this pathway, the study provides a fresh perspective on how the body fine-tunes glucose metabolism beyond the classic insulin-glucagon system. With diabetes affecting millions worldwide, this research highlights an overlooked yet vital piece of the metabolic puzzle that could lead to new strategies for managing diabetes, such as enhancing HYAL1 activity or manipulating HA levels after meals.