New research provides important insights into diabetic ketoacidosis

Many children who develop type 1 diabetes (the inability to produce insulin and process blood sugar) don't even know they have the condition until symptoms arise. These symptoms are often driven by a severe and sometimes fatal condition called diabetic ketoacidosis (DKA). As insulin levels drop, and blood sugar rises, the body generates molecules called ketones, which are toxic in high concentrations. Kids with DKA can experience organ failure and other serious issues, but why these complications occur is not well understood.

Now, in a paper published in the journal BMJ Open Diabetes Research & Care, researchers have identified inflammatory molecules that increase during DKA. These findings could eventually help clinicians determine why complications occur during DKA treatments.

Recent studies have shown that DKA episodes increase the risk of some long-term diabetes complications, such as kidney disease and declines in cognition. The current study provides important insights into the link between DKA episodes and the increased risk of long-term complications.

"We want to know why some patients who have DKA have increased risk of cognitive decline or diabetic kidney disease later in life, and others are fine," said Nicole Glaser, professor and pediatric endocrinologist at UC Davis Health and senior author of the study. "We want to understand what's responsible for that difference."

Cataloguing inflammatory signals

While it has long been known that DKA is an inflammatory condition, no one comprehensively identified the molecules involved. To learn more, the researchers analyzed blood samples from 123 children, many of them patients with DKA, over a two-year period.

The analyses showed DKA activated a wide range of pro-inflammatory molecules, including cytokines, chemokines and matrix metalloproteinases (MMPs). These inflammatory signals remained elevated for several days after patients recovered.

Linking these inflammatory molecules to the condition could help researchers better understand DKA-related damage. Eventually, these molecular signatures could help physicians determine which kids are at higher risk for long-term health issues related to DKA.

Perhaps the most important and surprising finding was that MMPs were strongly boosted in DKA. MMPs break down other proteins, which give them great potential to cause organ damage. Illuminating MMP roles in DKA could clarify the mechanisms causing that damage.

"Until this study, no one had tried to broadly characterize the inflammatory profile in DKA," Glaser said. "We were surprised to find MMPs playing such a dominant role, and that could really help us. We know that elevated MMP levels can damage the kidneys as well as the blood-brain barrier, which can allow other inflammatory factors or toxic substances to enter the brain and cause damage."

The clinical perspective

Glaser and colleagues have been studying DKA in the lab because they often see these patients in the clinic and have wanted to better understand the disease.

"I became interested in DKA after caring for children who developed severe brain swelling during their treatment," said Zachary Chaffin, assistant clinical professor and first author on the study. "It's a relatively rare complication but it's very dangerous and hard to treat, which in turn makes it hard to forget once you've seen it."

While this DKA inflammatory profile will not immediately influence clinical care, the authors believe the new information could eventually help predict organ injury and support more effective interventions. In addition, now that they've seen how active MMPs are in DKA, the research team plans to refocus their investigations on these potentially dangerous molecules.

"There's very little we can do to change the course of a disease without knowing why it happens," Glaser said. "We really want to understand these inflammatory connections so we can jumpstart the process of developing better therapeutic approaches."