It is known that being overweight or obese leads to poor health, but it may be less known that abdominal fat is the most harmful type. Until now, researchers were unsure of the mechanisms responsible for this—but now, they reveal how an enzyme produced by our liver raises the risk of diabetes.

When it comes to the harmful consequences of excess fat, the way it is distributed across the body is key.

Recent studies have shown that abdominal fat is deeply tied to type 2 diabetes and heart disease.

We have also covered studies suggesting that women, in particular, could be at an increased cardiometabolic risk if they have a higher waist-to-hip ratio.

Additional research has found that belly fat is particularly dangerous when inflamed. Older studies have shown that local inflammation in the adipose tissue leads to cardiometabolic abnormalities, such as insulin resistance.

But the exact mechanism responsible for this connection between adipose tissue inflammation and cardiometabolic disorders has remained somewhat unclear—for instance, researchers have wondered whether the inflammation is "a cause or a consequence of insulin resistance."

Now, researchers at Columbia University Irving Medical Center in New York City, help to shed some much-needed light on the issue; they reveal that the liver contributes to this inflammation.

The team was led by Dr. Ira Tabas—who is the Richard J. Stock Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons—and the findings were published in the journal Nature.

The key role of DPP4 inhibitors in diabetes

Dr. Tabas and his colleagues used obese mice to test whether blocking an enzyme called DPP4 would lower the inflammation in their abdominal fat.

The researchers focused on DPP4 because humans who already have diabetes are prescribed DPP4 inhibitors to help them manage their symptoms. DPP4 inhibitors work by preventing the enzyme from interacting with an insulin-boosting hormone.

In this study, DPP4 did not lower abdominal inflammation in mice. Dr. Tabas explains these findings, suggesting that they may be down to the difference between how DPP4 inhibitors work in the gut vs how they work in the liver.

"DPP4 inhibitors lower blood sugar by inhibiting DPP4 in the gut. But we have some evidence that DPP4 inhibitors in the gut also end up promoting inflammation in fat," he states. "That cancels out the anti-inflammatory effects the drugs may have when they reach inflammatory cells, called macrophages, in the fat."

"From our studies," adds Dr. Tabas, "we know that DPP4 interacts with a molecule on these cells to increase inflammation. If we could block that interaction, we might be able stop the enzyme from causing inflammation and insulin resistance."

So, the researchers targeted DPP4 in the liver cells instead of the gut. This reduced adipose inflammation and lowered insulin resistance.

DPP4 inhibitors also decreased blood sugar.

Toward human clinical trials

As Dr. Tabas reports, "Inhibiting DPP4 specifically in liver cells attacks insulin resistance—the core problem of type 2 diabetes—at least in our preclinical models."

The researchers explain what the findings mean for future treatments of type 2 diabetes. Dr. Tabas says, "If we can develop ways to target liver DPP4 in people, this may be a powerful new way to treat obesity-induced type 2 diabetes."

Dr. Ahmed A. Hasan, a medical officer and program director in the Atherothrombosis & Coronary Artery Disease Branch of the National Heart, Lung, and Blood Institute, also comments on the findings.

He says, "This study reveals a potential new target for the treatment of type 2 diabetes and cardiometabolic disorders."

"These findings may pave the way for a future clinical trial to test whether a new treatment approach based on this target could improve insulin resistance in diabetic patients. More research is needed."

Dr. Ahmed A. Hasan