In type 2 diabetes, the liver floods the bloodstream with three times more glucose than does a healthy liver, while at the same time storing more and more fat that can lead to chronic liver disease, cirrhosis, and liver cancer.
The reason we like fat and sugar is obvious, but the diabetic liver is an enigma to diabetes researchers. Though glucose production goes up because the liver ignores insulin’s signals to turn it off, fat increases because the liver paradoxically continues to obey insulin’s signals to store fat.
This fact presents a conundrum for researchers trying to develop diabetes drugs. Drugs cannot reduce the liver’s sugar production without also increasing its fat content.
Now two physician-scientists at Columbia’s Naomi Berrie Diabetes Center may have found a solution. Reporting in Nature Medicine, Utpal Pajvani MD, PhD, and Domenico Accili, MD, show that, in mice, inhibiting a protein in the liver called Notch reduces glucose production and decreases liver fat at the same time.
“Even when the animals are fed a high-fat diet and gain weight, inhibiting Notch protects from diabetes, insulin resistance, and fatty liver,” Pajvani says.
Until now, Notch wasn’t known to be active in the adult liver. But because it’s well known in cancer, drugs that inhibit Notch are already being tested in clinical trials for leukemia and other cancers.
Although multiple medications are approved for type 2 diabetes, few address the underlying problem
“Although multiple medications are approved for type 2 diabetes, few address the underlying problem—insulin resistance,” Pajvani says. “In addition, no medications are approved for fatty liver disease, the number one cause for chronic liver disease and fastest-growing reason for liver transplantation. Notch inhibitors, if efficacious in clinical trials and approved for this purpose, may have immediate impact on both patient populations.”