Obesity and damaged liver are considered the main causes of type 2 diabetes. However, studying the degree each has on the disease has been difficult. In a new report published in FEBS Letters, CiRA researchers describe a new mouse model that explains how insulin intolerance develops with only hepatocyte injury. This finding could provide new therapeutic strategies for patients without obesity.

The risk of diabetes has been well associated with a person's genes. "People with a specific variant of the Prox1 gene show more fat and are more at risk of diabetes," says CiRA Professor Yoshiya Kawaguchi.

The role of Prox1 on fat is relatively well established, but its role in hepatocyte injury is relatively unknown. "We know how Prox1 regulates liver development," he added, "but we do not know its role in adult liver," which is when type 2 diabetes is more likely to occur.

The Kawaguchi lab therefore prepared mutant mice in which the Prox1 gene could be inactivated exclusively in hepatocytes. The mice showed glucose intolerance and impaired liver function but no additional fat accumulation. The liver dysfunction was attributed to hepatocyte injury, but surprisingly to a very specific region of the liver.

"Hepatocytes can be divided into regions based on their metabolic function," explains surgeon Dr. Toshihiko Goto, who first authored the study. "Perivenous hepatocytes conduct glycolysis," and "periportal hepatocytes conduct OXPHOS (oxidative phosphorylation)," he said.

The inactivated Prox1 caused injury to the perivenous region of the liver, where hepatocytes showed defective glycolysis and energy starvation , which stimulated autophagy to meet the energy demand. On the other hand, periportal hepatocytes showed no morphological changes.

Interestingly, mitochondria in the perivenous hepatocytes resembled those in periportal mitochondria, which suggested a change in energy metabolism. "We think hepatocyte injury in the perivenous hepatocytes caused glycolysis to switch to OXPHOS," said Goto.

Because the glucose intolerance was only accompanied by changes in hepatocyte metabolism, Kawaguchi proposes the study could indicate the possibility of diabetes treatment for non-obese patients.

"Our findings suggest if we can find drugs that control the liver metabolism, we may be able to prevent or even reverse glucose intolerance," he says.

• doi: 10.1002/1873-3468.12570