Drs. Adria Giacca's & Gary Lewis's Perspective Featured in Special Insulin Issue of Cell Metabolism

Drs. Giacca and Lewis were invited to contribute a perspective on “Direct and indirect control of hepatic glucose production by insulin” for a special issue of Cell Metabolism celebrating 100 years of insulin, along with additional co-authors who have done recent work on the subject. 

Giacca and Lewis explained that one of the most important things insulin does is to act as a highly regulated brake on the production of glucose by the liver.

Typically, the pancreas drains insulin into a big vein called the portal vein, it’s “filtered” there and about half goes out via the general circulation to the rest of the body. 

“One would assume that insulin is just acting directly on the liver to suppress its production of glucose,” Lewis said. “But over the years, we've realized that insulin also controls the production of glucose by the liver indirectly, in various ways.” These indirect actions include the reduction of fatty acids released by fat tissues, suppression of the hormone glucagon by the pancreas and the activation of certain neural signals in the brain, all of which in turn reduce glucose production by the liver. 

“And, so, the debate and the experiments over many years have been: ‘Which way is more important? Direct or indirect action?” Lewis continued. “Which dominates? And under what physiological conditions?’” Their review focuses on experiments conducted primarily by three research groups, including their own, that had both concordant and somewhat conflicting results.

“It’s still not been fully resolved,” Giacca said. “But what came out of the review was that Alan Cherrington’s team is right in claiming that the direct action is dominant. But the indirect action, postulated by the Bergman group, is also relevant and acts as a kind of Plan B.”

“Why is that important? Why do we care?” Lewis added. “Because, when people with diabetes are treated with insulin, they take it by injection or insulin pump under the skin, not into the portal vein that leads directly to the liver. This is the reverse of the normal physiology of insulin delivery to the body.  As a result, the insulin levels in the blood need to be much higher when you’re taking insulin under the skin to have the same glucose-suppressive effect on the liver. So, as we develop more physiological ways of replacing insulin, we need to consider the route of delivery.”

“Elucidating what’s going on physiologically could have an important effect on treatments,” Giacca concluded.