A "textbook" view of what the body does after a meal has been overturned by a team led by researchers from the Institute for Diabetes, Obesity and Metabolism (IDOM) at the Perelman School of Medicine, University of Pennsylvania.
The study appears online this week in Nature Medicine, in advance of print publication.Normally after a meal, insulin shuts off glucose production in the liver, but insulin resistance - when the hormone becomes less effective at lowering blood sugars - can become a problem.
The Penn group showed that mice without the genes Akt1 and Akt2 in their livers were insulin resistant and defective in their response to feeding with respect to blood sugar levels. In these mice, blood sugar levels remained high after a meal. When Akt is not present, another gene, Foxo, is on all the time, and the liver "thinks" the body is fasting. In response, glucose production stays on to keep cells supplied in energy-rich molecules. But then, says senior author Morris Birnbaum, MD, PhD, professor of medicine and IDOM Associate Director, "In further experiments, we expected that Akt and Foxo knockout mice - when we gave them a meal - to be locked into a fed state metabolically if both proteins were gone," says Birnbaum. "But, the liver responded normally after a meal, so we asked what is regulating the liver and glucose production in the absence of both the Akt and Foxo proteins?" These results are inconsistent with the textbook model of liver metabolism that the Birnbaum lab proposed a decade ago, in which the Akt protein is absolutely required for proper insulin signaling. The team surmised that there must be a backup pathway in the liver that governs glucose metabolism.Back ThenTen years ago, a study in Science by Birnbaum's research group described that the inactivation of the protein Akt2 led to diabetes in mice. The result was that insulin was not working in the fat cells and liver of these mice, proving that Akt is required for insulin to function properly. From then on, an accepted pathway for insulin control of blood sugar was that the Akt protein turned off Foxo1, a protein that governs genes that make glucose. Specifically, when Foxo1 is on, it drives glucose production.