The umbilical brain path for metformin was revealed 60 years later

“It has been widely accepted that metformin reduces blood glucose in the first place by limiting the production of glucose in the liver. Other studies have found that it works through the intestine,” said the opposite author, Dr. Makoto Fukuda, Associate Professor of Pediatrics – Baylaor. “We have looked at the brain because it is widely known as a major organizer of the full body glucose metabolism. We have achieved whether the brain contributes to the anti -scurn effects.”

The team focused on a small protein called RAP1, found in a specific part of the brain known as the abdominal hypothalamus (VMH). The researchers have discovered that metformin’s ability to lower blood sugar in clinically relevant doses depends on turning off the RAP1 in this brain area.

To test this, use the Fukuda laboratory and its genetically modified mice lacked RAP1 in VMH. These mice are feed in a high -fat diet to imitate type 2 diabetes. When it gave low doses of metformin, the drug failure to reduce blood sugar. However, other diabetes medications such as insulin and GLP-1 stimuli are still working.

To show that the brain is a main player, researchers injected small amounts of metformin directly into the brains of diabetic mice. The result was a significant decrease in blood sugar, even with doses smaller than what is usually provided by mouth.

Fukuda said: “We have also searched any cells in VMH that have participated in the effects of metformin,” Fukuda said. “We have found that SF1 nerve cells are activated when the metformin is inserted into the brain, indicating that they are directly involved in the functioning of the drug.”

Using the brain slices, scientists recorded the electrical activity of these neurons. Metformin has made most of them more active, but only if RAP1 is present. In the mice that lack RAP1 in these neurons, metformin had no effect, indicating that RAP1 is necessary for metformin for these “brain cells” and low blood sugar.

“This discovery changes how we think about Metformin,” Fukuda said. “It not only works in the liver or intestine, but also works in the brain. We found that while the liver and intestine need high concentrations of the drug to respond, the brain interacts with much lower levels.”

Although a few anti -diabetes drugs work on the brain, this study shows that metformin used widely was doing it all the time. “These results open the door to develop new diabetes treatments that target this path directly in the brain,” Fukuda said. “In addition, metformin is known for other health benefits, such as slowing the aging of the brain. We plan to investigate whether the RAP1 signals themselves are responsible for other effects of well -documented the drug on the brain.”

Among the other contributors to this work are Hsiao-Yun Lin, Weisheng Lu, Yanlin He, Yukiko Fu, Kentaro Kaneko, Peming Huang, Ana B De La Puente-Gomez, Chunmei Wang, Yongjie Yang, Feng Li and Yong Xu. The authors belong to one or more of the following institutions: Baylor College of Medicine, Louisiana State University, Nagoya University – Japan and Megi University – Japan.

This work was supported by: National Institutes of Health (R01DK136627, R01DK121970, R01DK093587, R01Dk101379, P30-DK079638, R01Dk104901, R01Dk126655), USDA/ARS (6250-51000-055), Heart Association American (14bgia20460080, 15post22500012) and the American Diabetes Association (1-17-PDF-138). More support was provided by the UEHARA Memorial Foundation, Takeda Science Foundation, Japan Applied Enzyme Foundation, Crot and Core Metabolism at Baylor College of Medicine.