Metformin is the most widely prescribed diabetes drug in the world. Apart from lowering blood sugar levels, it is also known to have a broad range of beneficial side effects such as against tumors, inflammations and atherosclerosis. However, although it has been used for more than 60 years now, its mechanism of action is still not clear, hampering the development of even better drugs against these conditions.

Kobe University endocrinologist Wataru Ogawa says: "It is known that diabetes patients experience changes in the blood levels of metals such as copper, iron and zinc. In addition, chemical studies found that metformin has the ability to bind certain metals, such as copper, and recent studies showed that it is this binding ability that might be responsible for some of the drug's beneficial effects. So, we wanted to know whether metformin actually affects blood metal levels in humans, which had not been clarified." To do so, Ogawa and his team enlisted about 200 diabetes patients at Kobe University Hospital, half of which took metformin and half of which did not, in a study to analyze their blood serum levels for those metals and various metal deficiency indicators.

In the journal BMJ Open Diabetes Research & Care, the Kobe University team now published the first clinical evidence of altered blood metal levels in patients taking metformin. They showed that drug-taking patients have significantly lower copper and iron levels and heightened zinc levels. Ogawa says: "It is significant that we could show this in humans. Furthermore, since decreases in copper and iron concentrations and an increase in zinc concentration are all considered to be associated with improved glucose tolerance and prevention of complications, these changes may indeed be related to metformin's action."

Recently, Japan has approved the use of imeglimin, a new diabetes drug that is a derivative of metformin but that should not be able to bind metals the same way as its parent. "Imeglimin is thought to have a different method of action, and we are already conducting studies to compare the effects the two drugs have," says Ogawa.

It is not just about understanding the current drugs, however. Ogawa explains the bigger picture, saying: "We need both clinical trials and animal experiments to pinpoint the causal relationship between the drug's action and its effects. If such studies progress further, they may lead to the development of new drugs for diabetes and its complications by properly adjusting the metal concentrations in the body."

This research was funded by the Japan Society for the Promotion of Science (grant 24H00638) and the Manpei Suzuki Diabetes Foundation. It was conducted in collaboration with a researcher from the Kagayaki Diabetes and Endocrinology Clinic Sannomiya.

With support from the Commonwealth of Virginia's Alzheimer's and Related Diseases Research Award Fund (ARDRAF), Fralin Biomedical Research Institute at VTC scientists Sharon Swanger and Shannon Farris are working to understand why this area is especially vulnerable.

Swanger studies how brain cells communicate across synapses in disease-susceptible brain circuits, while Farris focuses on how different circuits in the brain's memory center function at the molecular level. Their overlapping expertise made the collaboration a natural fit.

"We've both been studying how circuits differ at the molecular level for a while," said Swanger, an assistant professor at the research institute. "This new collaborative project brings together my work on synapses and Shannon's on mitochondria in a way that addresses a big gap in the Alzheimer's disease field."

"This kind of state-level support is critical," Farris said. "It gives researchers in Virginia the chance to ask questions that may eventually make a difference for people living with Alzheimer's. It's meaningful to be part of research that could help people facing that journey."

A key focus of their research is mitochondria -- tiny structures inside brain cells that provide the energy needed for a variety of cellular functions in neurons including synaptic transmission. In Alzheimer's disease, mitochondria stop working properly in the course of the disease.

Farris and Swanger are investigating whether mitochondria in a vulnerable memory-related circuit may become overloaded with calcium, a key signaling chemical for multiple neuronal and synaptic processes. That overload could contribute to the early breakdown of memory circuits.

"The connection between these cells is one of the first to fail in Alzheimer's," Farris said. "We found that this synapse has unusually strong calcium signals in nearby mitochondria -- so strong we can see them clearly under a light microscope. Those kinds of signals are hard to ignore. It gives us a model where we can really watch what's happening as things start to go wrong."

To test their hypothesis, the researchers will study brain tissue from healthy mice and mice with certain aspects of Alzheimer's pathology. By comparing how mitochondria function and how brain cells communicate across synapses in each group, they hope to find early signs of stress or failure in the entorhinal cortex-hippocampus circuit.

Swanger and Farris are members of the Fralin Biomedical Research Institute's Center for Neurobiology Research and also faculty in the Department of Biomedical Sciences and Pathobiology of the Virginia-Maryland College of Veterinary Medicine.