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Metformin Found to Change Blood Metal Levels in Humans

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Although metformin is the most widely prescribed diabetes drug in the world, its mechanism of action is still not clear. Kobe University endocrinologist OGAWA Wataru has now made significant progress, finding that it changes blood metal levels in humans. Photo by Towfiqu Barbhuiya on Unsplash

The widely used diabetes drug metformin may achieve its effects by changing blood metal levels in humans. The Kobe University study is an important step in understanding the drug’s many actions and designing better ones in the future.

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 tumours, 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 OGAWA Wataru 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 analyse 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.”

Source: Kobe University

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Zinc’s Surprising Role in Blood Pressure

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Source: Wikimedia CC0

Researchers have discovered that a trace element, zinc, plays a previously unknown role in the regulation of blood pressure.

While the role of metals like potassium and calcium have been long known in this process, a new discovery about zinc’s critical and underappreciated role offers a potential new pathway for therapies to treat hypertension. While hypertension had been known to be associated with low zinc levels, it was not clear as to why.

The findings were published recently in Nature Communications.

The smooth muscle cells lining blood vessels regulate the speed at which the blood travels around the body. As smooth muscles contract, they narrow the artery, increasing blood pressure, and as the muscle relaxes, the artery expands and blood pressure falls. Too low a blood pressure, and the blood flow will be insufficient to sustain body tissues. If blood pressure is too high, the blood vessels risk being damaged or even ruptured.

“Fundamental discoveries going back more than 60 years have established that the levels of the calcium and potassium in the muscle surrounding blood vessels control how they expand and contract,” said lead author Ashenafi Betrie, PhD, and senior authors Scott Ayton, PhD, and Christine Wright, PhD, of the Florey Institute of Neuroscience and Mental Health and The University of Melbourne in Australia.

Specifically, the researchers explained, potassium regulates calcium in the muscle, and calcium is known to induce the narrowing of the arteries and veins that elevate blood pressure and restrict blood flow. Other cells surrounding the blood vessel, including endothelial cells and sensory nerves, also regulate the calcium and potassium within the muscle of the artery, and are themselves regulated by the levels of these metals contained within them.

“Our discovery that zinc is also important was serendipitous because we’d been researching the brain, not blood pressure,” said Dr Betrie. “We were investigating the impact of zinc-based drugs on brain function in Alzheimer’s disease when we noticed a pronounced and unexpected decrease in blood pressure in mouse models treated with the drugs.”

The investigators discovered that coordinated action by zinc within sensory nerves, endothelial cells and the muscle of arteries triggers lower calcium levels in the muscle of the blood vessel. This causes the vessel to relax, decreasing blood pressure and increasing blood flow. The scientists found that the brain and heart’s blood vessels were more sensitive to zinc than blood vessels in other areas of the body, warranting further research.

“Essentially, zinc has the opposite effect to calcium on blood flow and pressure,” said Dr Ayton. “Zinc is an important metal ion in biology and, given that calcium and potassium are famous for controlling blood flow and pressure, it’s surprising that the role of zinc hasn’t previously been appreciated.”

This research also explains the fact that the genes that control intracellular zinc levels are known to be associated with cardiovascular diseases including hypertension, and hypertension is also a known side effect of zinc deficiency.

“While there are a range of existing drugs that are available to lower blood pressure, many people develop resistance to them,” said Dr Wright, who added that a number of cardiovascular diseases, including pulmonary hypertension, are poorly treated by currently available therapies. “New zinc-based blood pressure drugs would be a huge outcome for an accidental discovery, reminding us that in research, it isn’t just about looking for something specific, but also about just looking.”

Source: Medical Xpress