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Scientists have unveiled a potential new diabetes preventive strategy

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Obese mice are protected from diabetes-like metabolic alterations by an experimental drug.

A group of researchers has done encouraging early testing of a novel technique that might be used to prevent or cure type 2 diabetes in the future. Obese mice were used to test an experimental drug named IXA4. They discovered that the drug stimulates a natural signaling system in the animals that shields them from detrimental, obesity-related metabolic alterations that might otherwise lead to diabetes.

Scripps Research scientists have undertaken encouraging early testing of a novel technique that might be used to prevent or cure type 2 diabetes in the future.

The researchers used fat mice to test an experimental chemical named IXA4. Their findings were published in Nature Communications. They discovered that the drug stimulates a natural signaling system in the animals that shields them from detrimental, obesity-related metabolic alterations that might otherwise lead to diabetes.

“With this one molecule, we were able to activate this pathway in both the liver and the pancreas, which resulted in a large overall improvement in metabolic health in obese animals,” explains Luke Wiseman, PhD, of Scripps Research.

Enrique Saez, PhD, adds, “This is the first time anybody has proved that a little chemical stimulating this system in this manner helps to cure sickness in a live animal.”

The research was a partnership between Saez and Wiseman’s labs, who are both professors in Scripps Research’s Department of Molecular Medicine and co-senior authors on the current publication.

Type 2 diabetes is still a serious public health issue in the United States, with an estimated 30 million individuals suffering from it. It is characterized by the lack of normal blood sugar management and is associated with a slew of health problems, including an increased risk of heart disease, stroke, kidney disease, nerve damage, retinal degeneration, and several malignancies. There are several medicines available to treat type 2 diabetes, but none of them are effective for every patient.

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Wiseman’s team has been examining a signaling system including two proteins termed IRE1 and XBP1s for many years. When IRE1 is triggered by a certain form of cellular stress, it activates XBP1s, which then changes the activity of a large number of genes, including many metabolic genes, in an attempt to relieve cellular stress. Prior research suggests that this pathway’s activation may protect liver and fat cells from stress induced by obesity, at least in the short term — stress that might injure these cells in ways that promote diabetes.

However, the IRE1/XBP1s pathway is not an easy target for diabetic drugs. Keeping IRE1/XBP1 turned on for an extended period of time has been found to injure cells, cause inflammation, and increase overall metabolic dysfunction.

“IRE1/XBP1 signaling is a reaction to cellular stress, and having it on all the time effectively communicates the cell that the stress can’t be handled,” Wiseman explains.

The researchers found that IXA4, a molecule they discovered a few years ago, stimulates IRE1/XBP1s for just a few hours at a time in the latest investigation. Because it permits IRE1 to switch off in different ways, it may theoretically be administered daily without causing the harmful signals found with persistent IRE1 activation, making it an intriguing option for human therapy.

The researchers utilized IXA4 to treat obese mice that had been fed a high-fat, high-calorie diet. In comparison to untreated obese mice, the treated animals exhibited better glucose metabolism and insulin activity after only eight weeks, as well as decreased fat deposition and inflammation in the liver and no loss of insulin-producing cells in the pancreas.

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Because IXA4 can only reach a small number of organs, such as the liver and pancreas, the team is currently working on alternative chemicals that can reach a larger number of cells, including fat cells.

“We’re also looking at IXA4 as a possible therapy for other metabolic illnesses including fatty liver disease,” Saez explains.

Aparajita Madhavan, PhD, a graduate student in the Wiseman lab at the time, and Bernard Kok, PhD, a postdoctoral research associate in the Saez lab, were the study’s original authors.

IXA4 was created in partnership with Jeffery Kelly’s team at Scripps Research, where he is the Lita Annenberg Hazen Professor of Chemistry.

The National Institutes of Health provided funding for this research (AG046495, DK123038, DK114785).

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