How to preserve insulin-producing cells – The interactive doctor

Researchers develop a new strategy to preserve insulin-producing cells in diabetes

March 31, 2022. 1:02 pm

High blood glucose is responsible for various complications in type 1 and 2 diabetes. Researchers at the Karolinska Institute in Sweden have identified a new antidiabetic substance that preserves the activity of insulin-producing beta cells and prevents high blood glucose in mice, as published in the journal ‘Science Translational Medicine’.

Although several families of glucose lowering agents in the treatment of diabetes, none of them can stop or reverse the progression of the disease. Maintaining adequate beta cell activity is essential to prevent the progression of type 1 and type 2 diabetes.

HIF-1alpha protein levels

“In diabetes, beta cells are forced to produce large amounts of insulin –says the first author of the study, Erwin Ilegems, principal investigator of the Department of Molecular Medicine and Surgery of the Karolinska Institute–. Our study shows that this leads to a hypoxic state that increases levels of HIF-1alpha protein, which in turn reduces beta cell activity. By treating diabetic mice with the HIF-1alpha inhibitor PX-478, we were able to reduce their blood glucose levels.”

HIF-1alpha (hypoxia-inducible factor-1alpha) regulates the response to hypoxia. The discovery of HIF-1alpha was awarded the Nobel Prize in Physiology or Medicine in 2019 and this protein is implicated in many different diseases. The HIF-1alpha inhibitor PX-478 has already been tested in phase I clinical trials as an anticancer drug and was well tolerated in these patients.

In collaboration with the research group of Professor Jorge Ruas, from the Department of Physiology and Pharmacology of the Karolinska Institutethe authors were able to show that the antidiabetic effect of PX-478 was mainly due to enhancement of pancreatic beta-cell activity.

Since it is well established that insulin production decreases during the progression of diabetes, therapeutic strategies have so far primarily focused on enhancing beta-cell insulin production. However, this approach has not been as successful as initially anticipated.

“Current therapies targeting beta cells only have a temporary positive effect on insulin secretion,” says the study’s last author, Per-Olof Berggren, professor at the Department of Molecular Medicine and Surgery at Karolinska Institutet. “In the long term, these drugs lead to beta cell depletion.”

Unlike other treatments, PX-478 enhances beta cell activity without amplifying insulin secretion. Therefore, the researchers believe that it may prevent the depletion of beta cells and thus be more effective in the long-term treatment of diabetes.

“Now we plan to further investigate the translatability of our findings to hopefully pave the way for future clinical trials,” says Teresa Pereira, a researcher at the Department of Medical Cell Biology at Uppsala University (previously an employee of the Karolinska Institute), who is the co-author of the study–. investigate the impact of PX-478 on pancreatic beta cell activity humans using ‘humanized’ diabetic mice”.

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How to preserve insulin-producing cells – The interactive doctor