A drug used to treat malaria does not, after all, create new insulin-producing cells, according to a University of California study, refuting an earlier study.
In the US, around 30m people live with diabetes, according to the Centres for Disease Control and Prevention. So, any news of a potential new treatment is a big deal.
"First we had hoped that we would be able to replicate the findings, but they didn't hold up," said Mark Huising, in the department of neurobiology, physiology and behaviour, UC Davis College of Biological Sciences. "People with type 1 diabetes, they see these stories come out and they think maybe there's something on the horizon and then nothing ever follows through," Huising said.
The symptoms of type 1 and type 2 diabetes are quite similar but the underlying causes differ. In type 1 diabetes, the body fails to create enough insulin, a hormone produced by the pancreas that regulates cellular intake of nutrients. In type 2 diabetes, cells no longer respond efficiently to insulin.
Insulin is produced in hormone-producing regions of the pancreas called islets. Within the islets are alpha and beta cells. Beta cells are integral to creating insulin. "That's the cell that if you lose (insulin production), you get type 1 diabetes," said Huising. So, there is always interest in any process that might generate new beta cells to replace those lost in type 1 diabetes.
In early 2017, a European team reported that the antimalarial drug artemether could convert alpha cells into functional beta cells. While alpha cells converting into beta cells had been described before, this was the first time an existing drug had been reported to stimulate the process and it caused a lot of excitement in the field, Huising said.
Outfitted with the precision tools to capture alpha-to-beta cellular conversion, Huising enlisted graduate student Sharon Lee to assist with replicating the original experiment. "We were hoping, expecting, to confirm," Huising said. "We weren't able to."
For her experiments, Lee used pancreatic islets derived from mice. After around four months of experiments with artemether, it was clear that the drug was not triggering alpha to beta cell conversion, as the initial paper had claimed.
Lee and Huising's paper highlights the importance of reproducibility, a perennial and hotly contested topic of concern at all levels of scientific research. It also demonstrates how routine lab assignments meant to educate students can provide the foundations for published research.
"It's important to realise that our work has an impact in the real world," Huising said. "We should continuously strive to hold ourselves and our peers to a higher standard, particularly when we talk about discoveries that promise a possible cure for diabetes."
Pancreatic α cells retain considerable plasticity and can, under the right circumstances, transdifferentiate into functionally mature β cells. In search of a targetable mechanistic basis, a recent paper suggested that the widely used anti-malaria drug artemether suppresses the α cell transcription factor Arx to promote transdifferentiation into β cells. However, key initial experiments in this paper were carried out in islet cell lines, and most subsequent validation experiments implied transdifferentiation without direct demonstration of α to β cell conversion. Indeed, we find no evidence that artemether promotes transdifferentiation of primary α cells into β cells. Moreover, artemether reduces Ins2 expression in primary β cells >100-fold, suppresses glucose uptake, and abrogates β cell calcium responses and insulin secretion in response to glucose. Our observations suggest that artemether induces general islet endocrine cell dedifferentiation and call into question the utility of artemisinins to promote α to β cell transdifferentiation in treating diabetes.
Talitha van der Meulen, Sharon Lee, Els Noordeloos, Cynthia J Donaldson, Michael W Adams, Glyn M Noguchi, Alex M Mawla, Mark O Huising
[link url="https://www.ucdavis.edu/news/study-refutes-using-anti-malaria-drug-treat-diabetes"]University of California – Davis material[/link]
[link url="http://www.sciencedirect.com/science/article/pii/S1550413117306149"]Cell Metabolism abstract[/link]