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Scientists transform connective tissue from diabetic patients into insulin-producing cells

A promising step toward cell replacement therapies tailored to diabetic individuals, but only the first step of many

Contributor Si-Cheng Dai

Diabetes is a major worldwide health concern, affecting 463 million people in 2019. Those with diabetes suffer many complications—heart attacks, stroke, and kidney failure—all of which maylead to premature death. In 2017 alone, diabetes caused an estimated 4 million deaths.

Those with diabetes suffer from high blood sugar, specifically blood glucose. Typically, the hormone insulin causes your cells to take in glucose when the body detects high levels of it. However, diabetes hinders this uptake process. Type 1 and 2 diabetes both involve, at some point, the destruction of one’s pancreatic beta cells—the cells responsible for secreting that insulin. This leaves the affected individual with no way to lower their blood sugar.

Those in the advanced stages of diabetes often need pancreas transplants to restore their insulin production and glucose levels. However, donors are hard to come by, and the risks are substantial when transplanting an entire organ. As an alternative, researchers have been looking to cell replacement therapy. In diabetic patients, this approach involves transplanting working beta-like cells into the body to replace defective ones, restoring insulin function.

Recently, Dr. Kim and his colleagues at the Catholic University of Korea made strides toward this aforementioned goal . First, they took connective tissue cells from the buttocks of both type 1 and type 2 diabetic patients and transformed them into induced pluripotent stem cells (iPSCs), which have the potential to become any cell of the human body. And unlike stem cells derived from embryos, iPSCs are derived from the skin or blood cells of an adult human and do not raise any ethical concerns. In the next step, these researchers transformed the iPSCs into insulin-producing cells (IPCs). Their work was published in October 2020, in Stem Cell Research.

However, studies have already produced IPCs from the cells of healthy individuals. So, what makes Dr. Kim’s research special?

Autologous transplants are procedures that involve using one’s own cells for the treatment of their disease. Using this method, the body will not recognize introduced cells as foreign, meaning it will not launch an immune attack to destroy or reject the treatment. By deriving IPCs from the diabetic patients themselves, a future therapy using their own IPCs could also bypass the body’s natural alarm system.

Dr. Kim’s study is also the very first to perform the feat in type 2 diabetic patients. As the majority of those with diabetes are type 2, this study presents the future possibility of addressing their needs through autologous transplants.

In the experiment, pancreatic and duodenal homeobox 1 (PDX-1) was crucial in transforming iPSCs into IPCs. PDX-1 is a protein expressed in cells of the pancreas, and increases the production of certain molecules that help to mature and maintain beta cells. It is much like a foreman at a construction site, enlisting and coordinating different workers to construct and furnish buildings. Researchers modified PDX-1 so that it would be highly expressed, and then used a virus to integrate it into the DNA of the already-transforming iPSCs. Within a week of growing the cells under these conditions, they began to express insulin and pancreatic-specific messenger RNA. This lent some support for their new beta cell-like nature.

Importantly, Dr. Kim and his colleagues used PDX-1 alone to create IPCs during this step. Other studies have used PDX-1 alongside other construction site leaders of the pancreas, but the process was laborious. By developing a more streamlined procedure, these scientists more quickly produced these IPCs.

In a healthy individual, the amount of insulin that beta cells secrete depends on the amount of blood glucose. Higher blood glucose means cells should take up more of it, and so beta cells release more insulin. Dr. Kim and his researchers wanted to see whether this real-life functionality existed in their cells. They tested the IPCs in environments of high and low glucose, and confirmed that high glucose situations resulted in more insulin protein being secreted. In addition, the IPCs from the type 1 and 2 diabetics and a healthy participant all showed the same response to these two glucose levels. This meant that using cells from diabetic patients created similarly effective IPCs as cells from healthy individuals.

These results are very promising. Still, there is much work to be done. First of all, we do not know if these IPCs work quite the same as beta cells. Dr. Kim and his colleagues did find expression of pancreatic-specific genes in all of these cells, but only tested several genes,meaning that the genome has yet to be be fully analyzed. In addition, the derived IPCs from diabetic and healthy patients had similar expressions of insulin in low and high glucose conditions. However, the researchers did not test whether this output matched those in actual beta cells from healthy individuals. The bottom line is that we do not know how well these IPCs will perform if actually transplanted into a diabetic patient.

Moreover, if these IPCs do work well, it may be hard to mass-produce them. Only a small portion of iPSCs survive the transformation into IPCs. In addition, Dr. Kim found that the IPCs of all three participants expressed Ngn3, a gene not expressed by mature pancreatic cells. Some of the IPCs from the experiment were still immature, and this further reduced the number of viable cells. New innovations must develop to increase the quantity and quality of IPC production before it may become a viable treatment method.

These issues are in no way meant to discredit the work of these researchers. They have made new scientific advances: they generated IPCs from the connective tissue of type 2 diabetic patients, and did so using an accelerated method. They bring hope of cell replacement therapies that neither require embryos nor suppressants of the immune system. However, although these promising prospects loom on the horizon, they may not come nearly as soon as we would like.

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