Manipulated Beta Cells Control Blood Glucose

A new way of manipulating human pancreatic beta cells appears to mitigate the shortage of donor cells for transplantation to treat type 1 diabetes and the difficulty of expanding differentiated cells in vitro.

The new method allows cells to be treated to permit indefinite growth in vitro, then doctored so that they don’t produce tumors in vivo. When implanted into diabetic mice, investigators report, the manipulated cells retain the properties of primary beta cells and induce euglycemia for extended periods of time.

To overcome the inability of primary beta cells to proliferate in culture, Dr. Ji-Won Yoon, at Chicago Medical School, and his associates transduced a human pancreatic beta-cell line with a retroviral vector to express the immortalizing genes SV40 large T-antigen and human telomerase reverse transcriptase.

One clone was found to express beta-cell specific transcription factors and insulin but did not produce tumors.

Once the nontumorigenic clone had been expanded to produce large numbers of cells, the investigators removed the immortalizing genes so that they could be used safely in vivo. The reverted cells retained the ability to secrete insulin.

When the cells were transplanted into the renal capsules of diabetic mice, human insulin was produced at levels that decreased blood glucose levels to normal within 2 weeks, and remained so for 30 weeks, whereas nontransplanted mice died within 10 weeks. Glucose tolerance tests were normal, and there were no signs of tumorigenicity.

"This cell line offers continuous availability, uniformity and sterility, and may provide a source of beta-cells for the treatment of type 1 diabetic patients by transplantation," Dr. Yoon’s team concludes.

Dr. Christopher Newgard, from Duke University Medical Center in Durham, North Carolina stated that, "There have been no human beta cell lines in which we can investigate beta cell biology." "We’ve had to rely completely on rodent cell lines heretofore."

"So if we want to know how a drug may enhance insulin secretion for treatment of type 2 diabetes, it seems quite exciting that we may have a way to get at a human cell line (ie, the one produced by Yoon et al) that retains differentiated function.”

However, actual use of such cells in human patients probably remains a far way off, he said. "Certainly attempts to move it into the clinical arena will have to jump through some significant hoops with exhaustive studies to see if a carcinogenic gene is retained before the FDA would ever approve this kind of approach."

Nevertheless, he added, the study "serves as a foundation for the next step to a perhaps more safe system."
Published online in Nature Biotechnology Sept. 25, 2005 – Proc Natl Acad Sci USA 2005.

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