Editors' ChoiceDiabetes

A Sweet Success for Diabetes Research

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Science Translational Medicine  21 Sep 2011:
Vol. 3, Issue 101, pp. 101ec153
DOI: 10.1126/scitranslmed.3003212

For decades, the “holy grail” of diabetes research has been to create a renewable and unlimited source of engineered human pancreatic β cells to replace those lost in patients with diabetes. One roadblock to this goal has been the lack of a robust and functional human β cell line that can be used for mechanistic studies. Although rodent β cell lines have been extensively studied since the 1970s, emerging data highlight a number of important differences between human and rodent pancreatic β cells. Now, Ravassard et al. describe the creation of a genetically engineered human pancreatic β cell line using human fetal pancreatic tissue and lentiviral technology that should be a boon for diabetes researchers.

The effort to create a human β cell line required a multistep approach. Ravassard and colleagues first transduced human fetal pancreatic tissue with a lentiviral vector expressing the viral oncoprotein SV40 large T antigen (SV40-LT) under control of the insulin promoter. The transduced tissue was grafted into immunocompromised SCID mice, and the β cells proliferated, differentiated, and formed β cell tumors or insulinomas. Then the insulinomas were retrieved and transduced with a second lentiviral vector that expressed human telomerase reverse transcriptase (hTERT), a protein that acts to prevent cellular senescence. These hTERT-positive cells were then transplanted into more SCID mice for amplification, and, finally, the immortalized β cells were removed and expanded in vitro. After hundreds of individual experiments, the researchers were able to characterize one cell line called EndoC-βH1, which could be successfully frozen, thawed, and passaged in culture. EndoC-βH1 cells expressed key β cell proteins such as PDX-1, MAFA, and NKX6-1. Most important, EndoC-βH1 cells expressed high levels of insulin and secreted insulin in response to glucose and other secretagogues in a dose-dependent manner. As a final test, EndoC-βH1 cells were transplanted into diabetic mice, where they successfully produced insulin and reversed diabetes.

The creation of the EndoC-βH1 cell line represents a tremendous technical success for the diabetes research community. EndoC-βH1 cells will serve as a useful platform for high-throughput drug screening, and mechanistic studies performed on these cells have the potential to illuminate new aspects of human β cell physiology, ultimately allowing researchers to move one step closer to the development of cell replacement strategies for the treatment of diabetes.

P. Ravassard et al., A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion. J. Clin. Invest. 121, 3589–3597 (2011). [Full Text]

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