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September 01, 2017

Skin cells reveal why insulin cells die in diabetes

Japanese researchers at CiRA and Osaka University use iPS cell technology to prepare pancreatic beta cells, the cells that die in fulminant type 1 diabetes, from patient skin cells.

Type 1 diabetes is a disease of betrayal. For unknown reasons, the body's immune system kills pancreatic beta cells, the cells responsible for producing insulin. Fulminant type 1 diabetes (FT1D) is an especially aggressive form. The rapidity of cell loss means patients can die within a day if the ketoacidosis caused by the disease is untreated. A new study by Japanese scientists uses iPS cell technology to produce FT1D pancreatic beta cells in the lab and finds key differences between these and the beta cells in healthy donors.

Scientists depend on samples of inflicted cells to study disease development and test experimental drugs. In FT1D, however, almost all the pancreatic beta cells are destroyed. Reprogramming patient skin cells into beta cells could resolve this problem, which is why Osaka University professors and diabetes experts Akihisa Imagawa and Iichiro Shimomura approached CiRA Professor Kenji Osafune.

"We are experts in cell reprogramming to pancreatic lineage to study diseases and drugs," said Osafune.

Skin cells from three FT1D patients were reprogrammed into iPS cells and then differentiated into insulin-producing beta cells. Because the immune system is responsible for the cell death, the researchers mimicked the immunological environment of the cells by adding three standard immune cell secretions (the cytokines TNF, IL-1, and IFN) that activate apoptosis (cell death signaling).

"iPS cells from patient or healthy donors were equally likely to differentiate into beta cells using our protocol. The patient cells showed more caspase-3 activation. Caspase-3 is a marker of apoptosis," said Osafune, who added that the additional caspase-3 could make the cells more sensitive to stimuli that promote apoptosis.

These cells will be the basis of new human FT1D models to study experimental drug compounds.

Paper Details
  • Journal: Journal of Diabetes Investigation
  • Title: Insulin-producing cells derived from 'induced pluripotent stem cells' of patients with fulminant type 1 diabetes: vulnerability to cytokine insults and increased expression of apoptosis-related genes
  • Authors: Yoshiya Hosokawa1, Taro Toyoda2, Kenji Fukui1, Megu Yamaguchi Baden1, Michinori Funato2,3, Yasushi Kondo2,4, Tomomi Sudo2, Hiromi Iwahashi1,5, Marina Kishida2,6, Chihiro Okada2,7, Akira Watanabe2,6, Isao Asaka2, Kenji Osafune2, Akihisa Imagawa1,8, and Iichiro Shimomura1
  • Author Affiliations:
    1. Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
    2. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
    3. Department of Clinical Research, National Hospital Organization, Nagara Medical Center, Gifu, Japan
    4. Department of Diabetes, Endocrinology and Nutrition, Kyoto University, Kyoto, Japan
    5. Department of Diabetes Care Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
    6. Japan Agency for Medical Research and Development (AMED)-CREST, Tokyo, Japan
    7. Mitsubishi Space Software, Tokyo, Japan
    8. Department of Internal Medicine, Osaka Medical Colleage, Takatsuki, Japan
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