Research in A Rare Form of Diabetes:
A Path to Understanding Type 1 and Type 2 Diabetes

Researchers from the Naomi Berrie Diabetes Center, in collaboration with investigators at the New York Stem Cell Foundation (NYSCF) reported this week in the journal Diabetes, on an advance in a debilitating form of diabetes called Wolfram Syndrome, a genetic disorder that leads to blindness, deafness and early death.

The experiment was conducted as follows: Scientists produced induced pluripotent stem cells (iPS cells) from skin cells donated by Berrie Center patients with Wolfram Syndrome. From the iPS cells, scientists then produced pancreatic, insulin-producing beta cells—creating an in-vitro model of Wolfram Syndrome. Next, they showed how and why the beta cells failed to secrete insulin normally in Wolfram Syndrome: in these cells, an abnormal endoplasmic reticulum stress (ER stress) response leads to inability to compensate for misfolded proteins and ultimately, beta cell failure. Finally, they found that a drug, called 4-phenyl butyric acid, relieves this ER stress and prevents the beta cells from failing. These findings suggest a potential drug target for clinical intervention for patients with Wolfram Syndrome, and also for preventing beta cell demise in more common types of diabetes.

“These iPS cells helped us uncover an important mechanism that causes beta-cell failure in diabetes,” said Dieter Egli, PhD, a research fellow and investigator at NYSCF and a research scientist at the Berrie Center. “This represents a significant step forward in the study of this debilitating disease and toward the development of new treatments.”

Scientists hope that the Wolfram patient stem-cell model will lead to a greater understanding of more common forms of diabetes

“This report highlights again the utility of close examination of rare human disorders as a path to elucidating more common ones,” said co-author of the study, Rudolph L. Leibel, MD, the Christopher J. Murphy Professor of Diabetes Research and Co-Director of the Naomi Berrie Diabetes Center. “Our ability to create functional insulin-producing cells using stem-cell techniques on skin cells from patients with Wolfram’s Syndrome has helped to uncover the role of ER stress in the pathogenesis of diabetes. The use of drugs that reduce such stress may prove useful in the prevention and treatment of diabetes.”

Other contributors to the study were: Linshan Shang, Hector Martinez, David Kahler, and Matthew Zimmer of the New York Stem Cell Foundation Research Institute and from the Naomi Berrie Diabetes Center at Columbia University Medical Center: Haiqing Hua, Kylie Foo, Kazuhisa Watanabe, Wendy Chung, Charles LeDuc, Robin Goland and Matthew Freeby.

Funding for this study was provided by: The New York Stem Cell Foundation; the Leona M. and Harry B. Helmsley Charitable Trust; the Berrie Foundation Program in Cellular Therapies of Diabetes; the Hunter Eastman Scholar Award in Translational Diabetes Research; and two NIH grants.

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