“This is one of the very first studies of human iPSC models for type 2 diabetes, and it points out the power of this technology to look at the nature of diabetes, which is complex and may be different in different individuals,” says C. Ronald Kahn, MD, Joslin’s Chief Academic Officer and the Mary K. Iacocca Professor of Medicine at Harvard Medical School.
Until now, scientists examining the causes and effects of insulin resistance have struggled with a general lack of human cell lines from tissues such as muscle, fat and liver that respond significantly to insulin, Kahn says. Studying insulin resistance as it progresses through pre-clinical stages of type 2 diabetes has been particularly challenging.
“There have been no good human cell models to study insulin resistance, but such cells can now be made with iPSCs,” says Kahn, co-senior author on a paper about the study published in the journal Diabetes.
Generation of iPSCs typically starts with fibroblasts (connective tissue cells) from skin samples. Kahn and his colleagues used fibroblasts from three patients with severe insulin resistance brought on by mutations in the gene for the insulin receptor (IR)—a molecule that crosses the cell membrane and plays a key role in insulin signaling and glucose metabolism.
The Joslin researchers “reprogrammed” the fibroblasts into iPSCs by using viral procedures that activated four genes that together maintain cells in the iPSC state. The scientists then looked at gene activation in insulin signaling pathways for iPSCs and fibroblasts with IR mutations, and for corresponding cells derived from people without those mutations.
Among the study findings, IR mutations alter expression of many genes both in fibroblasts and iPSCs compared to normal cells, “but the impact is very much dependent on the cell type,” says Kahn. “You see one type of expression pattern in the fibroblasts and a different type of pattern in the iPSCs.”
Insulin is a key ingredient for the growth and proliferation of normal stem cells, and the study demonstrated that insulin resistance also reduces the ability of the iPSCs to grow and proliferate. That defect may represent a previously unrecognized mechanism that aids in developing diabetes, Kahn says, as well as helping to explain the problems in wound healing, tissue repair and even beta-cell growth that are common among people with diabetes.
“Our next phase of research is to make these iPSCs into liver, muscle and fat cells, and then see if we can use them to model those tissues in people,” he says.
In one line of research, Kahn adds, the Joslin team will examine how much of insulin resistance in type 2 diabetes is genetic and how much of it is acquired in the environment, because resistance acquired in the environment presumably will disappear in the iPSCs.
Joslin’s Salvatore Iovino and Alison Burkart were co-lead authors on the paper, and Joslin’s Mary-Elizabeth Patti, MD, was co-senior author. Other contributors included Katelyn Hughes, Kristina Kriauciunas, Michael Molla and Laura Warren of Joslin and Youn-Kyoung Lee of Harvard. The work was supported by the National Institutes of Health, the Novo-Nordisk Foundation, the Harvard Stem Cell Institute and the American Diabetes Association.
About Joslin Diabetes Center
Joslin Diabetes Center, based in Boston, Massachusetts, undertakes diabetes research, clinical care, education and health and wellness programs on a global scale. Joslin is dedicated to ensuring that people with diabetes live long, healthy lives and offers real progress in preventing and curing diabetes. Joslin is an independent, nonprofit institution affiliated with Harvard Medical School, and is recognized worldwide for driving innovative solutions in diabetes prevention, research, education, and care.
Our mission is to prevent, treat and cure diabetes. Our vision is a world free of diabetes and its complications. For more information, visit www.joslin.org.
About Joslin Research
Joslin Research comprises the most comprehensive and productive effort in diabetes research under one roof anywhere in the world. With 30‐plus faculty‐level investigators, Joslin researchers focus on unraveling the biological, biochemical and genetic processes that underlie the development of type 1 and type 2 diabetes and related complications.
Joslin research is highly innovative and imaginative, employing the newest tools in genetics, genomics and proteomics to identify abnormalities that may play a role in the development of diabetes and its complications. Joslin Clinic patients, and others with diabetes, have the option of participating in clinical trials at Joslin to help translate basic research into treatment innovations.
Joslin has one of the largest diabetes training programs in the world, educating 150 M.D. and Ph.D. researchers each year, many of whom go on to head diabetes initiatives at leading institutions all over the globe. For more information, visit www.joslinresearch.org.
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