Complications are understood on a relatively macro-scale. For example, doctors know eye disease develops when blood vessels leak and repair themselves in a haphazard manner. Going deeper, they even know which molecule (VEGF) causes that leakiness and rampant growth. The extent to which kidney disease, heart disease and other complications are currently understood allows for different forms of treatment, some more effective than others. But if researchers could understand the root causes of complications, they could create a medication to halt those diseases in their early stages or prevent them from developing at all.
Researchers at Joslin Diabetes Center have made headway in understanding exactly why diabetes complications occur. They recently discovered a broken chain of events in the cells of people who have developed severe complications. They have also noticed higher levels of a molecule that, when reduced, improved the functioning of the chain of events leading to improved repair mechanisms , potentially slowing or stopping the onset of complications.
Rohit Kulkarni, M.D., Ph.D., Principal Investigator in the Section on Islet Cell and Regenerative Biology and Professor of Medicine at Harvard Medical School, led a Joslin team that examined cells from people with varying stages of complications. Many of the participants came from Joslin’s Medalist program, a group of people who have had type 1 diabetes for at least 50 years. The team recruited some Medalists who had severe complications, some who had mild or no complications, and a separate group of people who didn’t have diabetes to act as controls.
First, they got skin cells from these volunteers. They then turned these skin cells into induced pluripotent stem (iPS) cells, which are cells that can be coaxed to develop any tissue in the body. Studying this primitive cell type allowed researchers to monitor the very basic genetics of diabetes complications, since these cells weren’t clouded by the genetics of being a skin cell.
When they analyzed the samples from the three different groups, they saw striking differences in the genes and proteins. The Medalists with complications showed changes in the processes that are in charge of repairing the DNA within cells. Damaged DNA means the cell can’t function and repair itself properly. This same pathway in both the Medalists with little to no complications and the healthy group worked fine indicating a normal ability to repair itself.
Probing deeper, they saw a higher-than-usual level of a molecule known to play a role in the DNA repair process. Decreasing the amount of this molecule allowed the repair process to function properly. This suggests that creating a drug that reduces this molecule could help control complications by improving the repair processes.
Their next step will be to clarify how the molecule works and why it is present in higher levels in people with complications. They also plan to turn those iPS cells into kidney, heart and other cells to watch and better understand the cellular development of these specific complications.
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