A landmark clinical trial in the mid-1980s changed the way type 1 diabetes is treated, but it also led to some lingering questions about the persistent effects of the disease. Now, researchers led by City of Hope's Rama Natarajan, Ph.D., director of the Division of Molecular Diabetes Research, may have found some answers.
So-called “metabolic memory” has puzzled scientists for decades. The condition refers to the enduring harmful effects of high blood sugar on the cardiovascular system. Researchers first uncovered the phenomenon during a long-running diabetes clinical trial that compared the effects of standard control of blood sugar versus intensive control.
Standard control involved one to two insulin injections per day and normal monitoring by a physician. Intensive control used three to four insulin injections and rigorous medical supervision aimed at keeping blood sugar as close to normal as possible. The study showed that intensive therapy significantly reduced the risk of many diabetes complications, such as kidney and eye disease, compared to standard therapy. The results were so clear it led researchers to propose that the intensive therapy be made the new standard of care.
Scientists were surprised by another result, however. Patients who started with standard diabetes therapy but switched to intensive therapy still had significantly higher risk of kidney, eye and cardiovascular diseases later in life. In other words, moving patients from standard to intensive therapy did not reverse or halt the harm done by high blood sugar levels. The body “remembered” the sugar’s effects, and damage to heart and blood vessel tissues continued to build over the years.
Natarajan and her team at City of Hope, along with collaborators from other institutions, found strong evidence that epigenetic modifications could be the culprit. These chemical changes, which occur within chromosomes, can hinder or boost the activity of genes.
The epigenetic changes that Natarajan pinpointed occur in certain white blood cells that already are known to cause blood vessel damage in patients with diabetes. The findings, which are the first to link human metabolic memory to epigenetics, suggest that high blood sugar must be countered early to avoid increased risk of various diseases of the blood vessels.
“We’re finally beginning to understand the role of epigenetics in metabolic memory and diabetes-related complications,” said Natarajan, the National Business Products Industry Professor in Diabetes Research. “Knowing the source of the problem takes us closer to finding potential treatments to reduce risk.”
Other City of Hope investigators on the study, which appears in the May issue of Diabetes, include Feng Miao, Ph.D., Zhuo Chen, M.S., M.D, Lingxiao Zhang, M.S., Xiwei Wu, M.D., Ph.D., Sierra Min Li, Ph.D., and Arthur Riggs, Ph.D.
Support for this research came from the JDRF (grant numbers 17-2008-900 and 17-2012-480).
Research reported in this publication was supported by the National Institutes of Health under grant numbers R01-DK-065073, R01-DK-058191, U01-DK-094176 and U01-DK-094157. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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