In type 1 diabetes, high glucose levels may boost heart damage from autoimmunity
Analysis of clinical results identifies potential biomarkers for increased risk of cardiovascular disease from autoimmune reactions.
BOSTON – (November 26, 2018) – Relatively little is known about what causes the high rates of cardiovascular disease among people with type 1 diabetes. Joslin Diabetes Center scientists now have discovered that people with type 1 diabetes are more likely to show signs of an autoimmune reaction to the heart if they have chronically high levels of blood glucose.
Investigator in the Section on Immunobiology at Joslin Diabetes Center. Assistant Professor of Medicine at Harvard Medical School.
The research also suggests that these signs of autoimmune reaction are linked to higher risks of cardiovascular disease, so they might act as biomarkers for early detection of this disease, says Myra Lipes, MD, an investigator in the Section on Immunobiology at Joslin and senior author on a paper describing the research in Circulation.
Over time, better understanding of this autoimmune reaction and its results may provide clues for targeted drugs that can slow the progress of the complication, says Lipes.
In previous research, her lab showed that following a heart attack, the immune system in patients with type 1 diabetes or in animal models of the disease develops persistently high levels of autoantibodies (a protein the immune system normally produces to counteract infections) to a heart muscle protein known as alpha-myosin. These responses were associated with further cardiac injury caused by myosin-reactive immune cells called CD4 T cells. In contrast, such responses did not develop following a heart attack in patients with type 2 diabetes or in control mice.
These earlier findings raised a question, Lipes says, about whether autoimmune responses might also develop in other types of heart injury settings in type 1 diabetic patients, and contribute to their increased risk for cardiovascular disease.
Initially looking at samples from a small group of patients with type 1 diabetes, Lipes and her group found that patients with very poor control of their blood glucose, but without symptoms of heart disease and otherwise in good health, were far more likely to have cardiac antibodies compared to patients with good control of their blood glucose. That finding suggested that chronically high levels of glucose could generate this autoimmune reaction.
The investigators tested that hypothesis by analyzing participants in the Diabetes Control and Complications Trial (DCCT), a pioneering study launched in 1983 which tested whether intensive blood glucose control could prevent or slow down the development of complications in type 1 diabetes.
At the start of DCCT, participants all had overall good health, with no symptoms of cardiovascular disease and a relatively short duration of diabetes. They were divided into two main groups. One group received the standard of care during that era, with one or two injections a day and minimal glucose testing. The second group was intensively treated, with much more frequent testing and multiple daily injections or use of insulin pumps. The group given intensive treatment displayed dramatically better measures of hemoglobin A1C (an indication of blood glucose levels over several months). These measures were associated with the prevention or delayed appearance of diabetes complications, such that the trial was shut down early.
“So DCCT was a really amazing resource to test our hypothesis,” Lipes says.
Drawing on annual blood samples stored over decades in the National Institute of Diabetes and Digestive and Kidney Diseases Central Repository, the researchers looked at samples from 83 subjects with mean A1C of 7% or less, and compared them to a group matched for age, gender and duration of diabetes with mean A1Cs of 9% or greater during DCCT. It turned out that the two groups also were essentially identical in risk factors for cardiovascular disease at the beginning and end of the six-year trial.
“We saw very clearly that over time patients with poor glycemic control were prone to develop cardiac autoimmunity, as measured by the appearance of two or more different types of cardiac antibodies, while antibodies were absent or gradually disappeared in those who underwent intensive glycemic control,” Lipes says.
Furthermore, people who developed two or more of the cardiac antibodies subsequently had elevated mean levels of C-reactive protein (a marker of systemic inflammation). Those combinations were associated with future coronary calcification (a measure of accelerated atherosclerosis) and increased risk for cardiac events.
“These findings raise the possibility that cardiac autoimmunity may be associated with a sort of inflammatory state, which in turn increases cardiovascular risk,” says Lipes.
She hypothesizes a scenario for the cardiovascular damage in type 1 diabetes that begins when chronically high glucose levels damage heart muscle, releasing and exposing proteins such as alpha-myosin to the immune system. The immune system then overreacts to this heart injury, with expansion of proinflammatory T cells and antibodies directed against alpha-myosin. The expansion begins to ramp up inflammation, which is shown by higher levels of C-reactive protein and linked with higher risks of coronary artery disease and cardiovascular events.
This pathogenic pathway is absent in type 2 diabetes. Working with Alessandro Doria, MD, PhD, an investigator in Joslin’s Section on Epidemiology and Genetics, the Joslin team examined more than 200 patients with type 2 diabetes in the Joslin Heart Study. The scientists found that patients with similarly poor glucose control levels did not develop these cardiac antibodies.
Lipes and her co-workers hope to soon broaden their work to study a larger number of DCCT patients, analyzing across a full range of glucose levels and with more cardiovascular outcomes. “If we can further validate the predictive value of cardiac autoantibodies for CVD events, this could enable the early identification of patients with type 1 diabetes at highest risk for developing CVD events,” Lipes says.
It may be possible, she adds, to block the heart autoimmune reaction with existing anti-inflammatory agents or eventually to create drugs targeted specifically to suppress the autoimmune trigger from alpha-myosin itself.
Joslin’s Giovane Sousa is lead author on the paper. Joslin contributors also include Alfonso Galderisi (who contributed to this work as a European Foundation for the Study of Diabetes Albert Renold Visiting Fellow in the Lipes lab), David Pober and HuiJuan Lv. Other co-authors include Liping Yu at the University of Colorado at Denver, Alexandre Pereira at the University of Sao Paulo in Brazil, and Mikhail Kosiborod of the University of Missouri at Kansas City. Funding was provided by the National Institutes of Health.