New Research Reveals Surprising Role for Skeletal Muscle in Type 2 Diabetes
How Muscle Cells Differ in Type 2 Diabetes
BOSTON — One of the body's largest metabolic organs, skeletal muscle regulates blood sugar in response to insulin levels in the blood. It also communicates with other organs through molecular signals that can alter their behavior. But, in the setting of type 2 diabetes (T2D), both of these functions become dysregulated. It’s not known whether this dysregulation is a cause or an effect of the condition.
In a study led by researchers at Joslin Diabetes Center, investigators identified key molecular differences between muscle cells from people with and without type 2 diabetes. The findings offer new clues about how insulin resistance develops and suggest that skeletal muscle may play a more active role in the disease’s progression than previously recognized. The findings are published in Signal Transduction and Targeted Therapy.
“While muscle insulin resistance is one of the earliest hallmarks of type 2 diabetes (T2D), it remains unclear whether muscle dysfunction is a symptom of the condition or whether skeletal muscle actively contributes to its progression by influencing other organs,” said corresponding author C. Ronald Kahn, MD, senior investigator at Joslin and a professor of medicine at Harvard Medical School.
To answer that question, the researchers collected cells from the muscles of people with and without T2D. They then reprogrammed the cells into induced pluripotent stem cells—immature cells capable of developing into many different cell types—and used them to grow new muscle cells in the laboratory, a technique known as "disease in a dish." By allowing the cells to develop outside the diabetic environment, the approach enabled researchers to determine whether differences seen in people with T2D were caused by the disease itself or were intrinsic to the muscle cells.
The team then examined the newly grown muscle cells from multiple angles, analyzing the genes they expressed, the proteins they produced, the molecular signals they released and the messages they sent to other cells. By combining these layers of information, the researchers were able to determine whether the differences observed in muscle cells from people with T2D persisted even when the cells developed outside the body and beyond the influence of the disease.
The researchers found that muscle cells derived from people with T2D remained fundamentally different from healthy muscle cells, even when allowed to develop away from the influence of the diabetic environment.
“What was particularly striking was that many of these changes affected protein production without altering the underlying genetic instructions; in other words, the cells appeared to be using the same blueprint to produce a different result,” said lead author Allah Nawaz, PhD, a research fellow in medicine at Joslin. “These findings reveal a previously underappreciated layer of biological regulation that contributes to insulin resistance and may open new avenues for developing therapies for insulin resistance and type 2 diabetes.
Co-authors included Marsel Lino, Nida Haider, Antonio S. Gomes, Anindya Ghosh, Eiichiro Satake, Arijeet K. Gattu of Joslin Diabetes Center.
This research was supported by the National Institutes of Health (grant DK082659) and a fellowship from the Manpei Suzuki Diabetes Foundation. The authors declare no competing interests.
About Joslin Diabetes Center
Joslin Diabetes Center is world-renowned for its deep expertise in diabetes treatment and research. Part of Beth Israel Lahey Health, Joslin is dedicated to finding a cure for diabetes and ensuring that people with diabetes live long, healthy lives. We develop and disseminate innovative patient therapies and scientific discoveries throughout the world. Joslin is affiliated with Harvard Medical School and one of only 18 NIH-designated Diabetes Research Centers in the United States.
