Could a leaky “battery” within our cells be at the core of the mechanism that sets off type 2 diabetes? New research by UCLA scientists may have opened a window to the answer.
A central question in diabetes research is why cells of the pancreas, known as beta cells, initially over-secrete insulin. The prevailing theory was that the body may be in the process of becoming “deaf” to insulin, so beta cells secrete more to compensate. But isolated beta cells still over-secrete insulin, which exposes a gap in that theory.
In the new study, researchers set out to understand what other mechanism beyond insulin resistance (that is, the body becoming “deaf” to insulin) and high glucose levels might explain why diabetes develops. The scientists found that a pathway independent of glucose, but sensitive to fatty acids, appears to drive insulin secretion in the early stages of diabetes.
The teams found that in beta cells from obese, pre-diabetic mice, a protein known as Cyclophilin D, or CypD, induced a phenomenon known as “proton leak,” and that this leak promoted insulin secretion in the absence of elevated glucose. The mechanism was dependent on fatty acids, which are normally incapable of stimulating insulin secretion in healthy animals.
“Beta cells are a remarkable sensor of glucose. They take the energy from the nutrients and store it in mitochondria, which are like miniature batteries,” explains Orian Shirihai, MD, PhD, professor of endocrinology and pharmacology. “Once the voltage in these batteries goes high, a unique combination of signals is transmitted to the cell membrane, leading to post-meal insulin secretion. For years, it has been known that beta cells from pre-diabetic humans and animals are very inefficient in delivering the energy from nutrients to secretion. The reason was attributed to a constant leak in their batteries, causing them to constantly lose energy.”
Once the team determined that the levels of leak closely predict the over-secretion of insulin, they decided to test what had not been previously considered: Perhaps in the pre-diabetic animal, it is the battery leak itself that produces an abnormal signal for secretion, even in the absence of elevated glucose. “Until that day,” Dr. Shirihai says, “we only considered a leak as a mechanism that will exhaust beta cells and impair their ability to respond to glucose. But we never tested the effect of such a leak in the absence of glucose. We were in for a big surprise that would require a significant shift in our thinking.”
The research further determined that obese mice who lacked the gene for CypD did not secrete excess insulin. The team confirmed the same process was taking place in isolated human pancreas cells. The results suggest new ways to prevent the development of insulin resistance and to treat diabetes, including halting its progression by blocking the proton leak in the beta cell.
— Alice Walton
“Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Non-Stimulatory Glucose Levels,” Diabetes, November 2019
