How the pancreas knows when to get going

"We established a new gene map that shows how the entire repertoire of factors produced in the pancreas maintain and anticipate daily changes in the external environment," says Joe Bass. "These factors are all tied to the rotation of the Earth—to the timekeeping mechanism that has evolved to control when we sleep, wake up, eat, and store nutrients each day." (Credit: iStockphoto)

A new study pinpoints thousands of genetic pathways an internal body clock takes to dictate how and when the pancreas must produce insulin and control blood sugar.

The findings could eventually lead to new therapies for diabetes.

The body’s circadian clocks coordinate behaviors like eating and sleeping, as well as physiological activity like metabolism, with the Earth’s 24-hour light-dark cycle.

There’s a master clock in the brain, as well as peripheral clocks located in individual organs. When genetics, environment, or behavior disrupt the synchrony of these clocks, metabolic disorders can develop.

In a previous publication in Nature, the investigators showed that a circadian clock in the pancreas is essential for regulating insulin secretion and balancing blood sugar levels in mice. The scientists demonstrated that knocking out clock genes led to obesity and type 2 diabetes, but they still had much to learn if they wanted to manipulate clock action to treat the conditions.

“We knew that the pancreas didn’t work if we removed these clock genes, but we didn’t know how the genes were affecting the normal function of the pancreas,” says principal investigator Joe Bass, chief of endocrinology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician.

Clock genes are responsible for producing transcription factors, special proteins that help tell a cell how to function.

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In the new study, published in Science, Bass’s laboratory revealed thousands of genes in the pancreas that the clock’s transcription factors control in rhythm with the planet’s daily rotation from light to dark.

“We established a new gene map that shows how the entire repertoire of factors produced in the pancreas maintain and anticipate daily changes in the external environment,” Bass says. “These factors are all tied to the rotation of the Earth—to the timekeeping mechanism that has evolved to control when we sleep, wake up, eat, and store nutrients each day.”

Bass’s team focused on cells in the pancreas called beta cells, which secrete insulin into the blood stream to help the body absorb glucose—sugar—to use for energy. Using genome-wide sequencing technology on beta cells with both intact and disrupted clock gene function, the scientists were able to lay out the map of transcription factors and genes.

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In ongoing research, Bass’s group continues to study how the body’s circadian clocks interact and how their rhythm is thrown off—not just in diabetes, but also during the normal aging process and from day-to-day conditions like jetlag, stress, or dietary changes.

“This study reinforces the idea that clocks operating in cells are fundamental to health,” Bass said. “They represent an important untapped target for improving the functions of cellysin the pancreas.”

Funding for the work came from the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, NIH National Institute on Aging, the Chicago Biomedical Consortium, Juvenile Diabetes Research Foundation, the University of Chicago Diabetes Research and Training Center, National Heart, Lung, and Blood Institute, and Defense Advanced Research Projects Agency.

Source: Northwestern University