Map of thousands of genes the clock controls suggests new therapeutic targets for diabetes
A new Northwestern Medicine study has pinpointed thousands of genetic pathways an internal body clock takes to dictate how and when our pancreas must produce insulin and control blood sugar, findings that could eventually lead to new therapies for children and adults with 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 2010 publication in Nature, Northwestern Medicine 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,” said principal investigator Joe Bass, MD, PhD, chief of Endocrinology in the Department of Medicine.
Clock genes are responsible for producing transcription factors, special proteins that help tell a cell how to function. In the new study, published Nov. 6 in Science, Dr. 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,” Dr. Bass said. “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.”
Dr. Bass’s team, which included co-investigator Grant Barish, MD, assistant professor of Medicine in Endocrinology, graduate student Mark Perelis and postdoctoral fellow Biliana Marcheva, PhD, 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.
In ongoing research, Dr. 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,” Dr. Bass said. “They represent an important untapped target for improving the functions of cells in the pancreas.”
Dr. Bass is also the Charles F. Kettering Professorship of Medicine and a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Other Northwestern authors include Kathryn Ramsey, PhD, Clara Bien Peek, PhD, and Hee-kyung Hong, PhD, ’05 GME, all three research assistant professors of Medicine in Endocrinology, Matthew Schipma, PhD, research assistant professor of Biochemistry and Molecular Genetics, Akihiko Taguchi, MD, PhD, Wenyu Huang, MD, ’07 PhD, ’09 ’12 GME, assistant professor of Medicine in Endocrinology, Chiaki Omura and Amanda Allred.
This study was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grant R01DK090625, NIH National Institute on Aging grant P01AG011412, the Chicago Biomedical Consortium S-007, Juvenile Diabetes Research Foundation grants 17-2013-511, 1-INO-2014-178-A-V and 1-INO-2015-23-A-V, University of Chicago Diabetes Research and Training Center grant P60DK020595; NIDDK T32 grant DK007169; National Heart, Lung, and Blood Institute T32 grant HL007909 and Defense Advanced Research Projects Agency grant D12AP00023.
(Feature image courtesy of Wikimedia Commons.)