Research shows how obesity sets the stage for diabetes
September 23, 2015
Surprisingly, when postdoctoral researcher and first author Yiguo Wang, Ph.D., mimicked the conditions of ER stress in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis. Instead, it switched on genes important for combating stress and returning cells to health. On closer inspection, Wang found that in this scenario CRTC2 did not bind to CREB but instead joined forces with another factor, called ATF6a.
What's more, like jealous lovers CREB and ATF6a competing for CRTC2's affection-the more ATF6a is bound to CRTC2, the less there is for CREB to bind to. "This clever mechanism ensures that a cell in survival mode automatically shuts down glucose production, thus saving energy," says Wang.
This observation led the researcher to ask what happens to ATF6a following the kind of persistent stress presented by obesity? They found that the levels of ATF6a go down when ER stress is chronically activated, compromising the cells' survival pathway and favoring the glucose production pathway; hyperglycemia wins in conditions of persistent stress.
Explains Wang, "Our study helps to explain why obese people have a stronger tendency to become diabetic. When ER stress signaling is abnormal glucose output is actually increased."
"It is possible that mutations in the highly conserved CRTC2 lead to a predisposition to inappropriate gluconeogenesis," says Montminy, who is now trying to identify natural mutations in CRTC2 that may lead to insulin resistance in carriers.
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