Researchers at the Salk Institute for Biological Studies have uncovered the connection between obesity and insulin resistance. Their explanation reveals how thin people too can become insulin resistant.
It had been well established that obesity promotes insulin resistance through the inappropriate inactivation of a process called gluconeogenesis, where the liver creates glucose for fuel and which ordinarily occurs only in times of fasting.
The researchers investigated the possibility that stress induced other changes to take place on the cellular level, specifically in the endoplasmic reticulum, a protein factory.
“When a cell starts to sense stress a red light goes on, which slows down the production of proteins,” explains Montminy. “This process, which is known as ER stress response, is abnormally active in livers of obese individuals, where it contributes to the development of hyperglycemia, or high blood glucose levels. We asked whether chronic ER stress in obesity leads to abnormal activation of the fasting switch that normally controls glucose production in the liver.”
Now, for the hard science portion of this lecture:
Glucose production is turned on by a transcriptional switch called CRTC2, which normally sits outside the nucleus waiting for the signal that allows it to slip inside and do its work. Once in the nucleus, it teams up with a protein called CREB and together they switch on the genes necessary to increase glucose output. In insulin-resistant mice, however, the CRTC2 switch seems to get stuck in the “on” position and the cells start churning out glucose like sugar factories in overdrive.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.
Although the detailed answer paints a complex picture, the main point is that high levels of glucose in the blood leads to insulin resistance. Understanding precisely how those mechanisms work will lead to better treatments in the future.