London, June 22 (ANI): Scientists at the Salk Institute for Biological Studies have discovered how obesity makes a person more prone to diabetes, and why thin people can become insulin-resistant.
Led by Dr. Marc Montminy, a professor in the Clayton Foundation Laboratories for Peptide Biology, the study has shown how a condition known as ER (endoplasmic reticulum) stress triggers abnormal glucose production in the liver, an important step on the path to insulin resistance.
ER stress is induced by a high fat diet, and is overly activated in obese people.
In healthy people, a "fasting switch" only flips on glucose production when blood glucose levels run low during fasting.
"The existence of a second cellular signalling cascade-like an alternate route from A to B-that can modulate glucose production, presents the potential to identify new classes of drugs that might help to lower blood sugar by disrupting this alternative pathway," Nature magazine quoted Montminy as saying.
However, not all obese people become insulin resistant, and insulin resistance occurs in non-obese individuals, which led researchers to suspect that fasting-induced glucose production was only half the story.
"When a cell starts to sense stress a red light goes on, which slows down the production of proteins. 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," said Montminy.
A transcriptional switch called CRTC2 turns on glucose production.
Normally, CRTC2 sits outside the nucleus waiting for the signal that allows it to slip inside and do its work and after entering 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.
But when the conditions of ER stress were mimicked in mice, CRTC2 moved to the nucleus but failed to activate gluconeogenesis, and instead switched on genes important for combating stress and returning cells to health.
On closer inspection, the researchers found that in this scenario CRTC2 did not bind to CREB, but instead joined forces with another factor, called ATF6a.
However, it was found that 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," said a co-author of the study.
The researchers then found the levels of ATF6a to go down when ER stress was chronically activated, compromising the cells' survival pathway and favouring the glucose production pathway.
Hyperglycemia wins in conditions of persistent stress.
"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," said a co-author.
"It is possible that mutations in the highly conserved CRTC2 lead to a predisposition to inappropriate gluconeogenesis," said Montminy.
The study has been published in the advance online edition of the journal Nature. (ANI)