How liver responds to food

Minutes after eating, as nutrients rush into the bloodstream the body makes massive shifts in how it breaks down and stores fats and sugars. Within half an hour, the liver has made a complete switch  from burning fat for energy to storing as much glucose, or sugar, as possible. It's too short a time span for the liver's cells to activate genes and produce the RNA blueprints needed to assemble new proteins to guide metabolism.

Liver cells store up pre-RNA molecules involved in glucose and fat metabolism. ''The switch from fasting to feeding is a very quick switch and human physiology has to adapt to it in the right time frame," says Satchidananda Panda, a professor in the Salk Institute's Regulatory Biology Laboratory. It was known that a RNA-binding protein called NONO was implicated in regulating daily ("circadian") rhythms in the body.

Researchers analyzed levels of NONO in response to feeding and fasting in mice. After the animals ate, speckled clumps of NONO suddenly appeared in their liver cells, newly attached to RNA molecules. Within half an hour, the levels of corresponding proteins-those encoded by the NONO-bound RNA increased.

After mice eat, it looks as if NONO brings all these RNAs together and processes them so they can be used to make proteins. When mice lacked NONO, it took more than three hours for levels of the same proteins involved in processing glucose to increase. During that time lag, blood glucose levels shot up to unhealthy levels.

Since blood glucose levels are also heightened in diabetes, the researchers think that the mice without NONO may act as a model to study some forms of the disease. NONO has been found at high levels in the brain and muscle cells.
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Diabetes has hepatic origins

Obesity increases the risk of developing metabolic conditions, and primarily type 2 diabetes. The molecular mechanisms by which obesity predisposes people to the development of insulin resistance are so far poorly understood. By deciphering how the protein PTPR-γ, which is increased in obesity, inhibits insulin receptors located at the surface of liver cells, the scientists open the door to potential news therapeutic strategies.

The expansion of fat cells, a characteristic of obesity, leads to an increase in inflammatory signals that have effects on the liver as well as on several other organs. Obesity-induced inflammation triggers the activation of a transcription factor called NF-kβ, which seems to be instrumental in the development of diabetes. Researchers examined various human cohorts-these human studies indicated that PTPR-γ content in liver increases upon inflammation, an effect that could directly affect insulin receptors by inhibiting insulin action.

The scientists modified the levels of PTPR-γ expression in mice, by either suppressing, normally expressing or overexpressing it, and observed the effect on insulin resistance. The mice totally lacking PTPR-γ, when put on a high-calorie diet, did develop obesity. But they did not show any sign of insulin resistance and seemed to be entirely protected from diet-induced diabetes. They also administered lipopolysaccharide, a toxin pertaining to certain bacteria of the gut microbiota associated with obesity and insulin resistance. Once again, the animals lacking PTPR-γ did not develop insulin resistance.

They reconstituted the expression of PTPR-γ at normal levels, but only in hepatocytes (liver cells ). The mice were again prone to insulin resistance, indicating the pivotal role of the liver. Moreover, a two-fold overexpression in the liver (mimicking the natural pathophysiology of obesity was sufficient to cause insulin resistance. The metabolic functions of this protein were never characterized; this discovery therefore opens the door for potential new therapies.

The very form of this protein allows for potential inhibition strategies: when two independent PTPR-γ molecules are brought together by a ligand, they cannot act any more. The researchers are now working on identifying the endogenous ligand produced by the body, or on developing molecules that could mimic its function.
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Broccoli can cure type 2 diabetes

Eating or drinking broccoli can reverse type 2 diabetes. Sulforaphane is an anti-cancer compound in cruciferous vegetables.

Sulforaphane is highly concentrated in cruciferous vegetables and could be used in a concentrated broccoli extract.
It can be used for treatment of type 2 diabetes.

Researchers examined  97 obese patients, those given concentrated broccoli sprout found their fasting blood glucose levels fell dramatically compared to controls who received a placebo.

Sulforaphane induces an antioxidant response. It reduced glucose production by liver cells growing in culture, and shifted liver gene expression in diabetic rats.


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