High-carbohydrate diets induce hepatic insulin resistance

Sometimes you get lucky and fall on something you wasnt actually looking for. I was doing some research on the possible relationship between FoxO1 and ChREBP in the liver ( more on that possible link in a moment ) when I found this little theory paper.

High-carbohydrate diets induce hepatic insulin resistance to protect the liver from substrate overload.

If anyone can link the full text id be interested ( its behind a paywall ), but anyway, the abstract tells you the gist of this guys thinking. Recall that ChREBP is a transcription factor activated by high concentrations of glucose in the liver.

One of the important jobs of ChREBP is go into the nucleus and start spitting out enzymes that convert carbs to fat. ( like fatty acid synthase ). However in the abstract we learn that ChREBP also codes for glucose 6-phosphatase, and this enzyme in turn, stimulates production of Glucokinase regulatory protein ( GKRC ).

In turn, GKRC inhibits liver Glucokinase.

Remember that the activity of glucokinase determines liver glucose uptake because it relives the concentration gradient of the GLUT2 receptors on the liver, allowing more glucose to flow into the liver from outside. Glucokinase is also a target for insulin and GLP-1, and the activation of glucokinase by GLP-1 is probably a primary way that GLP-1 helps diabetics.

Sorry I didnt mean for this to get so technical!

So , to condense this guys theory, he is saying that hepatic IR is caused by ChREBP inhibiting glucokinase.

But I think there may be slightly more to it than that, I also found this paper which says that FoxO1 inhibits ChREBP.

From the last post we saw that FoxO1 codes for enzymes for gluconeogensis, but, ChREBP codes for enzymes that convert carbs to fat. Its probably not a good idea to have both FoxO1 and ChREBP running at the same, because the glucose you make from FoxO1 will get converted to fat by ChREBP? Which just means your going around in circles.

FoxO1 is suppose to mediate the fasting state, where blood glucose concentration is constantly replenished and muscles become insulin resistant to conserve glucose for the brain during.

My theoretical speculation is this, if the level of ChREBP is the liver is elevated due to high carbohydrate consumption aswell as frequent consumption, does this inadvertently force FoxO1 to be higher? Is FoxO1 hyper-active BECAUSE ChREBP is elevated? And yes, ChREBP is elevated in the liver of obese people as pointed out by Lucas.

Inhibition of ChREBP in ob/ob mice improves insulin resistance while deficiency ChREBP actually prevents obesity in ob/ob mice. Is there a connection between leptin and ChREBP?

Yes!

Leptin activates AMPK  and in turn AMPK inhibits the activity of ChREBP. It is well reported that Metformin activates AMPK, so its looks like Metformin may also inhibit ChREBP, this is probably where the ability of Metformin to improve insulin sensitivity stems from. In that last study above they also report that vinegar supplementation ( 30ml per day ) slightly improved weight loss, acetic acid converts to acetate which activates AMPK and thereby inhibits liver ChREBP. The relation appears to be dose-dependent, so more vinegar = more weight loss. Up to 90ml per day was deemed safe.

Anyway, im quite convinced that it is liver ChREBP that causes hepatic insulin resistance. And if metabolic syndrome is the manifestation of hepatic insulin resistance then this implies liver ChREBP is the cause of metabolic syndrome.

Urgh, it IS the bloody carbohydrates!  

I think im just about done here..............