Possible Mechanism for the Carbohydrate Insulin Hypothesis?

I have long observed that some sources of carbs tend to be more fattening than others, and that the degree to which the carb source spikes your blood sugar is also a very good indication for how fattening that carb source is. Given that there is such a thing as the "low-GI" diet lends credibility to this theory, atleast in part.

Glycemic Index broadly speaking is defined as how fast a particular carb source spikes your blood sugar. I think this is missing 1 key aspect however, although I dont have a glucose carbon tracer study on hand to prove this, but I suspect that in the case of high GI foods that the total amount of glucose entering circulation is also higher in addition to the speed at which it raises blood sugar. Foods that contain a high density of simple glucose molecules should likely be the worst for blood sugar control, and probably also obesity.

This quote is from the wikipedia page on glycemic index

Recent animal research provides compelling evidence that high-GI carbohydrate is associated with increased risk of obesity. In one study,[15] male rats were split into high- and low-GI groups over 18 weeks while mean body weight was maintained. Rats fed the high-GI diet were 71% fatter and had 8% less lean body mass than the low-GI group.

A higher amount of glucose entering circulation is a massive problem because hyperglycemia is toxic, it also puts immense pressure on the peripheral to act as a glucose sink in order to return to normoglycemia. The "peripheral" mainly consists of muscle and adipose tissue. I have already posted previously my theory that the high leptin seen in fat people is primarily a result of high-levels of the carb -> fat  pathway inside adipocytes. This is why carbohydrate density of foods is associated with high leptin, ( 1 ), because foods with a high density of simple glucose molecules simply results in more total glucose entering circulation.

More glucose entering circulation leads to more insulin leads to more glucose uptake by adipocytes leads to more lipogenesis pathway and finally leptin secretion.

As I posted on Wooo's blog here, my theory is that a high carbohydrate density and/or food that consists of mainly simple glucose molecules results in a high mass flow rate of glucose in the portal vein, this puts pressure on your liver to work "quickly" to handle all that glucose before it hits circulation. Through the activation of glucokinase, the liver uptakes the glucose through GLUT2 via simple concentration gradient. Due to physical limitations, there will obviously be a maximal rate at which glucokinase can phosphorylate glucose and thus maintain the concentration gradient.

But there is also the complication that some people secrete less glp-1 in response to carbohydrates, and since glp-1 also activates glucokinase, such people would have even more total glucose hit circulation when consuming high-GI foods. ( btw at present, no-one knows why some people secrete less glp-1 in response to carbs, the latest research says it has something to do with the high expression of UCP2 in the cells of the gut )

I am not alone in my theory that foods containing high concentrations of simple glucose molecules is inherently fattening, this research group is also onto it.... ( 2 ) They show that high-carb diets always leads to higher adiposity than isocaloric high fat diets. However the really interesting part was the change in adipose tissue gene expression, which included increased levels of GLUT4 on adipocytes. This fits in exactly with the idea that weight gain and adipose tissue expansion is an adaptive and protective measure initiated to protect you from diabetes. Actually, scratch that, it is an adaptive and protective measure to protect you from hyperglycemia.

Genes regulating glucose transport, glycolysis, fatty acid and triglyceride biosynthesis, desaturation and elongation, adipogenesis, and adipokines were affected by High-carb diets.

The adipose tissue literally changes its gene expression to accommodate for increased glucose uptake. Your adipose tissue "learns" to be very good at sucking up excess blood sugar. The same conclusion was reached by this group of researchers ( 3 ). To quote......

However, increased total fat mass provides a sink for the excess of glucose and compensates for insulin resistance.

I would like to speculate that reversing the obesity associated with excess carbohydrate consumption would involve undoing the change in gene expression in adipocytes, particularly that of increased GLUT4 utilization. Not eating a diet that aggressively spikes blood sugar could communicate to adipocytes that their increased GLUT4 expression is no longer needed. Another thing that comes to mind is anaerobic exercise,  its quite well known that anaerobic exercise improves body composition. I think that what may be happening is that the hypoglycemia challenges during such exercise send an additional signal to adipocytes that their increased GLUT4 expression is starting to actually become harmful. In response they may down-grade gene expression for GLUT4. ( ofcourse exercise also improves muscle glucose uptake so that is another mechanism by which glucose flux into adipocytes is reduced ).

Increased expression of GLUT4 on adipocytes promotes obesity ( 4 ).

So yes, I still believe in the carbohydrate insulin hypothesis.