There is a strong trend between obese/diabetic people that they preferentially continue oxidising fat even in the face of an oral glucose load, and this ties in with IR. Insulin resistance is basically the cells way of saying that it is not interested in accepting glucose for oxidation at this point in time. Sorry, but its busy oxidising fat. Guess what though, peripheral IR and hepatic glucose production are also associated with something else. The fasting state.
Call me crazy, but it almost looks like the problem is that obese/diabetic people simply have an issue with transitioning from the fasted state into the fed state. More on this in a bit.
So what CAUSES hepatic IR? Most people would jump on the fatty liver bandwagon at this point, the study in the previous post is very good evidence that it is NOT the cause however.
Still not convinced?
Well have a look here, the authors of this paper manipulated malonyl-CoA to allow enhanced fatty acid oxidation at the mitochondrial level, and this was sufficient to reverse IR without any significant change in fatty liver. So now it looks like IR is mediated by something going on at the mitochondrial level. Also, look here, The title almost says it all....Mitochondrial dysfunction precedes insulin resistance and hepatic steatosis
So obesity/diabetes just means you have fucked up Liver mitochondria? I don't believe that. The fact that we have many rodent studies showing alleviation of IR with various interventions hints that perhaps the mitochondria are not on their last leg, but rather, they just aint getting the correct messages. Theres just a simple breakdown in communication somewhere. Perhaps.
I think now we can see why low-carb is so effective and important for metabolic syndrome sufferers, it bypasses most of the hepatic IR problem. I.E. it avoids dietary induced hyperglycaemia. It avoids exposing your periphery to an onslaught of glucose from both the Liver and the digesting meal. In addition, the more glucose you have flooding into your blood from the Liver and the digesting meal, the more insulin you will be secreting to deal with that glucose.
You see, beta cells secrete insulin in response to glucose exploding in their cytosol, Peter@Hyperlipid has already told us that the Liver is the main destination for dietary glucose, aswell as the main site for insulin degradation. So my guess is that having an even slightly IR liver could cause MAJOR increases in blood sugar and serum insulin, both from an inability to suppress hepatic glucose production and because insulin degradation in the liver is reduced.
Enter the fat cell!
With all the excess blood sugar and insulin swimming around, it has to go somewhere. Either it doesnt go anywhere, and you are therefore diabetic, or your fat cells suck it all up, and your not a diabetic. The ability of your fat cells to suck up all the excess insulin and glucose will determine how fat you can ultimately get, and ofcourse at what weight you will develop diabetes.
If your fat tissue is happy to expand and remain insulin sensitive forever, you will never get diabetes but each carbohydrate meal that you chug down will put you one step closer to entering the guinness book of records as the worlds most obese human. Alternatively, if your fat tissue is not happy with expanding much, youll get diabetes while being still relatively thin.
I am not sure what exactly determines fat tissue expansion capabilities precisely, certainly genetics will play a role. Oh and, in addition, ItsTheWooo pointed out in a comment in one of the Peter's post that hyperinsulinemia not only blocks fat breakdown, it also slows fat oxidation, so now we also see why obese people are lazy and tired.
I think now I finally understand why I have such a problem with tubers/rice VS fruit/honey. Simple carbohydrate meals containing lots of generic glucose molecules as opposed to other forms of more complex saccharide will storm past the insulin resistant liver just minutes after ingestion and cause incredible insulin secretion, and my fat cells will be more then happy to mop it all up. Cheers. So yes people, Glycemic Index MATTERS!
Phew, still with me so far? Ok, just a bit more....
Before I was talking about how obese/diabetic people appear as though they simply have difficulty transitioning into the fed state from the fasted state. Whats the difference between these two states? Remember, there is no receptor for calories. The difference is the Incretin affect! The incretin affect is the FIRST way that your body reacts hormonally to the food that you eat. All subsequent hormonal affects should just be downstream of the incretin affect, so if the incretin affect is not working as it should, chances are the rest of your metabolism wont be either.
We have already seen how obese people secrete less GLP-1 in response to carbs than lean people, they also secrete less bile acids than lean people. Opps, us fatties are not doing so good so far!
Its worth noting that one of the most effective treatments for morbid obesity is the roux-en-y gastric bypass, which significantly enhances both GLP-1 secretion and bile acids. Further, this surgery is able to almost completely reverse diabetes very shortly after operation, before any significant weight loss is achieved. However at this point this fact should NOT be surprising because as we established earlier in the post, cellular triglyceride content does not have any impact on insulin resistance.
Wouldn't it be nice if we could fine some link between GLP-1 and hepatic function? Well, if incretins and GLP-1 are so effective, why dont roux-en-y patients completely reverse their whole obesity and diabetes and return to being normal lean healthy people? The incretin system seems to play more of a role in post-prandial energy expenditure is the most likely explanation. In that study, they noted mice were able to consume significantly more food ( 25%-70% ) and yet not gain excess weight.
In this review , they talk about the first wave of incretins being released before any significant digestion or absorption of calories is done, indicating that the nervous system is likely key player in the incretin response. This brings me to this paper, it seems GLP-1 is present in the brain aswell as the gut, and brain GLP-1 signalling may be the most important of all.
Activation of central GLP-1Rs contributes substantially to the inhibition of endogenous glucose production
Ah Ha! Inhibition of hepatic glucose production! Thats EXACTLY what we want after eating a potato.
Lastly, heres one last and recent study confirming that GLP-1 signalling in the brain improves hepatic insulin sensitivity.
Summary
- Metabolic syndrome is primarily hepatic insulin resistance
- Fatty liver does not significantly contribute to hepatic IR
- Mitochondrial dysfunction seems to precede hepatic IR and fatty liver
- The more hepatic IR you have, the more glucose intolerant you are
- Obese/diabetics have difficulty transitioning from the fasted state to the fed state, which seems to be mainly driven by a poor incretin response.
- If you have hepatic IR, fat tissue keeps you out of diabetes if it has the ability to expand and make you obese.
- Insulin performs the same function in fat as it does in muscle, i.e. it makes them bigger.
- Low-carb is effective for Metabolic Syndrome because it reduces postprandial glucose momentum into the blood
- In Metabolic Syndrome, the worse foods are those containing large amounts of simple glucose molecules that enter the blood stream quickly. I.E. high glycemic index foods.
- Hyperinsulinemia doesnt just reduce fat breakdown, it inhibits fat oxidation
- The CAUSE of hepatic IR has not yet been pinpointed, although it currently looks like either mitochondrial garble or insufficient incretin action via the nervous system.
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