I’ll make an attempt to sum up some of my previous rambling.
When we talk about insulin resistance it is often important to include information on which tissues we are talking about. When insulin resistance is measured by clamp technique we are mostly measuring the hepatic insulin response.
The fact that insulin resistance is mostly measured at a whole body level, and that we thusly do not know how the resistance manifest itself in different tissues makes, finding a causal link difficult.
One of the main hypotheses proposed suggests that fat tissue become insulin resistant (poor response to insulin) and consequently sends out more fat than peripheral tissues can handle. The muscles for example, become resistant because they take up more fat without increasing fat oxidation and fill up with fatty byproducts like diacylglycerol and ceramides. Both muscle and liver insulin resistance and “fattening” have been blamed on increased FFA levels. Levels supposedly caused by the insulin resistant adipose tissue. Non alcoholic fatty liver diseases (often non-alcoholic steatohepatitis) seem to be getting more common by the day. A condition once found mostly in people with excessive alcohol consumption is now commonly found in association with lifestyle diseases.
I should mention though that serum FFA level does not only reflect adipose tissue lipolysis, but also intravascular lipolysis of triglyceride-rich lipoproteins (VLDL). These lipoproteins increase markedly on carbohydrate rich diets and decrease on low carbohydrate diets. The decrease in triglycerides is in fact one of the most notable changes observed when going from high carb to low carb.
We know that insulin resistant individuals very often have muscles that fill up with fat. But they don’t burn more fat and they become more insulin resistant. One of the big candidates for a causal factor for the skeletal muscle insulin resistance is this fat, more precisely diacylglycerol which impair insulin signaling.
Researchers also commonly propose mitochondrial dysfunction, as an underlying mechanism in the pathogenesis of insulin resistance. It is proposed as a cause of fat build up rather than as a consequence. This subject will definitely be discussed more in the years to come. Many will propose mitochondrial dysfunction as a cause of insulin resistance and will focus on finding very small molecules that can be blamed for all the metabolic havoc. Probably much will be written about transport molecules.
But there’s more trouble with insulin resistance. Endurance trained athletes also have large intramuscular fat stores, suggesting that fat in itself does not cause resistance. The athletes however, have a very high fat oxidation rate and highly insulin sensitive muscles, suggesting a causal role for whatever causes low fat oxidation. Athletes can increase the amount of IMTG in muscles by consuming a high fat diet, although in the more sedentary people, carbohydrates are the more likely cause of intramuscular fat build up.
The build-up of fat in muscles of the obese and overweight is coexisting with a low fat oxidation rate as measured by respiratory quotient. A low respiratory quotient (RQ) means you burn fat. A high RQ means you burn mostly carbohydrate. High RQ correlates with insulin resistance and it is therefore proposed as a causal factor. This is one proposed cause I don’t think we need to discuss for very long. Of course high RQ is common in the obese. That’s the whole problem. They burn glucose, because they eat high carbohydrate. If they were burning fat they wouldn’t be fat. If you take a muscle sample from an overweight person on a high carb diet you have a muscle sample with particularly ineffective fat oxidation skills. The muscles get good at what they do. Eat fat and burn fat and your muscles get good at burning fat. But to hypothesize that obesity may be caused by low fat oxidation is like saying obesity is caused by consuming more energy than you expend.
But just when it seemed that we had it all figured out and all the evidence were pointing at free fatty acids, along comes Taubes quoting Keith Frayn saying that FFA levels are not that different in the obese compared to the lean, which could then not explain their insulin resistance. Some studies have actually shown that the sensitivity or maximum insulin induced inhibition of adipose tissue lipolysis was greater in obese subjects than in normal weight controls. Some obese people display normal insulin sensitivity. One theory (supported by some animal models) says that these people have fat tissue with exceptionally large storage capacity which protect against lipotoxicity in nonadipose tissues. This suggest that enlargement of adipose tissue mass may protect against insulin resistance and diabetes.
The theory of free fatty acids causing insulin resistance is actually one of two major somewhat competing theories. The other being inflammation, which I will have to check out.