The trouble with insulin resistance

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Been thinking a lot about insulin resistance lately. Most importantly how a resistance in different tissues might cause different pathologies. Gary Taubes must have been thinking a lot about insulin resistance as well. Way more than me anyway. The following is largely based on his article in Science Magazine July 2009.  
It is better to be vaguely right than exactly wrong… I think…
There’s one factor that the major modern diseases have in common. Insulin resistance. Because obesity, cardiovascular disease and type 2 diabetes are so consistently co appearing they are commonly regarded as a single syndrome known as metabolic syndrome, previously known as insulin resistance syndrome. The syndrome is highly influenced by lifestyle factors and especially diet and exercise. In the middle of all this is the rather inconspicuous hormone, insulin. Its main function is to make sure our blood sugar doesn’t get to high and cause tissue damage.

So, how is insulin related to the tissues inability to respond to this very hormone?  One explanation is that once tissues are insulin resistant the pancreas compensates by producing more insulin, the tissues answer by becoming even more resistant and a vicious cycle is at hand. But how did the tissues get insulin resistant to start with?

The trouble with finding the mechanisms causing insulin resistance is that insulin is not an idle molecule. Insulin is busy indeed. It is the main regulator of all tissues nutrition and metabolism. It stimulates fat and glycogen synthesis, the two major forms of energy storage. It inhibits the body’s own production of glucose (in type 2 diabetes, insulin peaks at too high levels because the liver keeps producing glucose even though blood glucose is already high). It makes fat cells store energy and it increases protein synthesis and make our muscles grow. The liver, which can be viewed as the main energy distributor of the body, is at the mercy of insulin. Too much insulin makes the liver fill up with fat causing what is commonly known as non alcoholic fatty liver disease. In addition insulin affects a large number of other metabolic pathways and growth factors.

Insulin makes tissues take up glucose to keep blood sugar at a decent level, but measurements of insulin-stimulated glucose uptake have shown that even in healthy individuals the glucose uptake varies greatly (by 600-800% according to Taubes 2009). Physical fitness can explain some of the variations in glucose uptake as muscles are one important site for glucose uptake, and exercised muscles are better at taking up glucose. The general rule is also that the more obese you are the more insulin resistant you are, and weight can also explain some of the variations. But, insulin sensitivity also varies in obese subjects and some even seem to have normal sensitivity. Unless we know in which tissue(s) insulin resistance first occurs and which exact tissues are being resistant we will not find the answer to this and other apparent paradoxes.

Insulin sensitivity is usually not measured at a cellular level, but at a whole body level. The most common test is the hyperinsulinemic euglycemic clamp technique. In this procedure, insulin is administered to raise the insulin concentration while glucose is infused to maintain glucose level (euglycemia). The glucose infusion rate needed to maintain euglycemia tells us how well insulin works. In addition an oral glucose tolerance test (OGTT) gives an insulin resistance related measure.  But, not only do we not know which tissues are resistant, the resistance varies during the day and with different situations and lifestyle changes. If we do a fasting test for insulin sensitivity we mostly measure the liver response to insulin.

It was previously assumed that insulin resistance was directly related to the insulin receptors themselves. We now know that the primary defect is somewhere downstream in the insulin signaling pathway.

If fat cells become insulin resistant, we would expect an increased lipolysis and release of fatty acids into the bloodstream, as insulin makes fat cells store energy and the lack of insulin makes them release energy. Insulin resistance is in some studies correlated with an increased level of fatty acids (FFA) in the blood. Obese individuals may have double the level of FFA compared to lean. If your peripheral tissues aren’t in an acute need of energy and the fat cells keep releasing energy into the blood as free fatty acids, then other tissues need to take up this fat. Muscles do a large part of this work. Increased storage of fat in muscles cells are thought to contribute to muscle cell insulin resistance.

In the metabolic syndrome there is an excess storage of fat in muscles as intramuscular triacylglycerols (IMTG) or intramyocellular lipids (IMCL). It also seems that the excess fat storage is mainly in the slow twitch aerobic type I muscle fibers. In several different populations it holds true that the more fat inside the muscles the more insulin resistant they are. A funny side note to this is that in insulin resistance the muscles sometimes act as though they are starving, despite large intramuscular energy stores.

Our muscles utilize fat as fuel largely in proportion to the level of FFA in the blood. That is, the more energy your fat tissue provides the more fat do your muscles burn. This is some of the reason why high fat diets have frequently been tested as a means to increase endurance performance. But in obesity, where the level of FFA in the blood is high, the burning of fat in the muscles is not increased. And so the fat accumulates in the cells.

Obese individuals have reduced rates of fat oxidation compared to lean counterparts despite their apparent increased FFA levels. It also seems that this is related to the mitochondria; the site of fat oxidation.
Research has recently shown that the mitochondria of obese and type 2 diabetics can be 35% smaller than the muscle cell mitochondria of healthy lean individuals. In addition, the size of the mitochondria also correlates significantly with insulin action.

But as Berggren et al. 2008 reported, dramatic weight loss (~55 kg) using gastric bypass surgery significantly improved insulin sensitivity without changes in skeletal muscle fatty acid oxidation.

But none of the above can explain insulin resistance in lean individuals. And a correlation between body mass index and FFA level has actually proved hard to find, and increased FFA may not be as prevalent as previously thought. Increased levels of FFA do not seem to be a single causal factor for insulin resistance in muscles. Mitochondria might not work properly, but are they dysfunctional because of an excess lipid load or does lipids fill up because the mitochondria are dysfunctional?  Does muscle cell insulin resistance mean that other tissues are resistant as well?

More trouble with insulin resistance to come…

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