More trouble with insulin resistance

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.

Just a small reminder


”…low carbohydrate diet sets the stage for a significant loss of lean tissue as the body recruits amino acids from muscle to maintain blood glucose via gluconeogenesis.”
                          Exercise Physiology, Mcardle, Katch & Katch 2007
There is one aspect of human metabolism that is too often overlooked in the discussion of human nutrition and exercise metabolism. It is the simple fact that there are two energy sources for our cells. Energy from the food we eat and energy from energy stores in our body (glycogen and fat).
I am often met with the claim that muscles cannot hypertrophy if you are in a negative energy balance. I am willing to agree that the claim does seem plausible, but it is misunderstood. It is misunderstood because we have to view the energy situation from the muscles point of view.
The muscles do seem to require a positive energy balance to grow, but they require a local positive energy balance, not a whole body positive energy balance. Simply put, the muscles may have surplus energy even though we consume less energy than we expend, provided the energy stores give out enough energy.
Local cellular energy availability does not necessarily reflect whole body energy availability. This means that we can loose weight as fat while gaining muscle mass even if our body is in a negative energy balance.
Loss of muscle mass or lean body mass is common in weight reduction studies. The number is often as high as or higher than 30% of total weight lost. This is counterintuitive. The point of loosing weight when you are overweight is to lose fat not muscles.
It seems that in studies of low calorie diets that the muscles often lack the energy to maintain their size. In a recent study by Wycherley et al, 59 overweight persons with diabetes did calorie restricted diets combined with supervised resistance exercise 3 days a week. You would expect to see an increase in muscle mass from all this resistance exercise, but after 16 weeks the participants had lost on average 2kg of fat free mass.
To be fair, several studies have shown maintenance of fat free mass with weight loss from calorie restriction when combined with resistance exercise. But calorie restriction may not be the best way to tap into the body’s energy stores.
A low carbohydrate diet will increase the availability of the energy stored as fat. In addition, ketone bodies prevent a large use of proteins for glucose production. Contrary to what the quote at the start of this post claims.
In 2002 Volek et al  put overweight men on a 6 week diet with only 8% carbohydrate. The study caused an obvious decrease in fat mass, but in combination with a significant increase in lean body mass, without a resistance exercise intervention.
Willy et al put six overweight adolescents on a ketogenic diet and observed an average weight loss of 15.5kg in combination with 1,4kg increase in lean body mass. All in eight weeks.
Individual results in studies show that it is possible to markedly increase muscle mass while reducing fat mass. I’ve personally seen large reductions in fat mass in combination with more large increases in lean body mass from a combination of carbohydrate restriction and resistance exercise.
My point is that if muscles require a positive energy balance to hypertrophy, carbohydrate restricted diets offers an effective way of giving muscles the energy they need while reducing fat mass. Future studies will hopefully elucidate further.

By the way…


New exiting study in Diabetes Care.
It seems that if you put overweight people on a resistance exercise program three days a week for 16 weeks, they will lose about two kilos of muscle mass, if they are also cutting calories. 
Dietary protein content doesn’t seem to influence this much.
I wonder what would happen if you did a resistance exercise study and combined it with a ketogenic diet? Muscle mass retention?

The trouble with insulin resistance

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…