What Causes Insulin Resistance? Part I

Insulin is an ancient hormone that influences many processes in the body.  Its main role is to manage circulating concentrations of nutrients (principally glucose and fatty acids, the body's two main fuels), keeping them within a fairly narrow range*.  It does this by encouraging the transport of nutrients into cells from the circulation, and discouraging the export of nutrients out of storage sites, in response to an increase in circulating nutrients (glucose or fatty acids). It therefore operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a state in which cells lose sensitivity to the effects of insulin, eventually leading to a diminished ability to control circulating nutrients (glucose and fatty acids).  It is a major contributor to diabetes risk, and probably a contributor to the risk of cardiovascular disease, certain cancers and a number of other disorders. 

Why is it important to manage the concentration of circulating nutrients to keep them within a narrow range?  The answer to that question is the crux of this post. 


Cellular Energy Excess

There has been a tremendous amount of research into the molecular mechanisms of insulin resistance in the last few decades, and certain things have become clear about it.  The first is that it appears to be a 'deliberate' process-- cells activate specific signaling pathways that down-regulate insulin responsiveness.  The rationale for this becomes clear when one considers what insulin does: it drives energy into cells.  Insulin resistance is how the cell says "stop sending me more energy-- I have too much already!"  It is a deliberate response to mitigate the negative effects of cellular energy excess.


Why would a cell want to prevent energy excess?  Because, just as chronic energy excess is toxic to a whole person, it is toxic to the cell.  I read an interesting paper in 2009 titled "Insulin Resistance is an Antioxidant Defense Mechanism"  (1).  The authors presented compelling evidence that exposure to excess nutrients causes cells to produce excess reactive oxygen species, which in turn shuts down insulin signaling.  This was presumably due to the fact that the mitochondria, the cells' tiny furnaces, were overloaded with energy.  Adding powerful antioxidants to the cells prevented insulin resistance because it blocked this signal.  They also showed, using genetic models, that this process was operative in whole mice, and similar findings have been reported by Dr. Peter Rabinovitch's group here at UW (2).  Insulin resistance protects the mitochondria, and hence the cell, from damage due to energy excess.

This is consistent with countless other studies showing that exposing cells to excess nutrients, particularly free fatty acids, causes insulin resistance.  These findings have been extended many times to living, breathing humans as well.  Increasing circulating free fatty acids in humans rapidly induces insulin resistance (3, 4, 5, 6, 7).  Suppressing free fatty acid levels restores insulin sensitivity in obese people with insulin resistance, including type 2 diabetics (8).

For a somewhat technical discussion of the role of mitochondrial dysfunction in insulin resistance and obesity, see below**.

If a cell takes up more energy than it burns (which it will do if it is chronically exposed to excess), energy accumulates, typically in the form of fatty acid metabolites (acyl-CoAs, ceramides, diacylglycerols) in the cytoplasm.  These play a major role in insulin resistance (9, 10), and may represent a second mechanism by which this response is activated in response to cellular energy excess.

So if cellular energy excess causes insulin resistance, what causes cellular energy excess?  Consuming energy (food) in excess of what the body can constructively use-- sort of.  The answer to this is not totally straightforward, because we have a special organ, fat tissue, dedicated to mopping up circulating energy excess to keep it from damaging other tissues.  However, when energy intake chronically exceeds the amount of energy that is being consumed, and fat tissue accumulates, it begins to do its job less effectively, allowing the exposure of other tissues to excess nutrients (11, 12). 

Energy balance (energy in vs. out) has a powerful effect on insulin sensitivity.  Experimental overfeeding studies in humans have shown that increasing 'energy in' causes insulin resistance in parallel with fat gain (13, 14, 15).  Reducing calorie intake and losing body fat via virtually any diet imaginable, including simple calorie restriction, low-fat diets, and low-carbohydrate diets, causes an apparent increase in insulin sensitivity (16, 17, 18), and so does exercise, which increases the 'out' side of the equation (19).  People who practice long-term calorie restriction for life extension have very low fasting insulin and glucose, suggesting high insulin sensitivity (20).

This week, I came across a very interesting study from the Women's Health Initiative here in Seattle (Fred Hutchinson Cancer Research Center).  It investigated the relationship between energy intake and diabetes risk (21).  Other studies have shown little evidence for a relationship, which is puzzling given the fact that overfeeding and resulting fat gain causes insulin resistance in animals and humans, and insulin resistance is a major diabetes risk factor.  However, observational studies are known for the fact that participants misreport energy intake, and that the degree of misreporting varies.  For example, in this study of postmenopausal women, they reported eating 1,416 kcal/day. 

To correct for potential under-reporting, the investigators brought in a technique called doubly labeled water calorimetry, which permits the accurate and unbiased determination of calorie intake***.  They used it to derive an equation by which they were able to mathematically correct for under-reporting.  After correction, the average calorie intake was 2,073 kcal/day.  Also after correction, it was reported that a 20% higher energy intake (corresponding closely to the increase that has occurred in the US in the last 40 years) was associated with a 2.4-fold higher risk of developing diabetes.  This effect appeared to be due primarily to the fact that higher energy intake was associated tightly with higher body fatness. This reinforces the robust link between excess energy intake, insulin resistance, and the development of diabetes.

Conclusion

In summary, a variety of lines of evidence suggest that insulin resistance, in large part, is a cellular defense mechanism against energy excess.  Cellular energy excess is caused primarily by the chronic consumption of energy in excess of what is expended.  Fat tissue can mop up the excess energy for a while, but if the excess is chronic and fat tissue enlarges (particularly abdominal fat), other tissues will be exposed to progressively more energy (fatty acids and glucose), and cells will act to protect themselves by reducing insulin sensitivity.

In the next few posts, I'll discuss other causes of insulin resistance, and eventually, how it can be addressed.


* And particularly, keeping total circulating energy (glucose plus free fatty acids) relatively constant.  Therefore, when a mixed meal is eaten, as circulating glucose increases, insulin orchestrates a corresponding decrease in circulating free fatty acids.  As glucose declines back to baseline, fatty acids rise to baseline in parallel.  If fatty acids do not decline appropriately as glucose enters the bloodstream, as occurs in obesity due to fat tissue insulin resistance, cells are exposed to energy excess, which results in insulin resistance and sometimes cell damage/death in other tissues (e.g., lipotoxic and glucotoxic beta cell death).

** One of the ideas that has appeared in the blogosphere lately is that dysfunction of mitochondria, defined as a lowered capacity to oxidize fuel (particularly fat), causes insulin resistance. On its face, the idea is logical, and it has been the subject of a fair amount of research.  Reducing the mitochondria's ability to burn fuel should make it more easy to overload, and make it more likely to initiate the protective response of insulin resistance.  Diabetics have fewer mitochondria, and insulin resistant people have less mitochondrial oxidative phosphorylation in muscle tissue (22).  I would like to believe that mitochondrial dysfunction is a factor, but the evidence does not consistently support it (23).  One of the reasons is that deliberately reducing mitochondrial fuel oxidation in mice does not impair insulin sensitivity, to the contrary, it improves it (24, 25, 26).  The evidence connecting mitochondrial deficiency and insulin resistance/diabetes in humans and animals has not been very consistent.  There are two sides to this debate, each with valid points, and I don't think it has been resolved definitively yet.  I'm currently skeptical but open to new information. 

Then there is the idea that mitochondrial dysfunction causes obesity.  Now, we have entered into the realm of pure speculation.  This idea doesn't make sense to me on several levels, and my suspicions are reinforced by the fact that mice with reduced mitochondrial activity do not gain fat, and are in some cases leaner than normal (27, 28, 29).  As far as I know, obesity is not a general characteristic of humans with mutations in mitochondrial genes that cause dysfunction, although I'm not sure it has been studied systematically (30).  This idea is on very thin ice!

*** Actually, it measures energy expenditure, which can be used to calculate energy intake if body composition remains stable (or changes in ways that are measured).