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What Causes Insulin Resistance? Business Office I

Insulin is an ancient hormone that influences many processes inwards the body.  Its principal role is to larn by circulating concentrations of nutrients (principally glucose together with obese acids, the body's ii principal fuels), keeping them inside a fairly narrow range*.  It does this past times encouraging the carry of nutrients into cells from the circulation, together with discouraging the export of nutrients out of storage sites, inwards reply to an increment inwards circulating nutrients (glucose or obese acids). It hence operates a negative feedback loop that constrains circulating nutrient concentrations.  It also has many other functions that are tissue-specific.

Insulin resistance is a solid lay down inwards which cells lose sensitivity to the effects of insulin, eventually leading to a diminished might to command circulating nutrients (glucose together with obese acids).  It is a major contributor to diabetes risk, together with likely a contributor to the run a jeopardy of cardiovascular disease, surely cancers together with a number of other disorders. 

Why is it of import to larn by the concentration of circulating nutrients to continue them inside a narrow range?  The respond to that interrogation is the crux of this post. 

Cellular Energy Excess

There has been a tremendous amount of enquiry into the molecular mechanisms of insulin resistance inwards the terminal few decades, together with surely things receive got move clear nearly it.  The kickoff is that it appears to hold upwards a 'deliberate' process-- cells activate specific signaling pathways that down-regulate insulin responsiveness.  The rationale for this becomes clear when 1 considers what insulin does: it drives unloosen energy into cells.  Insulin resistance is how the prison theatre cellular telephone says "stop sending me to a greater extent than energy-- I receive got also much already!"  It is a deliberate reply to mitigate the negative effects of cellular unloosen energy excess.

Why would a prison theatre cellular telephone desire to foreclose unloosen energy excess?  Because, merely equally chronic unloosen energy excess is toxic to a whole person, it is toxic to the cell.  I read an interesting newspaper inwards 2009 titled "Insulin Resistance is an Antioxidant Defense Mechanism"  (1).  The authors presented compelling evidence that exposure to excess nutrients causes cells to reach excess reactive oxygen species, which inwards plough shuts downward insulin signaling.  This was presumably due to the fact that the mitochondria, the cells' tiny furnaces, were overloaded amongst energy.  Adding powerful antioxidants to the cells prevented insulin resistance because it blocked this signal.  They also showed, using genetic models, that this procedure was operative inwards whole mice, together with similar findings receive got been reported past times MD Peter Rabinovitch's grouping hither at UW (2).  Insulin resistance protects the mitochondria, together with hence the cell, from harm due to unloosen energy excess.

This is consistent amongst countless other studies showing that exposing cells to excess nutrients, peculiarly gratis obese acids, causes insulin resistance.  These findings receive got been extended many times to living, breathing humans equally well.  Increasing circulating gratis obese acids inwards humans quickly induces insulin resistance (3, 4, 5, 6, 7).  Suppressing gratis obese acid levels restores insulin sensitivity inwards obese people amongst insulin resistance, including type 2 diabetics (8).

For a somewhat technical give-and-take of the role of mitochondrial dysfunction inwards insulin resistance together with obesity, run into below**.

If a prison theatre cellular telephone takes upwards to a greater extent than unloosen energy than it burns (which it volition reach if it is chronically exposed to excess), unloosen energy accumulates, typically inwards the marker of obese acid metabolites (acyl-CoAs, ceramides, diacylglycerols) inwards the cytoplasm.  These play a major role inwards insulin resistance (9, 10), together with may correspond a instant machinery past times which this reply is activated inwards reply to cellular unloosen energy excess.

So if cellular unloosen energy excess causes insulin resistance, what causes cellular unloosen energy excess?  Consuming unloosen energy (food) inwards excess of what the torso tin constructively use-- carve upwards of.  The respond to this is non totally straightforward, because nosotros receive got a special organ, obese tissue, dedicated to mopping upwards circulating unloosen energy excess to continue it from damaging other tissues.  However, when unloosen energy intake chronically exceeds the amount of unloosen energy that is beingness consumed, together with obese tissue accumulates, it begins to reach its labor less effectively, allowing the exposure of other tissues to excess nutrients (11, 12). 

Energy residue (energy inwards vs. out) has a powerful final result on insulin sensitivity.  Experimental overfeeding studies inwards humans receive got shown that increasing 'energy in' causes insulin resistance inwards parallel amongst obese gain (13, 14, 15).  Reducing calorie intake together with losing torso obese via virtually whatever diet imaginable, including uncomplicated calorie restriction, low-fat diets, together with low-carbohydrate diets, causes an apparent increment inwards insulin sensitivity (16, 17, 18), together with and so does exercise, which increases the 'out' side of the equation (19).  People who practise long-term calorie restriction for life extension receive got real depression fasting insulin together with glucose, suggesting high insulin sensitivity (20).

This week, I came across a real interesting study from the Women's Health Initiative hither inwards Seattle (Fred Hutchinson Cancer Research Center).  It investigated the human relationship betwixt unloosen energy intake together with diabetes run a jeopardy (21).  Other studies receive got shown niggling evidence for a relationship, which is puzzling given the fact that overfeeding together with resulting obese gain causes insulin resistance inwards animals together with humans, together with insulin resistance is a major diabetes run a jeopardy factor.  However, observational studies are known for the fact that participants misreport unloosen energy intake, together with that the marker of misreporting varies.  For example, inwards this study of postmenopausal women, they reported eating 1,416 kcal/day. 

To right for potential under-reporting, the investigators brought inwards a technique called doubly labeled H2O calorimetry, which permits the accurate together with unbiased conclusion of calorie intake***.  They used it to derive an equation past times which they were able to mathematically right for under-reporting.  After correction, the average calorie intake was 2,073 kcal/day.  Also later correction, it was reported that a 20% higher unloosen energy intake (corresponding closely to the increment that has occurred inwards the the U.S.A. inwards the terminal forty years) was associated amongst a 2.4-fold higher run a jeopardy of developing diabetes.  This final result appeared to hold upwards due primarily to the fact that higher unloosen energy intake was associated tightly amongst higher torso fatness. This reinforces the robust link betwixt excess unloosen energy intake, insulin resistance, together with the evolution of diabetes.


In summary, a multifariousness of lines of evidence advise that insulin resistance, inwards large part, is a cellular defence forcefulness machinery against unloosen energy excess.  Cellular unloosen energy excess is caused primarily past times the chronic consumption of unloosen energy inwards excess of what is expended.  Fat tissue tin mop upwards the excess unloosen energy for a while, but if the excess is chronic together with obese tissue enlarges (particularly abdominal fat), other tissues volition hold upwards exposed to progressively to a greater extent than unloosen energy (fatty acids together with glucose), together with cells volition deed to protect themselves past times reducing insulin sensitivity.

In the adjacent few posts, I'll utter over other causes of insulin resistance, together with eventually, how it tin hold upwards addressed.

* And particularly, keeping total circulating unloosen energy (glucose summation gratis obese acids) relatively constant.  Therefore, when a mixed repast is eaten, equally circulating glucose increases, insulin orchestrates a corresponding decrease inwards circulating gratis obese acids.  As glucose declines dorsum to baseline, obese acids ascent to baseline inwards parallel.  If obese acids reach non reject appropriately equally glucose enters the bloodstream, equally occurs inwards obesity due to obese tissue insulin resistance, cells are exposed to unloosen energy excess, which results inwards insulin resistance together with sometimes prison theatre cellular telephone damage/death inwards other tissues (e.g., lipotoxic together with glucotoxic beta prison theatre cellular telephone death).

** One of the ideas that has appeared inwards the blogosphere lately is that dysfunction of mitochondria, defined equally a lowered capacity to oxidize fuel (particularly fat), causes insulin resistance. On its face, the persuasion is logical, together with it has been the discipline of a fair amount of research.  Reducing the mitochondria's might to burn downward fuel should move far to a greater extent than slow to overload, together with move far to a greater extent than probable to initiate the protective reply of insulin resistance.  Diabetics receive got fewer mitochondria, together with insulin resistant people receive got less mitochondrial oxidative phosphorylation inwards musculus tissue (22).  I would similar to believe that mitochondrial dysfunction is a factor, but the evidence does non consistently back upwards it (23).  One of the reasons is that deliberately reducing mitochondrial fuel oxidation inwards mice does non impair insulin sensitivity, to the contrary, it improves it (24, 25, 26).  The evidence connecting mitochondrial deficiency together with insulin resistance/diabetes inwards humans together with animals has non been real consistent.  There are ii sides to this debate, each amongst valid points, together with I don't intend it has been resolved definitively yet.  I'm currently skeptical but opened upwards to novel information. 

Then in that place is the persuasion that mitochondrial dysfunction causes obesity.  Now, nosotros receive got entered into the realm of pure speculation.  This persuasion doesn't brand feel to me on several levels, together with my suspicions are reinforced past times the fact that mice amongst reduced mitochondrial activeness reach non gain fat, together with are inwards merely about cases leaner than normal (27, 28, 29).  As far equally I know, obesity is non a full general feature of humans amongst mutations inwards mitochondrial genes that drive dysfunction, although I'm non surely it has been studied systematically (30).  This persuasion is on real sparse ice!

*** Actually, it measures unloosen energy expenditure, which tin hold upwards used to calculate unloosen energy intake if torso composition remains stable (or changes inwards ways that are measured).



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