Sunday, May 26, 2013

Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Part 3

The following questions still need to be answered to solve the paradox:

  • Why are some people overweight yet insulin sensitive? 
  • Why are some people normal weight yet insulin resistant?

Adipose Tissue


The number and size of adipocytes is perhaps the most important factor.  Large adipocyte cell size is associated with insulin resistance in obesity and also in those with a normal BMI (see Part 1 and 2) [1].  The number and size of adipocytes is probably largely driven by genetics and whether there has been any previous weight gain and weight loss.  Adipose tissue dysfunction can also increase adipocyte cell size, but I suspect it more likely just contributes to the vicious cycle rather than start it


The location of adipocytes is another important factor.  Abdominal fat is associated with insulin resistance [1] and partially explains why women have lower rates of insulin resistance (lower ferritin and higher estrogen levels and are probably some other reasons why women have lower rates of insulin resistance)

Other Organs

The Liver

Elevated liver triglycerides (such as in NAFLD) increases liver insulin resistance and doesn’t require obesity to occur [2].  Choline deficiency [3], high refined sugar in the context of a bad diet [2], and LPS* [4] are some of the things can cause NAFLD

* Although LPS is probably a cause of obesity as well (via SOCS3)


BMI sometimes isn’t an accurate predictor of body composition.  Two people could have the same BMI, yet different amounts of muscle and fat tissue.  Having a normal BMI with low muscle mass and high fat mass is called ‘skinny fat’ and is probably a feature of most of the insulin resistant normal weight.  Remember that insulin resistant normal weight has larger adipocytes [1], so unless they have fewer fat cells, they would have more fat stores

Exercise is probably another important factor as it can dramatically improve insulin sensitivity with (but usually only a small amount) or without weight loss [5] [6].  Some of this can probably be attributed to a change in body composition (lowering fat, increasing muscle) [7], some to short term post-workout effects (like GLUT4 (glucose transporter) not requiring insulin) [8], and some to longer term signalling (like AMPK) [9]

The Pancreas

Some of the ‘insulin resistance’ in people with a normal weight may actually be from a relative insulin deficiency caused by autoimmune attacks on the pancreas [2]

Other Factors

Elevated Lipolysis

Things that elevate lipolysis (ghrelin, stress hormones, growth hormone, testosterone, etc) are probably going to increase insulin resistance via FFAs without much effect on weight.  For example:

  • Acromegaly is a disorder of growth hormone hypersecretion where the people affected tend to weigh less and have more insulin resistance [10]. 
  • Anabolic steroids (usually testosterone analogues) tend to lower body fat, increase muscle mass, yet increase insulin resistance*. 
  • Psychological stress increases insulin resistance [11] [12].  In addition to increasing lipolysis, stress hormones such as adrenaline and cortisol also directly decrease glucose uptake by cells and increase liver glucose output**.

* However, testosterone replacement therapy reduces insulin resistance in T2D, hypogonadal men [13]

** Increasing liver glucose output doesn’t increase insulin resistance but would give someone a higher fasting glucose measurement

*** I’ve had a suspicion for a while that in some people stress promotes weight gain and in others promotes weight loss.  This doesn’t sound completely contradictory when you consider that the list of symptoms for depression includes overeating and loss of appetite


Inflammation is an obvious factor seeing as how pro-inflammatory cytokines increase insulin resistance by increasing lipolysis, JNK, SOCS3, PTP1B and IKKβ and by lowering adiponectin and AMPK (see Part 1).  The problem is that SOCS3 and PTP1B also increase leptin resistance and so inflammation promotes weight gain as well.  So it probably depends on the location of the inflammation (brain, liver or adipocytes).  Also, as changes in insulin signalling generally seem to be faster than changes in weight perhaps people who are insulin resistant due to inflammation and are currently at a normal weight are likely inflamed and should expect further weight gain from inflammation.


Some people may be more or less sensitive to things like the effects of inflammatory signals (for example) on insulin vs. leptin receptors, the homeostatic control of body fat, etc, based on various genetic polymorphisms, mutations and/or epigenetic factors

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