Sunday, June 2, 2013

Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Summary and Conclusions


Obesity and insulin resistance are strongly associated.  Many of the mechanisms (mitochondrial dysfunction/ER stress and inflammation) and signalling proteins (SOCS3 and PTP1B) cause both leptin resistance (obesity) and insulin resistance.  However, there are some people who are overweight but insulin sensitive and others who are normal weight but insulin resistant, which seems like a paradox.  This discordance only accounts for a small number, but it does exist

There are several differences between insulin resistant and insulin sensitive obesity.  People who have insulin resistant obesity have abdominal obesity, increased oxidative stress and inflammation, lower AMPK, PGC-1α and adiponectin, more liver and muscle fat accumulation, larger and fewer adipocytes, hypoxic adipocytes and macrophage infiltration in adipocytes.

Insulin resistant obesity mainly occurs due to overflowing adipocytes where elevated free fatty acids spill into the bloodstream and initiate an inflammatory cascade, resulting in insulin resistance.

Therefore people who are overweight and have smaller but a greater number of adipocytes are probably protected from insulin resistant obesity.  However, since leptin is released in proportion to adipocyte size these people may find it more difficult to lose weight.  This may be part of the explanation why losing the last bit of weight is more difficult than the first

I put forward some explanations of the paradox in Part 3, which are summarised in the table below

Insulin Sensitive
Insulin Resistant
Normal Weight
Probably Healthy
↔ Adipocyte Number
↔ Adipocyte Size
Some Excess Abdominal Fat
↑ Adipocyte Size
Low Muscle Mass
Not Exercising
Elevated Lipolysis
Type 1.5 Diabetes
↑ Adipocyte Number
↔ Adipocyte Size
Are Exercising
Recent Weight Loss
↑ Adipocyte Size

See Overweight but Insulin Sensitive and Normal Weight but Insulin Resistant: Part 1, 2 and 3


The similarity of mechanisms between insulin resistance and leptin resistance and the positive feedback loops involved suggest (to me) that in most, but not all cases insulin sensitive obesity and insulin resistant normal weight are simply intermediary states and two different pathways to the same endpoint - insulin resistant obesity (assuming no change in diet or lifestyle).  The differences between insulin resistance and leptin resistance just explain which path was taken.  Being insulin sensitive and overweight or insulin resistant and normal weight, while better than insulin resistant obesity, is sign that something isn’t right and needs fixing.

However, the exception to this rule is if a formally overweight/obese person has lost a significant amount of weight, but not all of it.  In this context they are still overweight, but have regained insulin sensitivity due to weight loss.  Their adipocytes may be greater in number, but of a normal size, potentially explaining why they are currently insulin sensitive and also why they have difficultly losing the last bit of weight.

Part 2 and part 3 contain a fair bit of speculation at times.  Don’t take this stuff as gospel

Further Reading and Other Stuff:
(1) Not all fat people get diabetes, and not all diabetics are fat
(2) Think skinny people don’t get type 2 diabetes? Think again.
(3) Fat Tissue Insulin Sensitivity and Obesity

As I was researching this post I came across a few papers: two discussing the similar role that insulin and leptin have in the hypothalamus [1] [2], and one on how men respond more strongly to the appetite suppressing effects of insulin, while women respond more strongly to the appetite suppressing effects of leptin [3].  Also check out this blog post by Todd Becker

I was considering doing a post on insulin resistance but while writing the last three blog posts I’ve covered a fair bit on the topic.  If you would like to learn more about insulin resistance Stephan Guyenet has a seven part series on the subject (see Part 1, 2, 3, 4, 5, 6, 7)

In part 1 Stephan mentions he is sceptical that mitochondrial dysfunction has a role in insulin resistance and obesity.  He uses studies of knock-out mice to back this up.  The knockout mice all have impaired oxidative phosphorylation (OXPHOS).  That doesn't necessarily mean they have mitochondrial dysfunction.  Inhibition of OXPHOS would reduce ROS production in the ETC, and this is one way by which uncoupling proteins are actually protective.  So long is the inhibition of OXPHOS is not mediated by pathological mechanisms like ROS and inflammation, and has the opportunity to signal feedback mechanisms (which is likely in a knockout mouse) then I'm not surprised there was no insulin resistance

Many studies find that mitochondrial dysfunction is associated with insulin resistance and is a cause of T2D.  There are fewer studies on mitochondrial dysfunction as a cause of insulin resistance, but they exist [4] and the mechanisms are very plausible.

As for mitochondrial dysfunction >> obesity: while I don’t have direct evidence for it, there’s evidence to support each step of this chain: mitochondrial dysfunction >> endoplasmic reticulum stress >> PTP1B >> leptin resistance >> obesity

Perhaps mitochondrial dysfunction ought to be better defined.  Maybe instead of less ATP production (because UCPs lower ATP production and reduce oxidative stress) mitochondrial dysfunction should be defined as satisfying these three criteria: lower ATP production, mitochondrial oxidative stress and mitochondrial DNA mutations.

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