Why does obesity cause insulin resistance?

[fado]

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Alright so this question has been plaguing me for the longest time...

So i know that obesity, which is excessive amount of adipose tissue can lead to diabetes because lipids, in particular fatty acids, have a toxic effect on insulin receptors in many tissues, especially the liver and skeletal muscle. What i don't get is what is the mechanism of this toxicity? What is the exact pathology that is taking place?

 

[Danlee07]

Well common sense wise, the insulin receptors are being fried and desensitized..

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC380258/?tool=pubmed (article on type 2 and obesity)

 

[myhandsarecold]

i thought it had to do with fat stores pretty much full so can't take in anymore even with enough insulin -> insulin resistance. Rx is by weight loss -> increase storage capacity for more sugar products, fats.

 

[da8s0859q]

Well common sense wise, the insulin receptors are being fried and desensitized..

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC380258/?tool=pubmed (article on type 2 and obesity)

This.

Also, remember that many hormones are secreted in a pulsatile fashion partially to prevent so-called receptor fatigue. With obesity and presumably the eating habits that go with it, you're subjecting yourself to all of this glucose, which leads to all of this insulin at a more consistent pace, which leads to all of this constant insulin exposure to these inducible GLUT-4 receptors over time that are generally intended for a more periodic expression... something's gotta give, basically.

At least that's how I think of it.

 

[fado]

alright, thanks guys.

 

[monkeys!]

No one truly knows the exact mechanism, but there are two main theories right now:

Abstract from this Science article by Gary Taubes (an excellent scientific Journalist).
http://www.sciencemag.org/content/325/5938/256.summary

Insulin resistance is the thread that runs through many chronic afflictions of modern times—obesity, heart disease, and, most conspicuously, type 2 diabetes. All are entangled with diet, and all are linked causally to a dysfunctional response to insulin, the hormone that orchestrates the body's use and storage of nutrients. Elucidating the causes of insulin resistance is one of the most critical endeavors in modern medicine, and two competing theories have now gained wide support. One is that cells essentially become poisoned by fat. This lipotoxicity or lipid overload hypothesis holds that normal processes break down when fat (adipose) tissue cannot store excess fat, and fat accumulates inappropriately in muscle and liver cells. The main rival to this idea, the inflammation hypothesis, holds that as fat cells increase in size with the accumulation of fat, they release inflammatory cytokines and molecules known as adipokines. It's these molecules, so this theory goes, that cause insulin resistance elsewhere in the body. Researchers are now confident that these inflammatory mechanisms play some role in insulin resistance. But they still can't say for sure whether those roles are causal.

 

[vanbamm]

We are all created with a set number of fat cells, but these fat cells can multiply into infinity if the intrinsic stores become full- the reason why it is so easy to become obese once you have been overweight is because these cells, once multiplied, never leave, they just shrink- as far as muscle and organ tissue turning into fat- fat can be stored there, and also, those cells can be transformed into fat cells, which is likely to happen in obese patients because of lack of activity- insulin resistance and fat cells play off each other (although fat cells are not the sole mechanism for this pathology)- high fat stores= high release of fatty acids= decreased sensitivity to insulin, excessive insulin= downregulation of insulin receptors...cortisol is released to counteract insulin and causes gluconeogenesis and further inhibits glucose utilization by the fat and muscle cells by decreasing GLUT4 receptors...again, this is only one mechanism, met x is a culmination of many things.

 

[Gary089]

We are all created with a set number of fat cells, but these fat cells can multiply into infinity if the intrinsic stores become full- the reason why it is so easy to become obese once you have been overweight is because these cells, once multiplied, never leave, they just shrink- as far as muscle and organ tissue turning into fat- fat can be stored there, and also, those cells can be transformed into fat cells, which is likely to happen in obese patients because of lack of activity- insulin resistance and fat cells play off each other (although fat cells are not the sole mechanism for this pathology)- high fat stores= high release of fatty acids= decreased sensitivity to insulin, excessive insulin= downregulation of insulin receptors...cortisol is released to counteract insulin and causes gluconeogenesis and further inhibits glucose utilization by the fat and muscle cells by decreasing GLUT4 receptors...again, this is only one mechanism, met x is a culmination of many things.

well explained something i found also here Obesity and Diabetes: Does Obesity Cause Diabetes?

 

[sliceofbread136]

We are all created with a set number of fat cells, but these fat cells can multiply into infinity if the intrinsic stores become full- the reason why it is so easy to become obese once you have been overweight is because these cells, once multiplied, never leave, they just shrink- as far as muscle and organ tissue turning into fat- fat can be stored there, and also, those cells can be transformed into fat cells, which is likely to happen in obese patients because of lack of activity- insulin resistance and fat cells play off each other (although fat cells are not the sole mechanism for this pathology)- high fat stores= high release of fatty acids= decreased sensitivity to insulin, excessive insulin= downregulation of insulin receptors...cortisol is released to counteract insulin and causes gluconeogenesis and further inhibits glucose utilization by the fat and muscle cells by decreasing GLUT4 receptors...again, this is only one mechanism, met x is a culmination of many things.

Is there any evidence that increased amount of fat cells actually make it easier to gain weight/harder to lose? Just curious

 

[Redpancreas]

Alright so this question has been plaguing me for the longest time...

So i know that obesity, which is excessive amount of adipose tissue can lead to diabetes because lipids, in particular fatty acids, have a toxic effect on insulin receptors in many tissues, especially the liver and skeletal muscle. What i don't get is what is the mechanism of this toxicity? What is the exact pathology that is taking place?

Sadly, no one knows the EXACT pathophysiology/mechanism which also bothered me as a pre-med/M1 when I was super interested in biochemistry/metabolism. There's a lot of components and you hit on one major component which is the toxicity of fatty acids on receptors/cells. The other is basically macrophages increased cytokines leading to some sort of insulin resistance. In biology, the answer is probably that it's everything. Regardless, out of the scope of exams. If you're still curious, you might as well start lit-searching and get involved in the basic science