Friday, October 28, 2011

The Brain Controls Insulin Action

Insulin regulates blood glucose primarily by two mechanisms:
  1. Suppressing glucose production by the liver
  2. Enhancing glucose uptake by other tissues, particularly muscle and liver
Since the cells contained in liver, muscle and other tissues respond directly to insulin stimulation, most people don't think about the role of the brain in this process.  An interesting paper just published in Diabetes reminds us of the central role of the brain in glucose metabolism as well as body fat regulation (1).  Investigators showed that by inhibiting insulin signaling in the brains of mice, they could diminish insulin's ability to suppress liver glucose production by 20%, and its ability to promote glucose uptake by muscle tissue by 59%.  In other words, the majority of insulin's ability to cause muscle to take up glucose is mediated by its effect on the brain. 

They went further, showing that an obesity-promoting diet suppresses the brain's ability to regulate peripheral glucose.  It has been known for a long time that these diets cause insulin and leptin resistance in the brain of animal models, and that this loss of hormone sensitivity contributes to the development of obesity.  Now, this paper suggests that brain insulin resistance contributes to whole-body insulin resistance under these conditions.

This isn't the first study to demonstrate that the brain regulates glucose metabolism in the rest of the body.  My excellent colleague Dr. Greg Morton recently wrote a detailed review paper on leptin's actions in the brain to regulate blood glucose (2)*, in which he described some previous studies that showed:
  • Suppressing insulin signaling in the hypothalamus (in the brain) causes insulin resistance in the liver
  • Increasing insulin signaling in the hypothalamus enhances the suppression of glucose production by the liver
Furthermore, Dr. Christoph Buettner published a paper this year showing that infusing insulin into the brain influences lipolysis, the release of fatty acids by fat tissue (3)**.  This demonstrates that the brain has direct control over the amount of fat leaving fat cells. 

All tissues contain nerves that are connected to the brain and allow the brain to monitor and influence various tissue processes.  In the 21st century, as our knowledge advances, I believe that mainstream research and clinical practice will come to see obesity, the metabolic syndrome and diabetes as disorders that are critically dependent on the functions of the brain.  This has already occurred for obesity, and diabetes may be next.

* Dr. Morton has been studying the fascinating phenomenon that leptin infused into the brains of rats can totally rescue them from "type 1" diabetes, even if they have no pancreatic beta cells left.  After a few days of leptin treatment, the rats have totally normal fasting blood glucose and normal glucose tolerance, despite the fact that they have no insulin whatsoever.  This demonstrates the powerful ability of the brain to regulate glucose metabolism in the whole body.  I will note that they use high doses of leptin-- this isn't an effect that a normal circulating concentration of leptin can produce. 

** One of the models he used to study this is the NIRKO mouse, which lacks insulin receptors specifically in the brain. These mice "exhibit unrestrained lipolysis and decreased de novo lipogenesis in [white adipose tissue] (4)."  To understand the full irony of this, consider that these mice are more susceptible to obesity than normal mice (5).  In other words, they get fatter than normal mice despite increased fat release from fat cells.  This illustrates the limitations of focusing on lipolysis to understand obesity.  Lipolysis doesn't reduce fat stores if the fat isn't being burned after its release, because it just does a loop through the circulation and ends up back in the fat tissue again (or possibly in muscle or liver, which is worse) via an increased rate of fatty acid esterification.  Changes in fat mass have to result from changes that alter the amount of energy entering or leaving the body, unless you're building a whole lot of muscle or storing fat in your liver/muscles (bad).  The body is designed to store excess energy in fat tissue at all costs, because failing to do so causes severe metabolic problems (e.g., lipodystrophy).  Therefore, excess energy will be stored in fat cells regardless of the amount of lipolysis occurring, as long as esterification is not severely impaired.  It appears that the body has redundant mechanisms for getting fat into fat cells (reducing noradrenaline produced by nerve terminals, increasing insulin, increasing ASP), demonstrating the importance of this process, although it is not fully redundant since uncontrolled type 1 diabetes causes excessive fat loss.


Todd Hargrove said...

Very interesting.

I see some parallels between your "brain centric" view of obesity and one of the subjects I write about at my blog - a brain centric view on pain and physical performance.

Despite some huge progress in pain science over the last twenty years, in which it has been shown that the brain plays a large role in many chronic pain conditions, many therapists remain completely unaware that pain is often the result of central as opposed to local problems.

There is a small and vocal community of therapists that are extremely frustrated that the "neurorevolution" has not arrived yet, and that most of their peers are extremely resistant to considering the idea that the central nervous system should often be a primary target of any attempt to improve movement.

I think it is very hard for people to understand how much control the brain has over the body. People get confused into thinking that local symptoms have local causes, or maybe that the brain's role in body problems implies some sort of new age idea about mind over matter.

I think it will be a while before the health community appreciates that the primary target of many therapies is the brain not the body.

Chris said...

When we talk about brain controlling systems be they pain or insulin, I think we need to be clear about how much of this is conscious and how much not. There is scope for confusion

Great post, as usual

Kindke said...

This bodes well for ketogenic diets as it was also reported recently that ketones improve insulin and leptin signalling in the brain.

gunther gatherer said...

Fascinating Stephan. The idea of fat "doing a lap" around the body in a futile cycle made me think of something:

I recently watched a documentary where HGs had their main subsistence food in crocodile meat, which must be hunted at night. Almost every night, they would come back at 3 or 4 am and eat a croc together.

Insulin theory would have us believe that this would ruin their nightly pattern of low insulin, causing bodyfat gain and disease over time. (Low carb dieters are often told not to eat after 6 or 7 pm in order not to disturb this "crucial" fat-burning period. And we're always told "during sleep is when most of your fat is burned"!)

However the HGs were quite skinny and had no diseases of civilisation, and this despite fairly poor sleep in the daytime due to their nocturnal hunting schedule.

gunther gatherer said...

Also, I'm slowly becoming aware of the implications of your assertion that the brain controls obesity, diabetes, glucose tolerance, metabolic syndrome, etc.

Barring local injury and infection, do you think the brain determines overall health and morbidity then?

Keenan said...

@kindke- ketones improve insulin and leptin signalling but does a ketogenic diet??? Not according to this study by the same authors

"In conclusion, KTD impairs energy and glucose homeostasis by exacerbating insulin resistance and attenuating hypothalamic leptin signaling in non-obese type 2 diabetic rats. These changes are not associated with increased serum ketone levels."

Thomas said...

I think extending the physiologic benefits of ketones to a ketogenic diet is a huge leap as "Rip & Clip" indicated. It's like extending the adaptive benefit of inflammation after a work out to an inflammatory diet.

David Pier said...

So, this probably ties in with the almost immediate improvement in insulin resistance after gastric bypass surgery. Perhaps also connected to the effectiveness of the Shangri-La diet? It would be interesting to measure if the Shangri-La diet causes the same immediate improvement in insulin sensitivity.

allison said...


How does mitochondrial dysfuction play into the brain/insulin equation? Does free radical leakage produce a signaling cascade that feeds back to the brain?

Ron Rosedale said...
This comment has been removed by the author.
Ron Rosedale said...

Good post. The control of the hypothalamus by leptin is extremely important to health and disease including the regulation of the liver's production of glucose and the accumulation of visceral (liver) fat when dysfunctional. Leptin likely excedes insulin's importance in the brain and for that reason is at least as important as insulin for metabolic diseases such as diabetes and obesity. I talked about this quite extensively 5 years ago at the American Society of Bariatric Physician's annual meeting. The pdf of the powerpoint and transcript can be seen here;
Thanks, Ron Rosedale

Dr. John said...

Not only does insulin suppress lipolysis, but this fundamental insulin property is mediated in a very large way in the brain. This is mediated through the sympathetic nervous system. Insulin reduces sympathetic nervous system activity in adipose tissue. Insulin fails to inhibit lipolysis, and serum fatty acids are elevated. This leads to increased inflammation and worsen insulin signaling. Vicious cycle.

Mike @TheIronYou said...

Great post, explains really well insulin and its ikmplications!

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Ned Kock said...

Stephan, an post-writing question: I checked the HTML code of your post and it seems that you enter the citation numbers (1, 2 ...) manually. That seems like a lot of work to me, especially if you need to add a new citation.

Am I correct about how you do it?

I want to find a way to enter citation numbers automatically, or include citations more easily, in my own blog posts.

BenSix said...

Hrm. Does this mean people who claim that artifical sweeteners fool the body into releasing insulin have enough of a point that I should break my diet soda habit? Damn.

All About X4 Extender said...

whoa! what was that? can you check Health Reviews for a Healthy Life? this is great! quite shocked somehow..

Sanjeev said...

on a related note, re: exercise

would exercise that involves gross, deliberate bodily movement (gymnastics, judo) be more beneficial[1] than equal-calorie-burn, seated, single-muscle-group exercise - situps, leg presses, "lat pull-down" and bench presses, cycling?

The requirements on the vestibular system and the greater requirements for control and awareness while being thrown in judo or doing a flip in gymnastics - the work required from the entire nervous system would appear to be so much higher.

I suspect this is so but have never seen any proof of this idea.

[1] encourage lower fat mass, greater insulin sensitivity in various tissues - nervous and muscular

Sanjeev said...

BenSix wrote ...
artifical sweeteners fool the body into releasing insulin
Insulin's a side issue in this case, maybe entirely a non-issue.

The central issue is, do the sweeteners make you want to eat more in the future - Stephan's view is they do.

First, in and of themselves they are obviously more rewarding than the simple diet - most are sweeter than dextrose or sucrose.

Second, they add variety, which is rewarding as a separate category.

JustJoeP said...

Sanjeev and BenSix - I have personally gone from 6-to-8 diet cokes a day to zero, over the course of 6 months (in 2008). Simultaneously, I eliminated gluten and greatly diminished carbs. My previously insatiable and voracious appetite where I used to carry "emergency food" with me everywhere I went, is now gone. My HA1C (which can't be "fooled") went from 6.5 to 5. HD cholesterol went from 25 to 65, and I dropped 45 lbs - 20% of my biomass.

Now, if I can just get my primary health care physician to reverse her diagnosis of type II mellitus - since i no longer have symptoms.

Artificial sweeteners, if your hypothalamus can not be fooled by them are fine. I found the influence of aspartame & acesulfame potassium to be too powerful personally, completely screwing up my insulin regulation. Now with caffeine provided by organic tea & sweetness by organic stevia, gluten free, synthetic sweetener free, and nearly-carb-free, I have rejuvenated energy & fitness levels that I thought were lost 25 years ago.

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leadership and team building said...

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Author Gabriel Land said...

This makes sense to me, but I have heard that the gut almost has its own brain. More serotonin in the gut than the brain, etc.

yolio said...


vladex said...

Of course brain controls every organ,hormone and a bodily process. Only some of those into extreme allopathic medicine and modern mainstream diet gurus could think that something or everything is out of brain's control and that you can affect one thing without exchanging entire balance.
When we talk about brain controlling systems be they pain or insulin, I think we need to be clear about how much of this is conscious and how much not. There is scope for confusion

Great post, as usual --------------
Thankfully it's all unconcious otherwise people would be falling by the wayside. Nature is smart and doesn't make mistakes unlike the allopathic medicine and diet gurus . As for insulin itself, it interacts widely with hypothalamus which is the oldest part of the brain and thus is very much programmed, automatic and very observant to the outside stimuli for its actions.

Roger L. Cauvin said...

Thomas said...

"I think extending the physiologic benefits of ketones to a ketogenic diet is a huge leap as 'Rip & Clip' indicated. It's like extending the adaptive benefit of inflammation after a work out to an inflammatory diet."

Good point of caution about equating ketones with a ketogenic diet.

However, instead of being so summarily dismissive, can we at least explore the possibility that a ketogenic diet might just result in greater concentration and use of ketone bodies in the brain, which in turn might improve leptin and insulin signaling?

Yes, the other study you cited suggested that a ketogenic diet might actually harm leptin and insulin signaling in non-obese type 2 diabetic rats. But did it increase the amount of ketone bodies circulating in those rats' brains? If not, isn't it fallacious to jump to the conclusion that it would affect humans the same way?

I thought it was well established (going way back to the fascinating studies on epileptic patients) that, in at least some humans, a ketogenic diet does precisely what its definition entails - generates ketones - and does so to the extent that those human brains eventually derive at least half of their energy from ketone bodies.

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