Tuesday, September 15, 2009

Hepatic insulin resistance

Jenny Ruhl pointed out this study not so long ago:

"These data demonstrate that IHTG [intra hepatic triglycerides], not VAT [visceral adipose tissue], is a better marker of the metabolic derangements associated with obesity"

which leads neatly to this article:

"These results show that progressive increases in IHTG content are associated with progressive impairment of insulin action in liver, skeletal muscle, and adipose tissue in nondiabetic obese subjects"

Both of these are interesting as they make the liver the centre of the changes commonly found in type 2 diabetes and its precursor, IGT. There are now quite a few observational studies suggesting that VAT is not particularly tightly associated with insulin resistance.

I don't think anyone would consider the central role of the liver surprising when you think about the involvement of fructose in this syndrome. Because fructose barely penetrates beyond the liver you would really expect the liver to be the site of its effect on the body.

The development of insulin resistance is usually associated with the accumulation of lipid in a given tissue (or I guess you should say the processes leading to that accumulation, it may not be the lipid per se). The metabolism of fructose guarantees that this occurs in the liver. There's a nice paper describing an intervention study here:

"A 7-d high-fructose diet increased ectopic lipid deposition in liver and muscle and fasting VLDL-triacylglycerols and decreased hepatic insulin sensitivity"

This is a study in PEOPLE, not rats!

Note that it only induced hepatic insulin resistance, systemic insulin resistance should take longer.

If the liver stops listening to insulin it will not take up glucose or store it as glycogen in response to "physiological" concentrations of insulin. It will then leak glucose in to the blood stream in totally unacceptable amounts. It is up to a combination of muscle and adipose tissue to keep the blood glucose level remotely acceptable. This will require lots of insulin, because there is lots of glucose available to leak from the liver. The palmitic acid from fructose will be shipped out as VLDLs and stored as fat by the enormous quantitiy of insulin needed to keep blood glucose remotely normal...

Ultimately, in the longer term, adipocytes will become so full that they too will become insulin resistant, which can then lead to inappropriate NEFA release, muscle insulin resistance and type two diabetes. Obviously there will be genes which determine at what size your adipocytes give up their unfair struggle. So we can look at the genetics of resistance to a functional poison or we can just avoid the poison. I know that latter is a silly idea, but I like it!

Makes it a bit hard to see how abdominal "fat-ectomy" might cure diabetes in rats and mice, which it does seem to do... Mind you, in dogs, visceral fat-ectomy improves peripheral insulin sensitivity modestly, so this would fit in with VAT accumulation being a down stream effect spreading hepatic insulin resistance to the periphery by NEFA, and only when VAT has given up listening to insulin itself...

So the accumulation of visceral fat becomes a consequence of fatty liver rather than a cause... In the short term fructose is perhaps the best trigger for hepatic insulin resistance. It can be achieved in other ways, I'll discuss giving a dog some bacon fat alongside its cr*p in a bag on another day...

Peter

20 comments:

Ed said...

I was wondering if galactose might cause some similar problems? I am an amateur at this whole nutrional physiology thing, but i was curious if galactose (half of lactose) might be problematic in quantity. A cursory google suggests that galactose is solely metabolized in the liver. Given that, perhaps it is possible that it might have detrimental liver effects like fructose?

Jenny said...

Peter,

It is my understanding that human studies have shown zero health benefit from the frivolously named serious surgery called the "tummy tuck." This is a plastic surgery operation where they remove almost all of the abdominal subcutaneous fat pad.

The plastic surgeons very much wanted to find health advantages for removing subcutaneous belly fat as that would have meant that U.S. insurers would have to pay for this extremely popular and very expensive surgery. That they could not suggests that the subcutaneous fat is a nonissue, health-wise.

I have seen a study that suggested SC fat it was actually linked to better health in some women.

In related news, there was a study cited in yesterday's Science Daily that linked exposure to second hand cigarette smoke to increased liver fat storage too.

Dave Lull said...

Sandy Szwarc recently posted on "The myth of unhealthy belly fat."

Peter said...

Hi Ed,

A quick scan of Moseby's Crash Course in Metabolism and Nutrition suggest the pathways are slightly different. Fructose in the liver goes via fructose-1 phosphate to glyceraldehyde, bypassing all control steps. Galactose is converted to glucose-6 phosphate and is still controlled by the rate limiting step of phospho fructokinase. It does bypass the hexokinase main control step and Moseby doesn't comment on the regulatory usefulness of the assorted steps from galactose to glucose-6 phosphate. That's my crib sheet exhausted!

Interesting all babies develop arteriosclerosis in the first few months of life. This appears to be completely normal and resolves in its own good time. The thrombosis hypothesis of arteriosclerosis has a certain amount to say on the adaptive effects of arterial thrombi in strengthening and developing the arterial tree. This does not usually require atheroma, certainly not unstable plaque, that's probably the system gone wrong. But there will be a basically adaptive system underlying the pigs-ear we have made of it!

Galactose certainly glycates better than glucose. Why should it be in milk if not for benefit to babies?

Hi Jenny,

I'd heard that liposuction was basically bad news from the metabolic point of view. Usually arguments about the ratio of visceral to peripheral fat depots get waved around. Ultimately you are removing adipocytes during liposuction and excess glucose/fat have to go somewhere. The loss of any fat tissue seems to put you closer to running out of the protective calorie glucose/calorie sump represented by adipose tissue, wherever it is.

If you performed the ultimate liposuction and removed ALL adipocytes from a human your victim would be in the same boat as some poor person with Beradinelli-Seip syndrome. Very thin and very diabetic.

Glad to hear there is little progress on getting here surgically.

Ta Dave, bit more reading to do there then! I really must book mark that blog.

Peter

Bryce said...

So general insulin resistance throughout the body is a downstream consequence of localized hepatic insulin resistence?

I got some of what you are saying, but a little elaboration on how, exactly, fructose causes this insulin resistence would be appreciated. I have read that the elevated triglycerides and VLDL associated with fructose metabolism are integrally involved, but I don't really understand the mechanism through which these elevations actually cause insulin resistence.

If you have another post that explains this, I'd appreciate it, and I'd hate to think that you were explaining something to me that you'd already written about elsewhere.

Thanks Peter,

Bryce

Feliciana said...

Great information.
http://acid-reflux-dd.blogspot.com

Peter said...

Hi Bris,

http://www.youtube.com/watch?v=dBnniua6-oM

gives you a lot of the answers. He gets a bit lost on fibre (thinks it is essential! I'm doomed). Also uric acid is nowhere near as simple as he makes out.

Somewhere around 1h 5 mins in to it he gives the mechanism for insulin resistance in the liver.

Basically:

Excess acyl-CoA and/or fructose activates JNK1 which serine-phosphorylates IRS1 which is then inactive. IRS1 is a key transmitter of insulin signaling (IRS1 = insulin receptor substrate one). Non active IRS1 = insulin resistance.

Peter

country mouse said...

bother. fruit is the only food I really enjoyed eating pre diabetes. and now it is restricted to the point of making me seriously unhappy. I read this article as saying I need to restrict fruit consumption even further or even eliminate it.

my dr is going to love this. I'm having a hard enough time eating as is. (look up migraine diet and subtract those foods plus dairy from the diabetic diet). fruit is the only appetite stimulant I have left.

Peter said...

Hi Country Mouse,

Stephan has discussed paleo diets for type 2 diabetes quite extensively and modest fruit is allowed. I guess it is a matter of how unhappy your liver might be vs fruit consumption. Bear in mind that apples, pears, pineapples, cherries etc aren't really fruit.

Sloes, wild plums and, as a real luxury, blackberries are probably real fruit. Crab apples too... And maybe the occasional wild blueberry.

Sorry

Peter

westie said...

Hi Peter,

what do You think if I suggest that cause for abnormal intrahepatic fat accumulation might be related to increased intestinal permeability and loss of tight junction integrity.

Here are two related articles:

Dietary fructose and intestinal barrier: potential risk factor in the pathogenesis of nonalcoholic fatty liver disease (The Journal of Nutritional Biochemistry Volume 20, Issue 9, September 2009, Pages 657-662)

Increased Intestinal Permeability and Tight Junction Alterations in Nonalcoholic Fatty Liver Disease (Hepatology Volume 49 Issue 6, Pages 1877 - 1887 Published Online: 23 Jan 2009)

Braesikalla said...

"All babies develop arteriosclerosis in the first few months of life."

That's interesting, indeed. Any ideas about the underlying mechanism?

Could it be that during birth and the first months of life oxygen supply of some tissues is critical.

Kwasniewski claims that tissues can extract oxygen from carbohydrates leaving plaque-forming cholesterol as byproduct.

Peter said...

Hi Westie,

I couldn't make out from the abstracts whether the coeliac people had NAFLD. They obviously have the permeability problem. I'd read that simple sugars produce an osmotic damage to mucosal integrity. It was one hypothesis bandied around as to why sucrose intake should be associated with inflammatory bowel disease, which it is. But if the coeliacs are negative for NAFLD that makes me suspect the gut damage from fructose and liver damage from fructose have a common cause (fructose) but separate mechanisms...

Braesikalla,

The full text about neonatal arteriosclerosis can be down loaded as a pdf from here

http://www.ncbi.nlm.nih.gov/pubmed/13447170

According to the thrombosis hypothesis damaged areas of blood vessels are patched with blood clot, possibly reinforced with Lp(a) or oxLDL (which may well be the same particle anyway). Damage is primarily pressure induced physiologically (ignoring smoking, hyperglycaemia, hyperhomocysteinaemia etc) and the birthing process is a high pressure process all right. The thrombus organises and develops in to thickened arterial lining in response to the initial injury, giving selective strengthening in high stress areas. The argument is that this is not pathology, this is absolutely correct as part of the development of the arterial tree. If your Lp(a) levels happen to be low you are then dependent on oxLDL to do the sticking and adding a glycating agent (galactose) to milk to give some oxLDL, without fatty liver, seems logical to me. Especially for babies who might really need it...

Ultimately the pathology we see as CHD has to be the perversion of a normal physiological process. If the apoB protein was simply lethal then we would have gotten rid of it long ago.

Notice the foetuses had no arteriosclerosis, only neonates which had been through the birthing process. It links well to Willis' ideas, downloadable here,

http://www.ncbi.nlm.nih.gov/pubmed/13116079

as to why arteriosclerosis localises where it does. It's likely that a chronic excess of linoleic acid in combination with hyperglycaemia provides too much damage and too much repair, amplified by insulin, to give atheroma formation. I really will try and tie all of this together some day.

BTW the scenario still leaves the option open for JKs ideas about extracting O2 from glucose by converting it to cholesterol. An alternative hypothesis. The localisation phenomenon pushes me towards Willis, but there is no reason for JK to be wrong, just it's not the answer in the specific arterial juvenile changes seen.

Peter

mark said...

Hey Peter.

I had some neat thoughts about glucose and fructose.

Is there a labelled condition such as hyperfructosemia (spelling)? I can't google it because I'm not a nomenclature enthusiast and the spell checker on google isn't correcting me.

How much of fructose enters the blood stream? I think it is metabolized quite quickly and given priority like alcohol. Does that mean that fructose affects insulin resistence entirely or largely through its metabolism? It must hit the blood stream in some amount, because it alters LDL so that the macrophages endocytosing it turn into foam cells and release debris into the blood.

Is fructose like LDL in that LDL correlates with oxLDL, and fructose correlates with glucose, so hyperlipidemia sometimes looks not too good because of the oxLDL and hyperglycemia looks not too good because of the fructose? Only problem is, as far as I'm aware, there are many cases of higher lipids correlating with health. Not aware of any cases for hyperglycemia.

A while back you posted a link to two studies about the glycosylating properties of fructose being 10-15 times (something in this range) more powerful than glucose. So fructose is a real bastard sugar. I really want to see studies separating glucose from fructose in blood readings.

JK has his ideas on pentose and hexose pathways for metabolising carbohydrate (he's often right, but I dunno here). Stan has a post about it. But I'm not sure what biological effect the pathways make.

Am I totally off base, and do glucose tests only measure glucose and overlook fructose? It would seem that a glucose test should only test for glucose, but a LDL test should test for LDL and it doesn't. So I am guessing a glucose test just checks for sugars.

Mark.

Terry H said...

Peter,

I am no biochemist, but suggest that if you buy Lustig's views about fructose and insulin resistance, set out in the above-mentioned video, then one also should look at the independent and/or coadjutant role of ethanol, in causing insulin resistance. This is on the basis that he argues the metabolic pathways are nearly identical.

When I search the literature I find little research on this potentially combined effect. Am I missing something?

westie said...

Peter wrote:

"The coeliac people obviously have the permeability problem."

I don't know much about coeliac disease but this seems quite interesting:

Presence of Bacteria and Innate Immunity of Intestinal Epithelium in Childhood Celiac Disease (Am J Gastroenterol. 2004 May;99(5):894-904)

It says:

"Rod-shaped bacteria were frequently associated with the mucosa of CD patients, with both active and inactive disease, but not with controls."

CD patients have increased permeability still when they are on a gluten free diet. Bacteria in the short intestine could be a causal factor.

Hey, they've just identified those bacteria:

Proximal Small Intestinal Microbiota and Identification of Rod-Shaped Bacteria Associated With Childhood Celiac Disease (Am J Gastroenterol. 2009 Sep 15.)

Peter said...

Hi Westie,

According to Gottschall coeliac disease is simply a small subgroup of more general family of IBD problems and, from what you have linked to, Gottschall's idea that it is a simple dysbiosis is perfectly appropriate. Coeliac is special in that there is a specific antibody or two which can be found to attach a specific disease label. But while removing the antibody "label" may make patients apparently asymptomatic it does not normalise their SI bacterial population (which should be near zero). Gotschall suggests that limiting carbohydrate to certain sub groups is what is needed. I think she is (was) correct. She liked lactobacilli too. Pretty well banned starches.

Hi Terry,

I'd expect them to be additive. While thinking about models and being totally misled by them, check out Dandona's problems caused by following his "white cell ROS generation" model of inflammation/damage in diabetes. I'm assured he is a very bright and very charming guy. But orange juice and alcohol as the ideal "food" for diabetics???? I think not.

Peter

epistemocrat said...

Hi Peter,

Thanks for all your wonderful work on hyperlipidity. My ancestor, Dr. Francis Pottenger (ppnf.org) would be quite happy.

In regards to CD and bad bacteria, I agree it falls under the general IBS umbrella, which applies to my analogy here:

http://epistemocrat.blogspot.com/2009/04/clostridium-difficile-weed-inside-your.html

I read the abstracts mentioned in the comments of this post, and it appears that fructose could serve as an adherent agent for 'bad' bacteria to invade your 'good' bacterial lawn. C. Diff was mentioned in those abstracts as one of these bad bacteria. C. Diff metabolizes fructose.

In light of Dr. Lustig's research and my family's experiences with IBS and C. Diff, fructose appears to be quite toxic in this regard.

My brother's physician, Mark Pimentel, wrote a book on this topic:

http://www.anewibssolution.com/excerpt.htm

He get's close to the logical nutrition conclusions.

They're getting warmer.

Best,

Brent

Braesikalla said...

Thank you, Peter, for your extensive explanation.

So in a nutshell are you suggesting that the oxidized LDL in an atheroma is part of a physiological repair process which has gone wrong by to much insulin floating around and causing to much anabolism at the site of endothelial injury?

Fascinating, I'm very keen on that upcoming post when you will explain things in more detail. Hope you'll find the time to do that.

I'm also very interested in the role of linoleic acid in the process and if there is a difference between this omega 6 fatty acid and its derivate arachidonic acid in atherogenesis.

trinkwasser said...

"The loss of any fat tissue seems to put you closer to running out of the protective calorie glucose/calorie sump represented by adipose tissue, wherever it is."

Yes that ties in with what my family does wrong: the people like me who have difficulty putting on fat leave the excess glucose and lipids rattling around in the blood rather than stashing them, the plumper folks measure significantly better on all aspects of metabolic syndrome. Then when I do put on fat it's visceral, the worst kind. Unlike subcutaneous fat VAT puts out gazillions of inflammatory cytokines which gemerate feedback loops culminating in the addition of yet more VAT.

My muscle IR responded well to reducing carbs, it seems to be related to BG spikes which shut down the GLUT 4 receptors, but my liver took some Alpha Lipoic Acid to get sorted (I couldn't get metformin) which seems to control both the under and overdumping of glucose.

Of course the dietician positively *enthused* over the fruit juice I was drinking (no added sugar, natch) probably one reason along with the extra wheat and Omega 6s as to why I became rapidly worse. Once you start to derange the system every factor seems to become additive, or multiplicative.

Small quantities of fructose, like sufficiently few berries to spike my BG, don't seem to do any harm. There's that J curve again.

westie said...

About coeliac and Gottschall again. I got full text of this article: "Is it true that coeliacs do not digest gliadin? Degradation pattern of gliadin in coeliac disease small intestinal mucosa."

Here's the conclusion:

"In conclusion, our data point to a possible contribution of specific CD mucosal-associated bacteria to the development of the disease, due to metallo-gliadinase activities."

Bacterial glianidase activity seems to be even enhanced during GFD.

I wonder how autoimmune responce developes. Does bacteria break gliadin and those parts in the bacterium media (endotoxin) starts immune responce to all gliadin which is adhered to mucosal cells?

Could you please little explain how coeliac related mucosal damage develops?