Thursday, November 12, 2009

Liver and insulin (not a cooking recipe...)

I'm umm-ing and ah-ing about posting this at all. In the end I'm going to hit post. It's up for shredding! Peter


The function of insulin is the inhibition of lipolysis. I cannot argue with this.

There is a widely held belief that insulin is also necessary for the cellular uptake of glucose. This is incorrect.

I hit on this paper as an accidental result of the Atkins and methylglyoxal searching. It grabbed my attention because it reminded me of a paper I had read many years ago (on vacation, I used to take British Journal of Anaesthesia on vacation!) which was probably this one. And this is the one where they got type one diabetics to skip their insulin and be studied in the hyperglycaemic an-insulinaemic state (see below).

This is my summary of some of the main concepts carried in the papers.


I started off with simple analogies to baths, bathwater, flows etc. Unless you have a very, very strange plumbing system, this doesn't work. Back to metabolism.

Life is simpler if you are fasting.

If you have 5mmol/l of glucose in your blood, you cannot get more than 5mmol/l inside your cells. There are no pumps for glucose, it follows a concentration gradient. If your cells are using large amounts of glucose there will be a bigger concentration gradient and so more glucose will flow through the GLUTs, but perhaps not enough. You might need more "holes" to let glucose through. Enter insulin, more GLUT4s, more flow, sustained metabolism. Still no pumping and still blood glucose is 5mmol/l because whatever the cells take is being replaced. From the liver (we're fasting). Nowhere else for it to come from.

Let us say there is no insulin. There will be a basal number of GLUT4s and a few other GLUTs, which will allow glucose to flow. How much? Not enough. Not enough if the blood glucose is 5mmol/l. But what about with a blood glucose of 30mmol/l?

Would a blood glucose of 30mmol/l force enough blood glucose through the few GLUTs that are present without the help of insulin and its extra GLUT4s?

Well, apparently that's a pretty easy question to answer using tritiated glucose and the answer is yes. With a blood glucose high enough you do not need insulin to allow as much glucose to be used as would be used when blood glucose is 5mmol/l in the presence of insulin. This is fact.

You can read the paper about the type 1 diabetics who volunteered to withdraw their insulin and were studied in the hyperglycaemic an-insulinaemic state. They burn glucose.

So, if insulin is not essential for glucose based metabolism, what is its primary function?

Insulin allows the pancreas to talk to the liver. The liver controls, under the influence of insulin, how much glucose it adds to that teaspoonful of glucose which is normally present in the total blood volume.

This is core. As core as insulin's inhibition of lipolysis.

In a normal person 85% of the glucose from a carbohydrate meal never makes it past the liver. Under conditions where a bulk supply of rapid uptake glucose is unavailable, I doubt that any glucose gets past the liver. The pancreas knows about dietary glucose, the liver knows. It's their secret from the rest of the body. The liver rations out the glucose.

Diabetics, type 1 or 2, are not hyperglycaemic because they cannot use glucose. They are hyperglycaemic because their liver can no longer hang on to its glucose hoard. The liver's inability to be influenced by insulin is central to diabetes.

So the aim, in diabetes management, should be the control of leakage of glucose out of the liver. You can actually force a fructose damaged, insulin resistant liver to listen to insulin in exactly the same way as you can replace pancreatic insulin in type 1 diabetes. Use exogenous insulin. But it's hard.

Your liver does not listen to your subcutis, which is where injected insulin comes from. It listens to your pancreas. The pancreas secretes insulin in to the portal vein which has a blood flow of about a 1000ml a minute. A minute's worth of secreted insulin will be carried in 1000ml of blood. From the liver that minute's worth of insulin enters the systemic circulation and mixes with the cardiac output, which at rest is about 5000ml/min, so is clearly diluted. Peripherally measured insulin is always less than what the liver "hears" when it listens to the pancreas. What was in 1000ml/min of blood is now in 5000ml/min of blood. Of course insulin recirculates so systemic concentration won't be as low as one fifth of portal concentration.

So the normal liver should be seeing more insulin than is detected in peripheral blood. Adipocytes and muscle cells only see peripheral blood. When you inject insulin under your skin it is carried by the full cardiac output and will be delivered in dilute form to the liver compared to what should have happened if the same amount had come from the pancreas. Muscles will get the full hit.

A high carbohydrate diet, coupled with industrial doses of peripheral insulin, is doomed to fail. You cannot effectively inhibit glucose release from the liver without hitting the peripheral tissues with a relative overdose of insulin. This opens the GLUT4 floodgates in to the peripheral cells in the process of trying to stop glucose release from the liver. This sort of balancing act, high insulin, high glucose throughput, has to rely on hyperglycaemia to keep you safe from hypoglycaemia. Hello ADA.

EDIT: The papers discuss ketones as producing blockade of peripheral glucose metabolism, as we know they do. Palmitic acid is my idea.

The only sensible solution is to make the peripheral tissues as resistant to insulin as possible (so minimal extra GLUT4s pop up as a result of exogenous insulin) and then supply enough exogenous insulin to inhibit hepatic glucose release, delivering it through the hepatic artery as well as the portal vein. Two things allow this to work. Palmitic acid and ketones. Palmitic acid can be delivered through chylomicrons or VLDLs, it causes insulin resistance, thank goodness, so makes exogenous insulin less effective on muscles (where most of the GLUT4s are). It's worth noting that MCTs (I would guess through ketones) raise peripheral insulin resistance but still dip blood glucose (ie they allow the liver to listen to insulin). Ketones are made by the liver. I can't see ketones making the liver insulin resistant. They will inhibit peripheral glycolysis independent of glucose uptake. They effectively replace the insulin/glucose combination in metabolism. Insulin can then be given to the liver to inhibit glucose release without turning the muscles in to a glucose sump. Most tissues outside of the brain and a few other places can run perfectly well on the palmitic acid.

Low carbing is the solution, aiming for mild ketosis, intense physiological insulin resistance and minimal insulin doses (aimed at the liver). Bernstein is the guru, Kwasniewski has a slightly more relaxed approach. Both seem correct to me. Neither shuns saturated fat. But it doesn't seem as simple as balancing insulin against carb intake (though this is an excellent, and probably the only practical, rule of thumb). I would expect it to work better on a palmitic acid based diet than one using any unsaturated fatty acid for bulk calories. Using PUFA and oleic acid (to keep LDL down, dontcha-no) won't hack it in providing the physiological insulin resistance that should be helpful for tight glucose control.

As an afterthought; it is under low insulin levels that the liver ships out VLDLs too. More palmitic acid to the periphery.

We're back very close to low carbohydrate eating mimicking starvation, without the weight loss.

Peter

33 comments:

Nostril Damus said...

Peter

What do you make of all the research that links insulin to the "ageing process" itself ? Stuff by Cynthia Kenyon and others.

I like the idea that insulin flips the cellular machinery from concentrating on maintenance and repair to concentrating on reproduction, and would love your take on it.

Of particular interest to me is that fact that even unicellular organisms respond to insulin and yet have no vascular systems.

Cheers
Jordi

Stephan said...

Hi Peter,

Did you know that giving type 1 diabetic rodents high doses of leptin either systemically or lower doses ICV totally normalizes their diabetes? No insulin required. It actually brings their glucose tolerance almost back to normal. Here's one paper:

http://www.ncbi.nlm.nih.gov/pubmed/11919153

Jim Purdy said...

Through a lot of trial and error, I have found that the best diet for my overall health is high in fat, moderate in protein,and low in carbs. The results are really dramatic.

Peter said...

Jordi,

It's one of the things I really like about the Naked mole-rats, no one can find their insulin and they live to be 28 years old (and are still making babies at that age!). I've not come across much hard data on it though. There is even an insulin like peptide used by plants. I first met the concept through that transcript of Dr Rosedale's talk that was a starting point for many of us on this route.

Not seen that Stephan. Interestingly Rosedale now considers leptin to be the master hormone but I don't find any of his arguments terribly convincing. The paper you cite certainly does that job quite well. It ties in with vagotomy studies too, as well as the concept of the liver bing central to diabetes. Veeeerry interesting! It's nice how stuff fits together. Life should be logical!

Jim, I'm now wondering if a high fat diet mimics a CNS leptin infusion! But without the in dwelling cannula...

Peter

Sanjeev said...

I've been searching the blog but dan't seem to find this specifically - Are you seeking high palmitic meats and avoiding low-palmitic meats/foods?

If you have a minute, I'm curious what the following might say about my personal chemistry, if you want to venture a guess.

Back when I first tried Atkins around 1994 I could NOT get ketonuria on a mostly beef, heavy cream and fatty cheese diet.

At all. I was riding a bicycle 40 kilometers per day.

About 3 months into it, I took a spoonful of flax seed oil.

Within a day (and I remember clearly, that day I did no exercise) my urinary ketones had exploded into the darkest reading.

AFter regularly taking the spoon or 2 of flax seed, one day after riding my bicycle 60 kilometers, I completely fell off the diet and for a treat I had about a pound of french fries and 2 litres of ice cream.

Even after THAT I was still in heavy ketonuria.

Kurt G. Harris MD said...

So perhaps the confusion about insulin resistance can be resolved thus:

The physiologic insulin resistance with VLC diets is peripheral and due to palmitic acid (or ketones). If an OGTT is given, the "defective" handling of the glucose bolus is solely due to the peripheral IR, as the liver remains normally sensitive to Insulin.

The pathologic insulin resistance in the metabolic syndrome is in the liver. Resulting hyperinsulinemia may cause peripheral insulin resistance as well to avoid glucose flooding the cells, but the hyperinsulinemia is in response to the abnormal liver IR, which is..(going out on a limb here) due to damage by fructose!

The papers published by lipophobes focusing on how NEFAS or high fat diets induce insulin resistance are conflating a normal part of the randle cycle that has been known since the 1920's with the pathologic IR that is due to liver damage.

The only thing physiologic IR and pathologic liver IR have in common is they both show impaired glucose tolerance on an OGTT when compared to someone on the SAD who does not yet have diabetes.

LeenaS said...

Thanks, peter!

We've had another Sonksen paper circulating in our discussions, namely this: http://bja.oxfordjournals.org/cgi/reprint/85/1/69

The only thing that I'm slightly dubious (and I may be wrong) is your suggestion that only 15% of the glucose eaten by a normoglycaemic, healthy person on HiCarb would hit the peripherals. There are quite a bit of storage room for glucose out there, and glucose might actualy hit those storages in a healthy kitavan? That said, the use of liver glycogen storages IS much more dynamic, so stuff flows there much faster...

Regards,
LeenaS

Ken said...

The Relationship Between Leptin Level and Oxidative Status Parameters in Hemodialysis Patients

"Hyperleptinemia seems to be associated with increased oxidative stress in HD patients, and this association may provide better understanding about the disorders related to either elevated serum leptin levels and/or increased oxidative stress in HD patients"

Matt Stone said...

Insulin and leptin resistance go together like, um, peanut butter and bananas. Or let's say Mary Kate and Ashley.

What decreases leptin resistance decreases insulin resistance and vice versa. I suspect it's a two-way street. Type 2's produce way too much of both. It was always hypothesized - since the infancy of the leptin discovery, that the obese and type 2 diabetics had leptin deficiencies and could be cured by injecting more. Then the opposite was found. There was plenty of leptin to go around for the whole family.

But this post is still written under the pretenses that carbohydrate consumption leads to high insulin levels, hyperglycemia, and insulin resistance. That is simply not true. I've done nothing but lower my postprandial glucose readings by eating carbohydrates. Glucose response and insulin sensitivity can be improved, but it's not done best following a low-carb diet. That is just a way to minimize the damage that carbohydrates do when you are insulin resistant, but it in no way improves insulin resistance.

Peter said...

I think it would be better to describe this post as being centered around the inability of the liver to inhibit glucose release in response to insulin (or to cope with absolute insulin deficiency). I doubt very much that this can be corrected by consumption of carbohydrate. I can conceive of partial recovery in the liver following the withdrawal of fructose and alcohol, but hepatic fibrosis is not going to go away and the regenerated tissue produced by the cirrhotic liver is not normal and is unlikely to ever become so.

If you aren't broken, carbs may well be fine. Many people are broken. Treating them with carbohydrate is the territory of Dean Ornish or the Naturopaths. I'd rather not go there. Insulin resistance is core to fasting, a fully physiological state of insulin resistance. I make no "pretence" of a cure for this insulin resistance. If anything I augment it.

It's better than beta blockers for atrial fibrillation! Mind you, it would be great to fix AF with spuds.

Peter

jon w said...

this will be at the top of the list for everyone who searches "liver recipe"

David said...

Peter,

If I understood your post correctly, the effect of MCTs on peripheral IR makes sense as a mimic of starvation. In starvation, your body wants to shut down glucose metabolism in the muscles in order to preserve glucose for the brain and to keep from having to break down muscle to get it.

Now what I don't understand... If MCTs are added to a high carb diet, what happens to all the extra glucose? It is not being shoved into muscles and burned off, so would the peripheral IR hypothetically lead to higher fat storage of the extra carbs? That doesn't seem to jive with studies showing greater fat loss with MCTs: http://www.ncbi.nlm.nih.gov/pubmed/18326600

Thanks for any insights!!

-David

Peter said...

Jon, I tried the google, phew, no hits!

David. Yes, I've been reading DrBG on MCTs and weight loss too and wondering how it happens. How's this for an idea: MCTs to the liver without causing hepatic insulin resistance as they are rapidly converted to ketones. The liver listens to the extra insulin and stores the glucose as glycogen. Peripheral glucose rejection (it's not really insulin resistance in so far as it doesn't seem to involve GLUT4s) allows effective hepatic storage. When insulin levels fall late post prandially the glycogen can be released, never having been converted to hepatic fat and never having entered an adipocyte. Ultimately calories in and calories out do balance and MCTs do seem to do thermogenesis in the liver quite well... Thinking on my feet there. Any other ideas?

Peter

Kennedy said...

Wow, thanks for this. I thought I had it understood, but no.

I imagine this would explain some pretty hardcore aging of the skin in diabetics as well then. And some hefty destruction in the brain too.

David said...

Peter,

As a follow-up, the glucose lowering effect of ketones may be linked to lactic acid metabolism.

First, in rats, "Since the efficiency of the lactate pathway was increased by the addition of B-hydroxybutyrate [ketone] (going from 40% up to 60% in the present study), it may be concluded that ketone bodies exert a further inhibitory effect at the pyruvate decarboxylase step... Thus, a double mechanism of glucose sparing appears to take place when B-hydroybutyrate is added: diminution of glucose uptake and channeling of its metabolism into lactate..." (http://jn.nutrition.org/cgi/reprint/108/4/621.pdf) [at page 7 of *.pdf]

Second, also in rodents, "We first report that in the absence of insulin treatment, ICV lactate administration lowered glucose production and glucose levels in rodents with uncontrolled diabetes..." and "CONCLUSIONS—Central lactate metabolism lowered glucose production in uncontrolled diabetic and normal rodents with hypoinsulinemia and in rodents with diet-induced insulin resistance. These data suggest that insulin signaling is not required for central lactate to lower glucose production and that the activation of hypothalamic lactate metabolism could consequently bypass insulin resistance and lower glucose levels in early-onset diabetes and obesity." (http://diabetes.diabetesjournals.org/content/57/4/836.full)

So ketones inhibit pyruvate decarboxylase, increase lactic acid metabolism, and lactic acid metabolism lowers glucose levels independent of insulin. I think I'll want to look into this more.

-David

Peter said...

Hi David,

Westie and I have been batting this about off blog and come to a similar conclusion. Also lactate and tumours and ketones need throwing in to the mix. I just need the time, there is a stack of other posts waiting too.

Peter

Peter said...

Hi LeenaS, forgot to comment: The 15% seems low to me too but 5g will double blood levels and this must be shifting quite fast to keep blood levels under 7mmol/l, so maybe. That statement was, like many others in the paper, unreferenced. It came over as a bit of an opinion piece, but probably correct in most aspects...

Peter

Mikael said...

David,

Does this have any effect on protein metabolism, i.e. if ketogenic diets could either a) require less protein for energy, and thus could contribute to muscle gain, or b) let you get by just eating a few egg yolks and a crapload of butter?

Venkat said...

Peter,

Thanks for this post. But, I read this post thrice and was not able to understand. Sorry. I am a layman and not a healthcare professional. Can you sum up the conclusions in a plain english?

Thanks and Sorry once again.

Thanks

Venkat

Ed said...

Can omega-6 PUFAs damage the liver in a way that causes it to become insulin-deaf, similar to what excess fructose and alcohol do?

MCT said...

Hello Peter
continuing on the fat-loss effects of MCTs, I've come across a few studies which may yield a couple more ideas. Such as fat cell apoptosis, inactivation of PPARgamma, easier mobilization from fat cells compared to other fats. You can just read the studies here for yourself if you're curious.

From personal anecdotal experience, when my MCTs get to around 50% of my energy intake, I've noticed that even mild muscular activity gets me breathing hard. Your post helped me make some sense of that.

Peter said...

Hi MCT,

I've been looking in to whether FFAs in general cause hepatic insulin resistance, which is the driver of glucose dysregulation, and from what I can find they (probably) don't. That puts dietary MCTs and FFAs from adipocytes in to the benign category. After that MCTs are free to do all sorts of beneficial things without having to worry about direct effects on the liver. Nice links...

Peter

Btw, FFAs are not 100% benign, there is a weight loss syndrome of hepatic lipidosis in cats which is complex and probably needs both omega 3 deficiency and some degree of hepatic insulin resistance to trigger it, but it does seem to be FFAs from adipose tissue which end up in the liver. But I need to read more on that one!

Peter said...

Hi Venkat,

I think I am trying to say that we should have a liver centred view of diabetes, then Stephan points out (very correctly) that the brain controls the liver.

I think in practical terms it comes down to the need for people with diabetes (which is not all of us) to be looking at ways to minimise the need for the liver to work its cotton socks off to keep glucose levels in the blood within normal limits. This basically means running on fatty acids for bulk energy supply and the only ones were are adapted to are a mix of saturates with some monounsaturates. After that the biochemistry should take care of itself, at least for the majority of people which diabetic issues.

Peter

Peter said...

Ed, I think Stephan has posted on this. I can certainly see how omega 6 PUFA would convert NAFLD to NASH as they are far more unstable than saturated fats. There is an old book, "The Drinking Man's Diet" which suggest that LC, sat fat diet protects against alcoholic cirrhosis. I don't see why the same shouldn't work for fructose poisoning, while eliminating the on going fructose ingestion. Omega 6 PUFA high fat diets, in rats anyway, don't do this. Neither do bulk calories from omega 3s, though small amounts are probably beneficial.

Peter

Ed said...

Peter, I need to go re-read Stephan's posts on this.

In general I understand that excess omega-6 PUFAs can cause liver damage, but the dots I had not mentally connected were regarding whether that particular damage specifically causes the liver to be insulin-deaf.

Or, does all liver damage cause it to come unglued and just spew glucose?

I didn't want to assume that all liver impairment was the same.

David said...

Mikael,

I don't know enough about lactic acid metabolism to answer your question about its effects on protein intake.

MCT, thanks for the link to the additional information on MCTs effects on fat cells. Fat cell apoptosis sounds good to me!

MCT said...

David no prob :)

Revisiting insulin resistance, one of the study links, at the end of the abstract, says "The consumption of high fat diets led to a 1.5-fold increase in liver PEPCK activity."

Greater expression of liver PEPCK seems to be linked to greater EGP and signs of type-II diabetes.
but whoa - did I learn a few new things about PEPCK.

Here is one link I found useful in learning more about the functions of PEPCK with respect to a ketogenic diet. excerpt: "... even if hepatic gluconeogenesis is abolished, normal blood glucose levels can be maintained in rats. "

more related to ketogenic dieting and PEPCK:

(pg 593) of this PDF

"PEPCK-C mice create energy chiefly by use of fatty acids rather than the normal behavior of burning carbohydrates."

I'm trying to draw a conclusion from all this information. Peter?

MCT said...

oh and forgot to add,
see the discussion

Peter said...

MCT,

That last paper is a gem. I have another which will twin with it nicely, talking about the little pockets of honesty in the nutrition research world. They do exist!

The best line was the one which actually specified no sucrose in the ketogenic diet. Plenty in high fat diet. Actually getting the data you need is so refreshing after reading the published work of some of the clowns out there.

No time for more.

Peter

Peter said...

Hi Sanjeev,

Sorry about the delay, I missed getting a prompt answer out and it got buried! In general I don't do specific choices on this basis, more a matter of eat what is close to food and let the rest take care of itself. But ruminant fat is the least affected by dietary intake so I lean this way. Butter and cream are my biggest single source of calorie intake.

The flax oil is interesting, omega 3s are undoubtedly PPAR agonists and may promote more effective fat usage. Makes me wonder if you were absolutely or relatively deficient until that time. Omega 3 fats do, to some extent, protect cats against hepatic lipidosis during weight loss (a serious problem).

The more I fat adapt the harder I personally find it is to stay out of ketosis but I have no idea if this is a generic trait. Of course there is a certain amount of MCTs in dairy which will produce ketones in the face of carbohydrate anyway and I certainly eat a lot of this....

Peter

Peter said...

Ed,

There is a post on alcohol, cirrhosis and PUFA coming up and, if you just substitute fructose for alcohol, you can see that PUFA are potent promoters of liver damage given a trigger...

Peter

Kurt G. Harris MD said...

Peter

If I might ask, how do your ketostix (or whatever you use) run? I am always at least 15 and sometimes 40.
My main sources of calories are cream, pastured butter and ruminant fat as well. I eat perhaps 25g per day carbs (onions tomatoes mushrooms green beans, asparagus and nuts) since cutting sucrose down to 5g/day or less. I would have to go up to 75g or more to get out of ketosis by adding lactose or starchy veggies, which, having been VLC for bearly two years, does not agree with me (the starch, not the lactose).

I am still looking for evidence that it might be healthier to "stay just out of ketosis" but haven't seen much.

Thoughts?

Kurt G. Harris MD said...

sorry, that should be "nearly" not "bearly" :)