Monday, August 10, 2009

Heart failure and insulin resistance

While I was off line for several weeks I had a browse through some of the random texts lying around my hard drive. This one in particular caught my eye and has started of a train of thought which seems interesting. This is the basics of the paper:

The healthy heart likes non esterified fatty acids:

"NEFA are the preferred metabolic substrate because of the high yield of ATP when NEFA are fully oxidized"

NEFA burn primarily in the mitochondria. But without oxygen there is no possibility of doing this, you cannot oxidise fats without oxygen. Glucose to lactate, an anaerobic process, yes:

"However, under circumstances of increased myocardial work or limited oxygen availability, the heart turns to glucose as the more efficient fuel for ATP generation"

Glycolysis, with its poor ATP yield, is better than no ATP at all and quite logical when there is insufficient oxygen to keep the mitochondria working. But when the heart is going in to failure it comes to prefer glucose, ultimately even at tickover:

"When the heart is injured and left ventricular (LV) function is depressed on a chronic basis, there is a shift to glucose as the preferred substrate under basal circumstances"

Why should this be? Why not stick with fat. NEFA are the devil you know and a very benign devil they are too... The problem is that the whole system for burning NEFA, from the cell surface receptor to the mitochondrial transport system has, by this stage, already been deliberately shut down:

"this shift in substrate preference is a highly regulated transcriptional event. Importantly, the changes in gene transcription involve down-regulation of transport mechanisms and enzymes involved in fatty acid oxidation. This includes decreases in the NEFA receptor—peroxisome proliferator activated receptor- alpha (PPAR alpha)—and its co-factor, the retinoic acid receptor RXR, as well as a series of enzymes, including carnitine palmitoyltransferase-1 (CPT-1), which is rate limiting in the transport of fatty acid coenzyme A (CoA) to the inner mitochondrial membrane".

You have to wonder why this is. It's not some accidental failure. The heart is sitting in a sea of both NEFA and glucose, and it carefully shuts down it's NEFA processsing equipment to rely on glucose, then shuts off glucose uptake and dies. This is not an adaptive process!

The shut down of glucose usage probably comes back to good old fatty acids causing insulin resistance. The body has sensors for detecting a decreased cardiac output. On an evolutionary basis the assumption is that a serious fall in cardiac output is due to a serious loss of blood volume. Fluid retention and increased sympathetic nervous system activity are standard adaptive responses to blood loss. Increased sympathetic nervous system activity not only boosts cardiac work (hence increases cardiac output to compensate for low blood volume, mimicked by the failing myocardium) at the cost of increased oxygen demand, but also releases free fatty acids from adipocytes to supply the evolutionarily preferred heart fuel. Actually, the NEFA will supply a large proportion of the whole body needs because if you been mauled by a tiger you're not going to go grubbing for tubers to run your metabolism on glucose. Free fatty acids are taken up by the heart down a concentration gradient. If they accumulate in the cytoplasm because the heart has shut down its fat burning system it's easy to see why triglycerides accumulate in the cell. This signals insulin resistance. There is enough fat, no need for glucose. This makes the heart say no to glucose, that's understandable.

Unfortunately, if the fatty acid burning system has been carefully and inappropriately shut down, saying no to glucose becomes catastrophic. Which it is.

The whole drive of the paper is to develop techniques to get the heart back running on glucose in the face of myocardial insulin resistance, for which we can read due to a failure to burn NEFA. Obviously a supra physiological infusion of insulin would overcome this, but it's a big volume to give to a heart failure patient and causes issues with sodium retention anyway, another post there. So insulin sensitisers are high on the priority list. Pity Actos and Avandia cause heart failure! Interestingly among the several postulated mechanism of action suggested for metformin, one is increasing fatty acid oxidation. In my simplistic view this would decrease intracellular triglycerides and allow a reduction in insulin resistance. Thiazolidinediones and other insulin sensitisers are the drugs the paper is thinking about:

"At present, concerns about peripheral edema have limited the use of TZDs (Thiazolidinediones [Actos and Avandia]) in patients with heart failure, although the mechanisms of this phenomenon have not been elucidated. An attractive alternative might involve the derivatives of the proglucagon family, the glucagonlike peptides, which possess insulinotropic, insulinomimetic, and glucagonostatic properties. Importantly, these naturally occurring incretins are largely devoid of hypoglycemic risks, as their insulinotropic properties are attenuated when plasma glucose falls below 70 mg/dL. The short duration of action requires continuous subcutaneous infusion, which constitutes a potential drawback to chronic treatment"

OK, hands up who has spotted the missing idea? Yes, right in one, ketone bodies. Straight to the mitochondria without insulin, CD38 or CPT-1. Increased cardiac work/output without increased oxygen demand. They completely by pass insulin resistance. So they're a nice sticking plaster on a much more interesting problem.

The interesting problem is: Why did the myocardium decide to shut down its fat burning system?

I think you can argue that it is because glucose is so toxic when it is present in high levels in the blood stream that it has to be burned first. While it is still within the power of the pancreas to force glucose in to muscles cells, those cells burn it rather than having it lying around glycating every protein in sight. A little can be stored as glycogen, but if you are on the SAD (including the 3.00am refrigerator raids, and that's not roast beef in the fridge...) and chronically hyperglycaemic/hyperinsulinaemic, glycogen stores are going to be more than full. No, chronic excess glucose oversupply needs burning as fast as possible, you can pack away the far burning system if blood glucose concentration is always being pushed upwards. Maintain this for long enough and it becomes a way of life, and eventually a way of death. Burning glucose in the face of increasing insulin resistance due to the sympathetic nervous system freeing up NEFA, being unaware of the catastrophic loss of fat burning ability, is a non starter.

Ketosis and normolgycaemia would allow the unpackaging of that stored fat burning system. It's not gone for ever, the genes are still there.... Given a few tools NEFA no longer need be the enemy, rather the preferred fuel once again. As the primary fuel the fact that they are present in the cytoplasm signalling the rejection of glucose by signalling insulin resistance is no problem. With efficient fat burning, as soon as the NEFA supply drops cytoplasm trigycerides will drop and insulin can get back to work to allow glucose to be used.

Things can get back to the way they were meant to be with NEFA as the primary fuel with the additional facility to use glucose in dire circumstances.

More on the shutting down of fat burning next.



mtflight said...

Peter, another brilliant post! Your narrative of how the body is interpreting things and how it's reactions are based on evolution and survival is my cup of tea. I feel like I need to print these out and study them closely.



Nicholas Dynes Gracey said...

Hi Peter,
Please update your comments having included consideration for GLUT4 receptor distribution ... especially within heart tissue [as compared to skeletal or adipose tissue].
Warm thanks; Nick
GMT 09:53hrs TUE.11.AUG.2009

Bris said...

Hi Peter. I am an 8 year low-carber. I am now at the stage where a can't tolerate more than about 5g of carbohydrate in a session or more than 20g/day. I suffer reactive hypoglycaemia if I eat even a teaspoon of sugar.

Peter said...

Hi Nick,

Did I miss something in your links? As far as I can see the GLUT4 transporter is active in both skeletal and cardiac muscle... Am I wrong on this? I found lots of interesting stuff while sniffing around this topic... Stuff on GLUT3 and stuff on the localisation of GLUT4 receptors in severe insulin resistant states..... Few other things to post first.


We've always run a reasonable carb intake and don't see any sort of problem. Even when I carb loaded and did an OGTT, the reactive hypoglycaemia (from 4.3mmol/l pre glucose to 3.4mmol/l at the 1.5h mark) was mild and asymptomatic. Hard to guess what's gong on. Nick seems to be well in to hypoglycaemia problems, maybe he'll comment. In general LC fixes reactive hypoglycaemia. I guess you knew that...


B said...

Fascinating post, Peter.

You may be interested in Skinner's work showing that the autonomic system is implicated in sudden cardiac death as well (in addition to heart failure.)

anand said...

Hi Peter,
I just found your blog and enjoy your topics and writing style. Regarding high fat/paleo diets and cardiomyopathy, do you feel that this type of diet is appropriate for a moderate dilated cardimyopathy?

botski said...

”More on the shutting down of fat burning next....”

Been waiting for next post on this for some time. Also please comment on dilated cardiomyopathy.



Peter said...

Hi Jukka, almost 10 years! I have no idea what I was going to go on to say (might have been CD36 related, dunno). DCM is a mix of problems from taurine deficiency through to the end stages of hypertrophic cardiomyopathy. But if you are going to fix any cardiomyopathy I suspect dropping glucose, dropping insulin and side stepping insulin resistance by a combination of FADH2 input at ETFdh of the ETC and maybe some ketones is probably it.... Getting rid of omega 6 PUFA might improve your cardiolipin anchors too.