Friday, September 30, 2011

Insulin resistant and slim. How slim?

This Figure 4 from the paper by Shulman's group on mitchondrial dysfunction in the offspring of T2DM parents, the one the EMs came from in the last post. It gives a nice outline of the way they are thinking:

and this is a summary of some of the points which came up in the comments (there is a lot of information and links from the comments about possible causes and management for those interested) added to the figure:

While I was raiding this paper I thought I would also put up Table 1, the characteristics of the control and diabetic offspring groups:

Now you have to be very, very careful with these groups. They have been exceedingly carefully preselected. Fortunately the pre selection process is laid out in some detail in a previous paper from 2004:

"All subjects were recruited by means of local advertising over a two-year period (2001 to 2003) and were prescreened to confirm that they were in excellent health, lean, nonsmoking, and taking no medications. A birth weight above 2.3 kg (5 lb) and a sedentary lifestyle, as defined by an activity index questionnaire,(21) were also required. Qualifying subjects (more than 150 persons) underwent a three-hour oral glucose-tolerance test (with a 75-g oral glucose load), after which two subgroups of subjects were consecutively selected to identify extreme phenotypes for insulin resistance and increased insulin sensitivity.

Insulin-resistant subjects (3 men and 11 women) were defined as having an insulin sensitivity index (22) of less than 4.0 (indicating insulin resistance; lower values indicate greater insulin resistance), at least one parent or grandparent with type 2 diabetes, and at least one other family member with type 2 diabetes. Insulin-sensitive control subjects (five men and seven women) were defined by an insulin sensitivity index of greater than 6.3 (with or without a family history of type 2 diabetes)."

As I read this it looks like over 150 people were screened for insulin resistance. Of those 150 those with the best and worst insulin sensitivity were selected as controls or subjects respectively. BUT you were only allowed in to the insulin resistant group if you did have a relative with T2DM. We get no idea of how many people had awful ISI and no diabetic relatives, ie if there were any index cases who might represent the red scrible on the second picture. Maybe there were loads, maybe not. I can't find that information in the paper. So we have to be very careful, the T2DM-relatives aspects MIGHT be a complete red herring. The insulin resistance is not.

Soooooo, with that caveat in place, we can see that (completely observationally) the insulin resistant group had, by definition, elevated insulin (and poor ISI) and the control group didn't. The control group weighed 61kg, the insulin resistant group weighed 66kg. Hmmmm. Observational, cross sectional. Fascinating.

You could simply say that the insulin resistant group were only hyperisulinaemic BECAUSE they were 10% porkier than the svelt control group. Indeed, if you consider porkiness to be a result of simple overconsumption of calories, for whatever reason, this would have to be an effect, not a cause.

Shulman's group extend the concept of mitochondrial failure in muscles to a potentially related mitochondrial failure in beta cells during the discussion. That's an interesting idea. Let's go one further and think about mitochondrial failure in adipocytes... I know it's odd to think that adipocytes (or indeed their mitochondria) might have anything to do with obesity, but stranger ideas have been floated.


BTW they also mentioned genes which control mitochondrial biogenesis:

"In this regard it is of interest that a common Gly482Ser polymorphism of the peroxisome proliferator–activated receptor γ coactivator 1, a transcriptional regulator of genes responsible for mitochondrial biogenesis and fat oxidation, has been linked to an increased relative risk of type 2 diabetes in Danish populations as well as to altered lipid oxidation and insulin secretion in Pima Indians."

I just noticed that the alpha form of peroxisome proliferator–activated receptor γ coactivator 1 got an honourable mention back in one of the Fiaf posts on the control of host metabolism by the gut mircobiota...

Thursday, September 22, 2011

Did you over eat yourself in to obesity or T2DM?

I have read Mary Rogge's paper on the concept that impaired fatty acid oxidation leads to obesity. This post is not aimed as a criticism of her ideas but modifies them somewhat, simply by following references she cites in her text and maintaining an insulocentric viewpoint. Obviously the failure of beta oxidation is strongly challenged by the success of low carbohydrate dieting and supported by the success of (extremely) low fat dieting. Is it correct?

There are a fantastic number of pieces to the jigsaw puzzle of obesity in this paper, many of which are probably very important and I'll run through them as soon as I can get my head around which ones matter most.

The basic concept is that there are excessive fatty acid derivatives in the cytosol of muscle cells (and probably other tissues, the main thrust of the paper is toward muscle metabolism). Why I view this as supportive of the carbohydrate/insulin hypothesis of obesity is yet another post. This particular post is on some of the problems I have with the concept of a simple defect in fat metabolism as the cause of the accumulated fatty acid derivatives.

As so often there will be a series of stolen diagrams, scribbled over using Powerpoint, which probably break every copyright rule in the book... Oops. Here we go.

Okay, here is the basic concept as a straight copy-paste:

Uptake of long chain fatty acids in to the mitochondria is mediated through carnitine palmitoyltransferase 1 (CPT1, green box upper left hand side). This is suggested as the failed step.

But there are problems with the diagram. Look here:

Here we have citrate being exported from the mitochondria and converted to malonyl-CoA via "fatty acyl-CoA". I think it would have been much better to actually specify acetyl-CoA at this point rather than "fatty acyl-CoA", but that may be nit picking on my part. But it is ONLY acetyl-CoA which is liberated by the citrate shuttle. The function of the citrate shuttle is to get acetyl-CoA out of the mitochondria and in to the cytosol for fatty acid production...

Next we have this feature:

I'm not sure whether this arrow suggests that fatty acyl-CoA, straight from triglycerides, facilitates or activates the citrate shuttle (I can't find any suggestion of this being the case) or is being cited as a source of citrate, which it is not. For fatty acids to form citrate they have to under-go beta oxidation:

And this is not supposed to be happening because the malonyl-CoA is inhibiting CPT1 mediated transport of fatty acyl-CoA to the site of beta oxidation. Hmmmmm.

So where might the cytosolic malonyl-CoA be coming from? Is glucose supplying so much citrate that the obese can use it for malonyl-CoA production?

If we flick to this fascinating reference we can look at the TCA cycle itself, to see whether glucose is producing enough citrate to export for conversion to malonyl-CoA as the spanner in the works.

From the paper we can see that if you have a very complex magnetic resonance spectroscopy machine, which you are willing and able to home-modify (read the methods text!), some exceedingly complex computer models and a supply of carbon 13 labelled acetate tracer you can actually work out how active the TCA cycle is in normal vs insulin resistant muscle tissue. This paper is so cool.


The offspring of diabetic parents have crap TCA cycle activity in their muscle tissue. It will not be producing the amounts of citrate which might be exported for fatty acid synthesis. This is not a failure of beta oxidation. It is a failure of the TCA cycle in its entirety. The fact that obese people run their metabolism on glucose does not mean that they run it well on glucose.

Why is the TCA cycle so compromised?

This study has some excellent pointers. Look at this picture, it could be from an obese or diabetic individual:

These folks have odd muscle tissue.

a) They don't have many mitochondria, b) many of their mitochondria look crap and c) many of their mitochondria are dying.

They don't have a simple failure of fat oxidation, they have a failure of mitochondria full stop. It simply shows most clearly in the failure of beta oxidation.

I'll take a break now and put this post up. There are, of course, a whole stack of follow-ons to this. If you have duff mitochondria you accumulate fatty acid derivatives in your cytoplasm. They cause insulin resistance. Once you have insulin resistance you will be chronically hyperinsulinaemic and, in all probability, go on to develop obesity as a direct consequence of that hyperinsulinaemia. Let's make this plain. Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss.

Over eating is not causal. Whatever anyone tells you.

If you are an undamaged human being and you force overfeed yourself with FOOD, say in some tribal ritual, I would suggest that you will not do this to your mitochondria. You will continue to burn fat easily. You will not develop chronic hyperinsulinaemia. You will lose weight automatically after that cultural binge is, thankfully, finished and you can get back to life within your normal appetite.

Humans do such weird things to themselves! Culturally and accidentally.


Saturday, September 17, 2011

Back on line

Well that's me back from the AVA meeting in Liverpool. Highlights: Arterial blood gas sampling at the top of Everest, all rough quotes from memory:

"The peak was a bit 'peakier' that we had anticipated so we dropped down a few hundred feet to a more level patch before dropping out trousers in a 20 knot breeze at -24degC to stab each other's groins for arterial blood samples".

Getting to the top of Everest? "I never train" linked to "it's all mitochondrial" and "Ground level athletes really struggle on the big mountains, Ranulf Fiennes took three attempts to get to the top and it was very hard for him".

Reinhold Messner is STILL ALIVE (obviously he has remarkable mitochondria). OMG I thought he'd have made a single small mistake at some point before now. Having read some of his earlier achievements I'd never expected him to make old bones. But he must be older than me...

And the RN battlefield anaesthetist from Iraq/Afghanistan. "These guys come in needing one, two or even three amputations from an environmental temperature at up to 40 degC. One of the worst prognostic markers is hypothermia. We think it's mitochondrial".

A good friend (with an excellent brain, yes she has already read Power Sex and Suicide while moving from anaesthesia to obesity research) chatting about DMT2 in horses "It's all mitochondrial".

One of her co-workers on cartilage degeneration in arthritis "It's all mitochondrial".

I had a great meeting.

I got, without net access, to read through and analyse some of the implications of the downloaded papers on mitochondrial dysfunction in obesity from JS's page on metabolic flexibility. Needless to say these links are good but you HAVE to read the papers, follow the secondary links then read the methods. Needless to say there is a lot to say and I'm still not about to go carb loading.

Time to get the Baba-breakfast ready. I'll try to get to emails and read comments over the w/e, but life really is very busy.

Quote of the century: "It's all mitochondrial".

Oh, and it's not quite as simple as failure to burn fat.


Monday, September 12, 2011

A defect of fat metabolism and a few thanks

I have, in the past, been given a key piece of information, put it in my pocket and left it there.

This is unforgivable, I know. But if the key is important enough you will have to either go through you pockets or be given another copy.

I am grateful to the rather unpleasant episode with Stephan as it allowed someone to supply me with that replacement key.

Metabolic flexibility is a slight misnomer, it describes a defect in fat metabolism.

I thank Stephan for getting me off my arse.

I thank Nick Lane for Power Sex and Suicide.

I thank M. for getting me to mention metabolic flexibility in comments.

I deeply thank J Staton for doing all of the work for me, reading Hyperlipid and taking the trouble to get the key cut then posting it to me via the comments. Go read.

There is no need to re invent the wheel. After reading the yellow box warning you can read this perfect quote

"This is a long and detailed article, but it’s very important".

And from elsewhere, if the post hasn't been taken down:

"A defect in fat metabolism?" Cracking quote, that one.

This fits with so many things which have become very, very obvious to me over the years. Neatly, logically, tidily.

Thanks all

Peter, the shoe-horner with the inappropriate prefix.