Sunday, May 15, 2011

LIRKO mice (1)

I think we have to look at the LIRKO mouse. This fascinating beastie was brought to my attention by Chris Masterjohn and it's hard to know where to start with how amazing these animals are.

I suppose the first thing that grabbed me is that they are alive at all. They have no insulin receptors on their liver. None. You don't actually need insulin receptors on your liver to be alive... OK, they're pretty sick and go in to early liver failure, but they're definitely alive and reasonably functional at four months of age.

They have fed-state plasma insulin levels TWENTY times higher than those of control mice and fasting insulin levels eight times higher than controls. They are the ultimate model of hyperinsulinaemia.

They are, err, slim. Slimmer than control mice. Now that is cool!

So we have mice with massive levels of insulin. If you took an average mouse and injected enough insulin to peak its blood concentration at 20 times the physiological level it would rapidly become an ex mouse. It would be a late mouse. It would be no longer. But that's not what's happening.

These mice are eating CIAB and their liver wants nothing to do with the diet derived glucose. Nothing. The liver is utterly insulin resistant. No receptors, no response...

The mice eat Mouse Diet 9F which is 56.5% carbohydrate. Each mouthful of food pushes glucose toward the liver. The liver ignores it. Unharvested glucose hits the systemic circulation. The pancreas notices. The pancreas whispers insulin in to the portal vein and the liver ignores it. The pancreas speaks louder. The liver ignores it. The pancreas screams. The liver shrugs.

Where does the glucose go? With a blood glucose of 400mg/dl some goes down the loo (did I mention these mice were intensely diabetic? OK, they are intensely diabetic). The rest of the glucose tries its damnedest to get in to muscles. The muscles really don't want the glucose. They internalise their insulin receptors. Did I mention that these mice are intensely insulin resistant. OK, they are. Very. Whole body). The pancreas breeds extra beta cells then goes to the gym and pumps up those beta cells to steely muscled bulges of insulin hypersecreting islets. Insulin secretion goes up yet higher. It does no good. Not only do the beta cells multiply and hypertrophy, don't forget that the liver is the main sump for insulin degradation on a high carbohydrate diet. Not without insulin receptors it isn't. Hepatic insulin clearance is zero so insulin has almost nowhere to go. This too markedly contributes to the hyperinsulinaemia.

It would be interesting to see quite how high insulin would go if there was not the urinary route out for glucose... The bilateral nephrectomised LIRKO mouse. There's an interesting ICU challenge!

Does this massive hyperinsulinaemia inhibit lipolysis? Well, yes it does.

Interestingly FFAs are only reduced by about 40% compared to the control mice. But they are reduced. So why don't these mice become obese?

Ultimately they don't become obese because they cut calories. They are ad lib fed, they must cut calories because they're not hungry. Gasp.

Let's talk leptin. And insulin, of course.



Nigel Kinbrum said...

Hi Peter,

I'm confused. LIRKO stands for "Liver-specific Insulin Receptor Knock-Out". So, why is there no response to insulin in muscle & fat cells?


Peter said...

Nigel, any muscle will become insulin resistant with enough glycogen stuffed on board. Not an excess intracellular di- or triglyceride in sight. Spawn of Satan are not the only evil influence in the body, if they are at all.


Adipocyte insulin resistance, now there's a much more interesting kettle of fish.

Pål Jåbekk said...

Not to be confused with the FIRKO mouse, which is also quite interesting. Like the dead parrot sketch reference. Python at their best.

Drs. Cynthia and David said...

Some time ago I read a bunch of studies on rat physiology as a model for human exercise. Rats (and presumably mice as well) have predominantly fast twitch muscle, but store very little glycogen in their muscle tissue, relying primarily on liver glycogen delivery when needed. This is one reason why they are not good model systems for studying exercise physiology relevant to humans (since we are kind of the opposite).

In mutant animal models, much of the time the animals are not viable since they are lacking an essential system. Some other compensation must occur for them to survive at all, in order to create that strain of mice. So maybe there are other changes in addition to the knockout of interest, ones that are not readily apparent. Mandatory calorie restriction with a 56% carb diet makes sense with these animals, as the additional glucose has nowhere to go, as you say. Perhaps increased leptin sensitivity is essential for their survival? There is also non-insulin dependent disposal that may be regulated differently. Just speculating.

Adorable baby by the way!


Peter said...


Absolutely. The FIRKO mouse gets an honourable mention in the next post, almost postable. But the FIRKO mouse is, as you realise, very, VERY interesting.


Peter said...


The mice are exquisitely leptin sensitive. Better get that post tidied!


WilliamS said...

Stephan has now mentioned another LIRKO mouse study, but in this case they measured food intake and did not find a significant decrease compared to controls that might explain their low weight in the face of all that insulin. (I looked at the free full text, and it does look like the LIRKOs did eat just a tiny bit less; might be interesting if one could see the data by individual mouse).

Any thoughts?

Peter said...

What Stephan does not tell you (amongst a million other relevant snippets) is what the "calories out" through glycosuria are. BG is 400mg/dl, urinary calorie loss is not mentioned.

FFAs are low, insulin inhibits lipolysis, it doesn't stop it completely.

Appetite is normal due to enhanced leptin sensitivity (which means nothing until you go to the functions of leptin controlling mitochondria). Calories out through glycosuria are high.

Type one diabetics continue to eat and lose weight due to glucose exiting through their kidneys, until the complications from ketoacidosis kick in...

Stephan is the master of underinformation, selective. He will go far.