Hepatic insulin resistance in KD fed mice

Let's look this abstract. Thanks to Liz for the full text.

The key quote is, of course:

"In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications."

I'm not sure what the word for a collection of idjuts is. A moronity?

Despite this the data are very interesting.

Look at those hepatic diglycerides, up 350%!!!!!!

Failure to suppress hepatic glucose output. Not just reduced, but reduced to zero percent suppression. Zero percent!

Wow, are these mice gonna die of diabetes, fatty liver, metabolic syndrome, Spawn of Satan induced inflamasomation.... Okay, I'll calm down now.


These mice are running their metabolism on a combination of free fatty acids and ketone bodies. What would you expect their liver to be full of? Sugar?

Glycogen?

Maybe fatty acids?

Well, in ketosis FFAs come from transport by albumin or release by lipoprotein lipase as exactly that, free fatty acids. They are not stored in this form, they are re-esterified to triglycerides for hepatic storage. The 350% increase in diglycerides is not from being swamped with diglycerides exogenously. They are generated in situ specifically to stop the liver responding to insulin.

These mice have no source of dietary glucose. They are generating and outputting small amounts of glucose from their liver, despite extreme protein restriction, to keep their blood glucose levels compatible with life. Possibly from glycerol.

Then some joker comes along with an insulin infusion. What would happen if their ability to trickle out glucose actually did suppress in response to this malevolent tease? Death would ensue in a few minutes without a rescue glucose infusion as is needed for the mice on CIAB. Hepatic diglycerides are generated to stop the liver responding to insulin when survival makes this an absolute necessity. It's an absolute necessity under extreme ketosis conditions, even without the joker with a bottle of insulin.

To get a breath of KetoSanity we can go back to the paper by Maratos-Flier's group (thanks to John for the heads up on this "non conformist").

These folks didn't look at diglycerides but they did measured the liver triglycerides and found they were nearly twice those of the mice fed crapinabag. Gasp! Fatty liver is where it's at. But these folks did a little histopathology too, using PAS to stain for glycogen. As they say:

"PAS staining showed decreased glycogen deposition in KD animals vs. both HF- and C-fed groups (data not shown)"

If your liver is glycogen depleted what, exactly, should it have as an energy store? Thin air? A small nuclear reactor?

Maratos-Flier et al understand exactly what is going on and see no need to trot out hysteria about ketosis generating a fatty liver which is physiological. It has nothing to do with fatty liver under a carbohydrate based diet.

Now, what would happen if we increased the carbohydrate content of the diet to 15% of calories in the same way as Axen and Axen did in their 2006 blooper?

Ketosis would stop and hepatic insulin sensitivity would return. Probably within three days and certainly within the three weeks A & A allowed. The diglycerides would be gone. Probably so would the bulk of the triglycerides. Under these conditions carbohydrate would clear the fatty liver.

Would the mice be diabetic? You've got to be joking.

So why does carbohydrate restriction improve fatty liver in humans? I would suggest the lack of de novo lipogenesis due to fructose reduction coupled with chronically lowered insulin allowing VLDL output to clear the excess of hepatic triglycerides. The situation is completely different.

I doubt many LC dieters would push themselves to the ultra extreme of the diet enjoyed by these KD consuming mice. If they did, their hepatic lipids, especially diglycerides, would have to increase to produce an utterly essential survival gift of hepatic insulin resistance. Their hepatic triglycerides would rise too.

I think it's an open question about whether placing yourself at the very extremes of physiology is a good or a bad thing. It should certainly assist weight loss, but would it improve health? Interesting question.

Peter