Fructose (10) A can of cola

At some stage we have to transition from "fructose is good, it increases glycogen storage in the liver" through "if fructose is storing glycogen in the liver you can be damned sure it's storing lipid" through to "it causes hepatic insulin resistance" and the follow-ons from there.

This next study is pretty well supported by an established base of in-vivo and end-of-vivo studies which I think I can safely pass by and look at the induction in changes to insulin signalling, which might be interesting

Fructose Selectively Modulates c-jun N-Terminal Kinase Activity and Insulin Signaling in Rat Primary Hepatocytes

We're looking at this:

Aside: c-jun N-terminal kinase is what we expect to kill cells severely injured by being cultured in "fasting" levels of unadulterated palmitate plus glucose at 25mmol/l for 24 hours. You know the studies. Assume intolerable ROS. End aside.

The basic message from the paper is this:

The interesting parts of the paper allow us to ask hepatocytes very, very carefully, about the level of fructose exposure which inhibits insulin signalling. We can accept JNK activation as a crucial messaging step in converting fructose exposure to insulin resistance. The concept that this might be ROS driven is my own rather than anything in the paper per se.

This is the bar chart:

This model used steady state fructose exposure over four hours and is quite convincing that there is a "switch" somewhere between 0.4mmol/l and 0.6mmol/l. Our previous steady state study was that of dogs using fructose at 2.22 micromol/kg/min and this achieved a portal vein fructose of 0.1mmol/l:

Inclusion of low amounts of fructose with an intraduodenal glucose load markedly reduces postprandial hyperglycemia and hyperinsulinemia in the conscious dog

We can combine the data from both studies and suggest that, in summary, exposing hepatocytes to fructose a 0.1mmol/l is insulin signal augmenting and exposing them to fructose at 0.6mmol/l induces insulin resistance.

It is also perfectly reasonable to assume that the level of ROS which indicate that is a necessary time to induce insulin resistance are converted to a signal to be carried by the JNK pathway, exactly the one which carries the mitochondrial ROS indicator that it is necessary to induce insulin resistance.

Whether the pre-emptive signal generated by palmitic acid even at low delta psi is the same one as is generated by simple caloric overload (ie failure to resist insulin in time, ie linoleic acid) remains to be seen (by me at least, so far).

We can summarise that nibbling an apple might augment storage of a bowl of porridge as hepatic glycogen but downing two cans of fructose sweetened soft drink might do other things, not least of which is to induce hepatic insulin resistance.

Looking at things fundamentally, this is a story told by ROS signalling. All the signals downstream are certainly interesting and complex but tell us little about the underlying essential process, the information derived from which they are carrying and refining.

Peter