Systemic fructose is important

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TLDR: Be cautious of anyone who tells you fructose metabolism is limited to the liver.
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Fructose uptake by the liver is saturable. Drinking two cans of soda sweetened with high fructose corn syrup produces a peak plasma concentration 17mmol/l. Yes, 17mmol/l. On average.

Direct spectrophotometric determination of serum fructose in pancreatic cancer patients

Unfortunately the methods section makes no sense at all, so we have no idea how much fructose was actually consumed:

"In 3 of these subjects, intravenous access was obtained in an antecubital vein, and additional blood samples were taken at baseline and 15, 30, 45, 60, 90, and 120 minutes after ingestion (93 minutes) of two 75-mL cans of a proprietary soda, for determination of serum glucose and fructose concentration. Each 40-oz can of soda contained 75 g of high-fructose corn syrup, which consisted of 55% fructose and 45% glucose as constituent monosaccharides, equating to 41.25 g fructose and 33.75 g glucose, respectively".

Go figure. Two 40oz cans of soda? Some big cans there, even by USA standards!

Anyway, this is the graph they produced:

This next group seems to have managed to write an interpretable methods section but missed peak fructose levels by only sampling at 60 and 120 minutes.

Consumption of rapeseed honey leads to higher serum fructose levels compared with analogue glucose/fructose solutions

Ingesting 75g of neat fructose, as a solution, gives a blood concentration of 130mg/dl, ie they measured just over 7.0mmol/l in real units, at one hour post ingestion.

So fructose gets past the liver and will be taken up by any cells with GLUT3s on their surface. Whole body.

Like adipocytes.

This is a nice paper covering a lot of bases about how adipocytes deal with the fructose they are flooded with every time you down a couple of cans of soda. Or apple juice or.......

Metabolic fate of fructose in human adipocytes: a targeted 13C tracer fate association study

What do adipocytes do with fructose?

They don't oxidise much of it.

They don't convert much to lactate.

They do convert most of it to palmitate and a little to oleate.

They store the oleate.

They release the palmitate as FFAs.

You can't tell from the study how much this palmitate raises systemic FFAs because the study was being performed on "adipocyte-like" cells in cell culture. But, assuming that in most cases fructose would be co-ingested with glucose, you have here the classical situation of elevated free fatty acids, in combination with elevated glucose, in combination with elevated insulin.

This is my definition of metabolic syndrome. The hyperinsulinaemia will, until you become diabetic, eventually control the hyperglycaemia. It may well suppress the elevated FFAs. The glucose and FFAs will be pushed* in to any cell which will respond to insulin.

*Nothing is actually "pushed". Insulin facilitates diffusion (GLUT4s) and maintains a diffusion gradient by removing glucose to glycogen and FFAs to triglycerides.

The liver will be right in the frontline for accepting these FFAs, which should be in adipocytes, and experiencing sustained high levels of insulin (to control glycaemia) will make the hepatocytes hang on to those fatty acids. This is in addition to any intrahepatic trigycerides from fructose-driven DNL. Overall we end up with massively calorically overloaded liver cells. This is the prerequisite to hepatic steatosis and all that is then needed for the generation of inflammatory changes is a source of omega six PUFA. There is a desperate need for liver to say "no" to any more calories. It does by resisting insulin. Which it does by generating ROS. If those ROS meet linoleic acid, it's welcome to 13-HODE, 4-NHE and any other peroxide you care to dig up. These PUFA derivatives do cause insulin resistance per se (as well as 13-HODE stimulating cancer growth), but to me they are just an amplification system derived from what is already happening at the "front end" of the mitochondria... ROS generation by RET, essential to limit grossly excessive caloric ingress.

Peter