This little paper should have made a minor splash in the paleosphere last week, but no-one really knew what to do with it.
It has 20 authors. Success has a thousand fathers, they say.
Endogenous fructose production and metabolism in the liver contributes to the development of metabolic syndrome
Abstract
Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.
Carbohydrates with high glycaemic index are proposed to promote the development of obesity, insulin resistance and fatty liver, but the mechanism by which this occurs remains unknown. High serum glucose concentrations are known to induce the polyol pathway and increase fructose generation in the liver. Here we show that this hepatic, endogenously produced fructose causes systemic metabolic changes. We demonstrate that mice unable to metabolize fructose are protected from an increase in energy intake and body weight, visceral obesity, fatty liver, elevated insulin levels and hyperleptinaemia after exposure to 10% glucose for 14 weeks. In normal mice, glucose consumption is accompanied by aldose reductase and polyol pathway activation in steatotic areas. In this regard, we show that aldose reductase-deficient mice are protected against glucose-induced fatty liver. We conclude that endogenous fructose generation and metabolism in the liver represents an important mechanism by which glucose promotes the development of metabolic syndrome.
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| The Polyol Pathway |
To summarise - when extra glucose is consumed by mice, some of this is converted to sorbitol then to fructose. This is associated with elevation of AST and ALT. Mice that cannot convert convert glucose to sorbitol are protected from rises in fructose and liver enzymes. Therefore fructose is so bad for you that it even accounts for the metabolic harm of high glucose intakes.
"These studies show that glucose-mediated obesity, visceral fat accumulation, hyperinsulinaemia, hyperleptinaemia and fatty liver are all dependent in part on the conversion of glucose to fructose in the liver with the metabolism of fructose by KHK. In other words, the mechanism by which glucose induces its metabolic effects is largely dependent on fructose
metabolites resulting from the fructose generated from glucose by the polyol pathway".
But, one must insist - this is dietary glucose doing this, not dietary fructose. This is not evidence in support of the idea that fructose is the bad carb, and glucose is the good carb; it looks more like evidence that, in normal metabolisms, sugars are somewhat interchangeable.
If you consume an excess of glucose, hepatic metabolism will have to convert some of that excess to fatty acids. Palmitic acid will be synthesised, and some palmitic acid will be elongated to oleic acid (because you can't make a triglyceride with 3 SFAs - if there's no dietary MUFA, DNL oleate makes the process of esterification possible). But you'll also need glycerol, and fructose is said to be a better glycerol substrate than glucose (for some reason I don't understand, being hopeless at maths). Note the pyruvate as a source of fatty acids in the schema below - this could just as easily have come from glucose. Indeed, the acetyl-CoA to make fatty acids could have come from fatty acids. (This is what happens with linoleic acid in fatty liver disease. Indeed, this kind of futile cycling of lipid carbons seems to be a feature of NAFLD.)
In the context of hyperglycemia in the absence of dietary fructose, (one might speculate that) the generation of a little fructose makes sense, just as the elongation of palmitate to oleate makes sense, as a means of packing away energy from glucose into stable triglycerides (which can be exported from hepatocytes with VLDL, or stored more-or-less safely for a while) more easily than would otherwise be the case. Perhaps.
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| We fed the mice 10% glucose water and off they went. |
The knock-out mice that couldn't change glucose into fructose consumed less glucose. The authors pulled out some KO mice (n=4) that ate as much as 4 non-KO mice, to show that the KO mice were healthier - fully protected against the metabolic harm of fructose/glucose - but this kind of post-hoc tactic is a bit suspect. Interestingly the KO mice had higher serum beta-hydroxybutyrate (ketone body) levels. I guess that energy had to go somewhere (is this at all relevant to the claims that potatoes elevate ketones?).
There are humans who cannot metabolise fructose or sorbitol.
"Affected individuals are asymptomatic and healthy, provided they do not ingest foods containing fructose or any of its common precursors, sucrose and sorbitol. Most adult patients do not have any dental caries".
Bill Lagakos says that his nutrition tutors spent all of five minutes on the polyol pathway; R.D. Feinman, who should know, states "I never saw the point or function of the polyol pathway".
Wild speculation aside, that's fair comment. The polyol pathway is useful for blinding diabetics, but it doesn't seem particularly essential for life. At most it might once have provided a slight buffer against hyperglycemia, but today we have far too many copies of the amylase gene and the polyol shock absorber, if that is what it was, is easily broken, making things worse. Is that any explanation? Some mysteries, it seems, are going to remain mysteries.
Fructose is a factor in fibrosis of chronic Hepatitis C: but it's not a biggie.
Industrial, not fruit fructose intake is associated with the severity of liver fibrosis in genotype 1 chronic hepatitis C patients.Unhealthy food intake, specifically fructose, has been associated with metabolic alterations and with the severity of liver fibrosis in patients with non-alcoholic fatty liver disease. In a cohort of patients with genotype 1 chronic hepatitis C (G1 CHC), we tested the association of fructose intake with the severity of liver histology.
METHODS:
Anthropometric and metabolic factors, including waist circumference (WC), waist-to-hip ratio (WHR), dorso-cervical lipohypertrophy and HOMA were assessed in 147 consecutive biopsy-proven G1 CHC patients. Food intake, namely industrial and fruit fructose, was investigated by a three-day structured interview and a computed database. All biopsies were scored by an experienced pathologist for staging and grading (Scheuer classification), and graded for steatosis, which was considered moderate-severe if ⩾20%. Features of non-alcoholic steatohepatitis (NASH) in CHC were also assessed (Bedossa classification).
RESULTS:
Mean daily intake of total, industrial and fruit fructose was 18.0±8.7g, 6.0±4.7g, and 11.9±7.2g, respectively. Intake of industrial, not fruit fructose, was independently associated with higher WHR (p=0.02) and hypercaloric diet (p=0.001). CHC patients with severe liver fibrosis (⩾F3) reported a significantly higher intake of total (20.8±10.2 vs. 17.2±8.1g/day; p=0.04) and industrial fructose (7.8±6.0 vs. 5.5±4.2; p=0.01), not fruit fructose (12.9±8.0 vs. 11.6±7.0; p=0.34). Multivariate logistic regression analysis showed that older age (OR 1.048, 95% CI 1.004-1.094, p=0.03), severe necroinflammatory activity (OR 3.325, 95% CI 1.347-8.209, p=0.009), moderate-severe steatosis (OR 2.421, 95% CI 1.017-6.415, p=0.04), and industrial fructose intake (OR 1.147, 95% CI 1.047-1.257, p=0.003) were independently linked to severe fibrosis. No association was found between fructose intake and liver necroinflammatory activity, steatosis, and the features of NASH.
CONCLUSIONS:
The daily intake of industrial, not fruit fructose is a risk factor for metabolic alterations and the severity of liver fibrosis in patients with G1 CHC.
Excuse me, but OR 1.147 is not a huge correlation. It's as tiny as a red-meat-and-disease-of-your-choice correlation in a study run by vegans. What if they had looked at total carbohydrate? Or included fruit juice and high-GI glucose sources like bread and pasta? Do you think the OR would have been higher then? It was about OR 2.9for carbohydrate and fibrosis in the last Italian diet study I read.
If we can learn anything from the polyol pathway, it is, that carbs will be carbs.