Friday, February 8, 2013

Quick commentary on Dr. Lustig’s take on fructose




I’ve recently had the opportunity to skim through Dr. Robert Lustig’s book, Fat Chance.  I haven’t watched his YouTube lecture (and I don’t plan to), which people have used to justify the avoidance of fructose (and sugar) on, but I’m assuming that the main arguments in the lecture are summarized in his book.    I’m planning on addressing the entire book, bit by bit, but first, herein, I will provide commentary on each of Dr. Lustig’s conclusions about fructose, which can be found on pages 120 to 121.  Dr. Lustig’s comments are in red.


1. Triple the dose mean the liver needs triple the energy to metabolize this combo versus glucose alone, depleting the liver cell of adenosine triphosphate (or ATP, the vital chemical that conveys energy within cells).  ATP depletion leads to the generation of the waste product uric acid.  Uric acid causes gout and increases blood pressure.

This supposition was addressed briefly here.  

In short, there is no evidence that fructose, in the way that it’s consumed in the US now (i.e., with glucose), increases blood uric acid levels or causes gout.

Large doses of liquid fructose, unreflective of the consumption habits of the majority of the US population, does, in fact, raise uric acid levels, but this rise is only transient, no where near the levels seen in gout, and not necessarily harmful.


2. The fructose does not go to glycogen.  It goes straight to the mitochondria.  Excess acetyl-CoA if formed, exceeding the mitochondria’s ability to metabolize it.

Although the conversion of fructose to glycogen is a minor pathway, fructose results in more glycogen storage than glucose does.  In one of the few studies available, the infusion of fructose resulted in about 360 percent more liver glycogen than glucose infusion did, as measured by biopsy (Nilsson & Hultman, 1974).

Isotope tracer studies show that fructose is predominantly converted to glucose and lactate, supplying fuel to cells in the periphery.  In comparison, the conversion of fructose to fat–via acetyl-CoA–is a minor, and highly energy-consuming, pathway, as is its conversion to glycogen (Tappy & Lê, 2010).

The proportion of each pathway used by fructose is further fine-tuned by (1) the type of sugar co-ingested with fructose, (2) the amount of fructose ingested, and (3) the body’s energy needs at the moment.  Ingesting fructose with glucose, for instance, increases the oxidation rate of each sugar far more than if each sugar were ingested alone.  

As an aside, Dr. Lustig’s assertion here is especially hard to stomach because fructose, in a non-insulin dependent manner, (1) stimulates the trapping of glucose inside cells, which is the first step in synthesizing glycogen (e.g., McGuinness & Cherrington, 2003) and (2) increases the flux of glucose through the enzyme called glycogen synthase, which catalyzes the conversion of glucose to glycogen (Petersen, Laurent, Yu, Cline, & Shulman, 2001).  These processes are impaired in diabetics, who have been shown to have lower amounts of glycogen in their muscle and liver.

So although fructose doesn’t itself convert to glycogen in significant quantities, it does in fact stimulate the conversion of glucose to glycogen.  Moreover, fructose is unlikely to lead to the accumulation of acetyl CoA. (Nonetheless, much like alcohol, extra protein and nutrients provide further insurance against the accumulation of fat in the liver by high doses of pure fructose.)


3. The excess acetyl-CoA leaves the mitochondria and gets metabolized into fat, which can promote heart disease.

This is unfortunately wishful thinking.  The idea that fructose leads to the excessive accumulation of acetyl CoA and fat in the liver relies on (1) theoretical explorations of biochemical pathways and mechanisms and (2) studies in which fructose is given alone and in doses unreflective of the consumption habits of the population at large. 

In short, experimental evidence does not bear out the supposition here.  Fructose is predominantly converted to glucose and lactate, and oxidized to carbon dioxide.


4. Fructose activates a liver enzyme, which is the bridge between liver metabolism and inflammation.  This inactivates a key messenger of insulin action, leading to liver insulin resistance.

I think Dr. Lusting is alluding to protein kinase C (the epsilon [ϵ] isoform), which is an enzyme activated by diacylglycerol (though diacylglycerol is not unconditionally required for this activation).  In turn, the activation of protein kinase C impairs insulin signaling  (Samuel et al., 2007).

Recall that the excessive delivery of fatty acids to the liver leads to the accumulation of lipids therein–one of which is diacylglycerol (Samuel et al., 2004). Experimentally, because it doesn’t stimulate the secretion of insulin, fructose does not activate LPL on fat cells or HSL inside fat cells, thereby leading to an intense mobilization and delivery of fatty acids to the liver and other organs.

However, once again, because fructose is always present with glucose, and because glucose stimulates the secretion of insulin, fatty acid mobilization, free fatty acids, and the flux of fat to the liver (and subsequent inactivation of the insulin receptor) are kept in check.

Fructose in the liver could convert to fat more efficiently than glucose, but quantitatively the amount of fat synthesized is inconsequential (Chong, Fielding, & Frayn, 2007). 

Fructose increases energy expenditure, more than any other carbohydrate does, and so is least likely to result in an accumulation of fat in organs not designed to store much fat, and thus, to activate protein kinase C.  Inflammation, it turns out, although present in most cases of diabetes, is secondary to this accumulation of fat in organs and tissues as it relates to causing insulin resistance (Mayerson et al., 2002; Kitt Falk Petersen et al., 2005).


5. The lack of insulin effect in the liver means that there is no method to keep the glucose down, so the blood glucose rises, which can eventually lead to diabetes.

Earlier in his book, Dr. Lustig makes the point that fructose is always present with glucose.  High fructose corn syrup, for instance, contains either (1) 53 percent glucose and 42 percent fructose or (2) 42 percent glucose and 55 percent fructose.

So you can’t have it both ways, because with glucose, the dangerous increase in blood glucose levels is buffered against, as glucose stimulates the secretion of insulin (fructose, to a small extent, does as well).

Nonetheless, even the ingestion of pure fructose of upwards of 200 grams per day leads only to a modest decrease in hepatic and peripheral insulin sensitivity.  The hypercaloric feeding of pure fructose can increase the deposition of fat in the liver in humans, but, fortunately, no where near the levels seen, for instance, in NAFLD (Faeh et al., 2005; Lê et al., 2006, 2009).


6. The liver insulin resistance means the pancreas has to release extra insulin, which can force energy into fat cells, leading to obesity.  And the fat cells that fill up most are in the visceral fat, the bad kind associated with metabolic disease.

The faulty premise here, that fructose causes hepatic insulin resistance effectively nullifies Dr. Lustig’s deduction that fructose leads to hyperinsulinemia, obesity, etc.

(Note that carbohydrates suppress cortisol, which promotes fat storage in visceral storage sites more than any other single factor.)


7. The high insulin can drive the growth of many cancers.10

Fructose alone decreases blood insulin and glucose levels.


8. The high insulin blocks leptin signaling, giving the hypothalamus the false sense of “starvation,” and causing you to eat more.

See the answer to the above question.


9. Fructose may also contribute to breakdown of the intestinal barrier.  Normally the intestine prevents bacteria from entering the bloodstream.  The intestinal breakdown may lead to a breach in the walls of the intestines.  The result is a “leaky gut,”11 which could increase the body’s exposure to inflammation and more ROS.  This worsens insulin resistance and drives the insulin levels even higher.12

The conclusion drawn here, that fructose leads to “leaky gut," is based entirely on evidence that is circumstantial.

In the study that is linked to, subjects with NAFLD were compared with healthy subjects with respect to blood lipopolysaccharide (LPS) levels (an indirect measure of intestinal permeability) and fructose intake.

Although subjects with NAFLD had higher blood LPS levels that coincided with, on average, higher intakes of fructose as compared to healthy subjects, data of this type can’t provide causal information.  There are a myriad of reasons, aside from the differences in fructose intake, that could explain the differences in LPS levels observed. (Offhand the subjects with NAFLD, on average, were fatter, older and ate more calories.)  

Fructose alone could increase the generation of LPS because of its malabsorption in the intestines, thereby providing fodder for certain intestinal bacteria to proliferate.  But as I keep laboring the point, the co-ingestion of glucose greatly increases the efficiency of fructose absorption.  Because fructose is typically co-ingested with glucose, the LPS raising effect of fructose in this study is probably overblown and irrelevant.

(Unsaturated fats, starches, hypothyroidism and poor cardiovascular functioning [by diminishing circulation to the bowels] I think are greater contributors to intestinal permeability and the subsequent increase in LPS levels.)


10. Fructose undergoes the Maillard (browning) reaction 7 times faster than glucose, which can damage cells directly.  Although the experiments are in their infancy, preliminary results suggest that in a susceptible environment, fructose can accelerate aging and the development of cancer.

On paper, because it linearizes more readily than glucose does, fructose is postulated to glycate amine groups of molecules at a very high rate, which is the initial step of advanced glycation end product (AGE) formation (i.e., the Maillard reaction). 

It’s conceivable that in uncontrolled diabetes, the saturation of the polyol pathway, which leads to the accumulation of fructose and sorbitol, could lead to the uncontrolled generation of reactive aldehydes, namely methylglyoxal and 3-deoxoglucosone.  Methylglyoxal and 3-deoxoglucosone, in turn, form a myriad of AGE.

In reality, on absorption, fructose is cleared rapidly such that blood fructose levels hardly rise by more than 10 milligrams per deciliter in the blood.  Fructose also provides pyruvate, which is postulated to, via competition, prevent glycation reactions.  And, fructose, to some extent, curtails the flux of glucose through the polyol pathway, thereby preventing the accumulation of the reducing cofactor NADH, so the conditions that favor lipid peroxidation processes are thusly staved off.

Lipid peroxidation processes provide many of reactive aldehydes as well.  Some in vitro studies have shown that AGE are produced faster, and more abundantly, in the presence of unsaturated fat than sugar.  

It’s difficult to determine where AGE originate from  because glycation reactions happen quickly, there is great overlap in the AGE produced from glucose and fatty acids, and in vivo isotope tracer studies have not been conducted.  Nonetheless, the idea that sugar leads to the pathological accumulation of AGE is poorly substantiated.


11. The data on fructose and dementia in humans are currently correlative and indirect.  However, the data on insulin resistance and dementia show clear causation.  African Americans and Latinos are the biggest fructose consumers and those with the highest waist circumference (a marker for insulin resistance).  Coincidentally, they also have the highest risk for dementia.

I concur with Dr. Lustig about the relationship among insulin resistance, waist circumference (an indirect measure of visceral fat), and dementia.  As to how that happens, on the other hand, when more data becomes available, we will have ample opportunity to judge better.
                                                              

References

Chong, M. F.-F., Fielding, B. A., & Frayn, K. N. (2007). Mechanisms for the acute effect of fructose on postprandial lipemia. The American journal of clinical nutrition, 85(6), 1511–20. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17556686
Faeh, D., Minehira, K., Schwarz, J.-M., Periasamy, R., Periasami, R., Park, S., Seongsu, P., et al. (2005). Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes, 54(7), 1907–13. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/15983189
Lê, K.-A., Faeh, D., Stettler, R., Ith, M., Kreis, R., Vermathen, P., Boesch, C., et al. (2006). A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. The American journal of clinical nutrition, 84(6), 1374–9. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/17158419
Lê, K.-A., Ith, M., Kreis, R., Faeh, D., Bortolotti, M., Tran, C., Boesch, C., et al. (2009). Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. The American journal of clinical nutrition, 89(6), 1760–5. doi:10.3945/ajcn.2008.27336
Mayerson, A. B., Hundal, R. S., Dufour, S., Lebon, V., Befroy, D., Cline, G. W., Enocksson, S., et al. (2002). The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes, 51(3), 797–802. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2995527&tool=pmcentrez&rendertype=abstract
McGuinness, O. P., & Cherrington, A. D. (2003). Effects of fructose on hepatic glucose metabolism. Current opinion in clinical nutrition and metabolic care, 6(4), 441–8. doi:10.1097/01.mco.0000078990.96795.cd
Nilsson, L. H., & Hultman, E. (1974). Liver and muscle glycogen in man after glucose and fructose infusion. Scandinavian journal of clinical and laboratory investigation, 33(1), 5–10. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/4827760
Petersen, K F, Laurent, D., Yu, C., Cline, G. W., & Shulman, G. I. (2001). Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans. Diabetes, 50(6), 1263–8. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11375325
Petersen, Kitt Falk, Dufour, S., Befroy, D., Lehrke, M., Hendler, R. E., & Shulman, G. I. (2005). Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes, 54(3), 603–8. Retrieved from http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2995496&tool=pmcentrez&rendertype=abstract
Samuel, V. T., Liu, Z.-X., Qu, X., Elder, B. D., Bilz, S., Befroy, D., Romanelli, A. J., et al. (2004). Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. The Journal of biological chemistry, 279(31), 32345–53. doi:10.1074/jbc.M313478200
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X., et al. (2007). Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. The Journal of clinical investigation, 117(3), 739–45. doi:10.1172/JCI30400
Tappy, L., & Lê, K.-A. (2010). Metabolic effects of fructose and the worldwide increase in obesity. Physiological reviews, 90(1), 23–46. doi:10.1152/physrev.00019.2009