When I spoke with Dr. Tolan in 2020, many were not happy with what I relayed. He said that
in his most recent paper (2019), he cited animal model studies which showed that in mice given a diet high in starches (rice, breads, pasta and potatoes), these high-glucose foods induced a pathway to produce fructose endogenously which led to dehydration and long term damage to liver and kidneys. Although he gave the mice a diet that was very high in these starches (80%), even at lower percentages, starches may create a chronic, if not acute, problem for HFIers. He did not name the pathway in our conversation, but it is clear to me that he was referring to the polyol pathway!
He had also said that HFIers should avoid dextrose/glucose unless absolutely necessary (i.e. severe dehydration). With fever/illness, he said it is best to just push the water and that an HFIer should not get dehydrated as long as they are not consuming fructose or glucose. As for diet, he said as close to an Atkins diet as possible is the best course.
my son’s daily diet for a long time was Elecare Jr amino acid formula, meat, eggs, herbs, oils, fish, oats and rice crackers. A year ago, I started baking more foods for him – most of the baked goods are very high in fat (ghee) and protein (eggs) as well, but I noticed that if he had something with high carbs and no fat (i.e. plain rice noodles), he would not feel well. Or if he ate his birthday cake (made with dextrose), he would have GI upset/reflux and more frequent “head-sickness”. Like many of you, Remy only likes cooled baked goods, never fresh out of the oven.
This article (which came out around the same time as Dr. Tolan’s research) clearly supports the fact that starchy foods - especially if they dominate the diet- are harmful to those with HFI. Furthermore, it says glucose/dextrose (even if pure) will convert up to 30% of the time into endogenous fructose which triggers a cycle of decreased ATP--> increased uric acid --> increased mitochondrial dysfunction--> increased lipogenesis --> fatty liver and insulin resistance (metabolic syndrome). This could explain why so many (including Remy) continue to have deposits/lesions/hepatic steatosis (and even fibrosis) even after years on a fructose-free diet. These fatty deposits may persist due to the endogenous fructose production which may be triggered by by the consumption of starchy foods and dextrose. We have had the dextrose conversation so many times on this page, but we have been debating about THE WRONG ISSUE (i.e. the purity of the dextrose). It is now clear for my own personal experience and from this article the that issue with dextrose goes beyond purity. Even the purest of dextrose should not be used on a regular basis due to the fact that much glucose gets converted to fructose. I think the effect on the intestines has also been underestimated, and we all have to realize that a lot of the HFIers on here who have GI reactions may in fact be reacting due to endogenous fructose.
This article further explains why, when Remy was so ill as an infant, the elimination of fructose stopped him from having acute reactions, but it didn’t make him completely “well”. What made him thrive was when I found a geneticist who listened to me and he put him on levocarnitine. My son’s carnitine supplementation over the past 5 years has likely protected him during illness, growth spurts, and dextrose ingestion (birthday cakes). I thought it was interesting that the mitochondrial dysfunction and reduction of AMPK could contribute to fatty liver. Carnitine stimulates ATP production and improves the health of the mitochondria. Now, I wonder if AMPK supplementation could help HFIers with persistent liver damage!
This article makes it clear that any foods that raise glucose levels too quickly (high glycemic loads) can trigger the polyol pathway, thus inducing endogenous fructose. The article describes how the polyol pathway can even get triggered in the brain thus producing endogenous fructose in multiple organs/tissues. Remy has visible symptoms when he eats too many carbs and often gets “headsick” as he describes it. Many of you have described feeling “off” even when you have not ingested fructose or sorbitol accidentally. So, we may not always see the typical HFI manifestation of fructose toxicity when it is endogenously produced! In fact, on the second page, it clearly says that glucose metabolism does not cause an immediate nucleotide turnover or uric acids generation but some of the sugar (30%) is directly converted to fructose and this endogenously-produced Fructose could lead to metabolic syndrome. The fact that this polyol pathway can be activated anywhere in the body has huge ramifications for HFI. This is what Dr. Tolan was talking about; you might not notice the short-term impact of ingesting too many carbohydrates, but down the road, there will be a long-term effects on the intestines, kidney and liver.
Carrier symptoms have always been a major question with HFI and it’s being investigated with GSD (of which Remy and I are carriers). GSD gets far more funding. It is extremely interesting that higher uric acid were found in heterozygous who consumed fructose. This makes perfect sense to me as my mother suffered from severe hypoglycemia for years when she ate too many carbohydrates, and she has always avoided anything that tasted sweet.
You can see in the pathway that our geneticist gave us (circa 2006) that it’s been known for a long time that sorbitol dehydrogenase converts sorbitol to fructose, but what was missing from this pathway in 2006 is that aldose reductase can convert glucose into sorbitol. This discovery is what Dr. Tolan and the researchers in this study out of Colorado have now made clear (so now I have now penciled it into this pathway).
As I look at the pathways of fructose metabolism, I cannot help but wonder (and I will ask Dr. Tolan)- if we can stop the polyol pathway from ever getting activated, then could ALDOB deficiency become irrelevant?
Whether the fructose comes from diet or is produced endogenously, perhaps the inhibition of an enzyme early in the pathway is the key not just to controlling diabetes (which is where all the research funding has gone) but also to treating HFI! We’ve been waiting for enzyme therapy to induce ALDOB activity, but perhaps what we need to do is inactivate enzymes higher up on the pathway! The benign genetic condition known as Essential Fructosuria results from deficiency of the first enzymes in the pathway of fructose metabolism. In this article, endogenous fructose is never produced when the fructokinase enzymes is turned off in mice! Maybe aldose reductase could be inhibited to prevent the conversion of glucose into sorbitol which would end the pathway there or sorbitol dehydrogenase inhibited to prevent the conversion of sorbitol to fructose!
All of this screams to me that if we can mute these early enzymes, all the dysfunction in enzymes further down the path (i.e. ALDOB and F1,6BP) would be avoided because glucose and sorbitol when converted to endogenous fructose as well as dietary fructose would never get absorbed into the intestines and would never reach the liver to cause metabolic distress.
Can these enzymes be turned off in humans? I did some digging and found a study from 1974 which states that actinomycin D inhibits fructokinase. And, most interestingly, in 2019, Pfizer came out with a study showing a drug that is supposed to inhibit "an enzyme" (they didn’t name the enzyme) which reduces fatty liver/NASH (non-alcoholic steatosis). I bet the enzyme is khk (fructokinase) and the inhibition is brought on by actinomycin D. Again, the funding is going to research for diabetes/metabolic syndrome/NASH, so there is no mention of HFI in these studies. But, why can’t HFIers also benefit from early enzyme inhibition?
Until/Unless the pathway is deactivated, I truly think it is best to follow Dr. Tolan’s advice and avoid spikes in glucose levels by:
1. coupling carbs with fats and proteins to slow absorption
2. limiting salt intake (salt increases the enzymes involved in converting glucose to endogenous fructose)
3. limiting oxidative stress (to keep uric acid levels normal)
4. using dextrose only in an emergency, and even then, in small amounts over time instead of bolus treatment to reverse hypoglycemia.
It is not just severe and acute symptoms HFIers need to be cognizant of and try to avoid, but also long-term damage. I found research from 2020 (Dr. Tolan was one of the authors) which correlated fructose with increased uric acid and ultimately cancer which suggests that blocking fructose metabolism could also be a way to prevent cancer!
www.jci.org/articles/view/94427?fbclid=IwAR0Qhr6xTTRyffDJfg-DK_Nr2ikJTXf17KX_Z1Q1FT8GotHv5soe-FXNfqAlink.springer.com/article/10.1186/s40170-020-00222-9?fbclid=IwAR23p3G75IOLpiFJ48CFAnEuwnYf3XHe2zE1FqVmKZ4NKv0kHRAW3xi5oFo
