This is an aside but worth talking about.
Typically, we talk about heme and nonheme iron when we are going to discuss iron in biology. And one of the reasons I don’t worry about my hemochromatosis too much even though heme iron is more “bioavailable” and I like red meat is because the heme iron, the kind found in meat, is bound to a hemeprotein. That I eat red meat is contrarian.
In the case of hemoglobin this hemeprotein functions somewhat like a “conditional loop”, when pH is low and carbon dioxide is high (as in hypoxia i.e. generally a lack of oxygen to cells, tissues, organs, and the organism) hemoglobin will “release” oxygen to surrounding tissues.
When the situation is reversed higher pH and low carbon dioxide hemoglobin will “up take” oxygen. It is a controlled situation and hypoxia inducible factors seem to mediate part of this controlled situation.
My suspicion is that under normal atmospheric conditions being metabolically hypoxic (intake of significant amounts of fructose at sea level under normoxia) can be problematic and partially explains why sea level diabetics often have relief of symptoms at altitude. [This is a dynamic interaction with many environmental conditions to include energy substrates, the picture being painted will become clear as this series progresses.]
Fructose can chelate with inorganic iron. Ingested nonheme iron needs to be reduced to be absorbed and used appropriately which our intestinal cells can do. Prior to that conversion iron can react with compounds such as ascorbic acid or fructose.
In parallel, fructose tends to cause hemoglobin to release its bound iron and reduce oxygen affinity of hemoglobin and this is probably why we see iron implicated in many different phenotypical states (disease states), while the total picture is more complex than a single variable, iron is an important nexus to facilitate understanding. This unbound iron can do damage in the right contexts.
In diabetic-like phenotypes, fructose in erythrocytes (red blood cells) is about 3-4 times higher than it is in non-diabetic phenotypes. When hemoglobin is incubated with fructose, fructated hemoglobin forms (similar to glycated hemoglobin but with fructose instead of glucose). When ferrozine is added to a solution containing ferrous iron, the ferrozine binds with ferrous iron and produces a magenta colored solution. This is something you would do if you want to confirm that fructated hemoglobin is releasing its iron. Indeed, when ferrozine is added to a medium containing fructated hemoglobin it turns magenta reflecting the level of fructosylation/fructation, proportionally.
We know that fructose fructates hemoglobin, and we know it disrupts the heme protein causing an increase in free iron and this partly explains the interference with oxygen affinity. One other interesting thing to point out regarding iron containing protein complexes is that cytochrome p450 is an iron containing protein. Cytochrome p450 is involved with steroid hormone synthesis, xenobiotic and polyunsaturated fatty acid metabolism.
All cells are constantly turning over heme which is facilitated by heme oxygenase (HO) to produce carbon monoxide, ferrous iron (Fe2+) and biliverdin/bilirubin. Bilirubin binds to albumin and is transported to the liver where it binds with glucuronate and is excreted (glucuronidation). This is normal physiology.
In fructose induced nonalcoholic fatty liver states there is an increase in deposited iron that is attenuated by heme oxygenase. Heme oxygenase requires oxygen, protons (H+), and NADPH and increases superoxide dismutase activity. Acutely, our physiology can handle this when we are at our baseline phenotype. Chronically this reaction cannot sustain, and this is for several reasons, most importantly, failure of oxygen delivery inhibits palmitic acid driven mitochondrial oxidative phosphorylation and increases the reliance on glycolytic energy metabolism. One of the other over looked aspects of a reliance on glycolytic energy pathways is that the mitochondria participate in the generation of steroid hormones and normal cellular function, you need palmitic driven OXPHOS for this occur. The question is, which comes first disrupted oxygen delivery or inhibited OXPHOS by fructose? Or are they in parallel?
At sea level and in the context of sufficient sources of heme iron and saturated fatty acids hemoglobin is saturated with oxygen and oxygen transport occurs normally and is partially under the control of hypoxia inducible factors (HIF).
However, in the context of excessive fructose in conjunction with nonheme iron as well as fructose interfering with in situ hemoglobin causing iron release and affecting oxygen affinity (and interfering with cellular respiration as a result), fructose and liberated iron from hemoglobin will potentially react with the excess iron and oxygen released from these reactions as well as the oxygen delivered from organism level respiration (breathing) further interfering with oxygen delivery.
In essence—excess fructose in a higher oxygen environment not only disrupts in situ function of hemoglobin but also reacts with unbound nonheme iron and interferes with HO producing a hypoxic phenotype. Until fructose concentrations fall this is a vicious cycle that affects the protein, lipid, and carbohydrate structures of intact cells. Again, acutely we are equipped for such insults. Chronically this leads to accelerated degeneration.