Unifying biology (3) Ketogenesis and hypoxia

One of the questions I’ve been trying to develop an intellectually satisfying answer to for the past decade is: Why did Kwasniewski and Lutz seem to advise against ketosis, was it empirical or esoteric?

I find the hypoxic in utero environment of the fetus and subsequent metabolic transition of the neonate to a normoxic environment and eventual metabolic transformation fascinating. After gestation interesting things are occurring metabolically, increases in lactate, increases in ketogenesis and gluconeogenesis. The scant number of tracer studies looking at infant metabolism seem to indicate that exogenous lactose from breast milk and endogenous glucose as a result of gluconeogenesis is being shunted towards biosynthetic pathways and glucose is metabolically spared. In breast fed infants, glucose concentrations increase cyclically maintaining normoglycaemia. In contrast, infants administered oral solutions of glucose develop cyclical hypoglycemia.

I suspect there are morphological and functional differences between infant and adult mitochondria. There are reasons for this suspicion. Infants administered glucose less than 1 month after gestation present with glucose intolerance and glucose tolerance subsequently increases over the following months of development; additionally, the metabolic substrate profile points in that direction.

Infants have generous amounts of adipose tissue and as the infant transitions to a toddler and child, adipose tissue declines. I would suggest this is a result of maturing mitochondrial morphology and function; and that elevated lactate and ketones reflects fatty acid oxidation (FAO) capacity. This physiological metabolic transition is a result of adapting to an externally normoxic environment. Interestingly, for every 1000 meter increase in elevation there is a reduction in neonate mass and an increase in the incidence of fetal death.

One of the central tenets of my hypothesis is that ketone formation indicates hypoxia be it a histophysiological adaptation to external environmental conditions and physiological stimuli or; a pathophysiological disorder resulting from chronic exposure to compounds and energy substrates that interfere with or block normal histophysiological adaptations. In other words, anything that chronically interferes or blocks normal homeostatic processes produces a maladapted and eventually, unadaptive state, leading to entropy i.e. degeneration and death.  

There is a beautiful cyclical metabolic signature from conception to death reflecting our ability to deal with oxygen and lack thereof; the energy substrates that build and prepare us for an oxygenated environment are eventually the same energy substrates that kill us. We develop in a hypoxic in utero environment and adapt to an oxygen rich environment. After birth and in the presence of oxygen our physiology matures and develops reflecting the external environmental conditions. As our mitochondria learn how to breathe, we slowly loose the ketogenic capacity present during early stages of life and transition to a reliance on fatty acids and develop the capacity to rely on glucose, fructose, and ketones when intermittent hypoxia is present. When intermittent hypoxia is present our mitochondria temporarily uncouple and become physiologically insulin sensitive and glucose is used to facilitate adaptation via biosynthetic pathways.  

As we age our ketogenic capacity continues to decline along with a diminishing fatty acid oxidation capacity. In the context of this decline, not only do we lose the ability to produce adequate ketones to continually adapt to intermittent hypoxia, our mitochondria degenerate losing the ability to metabolize fatty acids and our physiology becomes more and more reliant on glucose as a metabolic substrate and as a result we lose the ability to maintain physiological insulin resistance. Slowly the adaptive state of intermittent physiological insulin sensitivity becomes pathophysiological and we lose the physiological insulin resistance of our youth.

As I have reflected on in the past, glucose is a primitive energy substrate, a glucose driven metabolism, contrasted with glucose used as a biosynthetic substrate in the context of a fatty acid driven metabolism, will drive primitive histophysiology and the subsequent degeneration of the orchestra. Every day the orchestra slowly goes out of tune and eventually the musicians slowly start disappearing, eventually the conductor has no musicians and he will turn to the audience, take a bow, and you will take your last breath.

In the end you will suffocate to death.

Why did Kwasniewski and Lutz seem to advise against ketosis?

  1. Whether they knew better or not, chronic ketosis indicates hypoxia.
  2. The conservative amount of glucose needed to stay out of deep chronic ketosis facilitates physiological insulin resistance and supports adaptive physiological insulin sensitivity during intermittent hypoxia.
  3. Ketosis reflects fatty acid oxidation capacity.  

Unifying biology (2) Aside on iron (Fe)

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.     

Unifying biology (1) Definitions and concepts

For the past year or so, I’ve been attempting to develop a hypothesis that unifies a lot of concepts in biology. My primary interest is understanding respiration at the cellular level and at the organism level; understanding the interplay between the two; and how that interplay, manifests as observable physiology, pathology, and psychology.

Just uttering the word unify in scientific circles if you are keen enough to notice, draws a target on your back, and rightfully so. There is no shortage of hair brained drain circling ideas out there. Criticism is welcome.

Though I work in the field of pathology, more specifically histology, I generally prefer the somewhat out of fashion term histophysiology to describe the things that interest me. Here is why:

Histophysiology: a branch of physiology concerned with the function and activities of tissues; structural and functional tissue organization.

Pathology: the study of the essential nature of diseases and especially of the structural and functional changes produced by them; something abnormal; the structural and functional deviations from the normal that constitute disease or characterize a particular disease.

Physiology: a branch of biology that deals with the functions and activities of life or of living matter (such as organs, tissues, or cells) and of the physical and chemical phenomena involved.

Pathophysiology: the physiology of abnormal states.

Histology: a branch of anatomy that deals with the minute structure of animal and plant tissues as discernible with the microscope; tissue structure or organization.

Its more useful from my perspective to understand how cells work rather than deviation from normal, as normal is subjective. I am more comfortable with classifying various diseases and pathologies as dynamic phenotypes.

This is important to me for several reasons. First, classifying various pathologies as phenotypes allows us to understand, at least in thinking, that a disease is an adaptation (bear in mind that adaptation does not necessarily mean the adaptation is subjectively beneficial). The abnormal (phenotype), if you will, is the dynamic response of the cell to dynamic conditions.

The problem with the word disease, with the way we perceive disease, is that it implies that the cell is responding irrationally and independent of the environment when in fact the cell is responding very rationally and quite dependently on the environment.

From a philosophical perspective it is a misunderstanding to say when environmental conditions produce abnormal phenotypes that the environment is somehow defected. In one sense this is true, but only in the sense of how we perceive what normal is. Cells respond to the environment and adapt to the conditions of the environment, rationally. Cells don’t respond independently of their environment for our sake.

While that may sound like semantics it is necessary.

There is a dynamic relationship that the cell has with its environment to include energy substrates. Certain types of cells prefer different kinds of energy substrates. And on a bigger scale, groups of cells that compose larger structures like tissue, control their local environment to ensure they receive proper energy substrates.

When the internal environment of a tissue type no longer has access to a preferred energy substrate the cell/tissue can intermittently physiologically adapt to another energy substrate. However, a chronic shift to an unpreferred energy substrate will eventually cause a shift in the cellular phenotype and through proliferation, eventually affect tissue structure and function. That may or may not be subjectively beneficial.

While cells certainly respond to the conditions of their environment, a group of cells can also generate an internal environment to support their group level goals by using other energy substrates via in situ structure to generate a gradient barrier. The generated gradient barrier that protects the group level preferred environment and access to the tissues preferred energy substrates is called an organ.

Via structure, energy substrates can then be routed to various locations and the preferred mixtures of energy substrates can be taken up by different cells and tissue types that have different requirements to maintain their preferred internal environment to support their overall structure and functionality. It is important to understand that this preferred functionality is interdependent on other tissues/organs behaving in their preferred manner and maintaining their preferred internal environment. The saying: One man’s trash is another man’s treasure applies. When all cells/tissues/organs are interdependently in concert we call this an organism.

When conditions change and a tissue can no longer access its preferred energy substrate, an intermittent physiological switch to another energy substrate occurs, if the access to the preferred energy substrate is chronically bottlenecked, the internal environment of a group of cells fundamentally changes. When this occurs this affects the energy substrate supply to other groups of tissues because the concert is over. A systemic phenotypical shift begins.

If the phenotypical shift is chronic, there is then deviation from the baseline phenotype, this deviation fundamentally alters tissue structure and function and the concert is now playing another piece which you may or may not enjoy.

As humans we strive to keep the original concert going. The piece we enjoy. The piece we call I ormyself. We all sense when something is out of tune. Sometimes its just one violinist others its the whole section and at our worst the whole orchestra is out of tune or no longer playing our favorite piece.

The question is how do we ensure the internal environment stays in concert playing I for as long as possible so you can adapt and respond appropriately to the external environment consciously and unconsciously.