**Draft WIP / Work in progress Part 2 of 4**
**Undergoing writing & readibility amends December 2023**

Following from part 1, the discussion continues in two sections - general overview of Vitamin D metabolism followed by insights by the opposition to Vitamin D supplementation.

Vitamin D ~ Overview & Metabolism. 

A condensed high level overview of Vitamin D's metabolism is outlined as follows from two source(s) ~ Sunlight and Exogenous.

1. Sunlight. UV light absorbs through the skin, where the initial form ~ 7-dehydrocholesterol ~ is formed which then undergo several metabolite conversions below, in their respective order ~
   1. From the initial 7-dehydrochoelsterol (skin) then;
   2. 25 OHD / Calcifediol (found in blood tests) then;
   3. 1,25 OHD / Calcitriol (the end / active form).
2. Exogenous - this refers to diet and/or supplemental form of VItamin D. Both the kidney and liver converts the inactive (25OHD or known as the Calcifediol)  to the active form (1,25OHD Calcitriol) elaborated as follows. It is worth noting that the inactive form, usually residing in commercial supplemementatino today is often the refering to the inactive form ~ cholecalciferol.

Once the above initial conversion from the inactive to active completes, then enables a complex series of mineral metabolisms, specifically calcium and phosphorus may all begin which govern the Bone Remodelling processes known as Osteoclast (bone resorption) and Osteoblast (bone formation).

(Elaborate) Metabolism pathway.

In a more elaborate overview, in reference to an established source (Arnson Y et al 2007) :

1. The very first / initial exogenous precursor - 7-dehydrocholesterol forms within the skin upon exposure to the UVB Sunlight radiation.
2. 7-dehydrocholesterol then undergo its initial conversion to Cholecalciferol; the initial form of Vitamin D commonly found in supplemental form ~ dry, water soluble, or with fat as delivery vehicles (EVOO, PUFAs, etc).
3. Further conversions then begin, starting with
   1. "25 OHD" ~ the Calcidiol ~ an inactive but found readily in the plasma. This is not considered active until the enzyme 25(OH)D₃‐1‐α‐hydroxylase takes place in the kidneys to undergo the next conversion .
   2.  "1,25(OHD)" ~ the Calcitriol ~ is then formed by the above enzyme.
4. Mobilisation, storage, then Bone Remodelling. The active Calcitriol then circulates and binds via Vitamin D Binding Protein (or VDP for short) towards all Vitamin D  reception / docking sites throughout all tissues; effectively commences the complex Bone Remodelling process.

What / which genes / enzymes are responsible throughout Vitamin D metabolism?

A number of key genes thought responsible throughout Vitamin D metabolism are shared below. Be aware these are for preliminary reading only and remain subjected to further scrutiny as new information, understanding and/or research proceeds.

1. Early stage (Sunlight to Skin or food source to Liver) = 7-DHCR / 7-dehydrochoelsterol
2. Conversion (initial) = CYP2R1 / 25-hyrozxylase. 
3. Conversion (intermediary - conversion of 25OHD calcidiol into calcitriol in the kidneys, primarily) = CYP27B1 /1 alpha hydroxylase
4. Catabolism stage (inactivation and excretion of 25OHD to urine; from the kidneys) = CYP24A1 / 24-hyroxylase 
5. Storage / reception / mobilisation = Vitamin D binding protein and the Vitamin D receptor. 

Supporting Discussions

The following outlines various supplementary discussions, that despite seemingly general at first, some are quite nuanced in specific regards to other health implications of Vitamin D supplementations. Hence, this section may prove useful for readers, irrespective pre-acquainted or not with Vitamin D ~  may find some of these noteworthy.

Vitamin D & Immune Health

Given our state of the COVID19 pandemic, at least one definitive randomised trial strongly suggests Calcifediol (the main metabolite, not the precursor of Vitamin D) at eliminating all ICU / intensive care hospitalisation (Castillo ME et al. 2020). Other supporting evidences in favour of Vitamin D can be found for further readings at Vitamin D Wiki (vitamindwiki.com/calcidiol).

Glycation End Products & other lesser known health supporting roles

In addition to Vitamin D widely proclaimed calcium handling and bone health, there are other lesser known / or discussed roles as suggested by these correlative research on various mortality-risk-factors.

Firstly, supplementation appears to be protective against dietary glycation end products formation (Owusu J et al. 2020)*. For psychology ~ In a study involving mental illnesses, low 25OHD status seemed to correlcate with high prevalence of these illnesses  (Gracious BL et al 2012). Likewise In a study on sacropenia / age related muscle and bone health degradation, Vitamin D deficiency seems well correlated (Tanner BS & Harwell SA 2015).

*Interestingly, Owusu J et al. 2020 concluded that supplementing 4kIU Daily is less effective at mediating plasma AGEs; within first three months of the study. However until six months of supplementation is reached, this efficacy appears at its fullest. Hence this implies there may yet be some sort of acclimatising period and/or dosing consistency that is required to achieve said-protection.

Mineral absorption competitions.

It is unknown at this stage, or at least difficult to ascertain if there are mineral-to-fat soluble interactions which may prove detrimental. Of particular mention is that of potassium and copper depletion as briefly speculated in a recent lengthy debate (Deering K et al 2021).

The above concludes the interim Self-Meta of This Author (AW) pragmatic course of action. Despite all convictions, all of this certainly warrants for more re-examining, exploration and adjustments as future confounders unfolds.

Vitamin D “resistance” & Coimbra Protocol

Vitamin D “Resistance” as according to a cited research (Lemke D et al. 2021) refers to a disturbed feedback system between PTH / parathyroid hormone and the 25OHD. The causality behind appears to be that of a pathogen or infection related; hence "blocking" the effectiveness of how Vitamin D is being received or utilised in the organism. To overcome this, the research citation above succesfully indeed curates a number of successful findings by overcoming the blockade by very high or "supra-physiological dosage range beyond conventional guidelines.

The cited research (Lemke D et al. 2021) proclaimed successful records at treating Multiple Sclerosis patients in both Brazil and Germany; through a intervention method widely known as Coimbra protocol, alongside a calcium restricted diet. The amount supplemented in this protocol was up to 1000IU per kilogram of body weight supplementation ;which equates to 68,000-70,000 IU per day for a 68kg male.

The theory behind Vitamin D resistance was first proposed in 1937 by researchers Albright, Butler and Bloomberg when they were treating rickets by way of very high Vitamin D dosages. Generally speaking, when 25OHD are high, PTH levels should ideally be low. For context - "PTH" is primarily responsible for maintaining plasma calcium. PTH is raised when plasma calcium is low and consequently ~ a leaching of calcium from the bones becomes inevitable to maintain plasma calcium to meet physiological demands. In individuals with auto immune diseases however, it is the paradoxical feedback disturbance between the PTH and the 25OHD ~ in that PTH levels remain high despite Vitamin D supplementation. High PTH is believed to be associated with higher risk of death.

Other factors that contribute to this "Resistance" include but are not entirely restricted to ~ genetic polymorphism, environmental, ageing & seasonal factors. Genetic polymorphism suspects include CYP2R1, CYP231, CYP27A1, CYP27B1, CYP24A1 and the VDR receptors all appear to be prime suspects; according to the above cited research ~ the VDR is thought to be the most sensitive and “vulnerable” to manifest such a resistance. Environmental factors include toxicity coming from pathogens, and glucocorticoids. Lastly, ageing & seasonal factors refer to general  inactivity, sedentary lifestyles and a lack of sun exposure.

There is much more to be discovered and/or read in regards to this phenomenon. However due to the limited capacity of this Self-Meta, readers are encouraged to read in further detail at their own end.

Vitamin D Utilisation

This mini section is reserved for enlightening absorption, and synergy with other nutrients and minerals. Be aware however these are not in anyway defenitive but only at best for (preliminary) convenience insights. All discerning readers must exercise further research collating at their own end.

What other minerals or synergist factors are there to Vitamin D utilisation and/or absorption? 

So far, a comprehensive research review on micronutrient interactions (Watts, D. 1990) reports that:

1. Calcium
2. Magnesium
3. Potassium
4. Manganese
5. Sodium
6. Copper
7. Selenium
8. Vitamin B12
9. Vitamin E

All appears to be synergistic.

As far as toxicity management ~ Magnesium appears essential as it appears to help prevent hyperphosphatemia (a marker of hypercalcemia) as widely discussed amidst contexts of CVD / cardiovascular events (Sakaguchi Y. et al 2017).

Perhaps a rarely discussed trace mineral interaction (synergistic) worth mentioning is Boron (Pizzorno, L. 2015) & (Dessordi R & Navarro MA 2017). Found only amidst select foods particularly raisins, pitted dates, almonds and select nuts ~ Boron appears to inhibit the 24-hydroxylase enzyme; which is thought responsible for the catabolic (note: catabolism - inferring to excretion as indicated) reactions on the plasma 25OHD. This effectively means that Vitamin D retention, upon supplementation is enhanced.

What minerals that are anta-gonistic or those that conflicts with Vitamin D?

Acccording to the micronutrient interactions research (Watts, D. 1990)   Chromium, and Vitamin A are said to be antagonistic. Further research on these unfortunately appear rare and few. At the very least, only drugs - particularly pharmacological ones are ~ able at inhibiting select genes and/or enzymes responsible for the utilisation and conversions. These granular topics are beyond the scope of this Self-Meta.

What delivery vehicle factors does Vitamin D require for maximal their GIT (gut) absorption?

Vitamin D has been widely delivered in three common delivery methods as dry (powdered using gluten or cellulose),  lipid in various triglyceride formats (PUFA, MUFA and SFA) and ethanol (Grossman, R & Tangpricha V 2010). As general reminder, Vitamin D is lipophilic (meaning soluble in lipids) as this is required for its  activation  (Maurya KV & Aggarwal M 2017) . Furthermore as interest, the study shared a hypothesis that acidic pH, alongside enzymatic release usually associated with protein digestion ~ especially trypsin, Pepsin ~ both appears synergistic at supporting Vitamin D absorption in the GIT / Gastro intestinal tract.

The type of fats also appears an important confounder despite recent studies proclaiming mixed conclusions. One trial amongst senior subjects (Sathit Niramitmahapanya S et al 2011) finds that MUFA, compared to PUFA and SFA appears to improve the most in terms of Vitamin D absorption. However another found no appreciable difference in 25(OHD) status inbetween PUFA and MUFA dominant meal intakes during Vitamin D supplementation (Dawson, H  2014 et al).

Does Vitamin D affect sleep? Does timing of intake affect sleep quality?

Sleep issues / insomnia as possible side effects has been an under discussed topic, which some proclaim that Vitamin D supplementation during nighttime is adversely correlated to sleep quality compared to daylight. Unfortunately likewise ~ published literatures on these seem so far very few . Hence drawing any conclusion based on this scarcity of research may remain warranted, at least for now.

At the very least we have a number of reported anecdotes (1,2) proclaiming that Vitamin D do interfere with melatonin production; effectively meaning that it may affect certain individuals response to sleep quality especially when taken at night.

This remains WIP work in progress.

Waldemar Brandt @ Unsplash

The negative correlation between Calcium intake and 25OHD status : an unresolved paradox.

(WIP began 25th September)

Of the more perplexing nuances here in this Self-Meta is that a key observational finding (Jorde R & Grimnes G 2020) suggests an inverse associations on plasma (25-OHD) Vitamin D status with increasing ~ calcium intake. Meaning ~ that as dietary calcium increases, the 25OHD status decreases.

To add complexity ~ not all literatures share the same findings. A study examining Vitamin D enriched Gouda Cheese intakes on postmenopausal female subjects (Moschonis, G et al. 2021) suggests a positive correlation with 25OHD with the dietary intake, alongside beneficial reduction in PTH marker. And there are several internal references that the authors of our first cited research (Jorde R & Grimnes G 2020.) have collated for convenient surface / bird's-eye awareness on this subject.

As the authors conclude from the first citation (Jorde R & Grimnes G. 2020):

"It is difficult to find a plausible explanation for the mainly negative association between calcium intake and serum 25(OH)D. One could hypothesize that in a situation with a low calcium intake it would be important for the body to conserve its 25(OH)D stores and therefore reduce the 24-hydroxylation of 25(OH)D to the inactive 24,25(OH)₂D form. However, low calcium intake and thereby low serum calcium levels stimulate the PTH secretion which increases the renal 1-hydroxylation of 25(OH)D to the active form 1,25(OH)₂D which in turn increases the intestinal calcium absorption. This process cause removal of 25(OH)D from the circulation." ~ (Jorde R & Grimnes G. 2020)

One way we can extrapolate however, as both peace of mind and assurance for general view of nutritional science ~ is that strictly dietary, more so than supplemenetal form of calcium as accordingly to rigorous bird's eye view / systemic meta-analysis ~ has been favourably associated as protective against various mortality markers not necessarily confined to bone related metabolism; but far and reaching to that including Diabetes / insulin resistance (Hajhasphemy Z et al. 2022) and especially synergistic also with Potassium for specifically addressing diabetic retinopathy (Chen YY & Chen JY 2022). However the mechanistic explanations so far at enlightening the how or why ~ behind the above seemingly unresolved paradox of calcium intake's negative correlation to 25(OHD) status  remains unfortunately confusing and not always accessible for the lay yet enthusiast nutritional science audience.

To be continued on Part 3.

In the next part we will outline the a reserved discussion surrounding Autoimmunity, and how Vitamin D, on the basis of research reviews thus far, suggests their elusive importance.

Live-it-forward,

AW.