Are Chronic Inflammation and its Metabolic Counterpart, Insulin Resistance, the Common Denominators for All Chronic Behavioral and Neurodegenerative Disorders? – A Review of the Evidence – Part VII

Depression – Its Connection with Chronic Inflammation, Vitamin B6 Depletion, Disturbances in Kynurenine Metabolism and Diabetes

In part VI of this series I ended with a discussion of the hypothesis by Oxenkrug (1, 2) that, when chronic inflammation combines with vitamin B6 deficiency, disturbances in kynurenine metabolism can ensue which can not only contribute to depression but type 2 diabetes. Does the author provide any clinical research to back up this hypothesis?  This evidence is provided in the paper “Increased plasma levels of xanthurenic and kynurenic acids in type 2 diabetes” by Oxenkrug (3).  Before discussing the research project described in this paper, though, I would like to point out a quote from this paper that reinforces the connection mentioned in previous installments of this series between stress, cortisol, chronic inflammation, and depression.  The papers I have discussed by Oxenkrug so far made no mention that the vitamin B6/chronic inflammation/kynurenine/diabetes/depression connection might be expanded to include stress and cortisol.  In the paper about to be discussed, the author demonstrates an intimate link that I have not discussed so far – the effect of cortisol on vitamin B6 metabolism in addition to all the factors previously mentioned that adversely affect B6:

“Stress hormones (e.g., cortisol) might cause P5P deficiency by activation of P5P phosphatase while inflammation induces P5P functional deficiency because of increased demand for P5P as a co-factor of more than 200 stress- or inflammation-induced enzymes.”

With the above in mind, Oxenkrug (3) expands his hypothesis about diabetes, vitamin B6, chronic inflammation, and kynurenine metabolism disturbances to include chronic stress:

“Thus, chronic stress and chronic low-grade inflammation directly activate enzymes of the upstream steps of the kynurenine pathway and divert downstream steps of the kynurenine pathway (due to P5P deficiency) from biosynthesis of NAD toward formation of diabetogenic downstream metabolites.  We proposed that resulting overproduction of diabetogenic kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, xanthurenic acid, and kynurenic acid is one of the mechanisms of chronic stress- or chronic low-grade inflammation-induced development of type 2 diabetes in pre-diabetes.”

This imbalance in the kynurenine pathway suggested to be common with diabetics is featured in the diagram below from the Oxenkrug (3) paper:

mnr01_2017jpgTo provide validation for this hypothesis, Oxenkrug (3) conducted a study where overnight fasting plasma samples were collected from 30 (18 female and 12 male) type 2 diabetes patients.  All were taking metformin.  24 (12 females and 12 males) healthy subjects acted as controls.  The diabetic subjects were 53.8 ± 8.3 years of age and the control subjects were 43.3 ± 10.9 years of age.

What were the findings of this study?  As you might expect from what has been stated thus far, some kynurenine pathway metabolites were elevated:

“Major findings of the present study are the increased plasma levels of kynurenine and downstream kynurenine metabolites, kynurenic acid and xanthurenic acid, in type 2 diabetes patients.”

These findings led Oxenkrug (3) to conclude:

“Our results provide further support of the ‘kynurenine hypothesis of insulin resistance and its progression to type 2 diabetes’ that suggested that overproduction of diabetogenic kynurenine pathway metabolites, induced by chronic stress or chronic low-grade inflammation, is one of the mechanisms promoting the development of type 2 diabetes from pre-diabetes.  Downstream metabolites of the kynurenine pathway might serve as biomarkers of type 2 diabetes and targets for clinical intervention.”


As I hope I have demonstrated, of all the micronutrients that are involved in inflammation/stress-induced disturbances in kynurenine metabolism, there is no question that, in terms of clinical relevance, vitamin B6 is the most important.  In addition, I feel the literature is clear that there is more to this story than what is generally assumed by most nutritional practitioners anytime micronutrient metabolism is considered – the problem is nothing more than a simple issue of poor dietary intake and/or poor digestion and absorption that can easily be resolved with a change in diet, supplements, and digestive support.  Therefore, I would now like to review two papers that examine the relationship between vitamin B6 and inflammation in depth.  As I hope you will see, chronic inflammation plays such a massive role in affecting vitamin B6 metabolism that, when chronic inflammation is present in significant amounts in any patient, optimizing dietary intake, digestion, and absorption alone, while important, will not be nearly enough.

The first paper I would like to review is “Evidence for increased catabolism of vitamin B-6 during systemic inflammation” by Ulvik et al (4).  The second paragraph provides an overview of research that points out vitamin B6 is significantly affected by disease and inflammation:

“A number of epidemiologic studies have shown reduced concentrations of circulating pyridoxal-5-phosphate (PLP) in association with chronic or acute disease.  Inverse associations have been shown between plasma PLP and the acute phase marker C-reactive protein but also to a wider panel of inflammatory markers.  Most evidence points to an altered tissue distribution as the main mechanism, whereas no conclusive evidence have been provided for increased catabolism.  Recently, we noted positive associations between 4-pyridoxic acid (PA) and 2 markers of T-helper 1 type immune activation neopterin and kynurenine:tryptophan ratio (KTR) both before and during vitamin B-6 treatment.  These results suggest an increased catabolism of vitamin B-6 during activated cellular immunity.”

The next quote goes into detail about the relationship between increased kynurenine pathway activity due to inflammation-induced increased IDO activity and vitamin B-6:

“The enzyme indoleamine 2,3-dioxygenase (IDO) converts tryptophan to kynurenine in hematopoietic and epithelial tissue.  On stimulation of inflammatory signals, most importantly interferon-g, IDO activity increases, leading to an increase in KTR in plasma.”

The study featured in this paper involved 2628 adults in Norway who had clinically diagnosed CVD.  Both inflammatory markers and markers of vitamin B-6 status were measured.  The vitamin B-6 markers were pyridoxal (PL), pyridoxal-5-phosphate (PLP), and the main catabolite of PLP, 4-pyridoxic acid (PA).

As determined by the ratio of PA to the sum of PL + PLP (PA:PL + PLP), it was found that catabolism of vitamin B-6 was significant in presence of elevated levels of several inflammatory markers, which include CRP, WBC, neopterin, and the kynurenine:tryptophan ratio (KTR).  These findings led Ulvik et al (4) to conclude:

“Broad-specificity enzymes upregulated to reduce oxidative and aldehyde stress could explain increased catabolism of vitamin B-6 during inflammation.  The ratio PA:(PL + PLP) may provide novel insights into pathologic processes and potentially predict risk of future disease.”

The second paper I would like to feature, “Inflammation, vitamin B6 and related pathways” by Ueland et al (5) provides a much more detailed overview of the impact of inflammation on vitamin B-6.  It begins with an interesting discussion on the basics of vitamin B-6 metabolism, pointing out a function of the vitamin about which I was not aware:

“As well as functioning as a co-factor, vitamin B6 has been described as a scavenger of reactive oxygen species, metal chelator and chaperone in the enzyme folding process.”

The next quote provides additional detail as to the specific impact of inflammation on vitamin B-6 metabolism:

“…inflammation leads to a marked reduction in plasma PLP, and small changes in erythrocyte PLP; both plasma and erythrocyte PLP show a minor response to pyridoxine supplementation, whereas PL increases markedly.  These observations suggest that depletion of PLP is confined to certain compartments, an idea supported by the results obtained in rats with adjuvant arthritis, which caused a marked reduction in PLP in liver and plasma, but not in muscle.  Plasma PLP probably reflects the vitamin B6 status in liver, which contains a rapidly exchanging PLP pool that is mobilized via circulation to the sites of inflammation.”

Of course, as I have repeatedly discussed in this series, cortisol production is intimately intertwined with inflammation.  Because of this, it would be natural to expect that increases in cortisol production due to various stressors would also have an impact on vitamin B-6 metabolism.  In agreement, Ueland et al (5) state:

“Cortisol has widespread effects in the body and is the main regulator of the physiological stress response including the upregulation of gluconeogenesis and degradation of protein in muscle, gut, and connective tissue.  The liberated amino acids may then be utilized for energy production, synthesis of immunomodulating proteins, immune cell proliferation, and tissue repair.  All of these processes require, and may therefore increase the cellular demand for PLP.  Moreover, an increase in intracellular PLP has been implicated in the modulation of the cell’s response to glucocorticoids.  Glucocorticoids may have profound effects on vitamin B6 metabolism and distribution as demonstrated in mice given long-term prednisone treatment.  Prednisone induced an increase in plasma PLP, PL and PA.”

Next I would like to feature a quote that provides an in depth explanation of the impact of depleted vitamin B-6 status on the kynurenine pathway:

“It has been consistently demonstrated that the concentrations of kynurenines in urine and plasma/serum are affected by vitamin B6 status in humans.  Vitamin B6 deficiency caused a more than 30-fold increase in urinary excretion of xanthurenic acid, kynurenine, and 3-hydroxykynurenine after a tryptophan load in women.  There was also a moderate increase in urinary 3-hydroxyanthranilic acid and quinolinic acid.  Supplementation of subjects having adequate vitamin B6 status with parenteral nutrition decreased urinary excretion of xanthurenic acid, kynurenine and 3-hydroxykynurenine after a tryptophan load, suggesting that PLP-dependent enzymes of the kynurenine pathway may not be fully saturated with the PLP cofactor.”

Before continuing, please note again the last sentence in the above quote.  For it suggests that, even though patients appear to possess “adequate” levels of vitamin B6, they may not possess optimal levels that would be sufficient to make the kynurenine pathway optimally functional.  Therefore, while excessive supplementation of vitamin B6 needs to be avoided due to concerns of the creation of neuropathies, if your patient appears to be borderline sufficient, it may be wise to consider additional intake in the form of supplementation.

The next quote discusses how metabolites of the kynurenine pathway can be viewed as indicators of vitamin B6 status:

“Urinary excretion of xanthurenic acid after a tryptophan load and the plasma 3-hydroxykynurenine/xanthurenic acid ratio have been established as functional markers of vitamin B6 status…”

As many of you know, urinary xanthurenic acid is measured on organic acids profiles that are available from several functional medicine labs.

In concluding their paper, Ueland et al (5) summarize the massive impact that inflammation and immune dysregulation has on vitamin B6 metabolism:

“Published results demonstrate that inflammation, immunoactivation and related diseases are associated with up to 50% reduction in plasma PLP, and minor changes in erythrocyte PLP and functional vitamin B6 biomarkers.  Low plasma PLP parallels reduction in liver PLP, whereas vitamin B6 in muscle is not affected.  Vitamin B6 intake or supplementation improves some immunological parameters in vitamin B6-deficient animals and humans.  The available results demonstrate that inflammatory conditions are linked to a tissue-specific alteration in vitamin B6 distribution.  These changes may reflect mobilization of vitamin B6 to the site of inflammation, but existing human or experimental data cannot distinguish between inflammation inducing localized vitamin B6 deficiency and deficiency promoting inflammatory processes; both mechanisms may actually be involved.”


When we think of vitamin B3 supplementation, for most of us niacin comes to mind because of its well documented impact on total, LDL, and HDL cholesterol.  Interestingly, even though it does not create a flushing effect like niacin, niacinamide supplementation has no impact on these cholesterol fractions.  Therefore, we rarely hear about use of niacinamide supplementation clinically.  This is indeed unfortunate since several papers, including those I am about to review, have documented the clinical value of niacinamide supplementation.  A general overview of the impact of niacinamide supplementation was provided by Rennie et al in their paper “Nicotinamide and neurocognitive function” (6):

“Nicotinamide has anti-inflammatory effects and has been used in clinical dermatology at doses of ~1.5g/day as a steroid-sparing agent in autoimmune blistering dermatoses such as bullous pemphigoid.  It has also shown some efficacy in acne and rosacea, atopic dermatitis, and skin photoageing.  Nicotinamide also has a range of photoprotective effects on the skin.  Repair of ultraviolent (UV)-induced DNA damage in skin is a highly energy-intensive process, and nicotinamide enhances DNA repair in cultured human keratinocytes and ex vivo human skin.  A likely mechanism of action in this setting is that nicotinamide replenishes adenosine triphosphate (ATP) or cellular energy in keratinoctyes after UV exposure.  DNA damage is also a key trigger of the immune suppressive, and hence tumour-promoting, effects of UV radiation on the skin, and nicotinamide has been found to prevent UV-induced immune suppression in the skin of healthy volunteers.  Two randomized, double-blinded controlled trials have found that nicotinamide at doses of 500 or 1000 mg daily reduces premalignant actinic keratosis and may prevent non-melanoma skin cancers in humans.

Nicotinamide has a well-established safety profile with few or no side effects at these doses.  At doses beyond ~3.5 g/day, however, there are isolated reports of reversible hepatotoxicity.” 

In addition, as noted above, unlike niacin supplementation, there is no flushing effect seen with niacinamide supplementation:

“The vasodilatory side effects seen with nicotinic acid, such as flushing, hypotension, and headache, are not observed with nicotinamide.”

Another significant body of research has also demonstrated that niacinamide supplementation is effective in inhibiting the powerful endogenously produced pro-oxidant substance poly (ADP-ribose) polymerase (PARP).  An overview of this effect was discussed by Kao et al in their study “Niacinamide abrogates the organ dysfunction and acute lung injury caused by endotoxin” (7):

“Niacinamide is a compound of the soluble B complex.  It exerts inhibitory effects on the poly (ADP-ribose) synthase (PARS) or poly (ADP-ribose) polymerase (PARP).  The nuclear enzyme can be activated by strand breaks in DNA caused by reactive oxygen species and peroxynitrite.  PARP is cytotoxic by massive depletion of intracellular nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate (ATP).  Inhibition of PARP activity reduces the ischemia-reperfusion injury of the heart, skeletal muscle, and brain.”


“The inhibitory effects of niacinamide or its related substances, nicotinamide and nicotinic acid, on the PARP activity are protective to cell damage caused by oxidative stress.”

Specifically in relation to its impact on tryptophan metabolism and the kynurenine pathway, Prousky states the following in his paper “Vitamin B3 for depression: Case report and review of the literature” (8):

“Niacinamide…alters tryptophan metabolism to increase serotonin synthesis while limiting the formation of ‘kynurenines.'”

Schrocksnadel et al (9), in their review paper on inflammation and kynurenine metabolism entitled “Monitoring tryptophan metabolism in chronic immune activation” go into more detail about how niacinamide supplementation can reduce the amount of tryptophan that goes down the kynurenine pathway by inhibiting indoleamine 2,3-dioxygenase (IDO) activity:

“An alternative strategy is to increase the tryptophan pool via supplementation with nicotinamide to suppress IDO activity. In patients with HIV infection, treatment with nicotinamide was found to increase plasma tryptophan concentration by 40% with no major side effects. As such, administration of nicotinamide might provide a valuable strategy to counteract tryptophan depletion by IFN-gamma-stimulated IDO in cells.”

The reference for the above quote is a paper entitled “Increased plasma tryptophan in HIV-infected patients treated with pharmacologic doses of nicotinamide” by Murray (10).  In this review paper, plus an earlier study published by the author (11), it is pointed out that HIV infected patients tend to demonstrate high levels of the pro-inflammatory cytokine interferon-g.  This, in turn, leads to an upregulation of the kynurenine pathway, which results in decreased plasma tryptophan and increased levels of the endpoint metabolite of the kynurenine pathway, niacin/niacinamide.  With this in mind, the author theorized that the increase in niacin/niacinamide production is an adaptogenic mechanism designed to actually slow down excessive tryptophan metabolism down the kynurenine pathway:

“Previous studies have shown that alterations in plasma tryptophan inversely correlate with markers of inflammation (e.g., neopterin) and oxidative metabolites of tryptophan (e.g., kynurenine).  The conclusion of other investigators, that plasma tryptophan is diminished in HIV-infected individuals because of interferon-g-induced indoleamine-2,3-dioxygenase, provides a potential mechanism for diminished tryptophan.  Our hypothesis, that tryptophan is diminished due to the shunting of tryptophan to niacin along the oxidative pathway in response to HIV-induced intracellular pellagra, suggests a potential homeostatic strategy.  These two concepts are easily integrated.”


“Elevated serum niacin levels in the presence of depleted tryptophan, serotonin, and NAD suggest that maintaining niacin levels is a metabolic priority in HIV-infected individuals.”

With the above in mind, Murray (10) hypothesizes that niacin/niacinamide supplementation might inhibit the primary enzyme that drives the kynurenine pathway, IDO:

“…niacin might feedback to inhibit excessive tryptophan oxidation by IDO in the same way as niacin can inhibit TDO.”

To test this hypothesis, Murray et al (11) supplemented HIV-infected patients with tablets containing 500 mg of niacinamide at a dose of two tablets three times per day for a period of two months.  The results were the following:

“There was an average 40% increase in plasma tryptophan in the four HIV-infected individuals who completed the 2-mo protocol.  This finding was specific in that four other amino acids, which have been shown to have significant plasma concentration alterations during HIV infection (i.e., cystine, methionine, taurine, and lysine), showed no significant change with nicotinamide therapy.”

In the paper “Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements” by Badawy (12, additional comments are offered concerning the clinical benefits of the high dose niacinamide supplementation utilized in the Murray {Murray MF, 2003 #2395) study, mainly in relation to the ability of niacinamide supplementation to suppress both IDO, as mentioned above, plus the other enzymatic driver of the kynurenine pathway TDO:

“This TDO inhibition results in increased serum tryptophan availability and enhancement of cerebral serotonin synthesis.  Nicotinamide can also reverse the glucocorticoid induction of TDO in rats during withdrawal of drugs of dependence and the resultant decreases in plasma tryptophan and brain serotonin synthesis.  Thus, nicotinamide can reverse the effects on plasma tryptophan of glucocorticoid induction of TDO and cytokine induction of IDO.”


With the above in mind, when considering the use of nutritional supplementation to optimize kynurenine metabolism in patients at risk for either behavioral or neurodegenerative conditions, both vitamin B6 and vitamin B3 in the form of niacinamide should be at the top of the list.  However, other supplemental and over-the-counter options exist, as noted by Schrocksnadel et al (9):

“It is interesting to note that the non-steroidal anti-inflammatory drug aspirin is capable of slowing tryptophan degradation at least in vitro.  Extracts of Hypercium performatum appear to act in a similar way and are used as an herbal remedy with antidepressant activity.”

 Another supplemental option that should come as no surprise since it is a tryptophan metabolite is melatonin.  Oxenkrug (1) states:

“Potential pharmacological interventions in at risk subjects…may include…:

“…administration of methoxyindoles (melatonin and N-acetylserotonin) that inhibit kynurenine formation from tryptophan and modulate the tryptophan-kynurenine pathway due to their inhibitory effect on production of cortisol…and proinflammatory cytokines.  Methoxyindoles (melatonin, in particular) might attenuate excitatory, glutamate-mediated responses triggered by kynurenine pathway metabolites.”

In “Kynurenines and vitamin B6: link between diabetes and depression” by Oxenkrug et al (2) it is pointed out that one of the most powerful inhibitors of IDO is berberine:

“The strongest IDO inhibitor is berberine, an isoquinoline alkaloid isolated from Berberis aristata, an herb widely used in Indian and Chinese systems of medicine.  Berberine exerts therapeutic potential in diabetic hamsters and diabetic patients.”

Concerning berberine and IDO inhibition, it is interesting to note that, according to Oxenkrug (13) in his paper “Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways,” berberine has a stronger IDO suppressant activity than the powerful pharmaceutical IDO inhibitor l-methyl-L-tryptophan:

“Berberine…inhibits IDO significantly stronger than l-methyl-L-tryptophan.”


As mentioned above, melatonin supplementation may be helpful in suppressing kynurenine pathway activity due to its anti-inflammatory effects.  In the paper “Increased IL-6 trans-signaling in depression: focus on the tryptophan catabolite pathway, melatonin and neuroprogression” by Anderson et al (14), more information on the relationship between melatonin and the kynurenine pathway is presented.  As an introduction, though, recall that melatonin is a tryptophan metabolite that is produced as a conversion byproduct from serotonin.  Also recall that, despite all the negative statements I have been making about the kynurenine pathway in this series, it is extremely vital to optimal human physiology for many reasons, not the least of which is that it leads to production of vitamin B3.   Therefore, the problem with behavioral and neurodegenerative disorders is not that the kynurenine pathway exists at all but that, due to chronic inflammation, it is hyperfunctioning.  Thus, the optimal goal is balance which, even in the face of significant metabolic imbalance, human physiology makes every effort to maintain.  One way it tries to maintain balance is the little known fact that, as noted by Anderson et al (14), serotonin production actually leads to production of inflammatory mediators that increase kynurenine activity:

“Serotonergic activation of the astrocyte serotonin-7r can also lead to the release of IL-6, which suggests that serotonergic activation of astrocytes, in addition to providing a substrate for melatonin and N-acetylserotonin synthesis, also contributes to local IDO and tryptophan catabolites (TRYCAT) induction.  Thus, IL-6 has local as well as systemic effects on the regulation of TRYCATs and tryptophan availability, respectively.”

However, as has been suggested repeatedly, prolonged release of a powerful inflammatory mediator such as IL-6 will eventually lead to depletion of serotonin and its metabolites, contributing to depression.  Anderson et al (14) point out:

“The loss of melatonin and N-acetylserotonin due to wider IL-6-induced IDO is also important to depression associated processes, including the decreased neurogenesis that is evident in depression.  Melatonin and N-acetylserotonin, as well as serotonin, increase neurogenesis.”

It is interesting to note that, in fact, serotonin and its metabolites, and melatonin in particular, act as adaptogens, depending on whether inflammatory mediator production needs to be stimulated or depressed.  As mentioned above, when needed, serotonin can stimulate inflammatory activity.  However, as noted in the quote below, when needed, metabolites of serotonin can attenuate inflammatory responses:

“The local production of melatonin and N-acetylserotonin is thought to be a major modulator of local inflammatory responses.  Melatonin and N-acetylserotonin, via their induction of prosurvival pathways and mitochondrial oxidative phosphorylation, are protective against oxidative and nitrosative stress, cell-mediated immunity and TRYCAT-driven neuronal toxicity.  Given that melatonin increases a non-inflammatory phagocytic phenotype in phagocytic cells, such as monocytes and macrophages, local decreases in melatonin may then contribute to heightened local inflammatory responses in depression.”

Unfortunately, prolonged inflammation that leads to upregulation of IDO will eventually upset the inflammatory balance that melatonin and N-acetylserotonin are able to maintain, thus contributing to depression:

“As such, IL-6-induced IDO may alter local melatonin and N-acetylserotonin regulation of inflammatory processes that are crucial to the local biological underpinnings of depression, as well as to the regulation of neurogenesis.”

With the above in mind, Anderson et al (14) conclude:

“By systematically contributing to IDO and TRYCATs, IL-6 may decrease levels of serotonin, melatonin and N-acetylserotonin production, thereby impacting key immune-inflammatory processes that underpin depression and associated conditions.  The plethora of data linking increased IDO and kynurenine/tryptophan ratio to depression/somatization and neurodegenerative disorders may then be closely linked to the regulation of IL-6 induced local and systemic IDO.”

So far in this series, I have been primarily discussing the impact of inflammation on neurologic disorders.  Given that the main title of this series also refers to insulin resistance, you may wonder why the only mention of insulin resistance so far has been in this and the previous installment in relation to vitamin B6.  Well, the time has come to speak expansively on insulin metabolism. In the next installment I will be addressing insulin metabolism in relation to the one neurologic illness in our society that is talked about as much as depression, and maybe even more if fear of disease is taken into account: senile dementia/Alzheimer’s disease.  As you will see, there exists a massive volume of research that not only suggests senile dementia/Alzheimer’s disease has an inflammatory basis, as has been discussed in previous installments, but also has a critical and vastly under-appreciated relationship with insulin metabolism.  In fact, in many research circles the relationship between senile dementia/Alzheimer’s disease and insulin is considered so important that senile dementia/Alzheimer’s disease has been referred to as “Type III diabetes.”      

Moss Nutrition Report #272 – 01/01/2017 – PDF Version


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