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 VI
10/01/2016 - MNR Newsletter #271
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 VI
DEPRESSION - DOES RESEARCH THAT DOWNPLAYS THE KYNURENINE PATHWAY CONNECTION IN FACT REFLECT SUBOPTIMAL NUTRIENT STATUS?
Much of part V of this series focused on research which provided strong support for the hypothesis that chronic inflammation creates depression via alterations in tryptophan metabolism that redirect tryptophan away from serotonin and melatonin production and towards the kynurenine pathway and neuroexcitatory and neurodestructive metabolites such as quinolinic acid that are products of this pathway. However, while the body of research supporting this connection is immense, it is not unanimous. What follows next is a review of some of the research that downplays the idea that disturbances in tryptophan metabolism that lead to upregulation of the kynurenine pathway have a significant relationship to depression. After that I will review some fascinating research that suggests the papers arguing against the depression/kynurenine pathway connection are flawed because of a variable that was not controlled for in the populations studied, nutritional status. As you will see, nutritional status, in fact, has a massive impact on both kynurenine metabolism and clinical depression.
RESEARCH SUGGESTING THERE IS NO CONNECTION BETWEEN DISTURBANCES IN KYNURENINE METABOLISM AND DEPRESSION
The first study I would like to review is "Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms?" by Quak et al (1). In their introduction the authors make three important qualifying points about the nature of the research that had been performed previous to this study that was used to prove the kynurenine/depression connection. First, most of the research has been animal studies. In the quote below that makes this point, indoleamine 2,3-dioxygenase (IDO), the key enzyme involved in the kynurenine/depression connection, is mentioned. The second qualifying point also made in the quote below that may even be more significant is the fact that virtually all the human studies that have supported the connection were not performed on individuals with pre-existing, chronic depression. Rather, the human studies establishing the connection were based on the impact of a side effect of the pro-inflammatory pharmaceutical interferon-alpha (IFN-α) therapy, an effect that may not necessarily be easily extrapolated to ongoing clinical depression:
"...to date, most of the evidence on the role of IDO was based on animal studies or on human studies in which depression was artificially induced by pro-inflammatory IFN-α therapy."
The third qualifying point is that some of the supportive human research was based on extrapolations from healthy populations:
"A first population based study in healthy young adults showed that IDO-activity was associated with depressive symptoms."
Next the authors make the somewhat surprising revelation that there exists no previous studies that were performed on real-life patients suffering from clinical depression:
"...as far as we know, no previous study has assessed a large group of depressed subjects or actually examined whether IDO-activity mediates the association between inflammatory markers and depressive symptoms."
As you can see, Quak et al (1) are not questioning the connection between inflammation and depression. What they are questioning is whether the effect is mediated by disturbances in kynurenine metabolism.
In this study 2812 individuals aged 18-65 years residing in the Netherlands were evaluated. Of the 2812 individuals, 1042 had been diagnosed with major depressive disorder. To determine the connection between depression, inflammation, and kynurenine metabolism, fasting blood levels of c-reactive protein (CRP), interleukin-6 (IL-6), tumor-necrosis factor alpha, kynurenine (KYN) and tryptophan (TRP) were measured.
What were the findings? As expected based on previous research, a link was seen between inflammatory markers and depressive symptoms. In addition, a link between inflammatory markers and the kynurenine:tryptophan ratio (KYN/TRP) was noted:
"In the present analysis we found, in addition to a replication of the...association between the inflammatory markers CRP and IL-6 and depressive symptoms, also an association between these inflammatory markers and KYN/TRP."
However, the authors could not establish a direct connection between all three - inflammatory markers, the KYN/TRP ratio, and depression:
"However, there were no significant indirect effects for CRP or IL-6 on depressive symptoms mediated by KYN/TRP. Thus, we could not confirm our hypothesis that KYN/TRP, which an estimation of IDO-activity, mediates the association between inflammatory markers and depressive symptoms, neither in the whole sample, nor in the subpopulation with current major depressive disorder (MDD)."
In fact, contrary to expectations of a high KYN/TRP ratio in the MDD group, the ratio was actually lower:
"There was a small, but significant, difference between KYN/TRP between patients with current MDD and the other participants, however contrary to our expectation the current MDD group had lower KYN/TRP ratio indicating lower IDO-activity in the depressed group."
What might explain the fact that kynurenine metabolism was lower in the current MDD group? One possible explanation is the use of SSRI antidepressants:
"Antidepressants explained the lower KYN/TRP in current depressed patients..."
Interestingly, use of tricyclic antidepressants (TCA) was associated with a higher KYN/TRP ratio:
"...opposed to that, higher ratio of KYN/TRP were found in TCA users."
What is the mechanism underlying the impact of the medications on the KYN/TRP ratio? The authors suggest:
"The first effect can be related to the antidepressant induced down regulation of the enzyme tryptophan 2,3-dioxygenase (TDO) in the liver. TDO is an enzyme that like IDO degrades tryptophan to kynurenine and therefore contributes to the KYN/TRP ratio. Antidepressant induced down regulation of TDO might subsequently lead to higher tryptophan and lower kynurenine levels and thus to a lower KYN/TRP ratio. In TCA users we found increased KYN/TRP ratio. This can be explained by the increased levels of inflammation reported for TCA users, which might induce IDO activity and thus increased KYN/TRP levels."
Given that close to 25% of the study population was ingesting antidepressant medication, it should be readily apparent, despite the findings of this study that there is no connection between depression and increased levels of kynurenine metabolism, the study cannot be considered in any way conclusive in terms of disproving the kynurenine depression connection.
The next study I would like to review is "Ongoing episode of major depressive disorder is not associated with elevated plasma levels of kynurenine pathway markers" by Dahl et al (2). This study, conducted in Norway, evaluated 50 MDD patients who were not on medication at the beginning of the study and 34 healthy controls. The study was divided into two parts:
· In the first part, the activity of the kynurenine pathway as assessed by key kynurenine metabolites and the KYN/TRP ratio was considered in both the MDD and control groups.
· In the second part, the 50 MDD patients were re-evaluated in relation to kynurenine metabolites after 12 weeks of therapy where therapy differed from patient to patient in terms of different types of medications. Furthermore, some patients were treated with non-medication modalities.
What were the results? For the first part of the study, even though the MDD patients had higher levels of inflammatory mediators at baseline compared to controls, there was no difference in the KYN/TRP ratio or levels of various kynurenine metabolites. Furthermore, while there was a relationship between the KYN/TRP ratio and levels of inflammatory mediators in the healthy controls, there was no consistent relationship between the KYN/TRP ratio and levels of inflammatory mediators in the MDD patients. This led Dahl et al (2) to conclude:
"The main finding of the present study is that the kynurenine pathway activity, as assessed by the plasma KYN/TRP ratio, was not significantly increased in depressed patients relative to healthy controls."
Our findings indicate that the biological mechanisms underlying MDD are likely to be different from those involved in cytokine-therapy induced depression and other subtypes of depression (such as suicidal depression), where the kynurenine pathway is activated by inflammation."
"The obtained results do not support the hypothesis that MDD depressive episodes are associated with elevated activity in the kynurenine pathway. This suggests that the pathophysiology underlying depressive episodes in common MDD differs from that of interferon induced depression."
Of course, on the surface, these findings seem very neat, clean and obvious. The dozens and maybe hundreds of studies suggesting a relationship between depression, inflammation, and kynurenine pathway disturbances, according to the authors, are wrong. However, one finding disturbs me that suggests there is more to this issue than what was suggested by Dahl et al (2). Why was the KYN/TRP ratio and levels of inflammatory mediators correlated in the healthy controls in contrast to the complete lack of correlation in the MDD patients? No answer was provided by the authors other than the suggestion that there is something different about MDD patients where tryptophan metabolism and inflammatory processes are not related. What is that "something different"? Could it be the uncontrolled variable of poor nutritional status, which is certainly more likely to be seen in the MDD patients as opposed to the healthy controls? Nowhere in the study do Dahl et al (2) mention that tryptophan is an essential nutrient that must be obtained from the diet. Therefore, if tryptophan intake is suboptimal, there will be an impact on the KYN/TRP ratio that is entirely independent of inflammatory mediator levels. In addition, as I will be discussing, several micronutrients, especially B vitamins such as vitamin B6, are intimately involved in kynurenine metabolism and could certainly affect the KYN/TRP ratio.
Even more disturbing are some of the findings in the second part of the study that bring considerable doubt to the conclusion of the authors that there is no connection between the kynurenine pathway activity and MDD. After the MDD group was treated for 12 weeks, which included various pharmaceutical and non-pharmaceutical modalities depending on the patient, the KYN/TRP ratio and certain kynurenine pathway metabolites actually increased from baseline despite a significant reduction in depressive signs and symptoms:
"The plasma levels of kynurenine and kynurenic acid in the MDD group were significantly increased from baseline; there was also a tendency toward an elevation of the KYN/TRP ratio, but the difference did not reach statistical significance."
If MDD is not connected with disturbances in kynurenine metabolism, as claimed by the authors, there should have been no change in kynurenine metabolite levels or the KYN/TRP ratio after treatment. Of course, as suggested by the Quak et al(1) study reviewed above, these findings could be caused by the medications employed, which were primarily SSRIs. However, as I have also suggested, in my opinion, there may be an uncontrolled variable that is affecting all of the findings in the study.
This uncontrolled variable of nutrient deficiency was specifically mentioned in the next study I am about to review which reports a lack of association between kynurenine metabolism and behavioral disorders, "Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects" by Coccaro et al (3). Based on much of the research I have already reviewed in this series, the authors expected to find a relationship between behavioral dysfunction, in this case intermittent explosive disorder (IED), increased inflammation, and disturbances in kynurenine metabolites with a specific increase in the KYN/TRP ratio:
"In this study, we sought to test the hypothesis that the elevated levels of inflammatory markers observed in impulsive aggressive subjects with intermittent explosive disorder (IED) would be associated with induction of IDO enzymes and, thus, associated with a reduction in circulating TRP, an increase in KYN, and variable differences in kynurenic acid (KA) and quinolinic acid (QA). In addition, we hypothesized that measure of life-time history trait aggression and/or trait impulsivity would correlate with TRP, KYN, KA, and picolinic acid (PA)."
(Picolinic acid is also a kynurenine metabolite)
The study was conducted on 52 subjects who met the criteria for IED, 56 subjects who had non-IED psychiatric illness, and 64 subjects with no evidence of any diagnosed psychiatric illness. Plasma levels of inflammatory mediators, TRP, and the kynurenine metabolites KYN, KA, QA, and PA were determined in all the study participants. What were the findings? Coccaro et al (3) point out:
"Despite the presence of a heightened inflammatory process among subjects with IED, plasma levels of TRP, KA, and PA were no different from that in healthy controls. In contrast, plasma levels of KYN were reduced in subjects with IED compared with healthy control subjects and levels of QA were reduced in IED compared with both control groups."
As noted in the quote below, these findings are the opposite of what Coccaro et al (3) expected:
"In this study, we report that elevated circulating inflammatory markers in IED subjects were associated with normal levels of TRP and reduced levels of KYN and QA metabolites, opposite to our initial hypothesis."
To explain these findings, the authors suggest several possible uncontrolled variables, one of which is nutritional status:
"...we did not collect data relevant to nutritional intake. While we have no reason to suspect differences in this regard, it is widely known that tryptophan intake is linked to plasma and brain tryptophan levels and that deficiency of pyridoxine (vitamin B6) can interfere with the breakdown of kynurenine."
In the next section of this installment I will be discussing the large body of research that makes a very strong case that Coccaro et al (3) were quite justified in their concerns that nutritional deficiency could skew research data on the relationship between behavioral disorders, inflammation, and kynurenine metabolites.
THE INTIMATE RELATIONSHIP BETWEEN NUTRITIONAL STATUS AND KYNURENINE METABOLISM
To introduce this discussion, please consider the following overview statement from the paper "Overview of the role of vitamins and minerals on the kynurenine pathway in health and disease" by Majewski et al (4):
"There is mounting evidence that L-tryptophan metabolism depends on the adequate availability of both vitamins and minerals which work as cofactors and coenzymes in metabolic reactions. L-tryptophan is an 'essential' amino acid for mammals, as they cannot make it themselves. Therefore, they must obtain it in the form of food."
The next set of quotes from this paper provide much more detail on the relationship between nutrient status and kynurenine metabolism. First, consider the following:
"The evidence presented in this paper suggests that the kynurenine pathway (KP) is highly sensitive to changes in the concentration of B group vitamins (B2, B6) as well as micro- (Fe3+, Mn2+, Zn2+, Cu2+, Co2+) and macro-elements (Mg2+). Both vitamins and minerals can work as coenzymes and cofactors in de novo synthesis of another B-vitamin niacin."
Next Majewski et al (4) point out:
"Minerals and B group vitamins at physiological concentrations can either directly up-regulate and/or down-regulate the activity of enzymes engaged in L-tryptophan metabolism. Vitamin B6 was found to be the most crucial vitamin engaged in L-tryptophan metabolism, since it is involved in the proper functioning of the serotonin pathway enzyme tryptophan hydroxylase, and the kynurenine pathway enzymes kynureninase (KYNU) and kynurenine aminotransferase (KAT)."
The next quote points out what I have been discussing concerning the allostatic load approach to chronic illness: that other lifestyle stressors can have an additive impact when combined with nutrient deficiency:
"Nutrient deficiencies plus coexisting physiological processes may have hyper-additive effects on biological systems, thus causing increased harmful effects. In other words, in alcoholics, people experiencing decreased food intake, and during high physical activity when the needs are increased, the concentration of L-tryptophan in the diet is not sufficient."
Factors that affect tryptophan availability for the kynurenine pathway
Of course, as suggested above, vitamin and mineral cofactors are important considerations and will be addressed in more detail later in this installment. However, quite obviously, the first consideration in determining levels of kynurenine metabolites is the availability of tryptophan. As I have suggested above, this is a crucial factor that has not been addressed by several researchers who have been examining the relationship between behavioral disorders, inflammation, and kynurenine metabolites. Fortunately, one researcher, Badawy, has examined this important issue in depth in the paper "Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, diet and nutritional supplements" (5).
To begin this discussion, consider the intricacies of tryptophan availability to various tissues and organs:
"Trp exists in plasma or serum largely bound to albumin, with only 5-10% freely and immediately available for uptake by tissues and organs."
"Trp availability for the kynurenine pathway (KP) therefore is a function of free Trp and a detailed assessment of this parameter is thus important. Free Trp is a labile parameter that can be influenced by many factors, including nutritional, hormonal, psychological and pharmacological agents."
In addition, there are gender considerations:
"Gender analysis of 54 males and 60 females shows a 31% higher free Trp and 15% lower total Trp in females. Accordingly, females have a 53% higher % free Trp, suggesting that Trp availability in general may be higher in females."
Another interesting variable that may be overlooked by researchers is the time of day blood samples are collected:
"That plasma Trp exhibits diurnal variations illustrates the need to define and consider the implications of the time point(s) at which determinations are performed. In humans, plasma Trp is at its lowest at 2-4 am, but rises by 50-80% to a plateau by late morning/early afternoon."
Why the diurnal variations?
"The above authors suggested that these changes are not the result of cyclical ingestion of dietary proteins and, although they are not truly circadian, they are of nutritional origin."
The next quote considers the impact of drugs and chemicals on tryptophan metabolism:
"Many drugs and other chemicals increase plasma free Trp by increasing non-esterified fatty acids (NEFA). Examples include adrenaline, noradrenaline, sympathomimetic amines and phosphodiesterase inhibitors, such as methylxanthines. By contrast, plasma free Trp is decreased by antilipolytic agents, e.g. insulin, naloxone, nicotinic acid and propranolol. Under these conditions, Trp availability for the KP can be expected to be impaired, with the exception of cerebral uptake after insulin."
The next quote considers the impact of one of the most frequently used drugs, aspirin:
"When displacement of Trp from albumin-binding sites by certain drugs, e.g. salicylate, or by a large increase in NEFA is strong and sustained, the increased tissue uptake of Trp in conjunction with the rapid equilibration between free and bound fractions causes significant decreases in total Trp."
Therefore, as I hope you can see, in accordance with allostatic load principles, all lifestyle stressors need to be considered when evaluating the relationship between behavioral disorders, inflammation, and kynurenine metabolism.
The kynurenine pathway and nutrient deficiency in detail
Next Badawy (5) looks at the relationship between nutrient deficiency and kynurenine metabolism in detail. First, consider protein intake which is often deficient in patients suffering from all chronic illnesses including behavioral disorders:
"Deficient protein intake clearly results in low plasma Trp and hence its availability."
As mentioned above, B vitamin deficiencies play a particularly important role in kynurenine metabolism:
"Deficiencies of B2 and B6, but not B1, exert profound effects on enzymes of the KP with clinical consequences and led Theofylaktopoulou et al. to suggest B2 and B6 as determinants of kynurenines and markers of IFN-gamma-mediated immune activation."
What about exercise?
"Plasma free Trp is elevated after exercise in both man and rat. This is caused by elevation of NEFA following enhanced lipolysis by adrenal medullary catecholamines. The elevated free Trp increases Trp availability to the brain, thereby enhancing serotonin synthesis, as shown in rats and potentially also for the cerebral KP."
What about age?
"In humans...plasma total Trp is moderately (~12%) lower in the elderly. Decreases range between 0 and 32% in males and 0-38% in females."
Thus, as I hope you can see, diet and numerous lifestyle factors can affect tryptophan availability and metabolism in the kynurenine pathway. Furthermore, these numerous lifestyle variables provide a more than adequate explanation why research on the level of involvement of the kynurenine pathway in various behavioral and neurodegenerative disorders will yield sometimes unpredictable findings when these variables are not controlled for in the study methodology. Therefore, I continue to be convinced of the veracity of the vast preponderance of studies that strongly support the hypothesis that chronic inflammation and its impact on tryptophan metabolism via the kynurenine pathway plays a major role in contributing to behavioral and neurodegenerative disorders despite the negative studies reviewed above.
The kynurenine pathway and B vitamins
As suggested above, of all the nutrients involved in kynurenine metabolism, it appears that B vitamins are the most important from a clinical standpoint, particularly vitamins B2, B3, and B6. What follows is a review, which will be concluded in the next installment, of several studies that discuss the relationship of these three B vitamins with kynurenine metabolism not only in terms of basic biochemistry and physiology but in terms of clinical application where B vitamin supplementation might be of value in improving behavioral symptomatology.
The first paper I would like to review is one that examines the relationship between vitamins B2 and B6 and the kynurenine pathway, "Vitamins B2 and B6 as determinants of kynurenines and related markers of interferon-gamma-mediated immune activation in the community-based Hordaland Health study" by Theofylaktopoulou et al (6). The first quote that I would like to feature from this paper makes it clear that, while important, we need to look beyond inflammation when considering factors that influence kynurenine metabolism:
"Factors other than inflammation may also influence tryptophan catabolism through the kynurenine pathway. Vitamins B2 and B6, in the form of flavin adenine dinucleotide (FAD) and pyridoxal 5'-phosphate (PLP), respectively, are cofactors for enzymes in this pathway. The conversion of kynurenine to 3-hydroxykynurenine by kynurenine mono-oxygenase requires FAD, whereas PLP is a cofactor for the conversion of kynurenine to anthranilic acid, and 3-hydroxykynurenine to 3-hydroxyanthranilic acid, both catalyzed by kynureninase, as well as for the conversion of kynurenine to kynurenic acid, and 3-hydroxykynurenine to xanthurenic acid, catalyzed by kynurenine aminotransferase."
The next quote points out research on clinical correlations supporting the idea that vitamins B2 and B6 have a major involvement in kynurenine metabolism:
"Early studies have described altered excretion of kynurenines in the urine during vitamin B2 or B6 deficiency. Increased excretion of xanthurenic acid in the urine following a tryptophan loading test has been used as a measure of vitamin B6 deficiency. More recently, a study in patients with stable angina pectoris has shown that plasma PLP was associated with several kynurenines, and suggested that plasma 3-hydroxykynurenine as well as substrate product ratios including kynurenines are potential metabolic markers of functional B6 status."
Can these clinical findings be extrapolated to the general population? To answer this question Theofylaktopoulou et al (6) evaluated 7051 residents of Norway. 3727 participants were aged 46-47 years and 3324 participants were aged 70-72 years. 45% of the participants were men. The findings of this study are as follows:
"The present study demonstrates that plasma concentrations of vitamins B2 and B6 are determinants of several kynurenines, in a large sample of apparently healthy individuals. The results confirm previous observations that PLP is inversely related to plasma 3-hydroxykynurenine, but positively associated with other kynurenines. In addition, it is shown that the association between plasma 3-hydroxykynurenine and PLP is independent of riboflavin, an observation that strengthens the case of 3-hydroxykynurenine as a metabolic marker of functional B6 status. For the first time, it is shown that the metabolites downstream of 3-hydroxykynurenine; xanthurenic acid and 3-hydroxyanthranilic acid, were positively related to riboflavin, with riboflavin and PLP acting as interactive determinants of xanthurenic acid."
These findings led the authors to conclude the following:
"These results demonstrate the significance and complexities of vitamin B2 and B6 status in the kynurenine pathway. Our findings motivate the incorporation of measurements of vitamin B2 and B6 status in the increasing number of epidemiological studies assessing the role of the kynurenine pathway in health and disease development."
Of these two B vitamins and their relationship with the kynurenine pathway, though, the one that has probably received the most attention is vitamin B6. This is largely due to the work of one of the early researchers looking at the relationship between the kynurenine pathway and depression, Gregory Oxenkrug, whose publications I mentioned earlier in this series. In fact, as you will see in the review of one of his papers that follows, his work on vitamin B6 has led him to conclude that the relationship between the kynurenine pathway, vitamin B6 and depression can be extended to include diabetes. This interesting relationship was explored in depth in the paper "Kynurenines and vitamin B6: link between diabetes and depression" by Oxenkrug et al (7).
The authors begin this paper by pointing out the often under-appreciated connection between depression and diabetes:
"The increased association between depression and diabetes mellitus is generally acknowledged. Observation of 65% increased risk for development of (mostly type 2) diabetes in a prospective study of clinically depressed patients supports the hypothesis that depression leads to diabetes."
What might be one of the most important factor underlying this relationship? The authors suggest vitamin B6 and its involvement with the kynurenine pathway:
"Vitamin B6 depletion results in drastic increase while vitamin B6 supplementation normalizes urinary 3-hydroxykynurenine and xanthurenic acid after tryptophan load in cardiac and obese patients and rats. The other consequence of P5P deficiency-induced down-regulation of kynureninase is the decreased formation of NAD that subsequently inhibits synthesis and secretion of insulin and triggers death of pancreatic beta-cells."
Clinically, the connection between disturbances in the kynurenine pathway involving increased production of xanthurenic acid and diabetes has been demonstrated via urine testing:
"Xanthurenic acid (XA) was the first kynurenine metabolite to be observed in the increased amounts in the urine samples of type 2 diabetes patients in comparison with healthy subjects."
Therefore, when disturbances in the kynurenine pathway also involve vitamin B6 deficiency and not just inflammation, both depression and diabetes can be the outcome. However, the underlying cause of both depression and diabetes is a more interesting and a bit more complicated than just a simple issue of vitamin B6 deficiency. In what way? Xanthurenic acid is not just an inert metabolite that just indicates vitamin B6 deficiency. In fact, xanthurenic acid itself has a major adverse impact on insulin metabolism. Therefore, it appears that the exact nature of the connection as it relates to vitamin B6 is that deficiency of vitamin B6 leads to disturbances in kynurenine metabolism and increases in xanthurenic acid production. In turn, increased xanthurenic acid adversely affects insulin metabolism, increasing the risk for diabetes. Oxenkrug elaborates on this point in the paper "Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders" (8):
"Increased XA might contribute to the development of insulin resistance by formation of chelate complexes with insulin (XA-In). XA-In complex in antigenetically indistinguishable from insulin but its activity was 49% lower than activity of pure insulin. In addition, XA might exert toxic effect in isolated pancreatic islets because of formation of complexes with Zn2+-ions in β-cells.
Since enzymatic formation of quinolinic acid and picolinic acid from 3-hydroxykynurenine requires vitamin B6 as a cofactor, deficiency of vitamin B6 results in increased formation of XA in the expense of quinolinic acid and picolinic acid formation. Inflammation-associated increased formation of kynurenine from tryptophan might lead to excessive production of XA in a B6 deficient population (e.g., elderly) and, considering the diabetogenic effect of XA, might cause and/or contribute to the development of insulin resistance. Combination of B6 deficiency in chronic inflammation with increased production of kynurenine and 3-hydroxykynurenine in depression might contribute to the increased incidence of diabetes in depressed patients."
Therefore, the suggestion made by Oxenkrug is that, when chronic inflammation combines with vitamin B6 deficiency (which may happen more often then we may expect, as I will demonstrate in the next installment of this series) even with optimal dietary intake of B6, chronic inflammation can cause vitamin B6 deficiency. Not only is depression a likely outcome but also profound disturbances in insulin metabolism.
What I have just described can be seen diagrammatically in the figure on page 9 that comes from the Oxenkrug paper (8).
In part VII of this series I will continue my review of Oxenkrug's research on the relationship between vitamin B6 deficiency and chronic inflammation and their impact on kynurenine metabolism, insulin dysregulation and depression. I will also discuss additional research on the important relationship between nutritional status, chronic inflammation, kynurenine metabolism, and behavioral and neurodegenerative disorders.
1. Quak J et al. Does tryptophan degradation along the kynurenine pathway mediate the association between pro-inflammatory immune activity and depressive symptoms? Psychoneuroendocrinology. 2014;45:202-10.
5. Badawy AAB. Tryptophan availability for kynurenine pathway metabolism across the life span: Control mechanisms and focus on aging, exercise, die and nutritional supplements. Neuropharmacology. 2015;Published online ahead of print.
6. Theofylaktopoulou D et al. Vitamins B2 and B6 as determinants of kynurenines and related markers of interferon-gamma-mediated immune activation in the community-based Hordaland Health Study. Br J Nutr. 2014;112:1065-72.
8. Oxenkrug GF. Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders. Journal of Neural Transmission. 2010;118(1):75-85.