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Xanthurenic Acid, Kynurenic Acid, Liver Function, and Blood Sugar Control.

The prevalence of metabolic syndrome (insulin resistance) and type II diabetes in the US population continues to increase and predisposes individuals to other diseases, including chronic inflammation, cardiovascular disease, kidney disease, depression, and dementia. (1,2) Early detection of insulin and blood sugar dysregulation is essential to prevent disease progression. (3) A better understanding of the liver's role in blood sugar balance and energy metabolism may allow clinicians to better interpret "early warning" laboratory results such as urinary xanthurenic and kynurenic acid. (4,5) The addition of both xanthurenic and kynurenic acid to a 24-hour urine or dried urine hormone profile may provide valuable clinical information about a patient's metabolic status. (6)

Disruption of the tryptophan-kynurenine pathway may result in elevations of xanthurenic acid (XANA) and kynurenic acid (KYNA), which may cause a decrease in liver nicotinamide adenine dinucleotide (NA[D.sup.+]) synthesis. (5) High levels of XANA and/or low levels of NA[D.sup.+] may alter the function of the liver and pancreas and result in damage to these organs. (7-9) This damage, combined with a Western diet and sedentary lifestyle, may contribute to metabolic syndrome, non-alcoholic fatty liver disease, type II diabetes, and other inflammatory disorders. It is vitally important to confirm a disruption in NAD+ synthesis prior to supplementing with niacin (vitamin B3), as high levels of the nicotinamide metabolite [N.sup.1]-methylnicotinamide may also contribute to the development of insulin resistance. High levels of this metabolite may accumulate during the consumption of a Western diet (meats and fortified grain products) or the accumulation may be due to inherited variation or acquired inhibition of the enzyme aldehyde oxidase (AOX1; riboflavin, molybdenum). (10)

The Tryptophan-Kynurenine Pathway

The tryptophan-kynurenine pathway controls tryptophan availability for serotonin synthesis in the gastrointestinal tract and the central nervous system. (5,11,12) The pathway also controls hepatic heme synthesis and disposes of excess tryptophan absorbed from the gut. The kynurenine pathway metabolizes tryptophan and produces immunoregulatory and neuroactive metabolites. The pathway also supplies quinolinic acid for the synthesis of niacin (as nicotinic acid) and the co-factor nicotinamide adenine dinucleotide (NA[D.sup.+]).

The rate of flux down the tryptophan-kynurenine pathway is determined first by the level of free circulating tryptophan and then by the activity of the enzymes tryptophan 2,3-dioxygenase (TDO2; heme) in the liver and indoleamine 2,3-dioxygenase 1 and 2 (IDO1, IDO2; heme) elsewhere in the body (Figure 1). (13-15) During homeostasis, the primary site of kynurenine pathway activity is the liver, where all of the enzymes to metabolize tryptophan into NA[D.sup.+] and NAD[P.sup.+] are found. In a healthy state the liver accounts for about 90% of tryptophan metabolism. Systemic metabolism of tryptophan via IDO increases when the immune system is activated, or when pro-inflammatory cytokines are present. When tryptophan metabolism is shifted to IDO in the periphery, NA[D.sup.+] may not be produced because not all of the pathway enzymes are found outside the liver. It is possible that these incomplete IDO-induced pathways outside the liver contribute to higher circulating levels of XANA, KYNA, and neurotoxic quinolinic acid.

Xanthurenic Acid, Kynurenic Acid, and Blood Sugar Regulation

Early detection and laboratory testing are important to prevent or reverse the progression of non-alcoholic fatty liver disease (NAFLD), metabolic syndrome and type II diabetes. (16) Routine screening for blood sugar dysregulation includes fasting blood sugar and hemoglobin A1c. Additional testing, such as the post-prandial insulin (Kraft/Hayashi) assay may improve the detection of insulin resistance, and urinary xanthurenic and kynurenic acids may provide further clinical insight (see Figure 2). (17) XANA and KYNA provide information regarding nutritional status, blood sugar regulation, and the capacity of the tryptophan-kynurenine pathway to synthesize NA[D.sup.+]. (5,18) Importantly, both XANA and KYNA must be evaluated for a complete analysis. (19) The comparison of XANA and KYNA values may provide insight as to the nature of the pathway dysregulation and the application of corrective therapies. (6)

KYNA and/or XANA may be formed when tryptophan is metabolized down the kynurenine pathway. Briefly, through a series of enzymatic steps, tryptophan is normally converted into kynurenine, then to 3-hydroxykynurenine via kynurenine 3-monooxygenase (KMO; B2, NAD[P.sup.+]), then 3-hydroxyanthranilic acid is formed by kynureninase (KYNU; B6), and proceeds down the pathway to become either acetyl-coA, picolinic acid or quinolinic acid, which is further converted into NA[D.sup.+] through another series of enzymatic steps. (5,11,12,20,21) If the pathway is blocked at either the KMO or the KYNU enzyme step, then the metabolites are shunted through a different set of enzymes and are instead converted into XANA and/or KYNA. If XANA and KYNA are synthesized instead, there is little substrate for NAD+ synthesis further down the pathway. (7)

KMO is dependent upon two cofactors, one is synthesized from vitamin B2 (riboflavin); the other cofactor is niacin-derived NA[D.sup.+] itself, in the phosphorylated form NAD[P.sup.+]. If an individual is deficient in either riboflavin or niacin, KYNA will elevate and XANA will be low. (19) Obesity is a known risk factor for both metabolic syndrome and type II diabetes. (22) Early evidence from human white blood cells indicates that obesity and inflammation may dysregulate the kynurenine pathway and increase the activity of KMO, elevating KYNA levels and lowering XANA levels. (18)

KYNU is a vitamin B-6 dependent enzyme, and it is the enzyme most sensitive to low B-6 levels in the kynurenine pathway. (5) The inhibition of KYNU may occur due to either clinical or sub-clinical B-6 deficiency. Such a deficiency may occur due to the presence of diabetes, chronic inflammatory disease, celiac disease, smoking, or alcohol use. (23) Nutritional requirements for B-6 (pyridoxine or pyridoxal 5'-phosphate) may be increased by the use of certain medications (oral contraceptives, isoniazid, hydralazine, benserazide, penicillamine, phenelzine, cycloserine, thiamphenicol carbidopa, etc.). (11,23) KYNU may also be inhibited by high levels of exogenous estrogens (oral birth control, bioidentical or synthetic hormone replacement) and the endogenous high estrogens of pregnancy. (24-27) The inhibition of KYNU elevates both XANA and KYNA. (5) High levels of XANA have toxic effects in pancreatic islets and can bind to insulin, decreasing its activity at insulin receptors. High urinary XANA levels have been associated with metabolic syndrome, gestational and type II diabetes in human studies. (5,25)

The primary signals regulating the kynurenine pathway are Cortisol and inflammatory cytokines, although the other hormones also contribute to kynurenine pathway signaling. Elevated Cortisol and inflammation are also common in metabolic syndrome, type II diabetes and NAFLD. (28-30)The effects of hormonal regulation become apparent during menopause, when estrogen levels decline, signaling pathways shift, inflammation increases, and more tryptophan is diverted down the peripheral kynurenine pathway. (5) Aging and menopause are associated with an increased incidence of insulin resistance. During menopause interferon gamma levels increase and induce peripheral IDO activity. (31) While the flux down the pathway increases, KYNU activity is partially inhibited, which may elevate both XANA and KYNA levels.

NA[D.sup.+], Liver Function, and Blood Sugar Regulation

The liver plays an important role in blood sugar regulation; it converts excess carbohydrate into glycogen for storage and metabolizes glycogen to glucose as needed for release into the circulation. (4,32) Excess dietary carbohydrates may also be converted into fatty acids and stored in the liver. The liver breaks down glucose for energy; NA[D.sup.+] is an essential cofactor for the synthesis of adenosine triphosphate (ATP) during cellular respiration. Low levels of NA[D.sup.+] affect blood sugar balance and regulation by preventing normal cellular respiration, which impairs liver functions. (7)

NA[D.sup.+] is an essential compound in the body; it is required for normal mitochondrial function, energy production from the tricarboxylic acid (TCA) cycle, and fatty acid oxidation. More recently, NA[D.sup.+] has been recognized as a signaling molecule in cells. (33) NA[D.sup.+] is a cofactor in DNA repair and a variety of biochemical processes, including insulin secretion, which is regulated by four separate NA[D.sup.+]-dependent signaling mechanisms. Evidence is accumulating that increasing age, combined with a sedentary lifestyle, high-fat diet and decreasing NA[D.sup.+] levels may play a role in the induction of nonalcoholic fatty liver disease. NAFLD, in humans, is strongly associated with the presence of metabolic syndrome and type II diabetes. (32)

The liver also regulates circulating tryptophan levels by synthesizing NA[D.sup.+] from dietary tryptophan; in the periphery, cells cannot synthesize NA[D.sup.+] but can recycle metabolized NA[D.sup.+] with the enzyme nicotinamide phosphoribosyltransferase (NAMPT; nicotinamide ribonucleotide). (7,34) NAMPT is the rate-limiting enzyme for cellular NA[D.sup.+] levels because it controls both NA[D.sup.+] recycling and the conversion of quinolinic acid (from the tryptophan-kynurenine pathway) into NA[D.sup.+]. Increasing age decreases both NAMPT expression and levels of NA[D.sup.+] in animal and human studies. Lower levels of NA[D.sup.+] increase cellular oxidative stress, disrupt cellular signaling, and impair mitochondrial function because the mitochondria must synthesize or recycle most of their NA[D.sup.+] independently. (33,34) In a recent study, subjects over 60 years old had, on average, 30-35% less NA[D.sup.+] in surgical liver samples compared to 45-year-olds. (7) In concurrent mouse studies, the investigators also observed that lower NAMPT expression both induced NAFLD and worsened diet-induced fatty liver inflammation. Other animal studies have also shown that high-fat diets decrease NAMPT expression and NA[D.sup.+] levels. The pancreas is also NA[D.sup.+] dependent. Increasing NA[D.sup.+] levels have decreased inflammation in experimentally-induced pancreatitis (animal studies). (9) Other avenues of research are targeting NAMPT activity and NA[D.sup.+] recycling as factors in pancreatic cancer. (8)

Human and animal studies both demonstrate that supplementation of NA[D.sup.+] precursors may restore intracellular NAD+ levels. (35) Several precursors may enter the NA[D.sup.+] synthesis or recycling pathways at different points: nicotinamide, nicotinic acid, nicotinamide riboside, and nicotinic acid riboside are all referred to as "niacin" or vitamin B3. (34) Of these different forms, NAMPT has high affinity for nicotinamide, and it is the form used by cells during NA[D.sup.+] recycling. Tryptophan may also be converted into NA[D.sup.+] in the liver, but the rate of exchange is high: 60 milligrams of tryptophan are required to synthesize one milligram of niacin equivalent. (36) Some individuals may not be able to use nicotinamide or nicotinic acid due to inherited or acquired cell dysfunctions. Animal and early human studies indicate that, in such cases, nicotinamide riboside may improve cellular NA[D.sup.+] status. (37,38) It may be important to recall that a true niacin deficiency (inherited or acquired) will present with symptoms of the skin, digestive tract and nervous system: diarrhea, sun-sensitive dermatitis, and neurological symptoms (headache, apathy, fatigue, depression, disorientation, and memory loss). (36)

Niacin has long been recognized as an effective cholesterol therapy in cardiovascular disease but is not often considered in the treatment of other medical conditions. (39) It is, perhaps, time to routinely consider B vitamin and NAD+ status in patients with other chronic inflammatory disorders such as metabolic syndrome and type II diabetes. Laboratory analysis of xanthurenic and kynurenic acids is available and may be used to evaluate the activity of the tryptophan-kynurenine NAD+ synthesis pathway. Early detection of low NA[D.sup.+], metabolic syndrome, type II diabetes, and fatty liver disease may prevent the progression of these reversible metabolic disorders into irreversible disease.

References

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by Andrea Gruszecki, ND

Andrea Gruszecki, ND, received her BA in ecology and evolutionary biology from the University of Connecticut, where she was exposed to a variety of research projects; her own research project examined the effects of diurnal cycles on Poeciliopsis species. Trained as a Radiologic Technologist and Army medic, she spent the years prior to graduation working in urgent care and hospital settings, gaining valuable clinical experience. She received her Doctorate in Naturopathy from Southwest College of Naturopathic Medicine. Upon her graduation from SWCNM, she worked with patients at the Wellness Center in Norwalk, Connecticut, before starting her own naturopathic practice.

Her experiences in private practice evolved into an inclusive model of medicine for use by conventional and CAM providers, designed to allow cross-specialty communication among health care providers ("Forward into the Past: Reclaiming Our Roots Through an Inclusive Model of Medicine." NDNR eNewsletter, June 2013). She has presented at a variety of venues, including the American Academy of Environmental Medicine, Integrative Medicine for Mental Health, International College of Integrative Medicine, and the California Naturopathic Doctors Association.

Dr. Gruszecki is a member of the consulting department at Meridian Valley Laboratory, where she may provide interpretive assistance with laboratory results, write interpretations, and create conference presentations.
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