Kynurenines and vitamin B6: link between diabetes and depression

The increased association between depression and diabetes mellitus is generally acknowledged. Recent studies suggest that depression leads to diabetes. However, the underlying molecular mechanisms for this association remain unclear. Literature and our data indicate that inflammatory and/or stress factors in depression up-regulate tryptophan (TRP) conversion into kynurenine (KYN), a substrate for nicotinamide adenine dinucleotide (NAD) biosynthesis. Deficiency of vitamin B6, a co-factor of the key enzymes of KYN – NAD pathway, shunts KYN metabolism from formation of NAD towards production of xanthurenic (XA) and kynurenic (KYNA) acids. Human and experimental studies reveal that XA, KYNA and their metabolites interfere with production, release and biological activity of insulin. We propose that inflammationand/or stress-induced up-regulation of TRP – KYN metabolism in combination with vitamin B6 deficiency is one of the mechanisms mediating increased risk of diabetes in depression. Consequently, monitoring formation of diabetogenic KYN derivatives might help to identify subjects-atrisk for the development of diabetes. Pharmacological down-regulation of the TRP – KYN – NAD pathway and maintenance of adequate vitamin B6 status might help to prevent the development of diabetes in depression and other conditions associated with inflammation/stress–induced excessive production of KYN and vitamin B6 deficiency, e.g., obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection. Oxenkrug Gregory F. goxenkrug@tuftsmedicalcenter.org Running title: Running title: kynurenines, B6, diabetes and depression Kynurenines and vitamin B6: link between diabetes and depression.


Introduction.
The increased association between depression and diabetes mellitus is generally acknowledged (1,2).
Observation of 65% increase risk for development of (mostly type 2) diabetes in a prospective study of clinically depressed patients (3) supports the hypothesis that depression leads to diabetes (4). Molecular mechanisms that mediate the increased risk of diabetes in depression remain undetermined although some hypotheses discussed elsewhere (2).
The possible mechanisms mediating XA contribution to the development of diabetes are 1). Formation of chelate complexes with insulin (XA-In). As antigens, XA-In complexes are indistinguishable from insulin but have 49% lower activity than pure insulin [28]; 2). Formation of Zn++-ions -insulin complexes in β-cells that exert toxic effect in isolated pancreatic islets [29,30]; 3).
Kynurenic acid. KYNA was found to be increased in urine of nonhuman primate and mouse models of type 2 diabetes mellitus in a recent metabolomic study [33], and in patients with diabetic retinopathy [27]. Plasma (serum) ratio of KYN to TRP (KTR) is a generally accepted clinical marker of IDO activity [14].   [58,59] (Fig.2).
Increased plasma neopterin levels were reported in depressed patients, further supporting the notion of IDO activation in depression [60].
Low plasma concentrations of P5P have been reported in depression (61). An increase in KTR and a deficiency in vitamin B6 might explain the increased production of XA in depressed patients (62).

Hepatitis C virus, depression and diabetes.
Depression is the often side-effect of interferon (IFN)alpha administration to patients with hepatitis C virus (HCV) infection. There is a strong correlation between increased production of KYN (and its derivatives) and severity of IFN-alpha-induced depression (63). We found an increased frequency of the carriers of high producer (T) allele, of IFNG(+874) T/A gene, that encodes production of IFNG protein, among HCV patients suffering from depression as a side-effect of IFN-alpha treatment (64). Serum neopterin concentrations were higher in HCV versus the non-HCV patient population [65] and predicted resistance to IFN-alpha therapy [66].
We found strong (r=0.68) and significant (p<0.0001) correlation between the serum KTR ratio and neopterin in 80 hepatitis C virus (HCV) patients treated with interferon-alpha [unpublished data].
Incidence of diabetes is higher among HCV patients than in non-HCV population [67]. HCV infection significantly lowers vitamin B6 levels [68]. IFN-alpha treatment was associated with increased risk of developing insulin resistance and higher incidence of type 2 diabetes in comparison with the groups of both non-viral chronic liver disease [69] and patients with chronic hepatitis B virus [70].   [74,75], and antidepressant, wellbutrin [76]. It is noteworthy that wellbutrin, contrary to tricyclic antidepressants, has a favorable metabolic profile [77]. The strongest IDO inhibitor is berberine, an isoquinoline alkaloid isolated from Berberis aristata, an herb widely used in Indian and Chinese systems of medicine [78]. Berberine exerts therapeutic potential in diabetic hamsters [79] and diabetic patients [80,81]. It is noteworthy that both berberine and minocycline prolonged life span and improved health span in the Drosophila model [82,83] aging , HCV and treatment with IFN-alpha [91]. It is noteworthy that pro-inflammatory activity of adipokines [92] and KYN production in white adipose tissue [93] has been reported along with higher plasma KTR in obese, but not lean, subjects [94].   Acknowledgements. GF Oxenkrug is a recipient of NIMH099517 grant.

Conflict of Interest Disclosure.
Paul Summergrad is a non-promotional speaker for CME outfitters, Inc., and consultant and non-promotional speaker for Pri-med, Inc.