Pharmacogenetics Meets Metabolomics: Discovery of Tryptophan as a New Endogenous OCT2 Substrate Related to Metformin Disposition

Genetic polymorphisms of the organic cation transporter 2 (OCT2), encoded by SLC22A2, have been investigated in association with metformin disposition. A functional decrease in transport function has been shown to be associated with the OCT2 variants. Using metabolomics, our study aims at a comprehensive monitoring of primary metabolite changes in order to understand biochemical alteration associated with OCT2 polymorphisms and discovery of potential endogenous metabolites related to the genetic variation of OCT2. Using GC-TOF MS based metabolite profiling, clear clustering of samples was observed in Partial Least Square Discriminant Analysis, showing that metabolic profiles were linked to the genetic variants of OCT2. Tryptophan and uridine presented the most significant alteration in SLC22A2-808TT homozygous and the SLC22A2-808G>T heterozygous variants relative to the reference. Particularly tryptophan showed gene-dose effects of transporter activity according to OCT2 genotypes and the greatest linear association with the pharmacokinetic parameters (Clrenal, Clsec, Cl/F/kg, and Vd/F/kg) of metformin. An inhibition assay demonstrated the inhibitory effect of tryptophan on the uptake of 1-methyl-4-phenyl pyrinidium in a concentration dependent manner and subsequent uptake experiment revealed differential tryptophan-uptake rate in the oocytes expressing OCT2 reference and variant (808G>T). Our results collectively indicate tryptophan can serve as one of the endogenous substrate for the OCT2 as well as a biomarker candidate indicating the variability of the transport activity of OCT2

The Relationship between Body Mass Index and Mental Health Among Iraq and Afghanistan Veterans

BACKGROUND: Obesity is a growing public health concern and is becoming an epidemic among veterans in the post-deployment period. OBJECTIVE: To explore the relationship between body mass index (BMI) and posttraumatic stress disorder (PTSD) in a large cohort of Iraq and Afghanistan veterans, and to evaluate trajectories of change in BMI over 3 years. DESIGN: Retrospective, longitudinal cohort analysis of veterans’ health records PARTICIPANTS: A total of 496,722 veterans (59,790 female and 436,932 male veterans) whose height and weight were recorded at the Department of Veterans Affairs (VA) healthcare system at least once after the end of their last deployment and whose first post-deployment outpatient encounter at the VA was at least 1 year prior to the end of the study period (December 31, 2011). MAIN MEASURES: BMI, mental health diagnoses. KEY RESULTS: Seventy-five percent of Iraq and Afghanistan veterans were either overweight or obese at baseline. Four trajectories were observed: “stable overweight” represented the largest class; followed by “stable obese;” “overweight/obese gaining;” and “obese losing.” During the 3-year ascertainment period, those with PTSD and depression in particular were at the greatest risk of being either obese without weight loss or overweight or obese and continuing to gain weight. Adjustment for demographics and antipsychotic medication attenuated the relationship between BMI and certain mental health diagnoses. Although BMI trajectories were similar in men and women, some gender differences were observed. For example, the risk of being in the persistently obese class in men was highest for those with PTSD, whereas for women, the risk was highest among those with depression. CONCLUSIONS: The growing number of overweight or obese returning veterans is a concerning problem for clinicians who work with these patients. Successful intervention to reduce the prevalence of obesity will require integrated efforts from primary care and mental health to treat underlying mental health causes and assist with engagement in weight loss programs. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11606-013-2374-8) contains supplementary material, which is available to authorized users

Functional oligosaccharides: application and manufacture.

Oligosaccharides are attracting increasing interest as prebiotic functional food ingredients. They can be extracted or obtained by enzymatic hydrolysis from a variety of biomass sources or synthesized from simple oligosaccharides by enzymatic transfer reactions. The major prebiotic oligosaccharides on the market are inulin, fructo-oligosaccharides, and galacto-oligosaccharides. They have been evaluated using a range of in vitro and in vivo methods, although there is a need for more large-scale human trials using modern microbiological methods. Prebiotics are being studied for their effects on gut health and well being and specific clinical conditions, including colon cancer, inflammatory bowel disease (IBD), acute infections, and mineral absorption. Developing understanding of the functional ecology of the human gut is influencing current thinking on what a prebiotic might achieve and is providing new targets for prebiotic intervention