Glucose ingestion after an overnight fast triggers an insulin-dependent, homeostatic program that is altered in diabetes. The full spectrum of biochemical changes associated with this transition is currently unknown. We have developed a mass spectrometry-based strategy to simultaneously measure 191 metabolites following glucose ingestion. In two groups of healthy individuals (n¼22 and 25), 18 plasma metabolites changed reproducibly, including bile acids, urea cycle intermediates, and purine degradation products, none of which were previously linked to glucose homeostasis. The metabolite dynamics also revealed insulin's known actions along four key axesproteolysis, lipolysis, ketogenesis, and glycolysis-reflecting a switch from catabolism to anabolism. In pre-diabetics (n¼25), we observed a blunted response in all four axes that correlated with insulin resistance. Multivariate analysis revealed that declines in glycerol and leucine/isoleucine (markers of lipolysis and proteolysis, respectively) jointly provide the strongest predictor of insulin sensitivity. This observation indicates that some humans are selectively resistant to insulin's suppression of proteolysis, whereas others, to insulin's suppression of lipolysis. Our findings lay the groundwork for using metabolic profiling to define an individual's 'insulin response profile', which could have value in predicting diabetes, its complications, and in guiding therapy.

Studies examining the relationship between total circulating 25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD) have yielded mixed results. Vitamin D–binding protein (DBP), the major carrier protein for 25(OH)D, may alter the biologic activity of circulating vitamin D. We hypothesized that free and bioavailable 25(OH)D, calculated from total 25(OH)D, DBP, and serum albumin levels, would be more strongly associated with BMD than levels of total 25(OH)D. We measured total 25(OH)D, DBP, and serum albumin levels in 49 healthy young adults enrolled in the Metabolic Abnormalities in College-Aged Students (MACS) study. Lumbar spine BMD was measured in all subjects using dual-energy X-ray absorptiometry. Clinical, diet, and laboratory information also was gathered at this time. We determined free and bioavailable (free + albumin-bound) 25(OH)D using previously validated formulas and examined their associations with BMD. BMD was not associated with total 25(OH)D levels (r = 0.172, p = .236). In contrast, free and bioavailable 25(OH)D levels were positively correlated with BMD (r = 0.413, p = .003 for free, r = 0.441, p = .002 for bioavailable). Bioavailable 25(OH)D levels remained independently associated with BMD in multivariate regression models adjusting for age, sex, body mass index, and race (p = .03). It is concluded that free and bioavailable 25(OH)D are more strongly correlated with BMD than total 25(OH)D. These findings have important implications for vitamin D supplementation in vitamin D–deficient states. Future studies should continue to explore the relationship between free and bioavailable 25(OH)D and health outcomes.

Neuropeptide hormone oxytocin has roles in social bonding, energy metabolism, and wound healing contributing to good physical, mental and social health. It was previously shown that feeding of a human commensal microbe Lactobacillus reuteri (L. reuteri) is sufficient to up-regulate endogenous oxytocin levels and improve wound healing capacity in mice. Here we show that oral L. reuteri-induced skin wound repair benefits extend to human subjects. Further, dietary supplementation with a sterile lysate of this microbe alone is sufficient to boost systemic oxytocin levels and improve wound repair capacity. Oxytocin-producing cells were found to be increased in the caudal paraventricular nucleus [PVN] of the hypothalamus after feeding of a sterile lysed preparation of L. reuteri, coincident with lowered blood levels of stress hormone corticosterone and more rapid epidermal closure, in mouse models. We conclude that microbe viability is not essential for regulating host oxytocin levels. The results suggest that a peptide or metabolite produced by bacteria may modulate host oxytocin secretion for potential public or personalized health goals.

Binocular rivalry is a classic experimental tool to probe the neural machinery of perceptual awareness. During rivalry, perception alternates between the two eyes, and the ebb and flow of perception is modeled to rely on the strength of inhibitory interactions between competitive neuronal populations in visual cortex. As a result, rivalry has been suggested as a noninvasive perceptual marker of inhibitory signaling in visual cortex, and its putative disturbance in psychiatric conditions, including autism. Yet, direct evidence causally implicating inhibitory signaling in the dynamics of binocular rivalry is currently lacking. We previously found that people with higher GABA levels in visual cortex, measured using magnetic resonance spectroscopy, have stronger perceptual suppression during rivalry. Here, we present direct causal tests of the impact of GABAergic inhibition on rivalry dynamics, and the contribution of specific GABA receptors to these dynamics. In a crossover pharmacological design with male and female adult participants, we found that drugs that modulate the two dominant GABA receptor types in the brain, GABA A (clobazam) and GABA B (arbaclofen), increase perceptual suppression during rivalry relative to a placebo. Crucially, these results could not be explained by changes in reaction times or response criteria, as determined through rivalry simulation trials, suggesting a direct and specific influence of GABA on perceptual suppression. A full replication study of the GABA B modulator reinforces these findings. These results provide causal evidence for a link between the strength of inhibition in the brain and perceptual suppression during rivalry and have implications for psychiatric conditions including autism.

Keywords vitamin D; innate immunity; cathelicidin; hCAP18To the Editor:Cathelicidins are a class of widely conserved antimicrobial peptides (AMPs) produced by essentially all mammalian species as part of the innate immune system. They have broad activity against both Gram-positive and Gram-negative bacteria and have additional effects including neutralizing lipopolysaccharide, stimulating leukocyte chemotaxis, promoting angiogenesis. There is only one known cathelicidin in humans. Although it is found in the secondary granules of neutrophils and other leukocyte populations, and a range of squamous epithelia including the skin, airways, mouth and intestine, it also circulates at high levels in the plasma.1 , 2 Impairment in cathelicidin or other AMPs has been linked to increased susceptibility to and severity of infection while overexpression of cathelicidin confers protection against sepsis in animal models.3 Dialysis patients with the lowest circulating levels of cathelicidin are at a greater than two-fold risk of death due to infectious causes.4The transcription of CAMP, the gene encoding cathelicidin in humans, is regulated by the vitamin D receptor. In vitro studies of human tissues, including epithelial cells, macrophages, and neutrophils, have demonstrated that cathelicidin levels can be increased following administration of 1,25-dihydroxyvitamin D. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Estimated glomerular filtration rate (eGFR) was calculated using the widely-used Modification of Diet in Renal Disease formula. Spearman correlation was performed to assess the relationship between vitamin D and cathelicidin levels; as vitamin D associated relationships may emerge only below a threshold, levels ≤32 ng/ml and >32 ng/ml were analyzed separately. Multivariate linear spline regression (with an inflection point at 32 ng/ ml) was used to confirm this approach and multiple linear regression was used to adjust for potential confounders. Stata 11.1 (StataCorp, College Station, TX) was used for all analysis. NIH Public AccessSubject characteristics are detailed in table 1. Subjects were predominantly female and white, and all subjects had normal renal function (eGFR > 60 ml/min). Median levels of 25(OH)D and cathelicidin were 30 ng/ml and 698 ng/ml, respectively. A positive correlation between 25(OH)D and cathelicidin was evident at 25(OH)D levels ≤32 ng/ml (r=0.45, P=0.005) but not at higher levels (r=0.12, P=0.58). This relationship was verified using a piecewise polynomial (linear spline) regression with an infection point of 32 ng/ml. The linear relationship was ...