To identify the mechanism underlying the exaggerated hyperglycemia during exercise in the heat, six trained men were studied during 40 min of cycling exercise at a workload requiring 65% peak pulmonary oxygen uptake (VO2peak) on two occasions at least 1 wk apart. On one occasion, the ambient temperature was 20 degrees C [control (Con)], whereas on the other, it was 40 degrees C [high temperature (HT)]. Rates of glucose appearance and disappearance were measured by using a primed continuous infusion of [6,6-2H]glucose No differences in oxygen uptake during exercise were observed between trials. After 40 min of exercise, heart rate, rectal temperature, respiratory exchange ratio, and plasma lactate were all higher in HT compared with Con (P < 0.05). Plasma glucose levels were similar at rest (Con, 4.54 +/- 0.19 mmol/l; HT, 4.81 +/- 0.19 mmol/l) but increased to a greater extent during exercise in HT (6.96 +/- 0.16) compared with Con (5.45 +/- 0.18; P < 0.05). This was the result of a higher glucose rate of appearance in HT during the last 30 min of exercise. In contrast, the glucose rate of disappearance and metabolic clearance rate were not different at any time point during exercise. Plasma catecholamines were higher after 10 and 40 min of exercise in HT compared with Con (P < 0.05), whereas plasma glucagon, cortisol, and growth hormone were higher in HT after 40 min. These results indicate that the hyperglycemia observed during exercise in the heat is caused by an increase in liver glucose output without any change in whole body utilization.

Activation of the phosphatidylinositol 3-kinase (PI3K) plays an important role in the mitogenic response of many cell types. Recently, two serine/threonine kinases Akt and p70S6k have been identified as physiological targets of PI3K. Observations that expression of activated forms of Akt led to the activation of p70 S6k implied Akt might mediate mitogenic signaling through activation of p70S6k . To clarify the relationship between signaling through these two kinases, we have examined their regulation by various mitogenic stimuli. In this study we have focused on the role of calcium in the regulation of each kinase in Balb/c-3T3 fibroblasts. Depletion of intracellular calcium stores by EGTA pretreatment has no effect on growth factor-induced Akt activation but completely abolishes p70S6k stimulation. Increase of intracellular calcium induced by ionomycin or thapsigargin results in a full activation of p70S6k , whereas little or no activation of Akt is observed. Furthermore, although PI3K in anti-phosphotyrosine immunoprecipitates is only very weakly activated by ionomycin, the calcium-induced stimulation of p70 S6k is completely inhibited by the specific PI3K inhibitor wortmannin. We conclude Akt and p70S6k lie on separate signaling pathways. Activation of signaling to Akt is insufficient for the activation of p70 S6k , which can be achieved independently of Akt. p70S6k requires a separate calcium-dependent and wortmannin-sensitive process that is likely to be independent of type I A PI3K family members.

ScopeMicronutrients are in small amounts in foods, act in concert, and require variable amounts of time to see changes in health and risk for disease. These first principles are incorporated into an intervention study designed to develop new experimental strategies for setting target recommendations for food bioactives for populations and individuals.Methods and resultsA 6‐week multivitamin/mineral intervention is conducted in 9–13 year olds. Participants (136) are (i) their own control (n‐of‐1); (ii) monitored for compliance; (iii) measured for 36 circulating vitamin forms, 30 clinical, anthropometric, and food intake parameters at baseline, post intervention, and following a 6‐week washout; and (iv) had their ancestry accounted for as modifier of vitamin baseline or response. The same intervention is repeated the following year (135 participants). Most vitamins respond positively and many clinical parameters change in directions consistent with improved metabolic health to the intervention. Baseline levels of any metabolite predict its own response to the intervention. Elastic net penalized regression models are identified, and significantly predict response to intervention on the basis of multiple vitamin/clinical baseline measures.ConclusionsThe study design, computational methods, and results are a step toward developing recommendations for optimizing vitamin levels and health parameters for individuals.

The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia. Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene tetrahydrofolate reductase (MTHFR), cystathionine β synthase (CβS), transcobalamin 2 receptor (TCN2) and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric and cognitive disorders. However, the effects of these polymorphisms are often quite small and many studies failed to show any meaningful or consistent associations. This review discusses previous findings from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated polymorphisms must take into account not just traditional demographics, but subjects' overall diet, relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate behavioral effects or nutritional status.