However, in the lipid infusion arm, glucose values were no different, but insulin levels did not fall over the course of the study visit. This is consistent with a greater requirement for insulin to maintain euglycemia following the standardized meal, consistent with peripheral insulin resistance. Formal assessment of peripheral insulin resistance,

using clamp techniques, was not performed in this study as demonstration of peripheral insulin resistance would not provide direct evidence for neuronal insulin resistance (Dresner et al. 1999; Shulman 2000). It is not Inhibitors,research,lifescience,medical possible to obtain hippocampal interstitial FFA levels or tissue biopsy samples from human healthy volunteers to confirm alterations in neuronal insulin Inhibitors,research,lifescience,medical signaling. Our experimental design, however, is based on proven models of peripheral insulin resistance (Dresner et al. 1999; Roden et al. 1999) taken together with recent evidence for transport of FFAs BIBR 1532 solubility dmso across the blood–brain barrier (Rapoport et al. 2001; Hamilton and Brunaldi 2007; Mitchell et al. 2011). The findings are consistent with published work by Karmi et al. (2010) demonstrating increased brain fatty acid uptake in humans with insulin resistance and

Inhibitors,research,lifescience,medical with McNay et al. (2010) work in animal models demonstrating increases in hippocampal glycolytic rates in response to insulin, and demonstration of impaired cognition in a model of insulin resistance induced by a high-fat diet (McNay et al. 2010). The cognitive test battery provided stimulation of the cognitive domains in which insulin resistance-associated Inhibitors,research,lifescience,medical deficits have been identified and is comparable in task difficulty with the test battery used by Baker et al. (2011). Impairment of the energy supply to sustain this activity would lead to depletion of the

intracellular energy stores. The primary purpose of the cognitive testing in this study was to stimulate neuronal activity, and hence the hypothesized stimulated Inhibitors,research,lifescience,medical neuronal glucose uptake via insulin signaling. The findings in this study of a reduction in PCr/ATP ratio with cognitive stimulation following lipid infusion to inhibit insulin signaling, and lack of change in the absence of lipid infusion to induce insulin resistance, Terminal deoxynucleotidyl transferase supports a role for insulin in maintaining neuronal glucose uptake and hence cellular energy production during increased neuronal activity. Observed performance on cognitive testing was not impaired following the lipid infusion, despite the reduction in PCr/ATP ratio. The 20-min cognitive test battery appears to have provided enough stimulation to result in a depletion of intracellular energy stores, and thus test the experimental hypothesis, but the sensitivity of the tests for subtle changes in performance after a brief intervention is limited.