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    • In conclusion atorvastatin but not pravastatin impaired gluc

    2021-12-16

    In conclusion, atorvastatin but not pravastatin impaired glucose utilization in C2C12 cells and glucose tolerance in HFD mice, which may be partly due to the inhibition of GLUT4 translocation in muscle cells. The decrease in the cholesterol level induced by atorvastatin may partly account for the inhibition of GLUT4 translocation (Fig. 7).
    Author contribution
    Introduction In peripheral tissues, insulin’s canonical effect is to regulate GluT4-mediated glucose uptake and glucose utilization [1]. Although neurons express both GluT4 and insulin receptors (IRs), the role of insulin signaling in controlling neuronal glucose utilization is less clear [2], [3], [4], [5], [6]. Because insulin stimulates GluT4 translocation from intracellular storage pools [via GluT4 vesicles (GSVs)] in neuronal cells [4], [6], it is possible that insulin can affect glucose transport and hence fuel supply in the ck1 inhibitor through GluT4. Insulin’s effects on memory are PI3K-dependent, but downstream mechanisms following PI3K-activation are not clear [7]. While some studies have shown an effect of insulin signaling on glucose utilization in the brain as a whole, others found no effect [7], [8], [9]. Because intrahippocampal glucose administration has similar cognitive effects as intrahippocampal insulin [7], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], and insulin’s well-established action in the periphery is to facilitate glucose utilization, it is possible that insulin’s cognitive effects are mediated through enhanced GluT4-mediated glucose uptake and subsequent glucose utilization in the brain. GluT4 shows primarily neuronal localization in specific brain regions in rat, and its expression is greatest in the perikarya. The hippocampus has high expression of GluT4 in pyramidal cells [23], [24], [25], [26]. GluT4 translocation occurs following stimulation by a variety of kinases including PI3K, several atypical protein kinase c (aPKC) isoforms, and Ca2+/calmodulin kinase II [CaMKII; [27], [28], [29], [30]]. Intriguingly, many of these proteins are necessary for memory formation [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42]. Thus, it is likely that GluT4 activation occurs during hippocampally-mediated memory formation, which is known to be sensitive to glucose supply and metabolism [43], [44]. In this study, we used pharmacological inhibition of GluT4-mediated glucose uptake to assess the involvement of hippocampal GluT4 in insulin-mediated memory enhancement and neuronal glucose utilization.
    Materials and methods
    Results
    Discussion In this study, we used selective inhibition of hippocampal GluT4 to probe the involvement of GluT4 in hippocampally-mediated memory. Our findings suggest that the acute effects of GluT4 inhibition on spatial working memory, at least in the SA task used here, are only detectable following insulin-stimulated GluT4 translocation. Blocking GluT4 alone did not impair glucose utilization in hippocampal neurons, but blocking GluT4 impaired insulin-stimulated glucose utilization suggesting that baseline levels of GluT4 do not have prominent effects on mediating neuronal glucose utilization. The implications of this study are that in the brain, the acute effects of supra-baseline insulin to enhance spatial working memory may require functional GluT4. We make specific note of “supra-baseline” insulin’s effects here, because a previous study found that inhibition of endogenous insulin (i.e. baseline insulin) in the hippocampus impaired SA performance [7]. This suggests, that supra-baseline insulin affects memory via distinct pathways (i.e. mediated through GluT4) from baseline insulin (i.e. not mediated through GluT4). Increased PM expression of GluT4 observed following SA testing as observed in Experiment 2 is unnecessary for SA performance. These data suggest that increased hippocampal GluT4 PM expression observed during the SA testing may be involved in memory processes different from spatial working memory, such as perhaps memory consolidation. In a previous study where we varied the retention interval between learning and testing, and used the inhibitory avoidance paradigm, we found that intrahippocampal administration of IND to the hippocampus did indeed impair memory when give 10min prior to the acquisition phase of testing [65]. Alternatively, increased PM GluT4 expression may be a response to increased metabolic load (including drainage of extracellular glucose) during memory, and might perhaps play a greater role during more prolonged cognitive demand.