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    • The High Fat Diet HFD

    2018-10-23

    The High Fat Diet (HFD) fed mouse is a widely used model to study insulin resistance (Winzell and Ahren, 2004), and the phenotype has many of the risk factors associated with metabolic syndrome (Grundy et al., 2004). The mice are obese, and have elevated cholesterol and blood glucose. The blood Deforolimus is only slightly increased since the HFD mouse compensate with increased insulin secretion, further fueling weight gain and insulin resistance (Winzell and Ahren, 2004). As many patients treated with statins have a high BMI, it is of interest to investigate the mechanisms explaining the effect of statin treatment on glucose homeostasis in HFD mice compared to mice fed a normal diet (ND). Here we have studied the integrated role of rosuvastatin on glucose homeostasis and aimed to understand the cellular mechanisms by which rosuvastatin acts on insulin secretion and glucose uptake.
    Materials and Methods
    Results
    Discussion Several studies propose an association between new on-set diabetes and statin treatment (Cederberg et al., 2015; Mora et al., 2010; Preiss and Sattar, 2012; Ridker et al., 2008; Ruscica et al., 2014; Sattar et al., 2010), but the precise mechanisms remain unknown. To obtain a better understanding of the possible cellular mechanisms by which statins influence glucose homeostasis we performed detailed analysis in mice on ND and HFD treated with rosuvastatin. Our data suggests dual effects on glucose homeostasis with improved insulin sensitivity and reduced insulin secretion. Current literature is conflicting concerning the effects of rosuvastatin on insulin sensitivity. Some studies speak in favor of statins and suggest that it improves insulin sensitivity (Guclu et al., 2004; Okada et al., 2005; Paolisso et al., 1991; Sonmez et al., 2003), whereas others report that statin treatment leads to increased insulin resistance (Cederberg et al., 2015; Jula et al., 2002; Ohmura et al., 2005), and some that statins have no effects on insulin sensitivity (Gannage-Yared et al., 2005; Koh et al., 2005). Our data show that rosuvastatin improves insulin sensitivity. In our in vivo experiments this was most obvious in mice on ND, but we could observe a tendency also in the HFD mice. The effect could be dose dependent, since mice on ND, where the effect on insulin sensitivity was most pronounced, had slightly higher water intake. Our HFD mice became insulin resistant, and the effect of HFD seems to override any effect of rosuvastatin. Our in vivo data is supported by in vitro measurements showing increased adipose glucose uptake in both ND and HFD mice treated with rosuvastatin. Interestingly, rosuvastatin raised primarily basal but also insulin-dependent glucose uptake. Hence, our data are in agreement with improved insulin sensitivity. In adipose and muscle cells, glucose uptake is facilitated through insulin-regulated glucose-transporter GLUT4, some situated in clusters at the plasma membrane (Stenkula et al., 2010). In the basal state, only a few GLUT4 transporters are present at the membrane (Stenkula et al., 2010). Thus, it can be suggested that rosuvastatin either increases the basal GLUT4 translocation, possibly through membrane alteration, or affects mechanisms downstream of the insulin receptor. We observed that rosuvastatin increased GLUT4 protein levels in the soleus muscle of ND mice, whereas in HFD mice it decreased GLUT4 levels. This might explain the larger improvement of insulin sensitivity in rosuvastatin treated mice on ND as compared to HFD, since the majority of glucose uptake in vivo is through muscle (Thiebaud et al., 1982). Insulin stimulation increases the number of GLUT4 in the plasma membrane, but muscle contraction also stimulates translocation of GLUT4 to the plasma membrane independent of insulin (Fushiki et al., 1989). How could the reported increased incidence of new on-set diabetes with statins be explained? Knowledge regarding statin effects on beta cell function is scarce, except for a recent study suggesting impaired insulin secretion with statins (Cederberg et al., 2015). We therefore also investigated beta cell function in more detail in vivo and in vitro. Our data confirms a rosuvastatin-induced impairment of beta cell function and reduced insulin secretion in vitro, but not in vivo. The observed differences might be explained by absence of the complex integrated response from e.g. incretins and neuronal input in the in vitro insulin secretion measurements on isolated islets. In vivo the most pronounced effect was observed in HFD mice, and the increase in insulin secretion by HFD was counteracted by rosuvastatin. The in vitro insulin secretion measurements were presented both as per islet and per insulin content and insulin content data is also given. The data obtained when measuring insulin secretion per islet is the summed effect by changes in insulin content and effects on the insulin secretion process. When insulin is expressed as per insulin content this factor is taken into account and the changes measured are due to direct effects on the insulin secretion process. In the three different scenarios measured here this suggests that 1) HFD increases insulin content and inhibits the insulin secretion process; 2) rosuvastatin treatment in ND mice mainly reduces insulin content; and 3) rosuvastatin treatment in HFD mice reduces insulin content and amplifies the insulin secretion process.