Blood Glucose Predicts Blood POHB Levels and Seizure Susceptibility in EL Mice

We next analyzed our data by using both simple linear regression and multiple logistic regression to determine if blood glucose levels were predictive of blood P-OHB levels and seizure susceptibility. These statistical analyses included mice considered to be outliers, i.e., mice that experienced CR but showed no changes in body weight, plasma glucose, or P-OHB levels (41). One outlier was found in the juvenile CR group and three outliers were found in the adult CR groups (two in the 15% CR group and one in the 30% CR group). The outliers were considered to be nonrestricted for caloric intake and similar to the mice in the AL-fed groups. These findings also emphasize that differences exist among inbred mice for food intake and energy metabolism (71). Hence, the efficacy of CR as an anticonvulsant therapy must be associated with reductions of blood glucose and body weight.

Fig. 6. Linear regression analysis of plasma glucose and P-OHB levels in (A) juvenile (n = 30) and (B) adult (n = 50) EL mice. This analysis included the values for plasma glucose and P-OHB levels of individual mice from both the AL and CR groups measured at wk 1,3, 5, 7, and 9. The linear regressions (r correlation coefficient) were highly significant atp < 0.001. From ref. 41, with permission.

Fig. 6. Linear regression analysis of plasma glucose and P-OHB levels in (A) juvenile (n = 30) and (B) adult (n = 50) EL mice. This analysis included the values for plasma glucose and P-OHB levels of individual mice from both the AL and CR groups measured at wk 1,3, 5, 7, and 9. The linear regressions (r correlation coefficient) were highly significant atp < 0.001. From ref. 41, with permission.

We used simple linear regression analysis to examine the relationship between plasma glucose levels (the independent or explanatory X variable) and P-OHB levels (the dependent or response Y variable) in both the juvenile (Fig. 6A) and adult mice (Fig. 6B). These variables were identified based on physiological and neurochemical studies indicating that plasma glucose levels determine plasma P-OHB levels during periods of fasting (13). This information is important because it addresses the issue of causality: i.e., circulating P-OHB levels are dependent on circulating glucose levels.

The slopes of the regression lines were highly significant, indicating that the plasma P-OHB levels increased as glucose levels decreased in both the juvenile mice and in the adult mice (41). These findings support neurochemical and neurophysiological findings that plasma P-OHB levels are dependent on plasma glucose levels and that glucose levels are predictive of P-OHB levels in all mouse groups.

Based on these observations, we used multiple logistic regression to quantify the risk of seizure associated with changes in plasma glucose levels in the juvenile and the adult mice. Because the simple linear regression indicated that P-OHB levels depend on glucose levels, the P-OHB levels could not be included in the logistic regression analysis (72). In the juvenile and adult mice, prior seizure testing and glucose were significant in predicting seizures. We found that for every decrease in 1 mmol per liter of glucose, the odds of having a seizure decreased by 2.6 and 1.9 in the juvenile and adult mice, respectively (41). Our findings indicate that plasma glucose levels are predictive of seizure susceptibility in EL mice at both juvenile and adult ages. These findings also support recent studies with flurothyl-induced seizures in rats, in which circulating glucose levels were positively correlated with seizure susceptibility (73).

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