Effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice.

Although rare, second-generation antipsychotic drugs cause severe hyperglycemia within several days after the initiation of therapy. Because glucose tolerance exhibits circadian rhythmicity, we evaluated an effect of a dosing-time on quetiapine-induced acute hyperglycemia in mice. A single intraperitoneal dose of quetiapine dosing-time-independently induced insulin resistance in fasted C57BL/6J mice. However, acute hyperglycemic effect was detected only after dosing of the drug at the beginning of an active phase. Under the conditions in which hepatic glucose production was stimulated by pyruvate administration, hyperglycemic effect of quetiapine was dosing-time-independently observed. In addition, the dosing-time-dependent hyperglycemic effect of quetiapine disappeared in the liver-specific circadian clock-disrupted mice in which circadian rhythmicity in hepatic glucose production is deranged. Furthermore, the dosing-time had little impact on the pharmacokinetics of quetiapine in normal mice. These results suggest that quetiapine acutely causes hyperglycemia only when hepatic glucose production elevates. Therefore, quetiapine therapy with once daily dosing at a rest phase might be safer than that at an active phase. Further studies are needed to confirm the hypothesis.

γGT and PCSK9 variants in subjects with hyper-LDL-cholesterolemia.

BACKGROUND AND AIM: Gain-of-function (GOF) variants of proprotein convertase subtilisin/kexin type 9 (PCSK9) gene cause high blood low-density lipoprotein (LDL) cholesterol and PCSK9 levels, which are respectively the markers of cardiovascular disease (CVD). High blood activity of gamma-glutamyl transpeptidase (γGT), a pro-oxidant induced by oxidative conditions, is also a marker of CVD. There may be an association between γGT and PCSK9 variants. We aimed to examine the γGT activity by a GOF variant, p.E32K, of PCSK9 in subjects with hyper-LDL-cholesterolemia, an at-risk state for CVD. METHODS: This study enrolled 114 subjects (mean age, 59 years; 38 males) with hyper-LDL-cholesterolemia who underwent a genotype assay for identification of p.E32K variant and enzymatic measurement of γGT activity. The relationship between the γGT activity and p.E32K was analyzed. RESULTS: γGT activity was significantly lower (median, 21 IU/L) in subjects with p.E32K (n = 12) than in those without the variant (30 IU/L, P < 0.05). The results remained confirmed by multivariate-adjusted analysis. CONCLUSIONS: An inverse association was found between γGT and p.E32K, a GOF variant. Elucidation of the mechanism for their association may help understand the development of CVD by PCSK9 variants.