Comparative effects of pravastatin and rosuvastatin on carbohydrate metabolism in an experimental diabetic rat model.

Statin treatment may increase the risk of diabetes; there is insufficient data on how statins affect glucose regulation and glycemic control and the effects of statins on liver enzymes related to carbohydrate metabolism have not been fully studied. Therefore, we aimed to compare the effects of the statin derivatives, pravastatin, and rosuvastatin, on carbohydrate metabolism in an experimental diabetic rat model. Female Wistar albino rats were used and diabetes was induced by intraperitoneal injection of streptozotocin. Thereafter, 10 and 20 mg kg-1 day-1 doses of both pravastatin and rosuvastatin were administered by oral gavage to the diabetic rats for 8 weeks. At the end of the experiment, body masses, the levels of fasting blood glucose, serum insulin, insulin resistance (HOMA-IR), liver glycogen, and liver enzymes related to carbohydrate metabolism were measured. Both doses of pravastatin significantly in creased the body mass in diabetic rats, however, rosuvastatin, especially at the dose of 20 mg kg-1 day-1 reduced the body mass signi ficantly. Pravastatin, especially at a dose of 20 mg kg-1 day-1, caused significant increases in liver glycogen synthase and glucose 6-phosphate dehydrogenase levels but significant decreases in the levels of glycogen phosphorylase, lactate dehydrogenase, and glucose-6-phosphatase. Hence, pravastatin partially ameliorated the adverse changes in liver enzymes caused by diabetes and, especially at the dose of 20 mg kg-1 day-1, reduced the fasting blood glucose level and increased the liver glycogen content. However, rosuvastatin, especially at the dose of 20 mg kg-1 day-1, significantly reduced the liver glycogen synthase and pyruvate kinase levels, but increased the glycogen phosphorylase level in diabetic rats. Rosuvastatin, 20 mg kg-1 day-1 dose, caused significant decreases in the body mass and the liver glycogen content of diabetic rats. It can be concluded that pravastatin, especially at the dose of 20 mg kg-1 day-1 is more effective in ameliorating the negative effects of diabetes by modulating carbohydrate metabolism.

Structural abnormality of hepatic glycogen in rat liver with diethylnitrosamine-induced carcinogenic injury.

Growing evidence confirms associations between glycogen metabolic re-wiring and the development of liver cancer. Previous studies showed that glycogen structure changes abnormally in liver diseases such as cystic fibrosis, diabetes, etc. However, few studies focus on glycogen molecular structural characteristics during liver cancer development, which is worthy of further exploration. In this study, a rat model with carcinogenic liver injury induced by diethylnitrosamine (DEN) was successfully constructed, and hepatic glycogen structure was characterized. Compared with glycogen structure in the healthy rat liver, glycogen chain length distribution (CLD) shifts towards a short region. In contrast, glycogen particles were mainly present in small-sized ß particles in DEN-damaged carcinogenic rat liver. Comparative transcriptomic analysis revealed significant expression changes of genes and pathways involved in carcinogenic liver injury. A combination of transcriptomic analysis, RT-qPCR, and western blot showed that the two genes, Gsy1 encoding glycogen synthase and Gbe1 encoding glycogen branching enzyme, were significantly altered and might be responsible for the structural abnormality of hepatic glycogen in carcinogenic liver injury. Taken together, this study confirmed that carcinogenic liver injury led to structural abnormality of hepatic glycogen, which provided clues to the future development of novel drug targets for potential therapeutics of carcinogenic liver injury.

Berberine alleviates hyperglycemia by targeting hepatic glucokinase in diabetic db/db mice.

Berberine (BBR) is a widely used anti-diabetic agent, and liver glucokinase (GK) has been reported to be involved. However, the mechanisms of BBR in regulating GK are still unknown. Here, we found that BBR upregulated GK immunofluorescence expression in AML12 cells cultured in high glucose and increased glycogen content simultaneously. BBR improved hyperglycemia in db/db mice, and increased liver glucose-6-phosphate/glucose-1-phosphate (G-6-P/G-1-P) was found by analyzing metabolites (serum, liver, and feces) based on gas chromatography-mass spectrometry (GC-MS) metabolomics. Pharmacokinetics-pharmacodynamics (PK-PD) assessment revealed enriched BBR distribution in the liver, and liver G-6-P had the same trend as the concentration-time curve of BBR. G-6-P is solely catalyzed by GK, and GK activity and expression showed a positive correlation with liver BBR levels. In db/db mice, BBR also upregulated GK in liver fractions (cytoplasm and nucleus) and liver glycogen content. GK functionally worked by dissociating from GK regulatory protein (GKRP), and although GKRP expression was not affected, we found a decreased ratio of GK binding with GKRP in BBR treated db/db mice. In conclusion, our study suggests the dissociation of GK from GKRP as the potential mechanism for liver GK increase upon BBR treatment, which contributes to the anti-diabetic effect of BBR.

Estudo morfométrico do fígado de ratos submetidos a doses supra fisiológicas de tiroxina / Liver morphological study of rats submitted to supra physiologic doses of thyroxine

Tireotoxicose é o estado hipermatabólico causado pelo excesso de hormônios tireoidianos circulantes, que exercem sua funçäo praticamente em todos os tecidos. No presente estudo avaliou-se, por métodos estereológicos, o fígado de ratos tratados com doses supra fisiológicas de T4 (20µg/10g de peso de corporal) durante 20 dias. Os níveis séricos de T4 desses animais estavam significantemente elevados (p=0,02). Houve tendência a perda de peso corporal dos animais tratados em relaçäo ao grupo controle (p=0,10), enquanto o peso do fígado teve aumento, embora näo significativo (p=0,08). A proporçäo do parênquima lobular foi maior (p=0,05) e a fraçäo volumétrica do parênquima lobular ocupada pelas células de Kupffer foi significantemente menor (p=0,05) nos animais hipertireóideos que nos controles. Houve depleçäo que nos controles. Houve depleçäo significativa do glicogênio hepático na parênquima lobular, em relaçäo ao grupo controle (p=0,008). Concluiu-se, entäo, que a tireotoxicose provoca hiperplasia e/ou hipertrofia dos hepatócitos, com reduçäo das reservas energéticas.