Exendin-4 is a stable peptide agonist of GLP-1 receptor that exhibits insulinotropic actions. Some in vivo studies indicated insulin-independent glucoregulatory actions of exendin-4. That finding prompted us to evaluate effects of exendin-4 on liver glucose metabolism. Acute and chronic treatment of exendin-4 resulted in increased hepatic glucokinase activity in db/db mice but not in lean C57 mice. The stimulatory effect of exendin-4 on glucokinase activity was abrogated by exendin 9-39, a GLP-1 antagonist. Exposure of hepatocytes isolated from db/db mice to exendin-4 elicited a rapid increase in cAMP, which was synergized by IBMX, an inhibitor of cAMP degradation. The GLP-1 antagonist, exendin 9-39, has abolished the cAMP generating effects of exendin-4 as well. Furthermore, chronic treatment of exendin-4 in streptozotocin-treated C57 mice resulted in restoration of hepatic glycogen, an indicator of improved glucose metabolism, without apparent changes in serum insulin levels. In conclusion, exendin-4 increased glucokinase enzyme protein and activity in liver via a mechanism parallel to and independent of insulin. Exendin-4-induced increase in hepatic glucokinase activity is more pronounced in the presence of hepatic insulin resistance. This beneficial effect of exendin-4 on liver glucokinase activity may be mediated by GLP-1 receptor.

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1. The present study was designed to investigate the neuroprotective effect of trimetazidine (TMZ) following focal cerebral ischaemia-reperfusion (I/R) injury in rat forebrain. 2. Cerebral I/R injury was induced in rats by middle cerebral artery occlusion (MCAO) for 2 h, followed by reperfusion for 22 h. Trimetazidine (5 and 25 mg/kg, i.p.) was administered 1 h after induction of MCAO. The effects of TMZ were investigated by measuring neurological deficit, volume of infarct and brain swelling after 22 h reperfusion. Oxidative stress and inflammatory reactivity were assessed by estimating anti-oxidant markers and myeloperoxidase (MPO) activity in brain homogenates. Rectal temperature was measured during the study. The effects of TMZ on blood-brain barrier (BBB) permeability and apoptosis were also investigated in rat brain. Apoptosis was observed by DNA fragmentation studies using agarose gel electrophoresis. 3. Treatment with TMZ significantly (P < 0.01) reduced infarct volume and brain swelling. Superoxide dismutase (SOD) activity was reduced in ipsilateral hemispheres of vehicle (saline)-treated reperfused (RI) animals. Treatment with TMZ significantly restored SOD activity (P < 0.01) and glutathione levels (P < 0.05) after reperfusion compared with RI animals. Lipid peroxidation, MPO activity, BBB permeability and rectal temperature were all significantly (P < 0.01, P < 0.05 and P < 0.001, respectively) reduced in TMZ-treated animals compared with RI animals. 4. These results suggest that TMZ protects the brain against cerebral I/R injury and that this neuroprotective activity could be mediated by its anti-oxidant properties. The reduction in rectal temperature by TMZ treatment may be responsible for maintaining the delicate energy balance during I/R injury in rat brain and could have contributed to the neuroprotective activity of TMZ.

1. One of the major causes of metabolic syndrome is elevated 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) in the liver and adipose tissue. High 11β-HSD1 expression contributes significantly to the diabetic phenotype in db/db mice. The purpose of the present study was to test the effect of the pharmacological inhibition of 11β-HSD1 inhibition by carbenoxolone in db/db mice, a genetic model of diabetes. 2. Inhibition of 11β-HSD1 by carbenoxolone was evaluated in liver homogenates obtained from untreated mice. At 0.4, 0.8, 1.6 and 3.2 μmol/L, carbenoxolone reduced the conversion of cortisone to cortisol by 21%, 48%, 82% and 95%, respectively. 3. In another series of experiments in which female db/db mice were dosed orally with carbenoxolone (10, 25 and 50 mg/kg, twice daily) for 10 days, dose-dependent decreases were observed in 11β-HSD1 activity in the brain, adipose and liver. In the case of 10 mg/kg carbenoxolone, the effects were not significant. In addition, the bodyweight of female db/db mice was reduced by 10% and 13% following treatment with 10 and 50 mg/kg carbenoxolone, respectively. Carbenoxolone treatment dose-dependently improved fat mass, energy expenditure, the serum lipid profile, serum leptin and insulin and glucose tolerance. Furthermore, 50 mg/kg carbenoxolone reduced both phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) activity in the liver by 75% and 52%, respectively. These decreases were associated with increased glucokinase protein expression and activity in the liver. 4. Carbenoxolone inhibition of 11β-HSD1 in the liver, adipose and brain significantly improves the symptoms of metabolic syndrome in db/db mice. These improvements can be attributed to increased energy expenditure, decreased activity of the gluconeogenic enzymes PEPCK and G6Pase in the liver and improved glucokinase function in the liver and pancreas.