Aims/hypothesis Rosiglitazone, an insulin sensitiser, not only improves insulin sensitivity but also enhances insulin secretory capacity by ameliorating gluco-and lipotoxicity in beta cells. Rosiglitazone can stimulate insulin secretion at basal and high glucose levels via a phosphatidylinositol 3-kinase (PI3K)-dependent pathway. We hypothesised that regulation of phosphorylation of the ATP-sensitive potassium (K ATP ) channel might serve as a key step in the regulation of insulin secretion. Methods Insulin secretory responses were studied in an isolated pancreas perfusion system, cultured rat islets and MIN6 and RINm5F beta cells. Signal transduction pathways downstream of PI3K were explored to link rosiglitazone to K ATP channel conductance with patch clamp techniques and insulin secretion measured by ELISA. Results Rosiglitazone stimulated AMP-activated protein kinase (AMPK) activity and induced inhibition of the K ATP channel conductance in islet beta cells; both effects were blocked by the PI3K inhibitor LY294002. Following stimulation of AMPK by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a pharmacological activator, both AICAR-stimulated insulin secretion and inhibition of K ATP channel conductance were unaffected by LY294002, indicating that AMPK activation occurs at a site downstream of PI3K activity. The serine residue at amino acid position 385 of Kir6.2 was found to be the substrate phosphorylation site of AMPK when activated by rosiglitazone or AICAR. Conclusions/interpretation Our data indicate that PI3K-dependent activation of AMPK is required for rosiglitazonestimulated insulin secretion in pancreatic beta cells. Phosphorylation of the Ser 385 residue of the Kir6.2 subunit of the K ATP channel by AMPK may play a role in insulin secretion.

Species or sub-species including Parazacco spilurus fasciatus, Candidia barbatus, Zacco temminckii, Zacco sieboldii, Zacco platypus, Zacco macrolepis, Zacco pachycephalus, some undetermined Zacco taxa formerly misidentified as Chinese Z. platypus and Opsariichthys uncirostris were sampled, and their mitochondrial cytochrome b genes were sequenced. In the phylogenetic analysis, the genus Parazacco forms the basal taxon for the remaining members of the opsariichthine fishes, which can be divided into two major groups. The first group includes species with one longitudinal stripe on the flanks and contains Z. temminckii, Z. sieboldii and C. barbatus with sequence divergences of 12Á7-16Á5%. The second group has species with 10 cross bars on the body and includes O. uncirostris, Z. macrolepis, Z. platypus, Z. pachycephalus and five undetermined Zacco spp. (A-E) lineages. The estimated divergence times of mtDNA lineages within the nominal species of Z. pachycephalus and C. barbatus are >2 million years ago. According to geological evidence, this predates the earliest possible time for their arrival in Taiwan Island and indicates that the population differentiations might have been taken place in mainland China before their subsequent dispersal to Taiwan.

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1. We found previously that propranolol augments hyperpnoea-induced bronchoconstriction (HIB). This study was performed to investigate the underlying mechanism of this aug- menting action of propranolol. 2. In the first series, 45 young Hartley guinea-pigs were divided into five groups: control; propranolol; adrenalectomy; metoprolol and reserpine. Each animal underwent three periods: baseline, hyperpnoea, and recovery. For each animal 1 ml of arterial blood was sampled during the baseline and recovery periods. 3. Treatments of propranolol, metoprolol, and reserpine caused significant decreases in both dynamic respiratory compliance (Crs) and forced expiratory volume in 0.1 s (FEV0.1) during the baseline period. Hyperpnoea caused slight but not significant decreases in Crs, FEV0.1, and maximal expiratory flow at 50% total lung capacity (TLC) (V(max50)) during the recovery period in the control group. Propranolol, but not other treatments, significantly augmented these decreases (indicating HIB). Plasma noradrenaline and adrenaline levels in the reserpine group were not detectable. The above treatments or hyperpnoea did not induce any significant effect on the plasma noradrenaline level. Plasma adrenaline level of the control group was higher than that of either adrenalectomy or reserpine group during the baseline and the recovery periods. 4. In the second series, we avoided repeated blood samplings. Forty-eight animals were evenly divided into two groups: control and propranolol. Each group was again evenly divided into three subgroups: baseline; hyperpnoea, and recovery. Five minutes into the recovery period, we demonstrated HIB in the control group. In terms of V(max50), this HIB was significantly augmented by propranolol. Plasma noradrenaline and adrenaline levels, however, were not significantly altered by either hyperpnoea or propranolol. 5. Taken together, these data suggest that propranolol-augmented HIB has no direct relationship with decreased catecholamine activity.