Abstract:
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 rosiglitazone-stimulated 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.
journal_name
Diabetologiajournal_title
Diabetologiaauthors
Chang TJ,Chen WP,Yang C,Lu PH,Liang YC,Su MJ,Lee SC,Chuang LMdoi
10.1007/s00125-009-1337-4subject
Has Abstractpub_date
2009-06-01 00:00:00pages
1112-21issue
6eissn
0012-186Xissn
1432-0428journal_volume
52pub_type
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