Beta-cell function progressively declines with age, giving rise to higher prevalence of impaired glucose tolerance and Type 2 diabetes in older populations. Glucose-dependent insulinotropic polypeptide (GIP) is a key incretin hormone, which potentiates glucose-induced insulin secretion. Therefore, the long-acting GIP-receptor agonist, N-AcGIP(LysPAL37), was employed to assess effects on glucose tolerance and plasma insulin responses to glucose in young (12-16 week old) and older (45-49 week old) mice. In older mice, body weights, basal plasma glucose and insulin concentrations were significantly higher than in young mice (P < 0.05-P < 0.001; n = 6). Intraperitoneal injection of glucose alone (18 mmol per kg body weight) revealed a significantly lower (AUC 1.7-fold; P < 0.05) insulin response in older mice, accompanied by an increased glycaemic response (AUC 1.4-fold; P < 0.05). Normal glucose-mediated insulin secretion was restored in older mice injected with N-AcGIP (LysPAL37) (25 nmol per kg body weight). However, the glycaemic excursion remained significantly impaired (1.7-fold; P < 0.05) in older mice after administration with N-AcGIP(LysPAL37), suggestive of impaired insulin action. Native GIP had a similar effect in both young and older mice. These data indicate that N-AcGIP(LysPAL37) significantly improved insulin secretion and beta-cell responsiveness in older mice, indicating that long-acting GIP agonists can counter age-related decline in beta-cell function, and may provide an option for halting glucose intolerance associated with ageing. P2Autocrine effect of insulin in human islets of Langerhans: insulin gene expression P4 Cyclic nucleotide phosphodiesterases in the glucagon-like peptide-1 secreting GLUTag cell line Activation of adenylyl cyclase and protein kinase A increases the synthesis and secretion of GLP-1, a major incretin hormone, suggesting a role for cyclic AMP (cAMP) and therefore the necessary presence of cAMP-degrading phosphodiesterases (PDEs). We characterised PDE isoforms in the GLP-1 secreting GLUTag cell line. Western blotting could not detect native PDE3A, PDE4A or PDE4B but detected PDE3B (supernatant fraction) and PDE4D, PDE7 (supernatant) and PDE10A (pellet and supernatant fractions). Cyclic AMP PDE enzyme activity was ª 2006 Diabetes UK, Diabetic Medicine, 23 (Suppl. 2), 31-138 inhibited by the non-selective agent IBMX (200 lmol/l) in both cytoplasmic (78.1 ± 8.5%) and pellet fractions (72.4 ± 5%). The PDE3 selective agent Org9935 did not produce a consistent inhibition, while the PDE4 selective inhibitor rolipram (0.001-10 lmol/l) consistently inhibited by a maximum of 44.5 ± 2.5% in the cytoplasmic fraction. In the presence of 10 mmol/l glucose, IBMX (200 lmol/l) increased GLP-1 secretion (232.5 ± 13.2% vs. control P < 0.01). Org9935 slightly increased secretion at 10 and 50 lmol/l (119.5 ± 3.2%; P < 0.001 and 129.4 ± 7.7%; P < 0.05). Rolipram potently (0.001-10 lmol/l) augmented secretion (maximum 170 ± 3.1%; P < 0.001; approximate EC 50