OBJECTIVE-We sought to determine whether alterations in meal absorption and gastric emptying contribute to the mechanism by which inhibitors of dipeptidyl peptidase-4 (DPP-4) lower postprandial glucose concentrations.RESEARCH DESIGN AND METHODS-We simultaneously measured gastric emptying, meal appearance, endogenous glucose production, and glucose disappearance in 14 subjects with type 2 diabetes treated with either vildaglipitin (50 mg b.i.d.) or placebo for 10 days using a double-blind, placebo-controlled, randomized, crossover design.RESULTS-Fasting (7.3 Ϯ 0.5 vs. 7.9 Ϯ 0.5 mmol/l) and peak postprandial (14.1 Ϯ 0.6 vs. 15.9 Ϯ 0.9 mmol/l) glucose concentrations were lower (P Ͻ 0.01) after vildagliptin treatment than placebo. Despite lower glucose concentrations, postprandial insulin and C-peptide concentrations did not differ during the two treatments. On the other hand, the integrated (area under the curve) postprandial glucagon concentrations were lower (20.9 Ϯ 1.6 vs. 23.7 Ϯ 1.3 mg/ml per 5 h, P Ͻ 0.05), and glucagon-like peptide 1 (GLP-1) concentrations were higher (1,878 Ϯ 270 vs. 1,277 Ϯ 312 pmol/l per 5 h, P ϭ 0.001) during vildagliptin administration compared with placebo. Gastric emptying and meal appearance did not differ between treatments.CONCLUSIONS-Vildagliptin does not alter gastric emptying or the rate of entry of ingested glucose into the systemic circulation in humans. DPP-4 inhibitors do not lower postprandial glucose concentrations by altering the rate of nutrient absorption or delivery to systemic circulation. Alterations in islet function, secondary to increased circulating concentrations of active GLP-1, are associated with the decreased postprandial glycemic excursion observed in the presence of vildagliptin.
Vildagliptin improves islet function in T2DM and improves glucose metabolism in peripheral tissues.
895The purpose of this double-blind, placebo-controlled study was to measure the effects of FTY720, a novel immunomodulator, on heart rate and rhythm in healthy volunteers. Subjects (n = 66) FTY720 is a novel immunomodulator that acts as a sphingosine-1-phosphate (S1P) receptor agonist, thereby reducing the recirculation of lymphocytes to blood and peripheral tissues, including inflammatory lesions and graft sites. [1][2][3][4] In contrast to classic immunosuppressants, FTY720 does not impair cellular or humoral immunity to systemic viral infection and does not affect the activation, expansion, or proliferation of T lymphocytes or immunological memory in preclinical models. 5FTY720 was effective in prolonging allograft survival in preclinical models of cardiac, renal, and hepatic transplantation. 4 Furthermore, a synergistic effect was noted when FTY720 was used in combination with subtherapeutic or therapeutic doses of cyclosporine in a number of different allograft models. 4 The results of phase II clinical studies demonstrated that FTY720 can be used effectively and safely in combination with classic immunosuppressive agents, including cyclosporine 6 and everolimus. 7 FTY720 has been well tolerated in comparative studies conducted in renal transplant recipients to date. However, a recurring finding in these trials has been a reduction in heart rate with initiation of FTY720 treatment. [6][7][8][9] This negative chronotropic effect appears to be temporally associated with the first dose of FTY720. A nadir in heart rate is observed within 4 to 12 hours of drug administration, with heart rate recovering close to baseline within 48 hours after a single dose of FTY720.6-9 The mechanism underlying the effect of FTY720 on heart rate appears to be mediated by its capacity to agonize S1P
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