Exenatide Exerts a Potent Antiinflammatory Effect

Objective: Our objective was to determine whether exenatide exerts an antiinflammatory effect. Research Design and Methods: Twenty-four patients were prospectively randomized to be injected sc with either exenatide 10 mu g twice daily [n = 12; mean age = 56 +/- 3 yr; mean body mass index = 39.8 +/- 2 kg/m(2); mean glycosylated hemoglobin (HbA1c) = 8.6 +/- 0.4%] or placebo twice daily (n = 12; mean age = 54 +/- 4 yr; mean body mass index = 39.1 +/- 1.6 kg/m(2); mean HbA1c = 8.5 +/- 0.3%) for 12 wk. Fasting blood samples were obtained at 0, 3, 6, and 12 wk. Blood samples were also collected for up to 6 h after a single dose of exenatide (5 mu g) or placebo. Results: Fasting blood glucose fell from 139 +/- 17 to 110 +/- 9 mg/dl, HbA1c from 8.6 +/- 0.4 to 7.4 +/- 0.5% (P < 0.05), and free fatty acids by 21 +/- 5% from baseline (P < 0.05) with exenatide. There was no weight loss. There was a significant reduction in reactive oxygen species generation and nuclear factor-kappa B binding by 22 +/- 9 and 26 +/- 7%, respectively, and the mRNA expression of TNF alpha, IL-1 beta, JNK-1, TLR-2, TLR-4, and SOCS-3 in mononuclear cells by 31 +/- 12, 22 +/- 10, 20 +/- 11, 22 +/- 9, 16 +/- 7, and 31 +/- 10%, respectively (P < 0.05 for all) after 12 wk of exenatide. After a single injection of exenatide, there was a reduction by 20 +/- 7% in free fatty acids, 19 +/- 7% in reactive oxygen species generation, 39 +/- 11% in nuclear factor-kappa B binding, 18 +/- 9% in TNF alpha expression, 26 +/- 7% in IL-1 beta expression, 18 +/- 7% in JNK-1 expression, 24 +/- 12% in TLR-4 expression, and 23 +/- 11% in SOCS-3 expression (P < 0.05 for all). The plasma concentrations of monocyte chemoattractant protein-1, matrix metalloproteinase-9, serum amyloid A, and IL-6 were suppressed after 12 wk exenatide treatment by 15 +/- 7, 20 +/- 11, 16 +/- 7, and 22 +/- 12%, respectively (P < 0.05 for all). Conclusions: Exenatide exerts a rapid antiinflammatory effect at the cellular and molecular level. This may contribute to a potentially beneficial antiatherogenic effect. This effect was independent of weight loss. (J Clin Endocrinol Metab 97: 198-207, 2012)