Exenatide exerts a potent antiinflammatory effect

Abstract

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 μg 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 μg) 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-κB binding by 22 ± 9 and 26 ± 7%, respectively, and the mRNA expression of TNFα, IL-1β, 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-κB binding, 18 ± 9% in TNFα expression, 26 ± 7% in IL-1β 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.

Figures

Fig. 1.

Percent change in fasting blood glucose (A), insulin (B), and FFA (C) after placebo and exenatide 10 μg twice daily for 12 wk and change in FFA (D) after a single dose of 5 μg exenatide or placebo in type 2 diabetic subjects. Data are presented as mean ± se; n = 12 each. * and **, P < 0.05 by RMANOVA (compared with baseline) in exenatide and placebo groups, respectively; #, P < 0.05 by two-way RMANOVA compared with control groups.

Fig. 2.

Percent change in ROS generation by MNC after placebo and exenatide 10 μg bid for 12 wk (A) and after 6 h of a single dose of placebo or exenatide (5 μg) (B) in type 2 diabetic subjects. Data are presented as mean ± se; n = 12 each. *, P < 0.05 by RMANOVA (compared with baseline); ^, P < 0.05 by paired t test (compared with baseline); #, P < 0.05 by two-way RMANOVA compared with control groups.

Fig. 3.

A, Gel shift assay showing the NFκB and Oct-1 binding to the double-stranded oligonucleotide containing NFκB DNA-binding site in the exenatide group after 6 h of a single dose of placebo or exenatide 5 μg (micg) and exenatide 10 μg twice-daily treatment for 12 wk (A). B–G, Change in NFκB/Oct-1 DNA-binding activity (B and C) and mRNA expression of TNFα (D and E) and IL-1β (F and G) from baseline (100%) after placebo and exenatide 10 μg twice-daily treatment for 12 wk and after 6 h of a single dose of placebo or exenatide (5 μg) in type 2 diabetic subjects. Data are presented as mean ± se; n = 12 each. *, P < 0.05 by RMANOVA (compared with baseline); #, P < 0.05 by two-way RMANOVA compared with control groups. W12, Week 12; SS, supershift; NSA, nonspecific antibodies.

Fig. 4.

Representative Western blot (A) and densitometry analysis showing percent change in JNK-1 (B), TLR-2 (C), and SOCS-3 (D) proteins in MNC after placebo and exenatide 10 μg twice-daily treatment for 12 wk (W) in type 2 diabetic subjects. Data are presented as mean ± se; n = 12 each. *, P < 0.05 by RMANOVA (compared with baseline); #, P < 0.05 by two-way RMANOVA compared with control groups.

Fig. 5.

Change in plasma concentrations of MCP-1 (A), MMP-9 (B), SAA (C), and IL-6 (D) after placebo and exenatide 10 μg daily for 12 wk in type 2 diabetic subjects. Data are presented as mean ± se; n = 12 each. *, P < 0.05 by RMANOVA (compared with baseline); #, P < 0.05 by two-way RMANOVA compared with control groups.