Exenatide exerts a potent antiinflammatory effect.
OBJECTIVE
Our objective was to determine whether exenatide exerts an antiinflammatory effect.


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.
Division of Endocrinology, Diabetes, and Metabolism, State University of New York at Buffalo, Buffalo, New York 14209, USA.
Ajay
A
Chaudhuri
Husam
H
Ghanim
Mehul
M
Vora
Chang Ling
CL
Sia
Kelly
K
Korzeniewski
Sandeep
S
Dhindsa
Antoine
A
Makdissi
Paresh
P
Dandona
D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D004334:Drug Administration Schedule; D000077270:Exenatide; D005230:Fatty Acids, Nonesterified / Q000097:blood; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007328:Insulin / Q000097:blood; D008875:Middle Aged; D009765:Obesity / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000276:immunology; D010455:Peptides / Q000008:administration & dosage* / Q000494:pharmacology*; D010919:Placebos; D017382:Reactive Oxygen Species / Q000097:blood; D016037:Single-Blind Method; D013997:Time Factors; D016896:Treatment Outcome; D014688:Venoms / Q000008:administration & dosage* / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D010919:Placebos; D017382:Reactive Oxygen Species; D014688:Venoms; D000077270:Exenatide