Incretin mimetic medications acutely downregulate inflammation via the NfkB pathway during the fasting state in humans with type 2 diabetes mellitus. Free fatty acids (FFAs) activate TLR4, stimulating NFkB and the production of IL-6, which downregulates insulin signaling via SOCS3. We investigated this pathway in the acute postprandial state—utilizing a high-fat meal and incretin mimetic therapies—in humans with prediabetes. Sixteen humans with prediabetes (age 50 ± 2 years, BMI 32.5 ± 0.4 kg/m2, HbA1c 5.96 ± 0.05%) participated in a randomized, crossover, double-blinded trial comparing exenatide, saxagliptin, and placebo. Blood was drawn at baseline (fasting) and 2 hours for the collection of peripheral blood mononuclear cells (PBMCs) and plasma. After baseline blood draw, subjects were given study medication followed by high-fat test meal. Procedures were repeated for all study arms. Subsequently, seven of these subjects (age 51 ± 2 years, BMI 33.3 ± 0.6 kg/m2, HbA1c 5.86 ± 0.17%) participated in an open-label extension study after the administration of exenatide extended-release (EXR) for six weeks. The above procedures were repeated. In the randomized trial, plasma FFA decreased in all groups (p<0.05), though the magnitude of decrease was smaller for exenatide. Plasma IL6 levels increased in all groups except the saxagliptin (p<0.05). Western blots of PBMCs showed no significant changes in levels of NFkB, TLR4, or SOCS3. Plasma insulin did not change in the exenatide group but increased in other groups. In the extension study with EXR, plasma FFA decreased between 0 and 2 hours (p<0.05), and to a greater extent than the prior exenatide group. Plasma IL6 levels decreased (p<0.05) and insulin levels increased (p<0.05). Western blots showed no significant changes in levels of NFkB, TLR4, or SOCS3. These data show that six weeks of EXR significant reduced postprandial FFA levels and IL-6 without any noted changes in NFkB pathway between 0 and 2 hours.
A.D. Gutierrez: Speaker's Bureau; Self; AstraZeneca, Med Learning Group. K. Bermudez: None. V. Hamidi: None. K. Riggs: None. S. Coverdale: None. A. Dursteler: None. N.K. Kumar: None. M. Ruscheinsky: None.