Abstract 21652: DPP4 Inhibition Improves Adipose Inflammation and Insulin Resistance via GLP-1 Independent Mechanisms
Objective: Inflammation of the adipose milieu in obesity is believed to play an etiologic role in insulin resistance and type 2 diabetes (T2DM). Dipeptidyl peptidase-4 (DPP4, CD26) inhibitors are a new class of drugs used for the treatment of T2DM via modulation of glucagon like peptide (GLP-1) function. We investigated the effect of chronic DPP4 inhibition (DPP4i) in a model of insulin resistance/obesity.
Methods: Male LDLR-/- mice were randomized to high fat diet and treated with placebo or oral alogliptin, a high affinity DPP4 inhibitor (40mg/kg/day). In-vivo metabolic parameters, adipose changes including monocyte/macrophage subsets in stromal vascular fraction, monocyte gene expression and in-vitro assays of DPP4i on monocyte activation/migration were conducted.
Results: DPP4i improved fasting and post-glucose load levels including HOMA-IR, HOMA-β and plasma lipid parameters without change in weight or food intake. Plasma GLP-1 levels in the DPP4i group were elevated compared to placebo (148±18 vs. 103±13 pM, p<0.05). DPP4i resulted in reduction of visceral adipose assessed by MRI (53±4 vs. 67±7% total abdominal fat, p<0.005). Decrease in visceral fat was accompanied by smaller adipocyte size, decreased CD11b+, CD11c+, Ly6chi monocytes in visceral adipose (6±0.3, 3±0.2, 2±0.2 respectively in placebo vs. 4±0.2, 2±0.2 and 1±0.1 respectively in the DPP4i group, all values x105/g adipose; p<0.05 vs. placebo). Adipose macrophages demonstrated reduced M1 markers, TNFα, IL-6, CD206 and IFNγ concomitant with an increase in M2 markers (CD163 and Ym1, 17±9, 2±1, fold-increase respectively, vs. placebo, p<0.05). DPP4 and GLP-1 receptor were expressed in CD11b+ cells with DPP4i down-regulating pro-inflammatory genes. DPP4i prevented monocyte migration in in-vitro migration assays (THP1) in response to TNFα (10-12M). These effects were reversed by the adenosine receptor 2A antagonist (ZM 241385) and the Rac1 inhibitor (NSC 23766) but not by exendin 7-37 (inactive GLP-1 fragment). Pretreatment of THP-1 cells with TNF-α (10-12M) resulted in actin polymerization, reversed by DPP4i.
Conclusion: Chronic DPP4i reduces adipose inflammation via GLP-1 independent, adenosine mediated inhibition of monocyte chemotaxis.
- © 2010 by American Heart Association, Inc.