Background DPP-4 inhibitors are increasingly used to accomplish glycemic targets in patients with Type II diabetes (T2DM). Since DPP-4 is expressed in inflammatory cells, we hypothesized that its inhibition will exert favorable effects in atherosclerosis. Methods and Results Male LDLR-/- mice (6 weeks) were fed with a high fat diet (HFD) or normal chow diet (NCD) for 4 weeks and then randomized to vehicle or Alogliptin, a high affinity DPP-4 inhibitor (40 mg/kg/day) for 12 weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden and indices of inflammation were obtained in target tissues including the vasculature, adipose and bone marrow with assessment of global and cell specific inflammatory pathways. In-vitro and in-vivo assays of DPP-4 inhibition (DPP-4i) on monocyte activation/migration were conducted in both human and murine cells and in a short-term ApoE-/- mouse model. DPP-4i improved markers of insulin resistance and reduced blood pressure. DPP-4i reduced visceral adipose tissue macrophage content (ATMs; CD11b+, CD11c+, Ly6Chi) concomitant with up-regulation of CD163. DPP-4 was highly expressed inbone-marrow derived CD11b+ cells with DPP-4i down-regulating pro-inflammatory genes in these cells. DPP-4i decreased aortic plaque with a striking reduction in plaque macrophages. DPP-4i prevented monocyte migration and actin polymerization in in-vitro assays via Rac dependent mechanisms and prevented in-vivo migration of labeled monocytes to the aorta in response to exogenous TNFα and DPP-4. Conclusion DPP-4i exerts anti-atherosclerotic effects and reduces inflammation via inhibition of monocyte activation/chemotaxis. These findings have important implications for the use of this class of drugs in atherosclerosis.

Evidence from both clinical and experimental studies indicates that Di-peptidyl peptidase-IV (DPP-4) inhibition may mediate favorable effects on the cardiovascular system. The objective of this study was to examine the acute effects of DPP-4 inhibition on vascular responses and to study the underlying mechanisms of alteration in tone. Aortic segments from C57BL/6 mice were treated with vasoconstrictors and exposed to various doses of alogliptin, a selective DPP-4 inhibitor. Vasodilator responses were evaluated using pathway specific antagonists to elucidate mechanisms of response. In parallel experiments, cultured human umbilical vein endothelial cells (HUVEC) were exposed to varying concentrations of alogliptin to evaluate the effects on candidate vasodilator pathways. Alogliptin relaxed phenylephrine and U46619 pre-constricted aortic segments in a dose dependent manner. Relaxation responses were not affected by the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin fragment 9–39 (88±6 vs. 91±2, p<0.001). Vascular relaxation to alogliptin was significantly decreased by endothelial denudation, L-NG-monomethyl-arginine citrate (L-NMMA) and by the soluble guanylate cyclase inhibitor ODQ. DPP-4 inhibition induced relaxation was completely abolished by a combination of L-NMMA, charybdotoxin and apamin. Incubation of HUVECs with alogliptin resulted in eNOS and Akt phosphorylation (Ser1177 and Ser473 respectively) paralleled by a rapid increase in nitric oxide. Inhibition of Src kinase decreased eNOS and Akt phosphorylation, in contrast to a lack of any effect on insulin mediated activation of the eNOS-Akt, suggesting that alogliptin mediates vasodilation through Src kinase mediated effects on eNOS-Akt. DPP-4 inhibition by alogliptin mediates rapid vascular relaxation via GLP-1 independent, Src-Akt-eNOS mediated NO release and the activation of vascular potassium channels.

Background: Donkeys appear to be more predisposed than large breed horses to suffer from hyperlipemia. The reason for that predisposition is unknown but anorexia is a consistent feature of the disease. Leptin, a protein synthesized in fat tissue, is one of the major inhibitors of appetite in mammals. Objective: We hypothesized that donkeys could have elevated plasma leptin concentrations compared to horses. Animals and Methods: Blood samples were obtained from 50 donkeys for measurement of leptin, triglycerides (TGs), glucose, and insulin. Glucose/insulin ratio, modified insulin to glucose ratio, and reciprocal of the square root of insulin were calculated. Based on their body condition score (BCS), donkeys were classified as lean (n ¼ 18), normal (n ¼ 16), or overweight (n ¼ 16). The results were compared with reference values from our laboratory and with a group of horses (n ¼ 25) used as an internal control. Results: Values of both leptin and TGs in donkeys were above the horse reference range and also significantly higher than those of the control horses: leptin (11.2 AE 1.7 versus 5.8 AE 0.5 mg/L, p < 0.05) and TGs (0.93 AE 0.1 versus 0.54 AE 0.1 mmol/L, p < 0.01). Overweight donkeys had leptin (19.3 AE 2.9 mg/L) and TG (1.3 AE 0.2 mmol/L) concentrations that were significantly ( p < 0.01) higher than normal (9.4 AE 3.3 mg/L and 0.85 AE 0.1 mmol/L, respectively) and lean (5.5 AE 1.0 mg/L and 0.66 AE 0.1 mmol/L, respectively) donkeys. A significant positive correlation ( p < 0.01) was found between BCS and leptin (r ¼ 0.43), TGs (r ¼ 0.46), glucose (r ¼ 0.41), and insulin (r ¼ 0.40). Conclusion: Donkeys have higher plasma leptin concentrations than horses and leptin is correlated with BCS.

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with openlabel eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population.