Dulaglutide exerts beneficial anti atherosclerotic effects in ApoE knockout mice with diabetes: the earlier, the better

Abstract

There has been no report about the mechanism for anti-atherosclerotic effects of dulaglutide (Dula) and/or about the difference of its effectiveness between in an early and a late phase of diabetes. To address such questions, streptozotocin (STZ) was intraperitoneally injected to ApoE knockout mice at 8 weeks of age. Either Dula or vehicle was administered to STZ-induced diabetic ApoE knockout mice from 10 to 18 weeks of age as an early intervention group and from 18 to 26 weeks as a late intervention group. Next, non-diabetic ApoE knockout mice without STZ injection were subcutaneously injected with either Dula or vehicle. In an early intervention group, atherosclerotic lesion in aortic arch and Mac-2 and CD68-positive areas in aortic root were significantly smaller in Dula group. In abdominal aorta, expression levels of some villain factors were lower in Dula group. In a late intervention group, there were no immunohistological differences in aortic root and expression levels of various factors between two groups. Furthermore, even in non-diabetic ApoE knockout mice, expression levels of inflammatory and macrophage markers were reduced by treatment with Dula. Taken together, Dula exerts more beneficial anti-atherosclerotic effects in an early phase of diabetes rather than in a late phase.

Cardiovascular Effects of Incretin-Based Therapies: Integrating Mechanisms With Cardiovascular Outcome Trials

“…Consistent with this, preclinical mouse studies have described the reduced progression of atherosclerosis with liraglutide and semaglutide through reduced residual inflammation in the atherosclerotic plaques of Western diet (WD)-fed Ldlr À/À and Apoe À/À mice (6). Dulaglutide treatment reduced the atherosclerotic plaque area and aortic arch macrophage infiltration in Apoe À/À mice with streptozotocin (STZ)-induced experimental type 1 diabetes (7). This benefit was also associated with reduced aortic expression of markers of inflammation and increased plaque stability.…”

Advanced Glycation End Products Induce Atherosclerosis via RAGE/TLR4 Signaling Mediated-M1 Macrophage Polarization-Dependent Vascular Smooth Muscle Cell Phenotypic Conversion

“…Animal Model Establishment and Treatment. Sixweek-old C57BL/6 background ApoE -/deficit mice purchased from Vital River (Beijing, China) were employed to establish the T2DM AS model according to previous descriptions with several modifications [13,14]. Animals were maintained in independent polypropylene cages in controlled ambient conditions and were free to water and standard chow.…”

Real-World Efficacy of Glucagon-like Peptide-1 (GLP-1) Receptor Agonist, Dulaglutide, on Metabolic Parameters in Japanese Patients with Type 2 Diabetes: A Retrospective Longitudinal Study

“…Interestingly, the changes in LDL-C, HDL-C and non-HDL-C were significantly associated with the change in HbA1c, which suggests a close association between the improvements of glycemia and lipid profiles by dulaglutide. In an animal study using ApoE knockout mice, both glycemic control and lipid profile were improved but only observed in STZ-induced diabetic model mice and not in non-diabetic mice [ 27 ]. The presence of diabetes or insulin resistance elevates the expression and activity of hormone-sensitive lipase in adipose tissue, which catalyzes lipolysis and the release of free fatty acid (FFA).…”