Abstract
AimWe recently reported that glucose-dependent insulinotropic polypeptide (GIP) prevents the development of atherosclerosis in apolipoprotein E-null (Apoe −/−) mice. GIP receptors (GIPRs) are found to be severely down-regulated in diabetic animals. We examined whether GIP can exert anti-atherogenic effects in diabetes.MethodsNondiabetic Apoe −/− mice, streptozotocin-induced diabetic Apoe −/− mice, and db/db mice were administered GIP (25 nmol/kg/day) or saline (vehicle) through osmotic mini-pumps for 4 weeks. The animals were assessed for aortic atherosclerosis and for oxidized low-density lipoprotein-induced foam cell formation in exudate peritoneal macrophages.ResultsDiabetic Apoe −/− mice of 21 weeks of age exhibited more advanced atherosclerosis than nondiabetic Apoe −/− mice of the same age. GIP infusion in diabetic Apoe −/− mice increased plasma total GIP levels by 4-fold without improving plasma insulin, glucose, or lipid profiles. GIP infusion significantly suppressed macrophage-driven atherosclerotic lesions, but this effect was abolished by co-infusions with [Pro3]GIP, a GIPR antagonist. Foam cell formation was stimulated by 3-fold in diabetic Apoe −/− mice compared with their nondiabetic counterparts, but this effect was halved by GIP infusion. GIP infusion also attenuated the foam cell formation in db/db mice. In vitro treatment with GIP (1 nM) reduced foam cell formation by 15% in macrophages from diabetic Apoe −/− mice, and this attenuating effect was weaker than that attained by the same treatment of macrophages from nondiabetic counterparts (35%). While GIPR expression was reduced by only about a half in macrophages from diabetic mice, it was reduced much more dramatically in pancreatic islets from the same animals. Incubation with high glucose (500 mg/dl) for 9–10 days markedly reduced GIPR expression in pancreatic islet cells, but not in macrophages.ConclusionsLong-term infusion of GIP conferred significant anti-atherogenic effects in diabetic mice even though the GIPR expression in macrophages was mildly down-regulated in the diabetic state.
Highlights
Type 2 diabetes is well known to accelerate the course of atherosclerosis, a condition associated with arterial endothelial dysfunction, macrophage foam cell formation, and vascular smooth muscle cell (VSMC) proliferation
In 2011, our group reported that glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), two native incretins, elicited anti-atherogenic effects in apolipoprotein-E-null (Apoe2/2) mice, an animal model of atherosclerosis [9]
The total plasma GIP concentration following subcutaneous infusion of human active GIP at a dose 25 nmol/kg/day was 130–170 pM. This was 4-times higher than the concentration in vehicle-infused mice, but not a super-physiological concentration [24]. These results suggest that GIP infusion at a level several-fold higher is sufficient to confer an anti-atherogenic effect via residual GIP receptors (GIPRs) that eluded the diabetes-induced down-regulation
Summary
Type 2 diabetes is well known to accelerate the course of atherosclerosis, a condition associated with arterial endothelial dysfunction, macrophage foam cell formation, and vascular smooth muscle cell (VSMC) proliferation. Incretin-based therapies have been reported to improve vascular inflammation and endothelial dysfunction beyond glucose normalization [3]. Several experimental studies have revealed that incretinbased treatments, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, significantly suppress the development of atherosclerosis in animal models [4,5,6,7,8]. More recently, we found that a DPP-4 inhibitor, an enhancer of endogenous GLP-1 and GIP, prevented the development of atherosclerosis in the same animal model [10]
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