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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Aorta, Apolipoproteins E, Ascitic Fluid, Atherosclerosis, Cells, Cultured, Diabetes Mellitus, Experimental, Down-Regulation, Foam Cells, Gastric Inhibitory Polypeptide, Gene Expression, Gene Knockout Techniques, Islets of Langerhans, Macrophages, Peritoneal, Mice, Mice, Knockout, Plaque, Atherosclerotic, Receptors, Gastrointestinal Hormone.
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Does glucose-dependent insulinotropic polypeptide prevent the progression of macrophage-driven atherosclerosis in diabetic apolipoprotein E-null mice? Context: We 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. Nondiabetic 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. Diabetic 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 [Pro(3)]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.
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Long-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. Final Decision: yes