Glucose-Dependent Insulinotropic Polypeptide Prevents the Progression of Macrophage-Driven Atherosclerosis in Diabetic Apolipoprotein E-Null Mice

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.

Glucose-Dependent Insulinotropic Polypeptide Stimulates Osteopontin Expression in the Vasculature via Endothelin-1 and CREB

“…Adding complexity to the vascular effects of GIP, recent studies of dyslipidemic apolipoprotein E knockout mice suggested antiatherogenic effects of GIP or DPP-IV inhibition, apparently via decreased CD36 expression in macrophages and decreased foam cell formation (68)(69)(70). In this mouse model, treatment with GIP significantly reduced plasma nonesterified fatty acid concentrations, which could in part explain the reduced CD36 and macrophage foam cell formation (71).…”

Preventive Effect of Dipeptidyl Peptidase-4 Inhibitor on Atherosclerosis Is Mainly Attributable to Incretin's Actions in Nondiabetic and Diabetic Apolipoprotein E-Null Mice

“…Upon reaching 17 weeks of age, they were switched to an atherogenic diet containing 30% fat, 20% sucrose, 8% NaCl, and 0.15% cholesterol (Oriental Yeast, Tokyo, Japan) [4], [14]. A DPP-4 inhibitor, vildagliptin, was kindly provided by Novartis Pharma (Basel, Switzerland).…”

“…It thus seems unlikely that GIP can exert its anti-atherogenic property in diabetes. In a recent study by our group, however, GIP infusion suppressed the development of atherosclerosis in streptozotocin (STZ)-induced Apoe −/− mice [14]. In the present study we tried to determine whether the endogenous elevation of active incretins in diabetic Apoe −/− mice by DPP-4 inhibition exerts an anti-atherogenic effect comparable to that seen in nondiabetic Apoe −/− mice.…”

Long-Acting Glucose-Dependent Insulinotropic Polypeptide Ameliorates Obesity-Induced Adipose Tissue Inflammation

“…The in vivo anti-inflammatory effect of GIP was suggested by studies showing reduced adipose tissue inflammatory cytokines in GIP-overexpressing transgenic mice (23) and by reduced atherosclerosis following administration of exogenous GIP (24,25). Nevertheless, the role of GIP in adipose tissue inflammation with respect to mobilization and function of immune cells has not been thoroughly investigated.…”

“…Nevertheless, the role of GIP in adipose tissue inflammation with respect to mobilization and function of immune cells has not been thoroughly investigated. The present study investigated the in vivo effect of short-term or long-term administration of a long-lasting GIP analog, [ ]GIP in rodent models (24)(25)(26)(27). Animals had unrestricted access to food and water, were housed in temperature and humiditycontrolled rooms, and were kept on a 12-h light/dark cycle.…”