title: Glucose-dependent insulinotropic polypeptide prevents the progression of macrophage-driven atherosclerosis in diabetic apolipoprotein E-null mice.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine, Tokyo, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Nogi
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nagashima
authors.forename: Michishige
authors.initials: M
authors.lastname: Terasaki
authors.forename: Kyoko
authors.initials: K
authors.lastname: Nohtomi
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D001202:Ascitic Fluid / Q000473:pathology; D050197:Atherosclerosis / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D015536:Down-Regulation; D005487:Foam Cells / Q000378:metabolism / Q000473:pathology*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology / Q000627:therapeutic use*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D007515:Islets of Langerhans / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D011964:Receptors, Gastrointestinal Hormone / Q000235:genetics / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D011964:Receptors, Gastrointestinal Hormone; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor