title: Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake.
abstract: Dietary advanced glycosylation end products (AGEs) have been linked to insulin resistance in db/db(++) mice. To test whether dietary AGEs play a role in the progression of insulin resistance in normal mice fed high-fat diets, normal C57/BL6 mice were randomly assigned to high-fat diets (35% g fat), either high (HAGE-HF group; 995.4 units/mg AGE) or low (by 2.4-fold LAGE-HF group; 329.6 units/mg AGE) in AGE content for 6 months. Age-matched C57/BL6 and db/db(++) mice fed regular diet (5% g fat, 117.4 units/mg AGE) served as controls. After 6 months, 75% of HAGE-HF mice were diabetic and exhibited higher body weight (P < 0.001), fasting glucose (P < 0.001), insulin (P < 0.001), and serum AGEs (P < 0.01) than control mice, while none of the LAGE-HF mice were diabetic despite a similar rise in body weight and plasma lipids. The HAGE-HF group displayed markedly impaired glucose and insulin responses during glucose tolerance tests and euglycemic and hyperglycemic clamps and altered pancreatic islet structure and function compared with those of LAGE-HF mice, in which findings resembled those of control mice. The HAGE-HF group had more visceral fat (by two- and fourfold) and more AGE-modified fat (by two- and fivefold) than LAGE-HF and control mice, respectively. In the HAGE-HF group, plasma 8-isoprostane was higher (P < 0.01) and adiponectin lower (P < 0.001) than control mice, while in the LAGE-HF group, these were more modestly affected (P < 0.05). These results demonstrate that the development of insulin resistance and type 2 diabetes during prolonged high-fat feeding are linked to the excess AGEs/advanced lipoxidation end products inherent in fatty diets.
authors.affiliation: The Brookdale Department of Geriatrics, Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, One Gustave Levy Place, Box 1640, New York, NY 10029, USA.
authors.forename: Oana
authors.initials: O
authors.lastname: Sandu
authors.forename: Keying
authors.initials: K
authors.lastname: Song
authors.forename: Weijing
authors.initials: W
authors.lastname: Cai
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.forename: Jaime
authors.initials: J
authors.lastname: Uribarri
authors.forename: Helen
authors.initials: H
authors.lastname: Vlassara
mesh_terms: D052242:Adiponectin; D000273:Adipose Tissue / Q000737:chemistry; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001835:Body Weight; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology*; D004041:Dietary Fats / Q000008:administration & dosage*; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D005215:Fasting; D005260:Female; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D017127:Glycation End Products, Advanced / Q000008:administration & dosage* / Q000032:analysis / Q000097:blood; D006965:Hyperplasia; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood; D007515:Islets of Langerhans / Q000473:pathology; D008055:Lipids / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D052242:Adiponectin; D001786:Blood Glucose; D004041:Dietary Fats; D017127:Glycation End Products, Advanced; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D008055:Lipids; C075750:8-epi-prostaglandin F2alpha; D015237:Dinoprost