Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake

Diabetes. 2005 Aug;54(8):2314-9. doi: 10.2337/diabetes.54.8.2314.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adiponectin
  • Adipose Tissue / chemistry
  • Animals
  • Blood Glucose / analysis
  • Body Weight
  • Diabetes Mellitus, Type 2 / etiology*
  • Dietary Fats / administration & dosage*
  • Dinoprost / analogs & derivatives
  • Dinoprost / blood
  • Fasting
  • Female
  • Glucose Clamp Technique
  • Glucose Tolerance Test
  • Glycation End Products, Advanced / administration & dosage*
  • Glycation End Products, Advanced / analysis
  • Glycation End Products, Advanced / blood
  • Hyperplasia
  • Insulin / blood
  • Insulin Resistance*
  • Intercellular Signaling Peptides and Proteins / blood
  • Islets of Langerhans / pathology
  • Lipids / blood
  • Mice
  • Mice, Inbred C57BL


  • Adiponectin
  • Blood Glucose
  • Dietary Fats
  • Glycation End Products, Advanced
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Lipids
  • 8-epi-prostaglandin F2alpha
  • Dinoprost