Improved Insulin Sensitivity Is Associated With Restricted Intake of Dietary Glycoxidation Products in the db/db Mouse

  1. Susanna M. Hofmann1,
  2. Heng-Jiang Dong2,
  3. Zhu Li1,
  4. Weijing Cai1,
  5. Jennifer Altomonte2,
  6. Swan N. Thung3,
  7. Feng Zeng1,
  8. Edward A. Fisher4 and
  9. Helen Vlassara12
  1. 1Division of Experimental Diabetes and Aging, Mount Sinai School of Medicine, New York, New York
  2. 2Institute for Gene Therapy and Molecular Medicine, Mount Sinai School of Medicine, New York, New York
  3. 3Department of Pathology, Mount Sinai School of Medicine, New York, New York
  4. 4Laboratory of Lipoprotein Research, the Cardiovascular Institute, Mount Sinai School of Medicine, New York, New York

    Abstract

    Advanced glycation end products (AGEs), known promoters of diabetic complications, form abundantly in heated foods and are ingested in bioreactive forms. To test whether dietary AGEs play a role in the progression of insulin resistance, C57/BL/KsJ db/db mice were randomly placed for 20 weeks on a diet with either a low AGE content (LAD) or a 3.4-fold higher content of AGE (high AGE diet [HAD]), including εN-carboxymethyllysine (CML) and methylglyoxal (MG). LAD-fed mice showed lower fasting plasma insulin levels throughout the study (P = 0.01). Body weight was reduced by ∼13% compared with HAD-fed mice (P = 0.04) despite equal food intake. LAD-fed mice exhibited significantly improved responses to both glucose (at 40 min, P = 0.003) and insulin (at 60 min, P = 0.007) tolerance tests, which correlated with a twofold higher glucose uptake by adipose tissue (P = 0.02). Compared with the severe hypertrophy and morphological disorganization of islets from HAD-fed mice, LAD-fed mice presented a better-preserved structure of the islets. LAD-fed mice demonstrated significantly increased plasma HDL concentrations (P < 0.0001). Consistent with these observations, LAD-fed mice exhibited twofold lower serum CML and MG concentrations compared with HAD-fed mice (P = 0.02). These results demonstrate that reduced AGE intake leads to lower levels of circulating AGE and to improved insulin sensitivity in db/db mice.

    Footnotes

    • Address correspondence and reprint requests to Susanna Hofmann, MD, Mount Sinai School of Medicine, Division of Experimental Diabetes and Aging, Brookdale Department of Geriatrics, Box 1640, One Gustave L. Levy Place, New York, New York 10029-6574. E-mail: susanna.hofmann{at}mssm.edu.

      Received for publication 22 October 2001 and accepted in revised form 12 April 2002.

      2-[3H]DG, [1,2-3H]deoxy-d-glucose; AGE, advanced glycation end product; CML, εN-carboxymethyllysine; ELISA, enzyme-linked immunosorbent assay; FPLC, fast-performance liquid chromatography; HAD, high AGE diet; IR, insulin resistance; ITT, insulin tolerance test; IVGTT, intravenous glucose tolerance test; LAD, low AGE diet; MG, methylglyoxal.

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