Restriction of Advanced Glycation End Products Improves Insulin Resistance in Human Type 2 Diabetes

Potential role of AGER1 and SIRT1

  1. Helen Vlassara, MD2
  1. 1Department of Medicine, The Mount Sinai School of Medicine, New York, New York
  2. 2Department of Geriatrics, The Mount Sinai School of Medicine, New York, New York
  1. Corresponding author: Helen Vlassara, helen.vlassara{at}mssm.edu.

Abstract

OBJECTIVE Increased oxidative stress (OS) and impaired anti-OS defenses are important in the development and persistence of insulin resistance (IR). Several anti-inflammatory and cell-protective mechanisms, including advanced glycation end product (AGE) receptor-1 (AGER1) and sirtuin (silent mating-type information regulation 2 homolog) 1 (SIRT1) are suppressed in diabetes. Because basal OS in type 2 diabetic patients is influenced by the consumption of AGEs, we examined whether AGE consumption also affects IR and whether AGER1 and SIRT1 are involved.

RESEARCH DESIGN AND METHODS The study randomly assigned 36 subjects, 18 type 2 diabetic patients (age 61 ± 4 years) and 18 healthy subjects (age 67 ± 1.4 years), to a standard diet (>20 AGE equivalents [Eq]/day) or an isocaloric AGE-restricted diet (<10 AGE Eq/day) for 4 months. Circulating metabolic and inflammatory markers were assessed. Expression and activities of AGER1 and SIRT1 were examined in patients’ peripheral blood mononuclear cells (PMNC) and in AGE-stimulated, AGER1-transduced (AGER1+), or AGER1-silenced human monocyte-like THP-1 cells.

RESULTS Insulin and homeostasis model assessment, leptin, tumor necrosis factor-α and nuclear factor-κB p65 acetylation, serum AGEs, and 8-isoprostanes decreased in AGE-restricted type 2 diabetic patients, whereas PMNC AGER1 and SIRT1 mRNA, and protein levels normalized and adiponectin markedly increased. AGEs suppressed AGER1, SIRT-1, and NAD+ levels in THP-1 cells. These effects were inhibited in AGER1+ but were enhanced in AGER1-silenced cells.

CONCLUSIONS Food-derived pro-oxidant AGEs may contribute to IR in clinical type 2 diabetes and suppress protective mechanisms, AGER1 and SIRT1. AGE restriction may preserve native defenses and insulin sensitivity by maintaining lower basal OS.

  • Received January 14, 2011.
  • Accepted April 12, 2011.

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