Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1
Jaime Uribarri, Weijing Cai, Maya Ramdas, Susan Goodman, Renata Pyzik, Xue Chen, Li Zhu, Gary E Striker, Helen Vlassara, Jaime Uribarri, Weijing Cai, Maya Ramdas, Susan Goodman, Renata Pyzik, Xue Chen, Li Zhu, Gary E Striker, Helen Vlassara
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.
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Source: PubMed