Journal Article

Restriction of Advanced Glycation End Products Improves Insulin Resistance in Human Type 2 Diabetes: Potential role of AGER1 and SIRT1

LI ZHU, GOODMAN, Susan, RAMDAS, Maya, WEIJING CAI, STRIKER, Gary E, URIBARRI, Jaime, PYZIK, Renata, VLASSARA, Helen, XUE CHEN

2011

Overview

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. 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. 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. 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.

• Publisher: American Diabetes Association
• Subject: acetylation / adiponectin / administration & dosage / adverse effects / Aged / Biological and medical sciences / blood serum / Care and treatment / Cells, Cultured / Diabetes / Diabetes Mellitus, Type 2 / Diabetes Mellitus, Type 2 - physiopathology / Diabetes. Impaired glucose tolerance / Diet / drug effects / Endocrine pancreas. Apud cells (diseases) / Endocrinopathies / Etiopathogenesis. Screening. Investigations. Target tissue resistance / Female / glycation / Glycation End Products, Advanced - administration & dosage / Glycation End Products, Advanced - adverse effects / Glycosylation End Products, Advanced / homeostasis / Humans / Hypoglycemic Agents / Hypoglycemic Agents - therapeutic use / Inflammation / Inflammation - therapy / insulin / Insulin resistance / Insulin Resistance - physiology / leptin / Leukocytes, Mononuclear / Leukocytes, Mononuclear - metabolism / Male / Medical sciences / messenger RNA / Metabolic diseases / metabolism / Middle Aged / Miscellaneous / mononuclear leukocytes / necrosis / noninsulin-dependent diabetes mellitus / Nutrition / Original Research / oxidative stress / Oxidative Stress - drug effects / patients / physiology / physiopathology / Public health. Hygiene / Public health. Hygiene-occupational medicine / Receptor for Advanced Glycation End Products / Receptors, Immunologic / Receptors, Immunologic - physiology / Sirtuin 1 / Sirtuin 1 - physiology / therapeutic use / therapy / tumor necrosis factor-alpha / Type 2 diabetes