AGE restriction in diabetes mellitus: a paradigm shift

Abstract

Persistently elevated oxidative stress and inflammation precede or occur during the development of type 1 or type 2 diabetes mellitus and precipitate devastating complications. Given the rapidly increasing incidence of diabetes mellitus and obesity in the space of a few decades, new genetic mutations are unlikely to be the cause, instead pointing to environmental initiators. A hallmark of contemporary culture is a preference for thermally processed foods, replete with pro-oxidant advanced glycation endproducts (AGEs). These molecules are appetite-increasing and, thus, efficient enhancers of overnutrition (which promotes obesity) and oxidant overload (which promotes inflammation). Studies of genetic and nongenetic animal models of diabetes mellitus suggest that suppression of host defenses, under sustained pressure from food-derived AGEs, may potentially shift homeostasis towards a higher basal level of oxidative stress, inflammation and injury of both insulin-producing and insulin-responsive cells. This sequence promotes both types of diabetes mellitus. Reducing basal oxidative stress by AGE restriction in mice, without energy or nutrient change, reinstates host defenses, alleviates inflammation, prevents diabetes mellitus, vascular and renal complications and extends normal lifespan. Studies in healthy humans and in those with diabetes mellitus show that consumption of high amounts of food-related AGEs is a determinant of insulin resistance and inflammation and that AGE restriction improves both. This Review focuses on AGEs as novel initiators of oxidative stress that precedes, rather than results from, diabetes mellitus. Therapeutic gains from AGE restriction constitute a paradigm shift.

Figure 1

Detrimental effects of overnutrition. a | The classic scheme: high levels of pro-oxidant AGEs result from chronic hyperglycemia and contribute to diabetic complications. Overnutrition promotes inflammation and insulin resistance. Excess nutrient availability (via neuroendocrine networks) stimulates food intake, which promotes weight gain and obesity. These conditions are associated with increased inflammation, known to underlie insulin sensitivity, β-cell injury and diabetes mellitus. Chronic hyperglycemia increases intracellular oxidative stress (that is, from mitochondria or the endoplasmic reticulum) and increases the risk of complications, including cardiovascular disease, retinopathy, chronic kidney disease and neuropathy, involving the central and peripheral nervous systems. b | A paradigm shift: AGEs precede diabetes mellitus. Modern food contains appetite-enhancing AGEs, which promote food consumption and overnutrition, leading to increased BMI, obesity and diabetes mellitus, as well as oxidant overload. Sustained influx of nutrient AGEs and ALEs leads to suppression of innate host defenses and a surplus of intracellular ROS, which increases the basal oxidant stress and inflammation. The combination of these processes can simultaneously cause β-cell dysfunction, impaired insulin secretion and insulin resistance, as well as diabetic complications. Restriction of food-derived AGEs reduces oxidative stress and prevents or improves type 1 and type 2 diabetes mellitus in mice. Abbreviations: AGE, advanced glycation endproduct; ALE, advanced lipoxidation endproduct; CNS, central nervous system; ROS, reactive oxygen species.

Figure 2

Synergism between AGER1 and SIRT1. Innate host defense cells, monocytes and macrophages normally bind, endocytose and degrade AGEs via the cell-surface AGER1 (also known as DDOST), the levels of which normally correlate inversely with intracellular levels of AGEs. Prolonged supply of external AGEs, however, depletes AGER1. Ensuing surplus ROS promotes inflammation via RAGE, TLR4, EGFR and other receptors regulating the activities of NFκB, AP-1, FOXO3 and other factors, via numerous pathways. These increase AGEs, ROS and inflammatory mediators, including RAGE and its ligands. AGEs, acting via ROS, are potent suppressors of NAD⁺, partly by reducing NAMPT and SIRT1 levels. Decreased SIRT1 levels promote NFκB p65 hyperacetylation and enhanced transcription of inflammatory genes consistent with an M1 macrophage profile. For instance, TNF induces an overlapping set of target genes, which contributes to insulin resistance. AGER1, by blocking AGEs, controls many of these effects. The protective effects of AGER1 may stem from its long extracellular tail with high-affinity AGE-binding, which competitively interferes with AGE–cell-surface interactions leading to ROS. This property may constitute the essence of the positive synergism between AGER1 and SIRT1. Though suppressed in humans and animals with chronic diabetes mellitus, monocyte/macrophage AGER1 and SIRT1 levels can be restored to normal following AGE restriction. Abbreviations: AGE, advanced glycation endproduct; AGER1, AGE receptor 1; EGFR, epidermal growth factor receptor; ERK1/2, extracellular signal-regulated kinase 1/2; FOXO3, forkhead box protein O3; MAPK, mitogen-activated protein kinase; MYD88, myeloid differentiation primary response protein MyD88; NAMPT, nicotinamide phosphoribosyltransferase; NFκB, nuclear factor κB; PKCδ, protein kinase C δ type; RAGE, receptor for advanced glycosylation endproducts; ROS, reactive oxygen species; SIRT1, NAD-dependent deacetylase sirtuin-1; TLR4, toll-like receptor 4; TNF, tumor necrosis factor.

Figure 3

Excessive AGEs impair insulin sensitivity in insulin-target tissues. In adipocytes, as in immune cells, AGE-mediated effects are normally controlled by AGER1, via ROS suppression, protecting SIRT1-dependent insulin functions. Excessive food-derived protein and lipid AGEs can suppress AGER1 and other host defenses, reversing this balance. For instance, exposure to AGEs reduces insulin receptor and IRS1 tyrosine phosphorylation and increases IRS1 serine phosphorylation, resulting in impaired insulin signaling and decreased glucose uptake. Enhanced NFκB p65 hyperacetylation of preadipocytes, endothelial cells and immune cells residing in adipose tissue can also promote inflammatory cytokine production, impair FOXO3α activity and further ROS production. Restored AGER1 and SIRT1, following AGE restriction in individuals with diabetes mellitus, coincides with markedly lower plasma insulin levels and higher adiponectin levels —evidence of a crucial crosstalk between host defenses and metabolic pathways in diverse tissues and cells. Abbreviations: Acl, acetylation; AGE, advanced glycation endproduct; AGER1, AGE receptor 1; ALE, advanced lipoxidation endproduct; FOXO3α, forkhead box protein O3 α; GLUT4, glucose transporter type 4; IR, insulin receptor; IRS, insulin receptor substrate; NFκB, nuclear factor κB; pAkt, phosphorylated serine/threonine-protein kinase AKT; pSer, serine phosphorylation; pTyr, tyrosine phosphorylation; ROS, reactive oxygen species; SIRT1, NAD-dependent deacetylase sirtuin-1; SOD2, mitochondrial superoxide dismutase 2 [Mn].

Figure 4

AGEs impair insulin secretion in pancreatic islet β cells. This process can occur via several pathways: by iNOS induction, and through the generation of mitochondrial ROS, AGEs suppress cytochrome C oxidase levels and ATP generation, reducing membrane depolarization and insulin release; by suppressing insulin gene promoter activity; by suppressing SIRT1, which regulates UCP2, impairing β-cell depolarization and secretory function; by promoting immune cell (T cell, macrophage) recruitment, activation and β-cell cytotoxicity, apoptosis or cell death. AGER1 normally suppresses the effects of AGEs and ROS and may enhance SIRT1 expression and function in β cells, positively regulating insulin secretion. Under chronic high-level AGE conditions, AGER1 is downregulated, which may contribute to β-cell dysfunction or destruction. Abbreviations: AGE, advanced glycation endproduct; AGER1, AGE receptor 1; CytC, cytochrome c; iNOS, inducible nitric oxide synthase; SIRT1, NAD-dependent deacetylase sirtuin-1; UCP2, mitochondrial uncoupling protein 2.