Hyperglycemia and Glycation in Diabetic Complications

Diabetes mellitus is a multifactorial disease, classically influenced by genetic determinants of individual susceptibility and by environmental accelerating factors, such as lifestyle. It is considered a major health concern, as its incidence is increasing at an alarming rate, and the high invalidating effects of its long-term complications affect macro- and microvasculature, heart, kidney, eye, and nerves. Increasing evidence indicates that hyperglycemia is the initiating cause of the tissue damage occurring in diabetes, either through repeated acute changes in cellular glucose metabolism, or through the long-term accumulation of glycated biomolecules and advanced glycation end products (AGEs). AGEs represent a heterogeneous group of chemical products resulting from a nonenzymatic reaction between reducing sugars and proteins, lipids, nucleic acids, or a combination of these. The glycation process (glucose fixation) affects circulating proteins (serum albumin, lipoprotein, insulin, hemoglobin), whereas the formation of AGEs implicates reactive intermediates such as methylglyoxal. AGEs form cross-links on long-lived extracellular matrix proteins or react with their specific receptor RAGE, resulting in oxidative stress and proinflammatory signaling implicated in endothelium dysfunction, arterial stiffening, and microvascular complications. This review summarizes the mechanism of glycation and of AGEs formation and the role of hyperglycemia, AGEs, and oxidative stress in the pathophysiology of diabetic complications. Antioxid. Redox Signal. 11, 3071–3109.

1. Introduction

2. Oxidative Stress and Metabolic Dysfunction in Acute Hyperglycemia and Diabetes

   1. Oxidative stress: Generalities

   2. Acute hyperglycemia, glycemia variability, and oxidative stress

      1. Acute hyperglycemia and oxidative stress in vivo

      2. High glucose induces ROS generation in cultured cells

   3. Chronic hyperglycemia and oxidative stress

      1. Hyperglycemia and mitochondrial free radical production

      2. ROS in the pathogenic mechanisms of diabetes complications

3. Glycation and AGEs: Formation, Excretion, and Biologic Effects

   1. Glycation and AGEs formation

      1. Chemical mechanisms of glycation and AGEs formation

      2. Exogenous glycation and AGEs formation

      3. Endogenous glycation and AGEs formation

   2. Defenses against glycation and AGEs

      1. Glucose has low glycating activity

      2. The digestive barrier limits the absorption of diet-derived AGEs

      3. Cellular defense mechanisms

         1. Low-molecular-weight agents

            1. Reduced glutathione

            2. Carbon monoxide

            3. Bilirubin and biliverdin reductase

            4. Uric acid

            5. Vitamins

         2. Cellular antioxidant defenses

            1. Superoxide dismutase

            2. Catalase

            3. Glutathione peroxidase

            4. Glutathione reductase and glutathione S-transferase

            5. Heme oxygenase

            6. Thioredoxin

         3. Cellular defenses against glycation and AGEs

            1. Amadoriases

            2. Glyoxalase system

         4. Proteolytic degradation by proteasome

      4. Role of the kidney and liver in the excretion of AGEs

   3. Molecular and cellular consequences of glycation and AGEs formation

      1. Glycation of circulating proteins

         1. Hemoglobin

         2. Insulin

         3. Serum albumin

         4. Lipoproteins

            1. LDL and VLDL

            2. Increased sensitivity to oxidation

            3. Foam cell formation

               1. 3072Glycated LDL-mediated inflammatory signaling

               2. Mitogenic and apoptotic effects

               3. Alteration of platelet function and procoagulant activity

               4. HDL

      2. Molecular and cellular effects of AGEs modification

         1. RAGE- (and related receptors)-dependent effects

            1. RAGE

               1. Structure of RAGE

               2. RAGE gene and polymorphisms

               3. Alternative splicing

               4. RAGE expression

               5. Ligand specificity

                  • AGEs

                  • S100 calgranulins

                  • High-mobility-group box protein-1

                  • Amyloid-β peptide and β-sheet fibrils

            2. AGEs receptors and scavenger receptors

               1. AGE-R1 or OST-48 (oligosaccharyl transferase-4)

               2. AGE-R2 (80K-H or PRKCSH)

               3. AGE-R3 or galectin-3

               4. Scavenger receptors

                  • CD36

                  • MSR-A

                  • SR-B1

                  • LOX-1

                  • Other AGEs-binding proteins

            3. AGE/RAGE-dependent cellular effects

               1. NF-κB activation and inflammatory signaling

               2. Arachidonic acid cascade

               3. Nitric oxide synthase

               4. Endothelium activation

               5. Cell proliferation

               6. Angiogenesis

               7. Cytokines, growth factors, and chemokines secretion

               8. Differentiation

               9. Thrombosis

               10. Apoptosis

               11. RAGE-mediated immune responses

         2. RAGE-independent effects

            1. Biologic consequences of AGEs formation on extracellular matrix

            2. Biologic consequences of AGEs formation on cellular proteins

            3. Biologic consequences of AGEs formation on DNA

            4. Biologic consequences of AGEs-modified lipids

   4. Glycation and AGEs in the pathophysiology of diabetes complications

      1. Pathophysiologic role of dietary AGEs

      2. Accelerated diabetic atherosclerosis

      3. Arterial stiffening

      4. Restenosis

      5. Microvascular complications

         1. Retinopathy

         2. Nephropathy

         3. Neuropathy

         4. Wound healing

      6. Alzheimer's disease

      7. Cancers

      8. Osteoporosis

4. Conclusions and Perspectives3073