PRIME Journal Vol. 10 Issue 6

Figure 3 Vicious cycles induced by glycative stress changes greatly. The formation of 2SC-adiponectin 3 , 2SC- GAPDH (glyceraldehyde-3-phosphate dehydrogenase) 4 has been reported 4 . These two reactions are representative modifications after protein translation caused by glycative stress. Glycative stress causes diabetic complications and various disorders, such as cataracts (glycated crystallin), dementia (glycated β -amyloid), osteoporosis (glycated type I collagen), and skin ageing (glycated collagen and elastin) 1 . The parentheses indicate the name of glycated proteins that plays a pathogenetic role in each disease. Furthermore, glycative stress damages the pancreas, kidney, visceral fat and skeletal muscles, and it was found that these ‘vicious’ cycles cause glycative stress to be further intensified through these disorders 5 . In this article, wewill explain themechanismof these cycles caused by glycative stress ( Figure 3 ). Insulin disorder Type 2 diabetesmellitus (T2DM) is a representative disease inwhichglycativestressishigh,progresseswithinadequate insulin secretion, and prolonged elevated circulating glucose levels. It is confirmed through experiments that when AGEs are topically applied onto pancreatic β -cells, insulinmRNA began decreasing as well as the syntheses of proinsulin and insulin secretion 5 . If the additive amount of AGEs is larger, it causes apoptosis in β -cells. The structure of insulin, a peptide hormone, is shown in Figure 4 5 . Initially, it is biosynthesized as pre-proinsulin in the endoplasmic reticulum (ER). The signal peptide is then cleaved off and becomes proinsulin. Proinsulin is a peptide combined with chains in the order of B chain, C chain, and A chain. After being carried to the Golgi body, proinsulin is cleaved by protease, C-chain (C peptide) is removed, and insulin is produced. The structure of human insulin (molecular weight: 5,807) is one which A chain with 21 amino-acid residues and B chain with 30 peptide chains are combined by disulfide bonds. There is also one disulfide bond in the A chain. If 2SC is formed, A chain and B chain may not combine. In conditions with high glycative stress, the synthesis and secretion of insulin is reduced in β -cells 6–8 . Open-chain glucose, open-chain fructose, or aldehydes (i.e. GA, 3-DG, GO, MGO) coming fromoutside the cell react with pre-proinsulin and proinsulin within cells. Protein modification is then caused by carbonylation, which is then further metabolized and finally forms AGEs. Arginine and lysine are susceptible to carbonyl modification among amino acid sequences of insulin, both of which are dibasic amino acids. This is because dibasic amino acids can retain another amino group (-NH2) even after an amino group was used for peptide bonds. We have a hypothesis that if arginine and lysine at both ends of C-peptide are modified, protease resistance increases, and as a result, C-peptide becomes unable to be disconnected and insulin synthesis decreases. In the case of patients with T2DM, because 9% of insulin in the serumchanges to glycated insulin, insulin resistance becomes elevated 9 . Glycated insulin has no function to uptake glucose into cells and cannot exert an insulin Blood glucose GLUCOSE SPIKE Postprandial hyperglycemia 150mg/dL INSULIN RESISTANCE AGEs ER stress Cytoplasm Scavenger receptors ß Cell IL-6 TNF- α Cytokine formation RAGE Cell Deposit GO,MGO, 3DG, GA Aldehyde Spark Enzyme function 2SC-GAPDH 2SC - Adiponectin Glycated Insulin TCA cycle disorder 2SC-Protein Hormone function Fumarate GA Mitochondria disorder Carbonylated protein INSULIN SECRETION GLYCATIVE STRESS Figure 1 Two ways from glycative stress to proteinmodification GAPDH activity GA Glycative stress Adiponectin Insulin resistance Glycated insulin T2DM stage Glycative stress AGEs Insulin secretion Mitochondria damage 2SC-Adiponectin Glucose spikes Aldehyde sparks Glucose Aldehyde Fumarate 2SC-GAPDH ER stress in ß-cells Fumarate Figure 2 TCA cycle disorder induced by glycative stress and cysteine succination High Glucose TCA cycle disorder Fumarate H Cysteine + Michael addition reaction 2SC S-(2-succinyl)cysteine C C HOOC H COOH S CH 2 H 2 N CH COOH CH 2 COOH CHCOOH S CH 2 COOH CH H 2 N Figure 1 Two ways from glycative stress to protein modification. AGE, advanced glycation end product; RAGE, receptor for AGE; GO, glyoxal; MGO, methylglyoxal; 3DG, 3-deoxyglucosone; GA, glyceraldehyde: 2SC, S-(2-succunyl)cysteine; GAPDH, glyceraldehyde-3- phosphate dehydrogenase; LDL-C, low-density lipoprotein-cholesterol; TCA, tricarboxylic acid. Figure 2 TCA cycle disorder induced by glycative stress and cysteine succination Figure 3 Vicious cycles induced by glycative stress. T2DM progresses by vicious cycles, which must be ceased by anti-glycation therapy. AGEs, advanced glycation end products; ER, endoplasmic reticulum; T2DM, type 2 diabetes mellitus; 2SC, S-(2-succunyl)cysteine; GA, glyceraldehyde; GAPDH, glyceraldehyde-3-phosphate dehydrogenase | GLYCATIVE STRESS | AESTHETIC FEATURE | November/December 2020 35