Glycative Stress Research
Online edition : ISSN 2188-3610
Print edition : ISSN 2188-3602
Received : January 3, 2020
Accepted : January 31, 2020
Published online : March 31, 2020
doi:10.24659/gsr.7.1_13

Review article

Stop the “Vicious Cycle” induced by Glycative Stress.
Yoshikazu Yonei, Masayuki Yagi, Wakako Takabe
Anti-Aging Medical Research Center and Glycative Stress Research Center,
Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan

Abstract

Glycative stress causes post-translational modifications of protein at the molecular level and increases the risks ofvarious aging-related diseases, such as diabetic complications. There are two representative processes of the unphysiologicalprotein modifications, i.e. (1) the carbonylation caused by aldehyde derived from glucose and lipids and the formation ofadvanced glycation end products (AGEs), and (2) cysteine succination derived from a disorder of the TCA cycle. Endoplasmic
reticulum (ER) stress increases in pancreatic β-cells due to the formation of AGEs caused by glycative stress, and causes a
reduction in insulin secretion. Lysine and arginine in amino acid sequence of insulin are susceptible to carbonyl modification
and are resistant against the enzyme reaction to insulin from proinsulin. As a result, insulin synthetic quantity decreases.
Approximately 9% of insulin in serum of patients with diabetes becomes glycated insulin, and it causes the patient’s insulin
resistance. These findings show that glycative stress is involved not only in diabetic complications, but also the onset anddevelopment of diabetes. It has also become clear that there is a “vicious cycle” to increase the onset of diseases caused byglycative stress. Similarly, “vicious cycles” also exist through visceral fat, kidney and skeletal muscles. Recently the diseases
caused by glycative stress are increasing worldwide. In order to prevent the onset and development of these diseases related toglycative stress, it is important to (1) implement countermeasures against glycative stress at an early stage and (2) understandthe mechanisms of these vicious cycles and prevent them.

KEY WORDS: advanced glycation end products (AGEs), glyceraldehyde,		dehydrogenase (GAPDH), TCA cycle, succination

Introduction: What is Glycative Stress?

Glycative stress is the condition where various aldehydes
derived from reducing sugars, lipids and alcohol are
generated in excess in the living body. These aldehydes reactwith the substances in the body such as protein and generate
carbonyl modified proteins and advanced glycation end
products (AGEs), enhance the secretion of inflammatory
cytokine by stimulating AGEs/RAGE (receptor for AGEs)
signals, and causes various disorders in cells and tissues 1, 2).
Furthermore, glycative stress causes disorders of TCA cyclein mitochondria and causes succination of protein 1). These
two reactions are representative modifications after proteintranslation caused by glycative stress.
The causes responsible for glycative stress are (1)“glucose spike” and (2) dyslipidemia (hyper-triglyceridemia
and hyper-LDL cholesterolemia) and (3) excessive drinking.

What is common to these three causes is aldehyde. There arequite a few people whose blood glucose level becomes higher
than 140 mg/dL after a meal even though their fasting blood
glucose level is normal. This type of postprandial blood
glucose is called a glucose spike and it has become known toaccelerate the progression of arteriosclerosis and is closely
related to the onset of cerebro-cardiovascular events. Glucose
spikes evoke an “aldehyde sparks” and furthermore, a varietyof aldehydes with strong reactivity are generated at once bychain reactions 3, 4).
Glycative stress causes not only diabetic complications
but is also involved in the onset and development of various
disorders such as cataract (glycated crystallin) 5, 6), dementia(glycated β amyloid ) 7, 8), osteoporosis (glycated type I
collagen) 9, 10), and skin aging (glycated collagen and elastin)2, 11, 12). Furthermore, glycative stress damages the pancreas,kidney, visceral fat and skeletal muscles, and it was foundContact Address: Professor Yoshikazu Yonei, MD, PhD
Anti-Aging Medical Research Center / Glycative Stress Research Center,
Graduate School of Life and Medical Sciences, Doshisha University
1-3, Tatara Miyakodani, Kyotanabe , Kyoto, 610- 0394 Japan

Tel / Fax: +81-774-65-6394 e-mail: yyonei@mail.doshisha.ac.jp
Co-authors: Yagi M, myagi@mail.doshisha.ac. jp ;Takabe W, wtakabe@mail.doshisha.ac. jp

Glycative Stress Research 2020; 7 (1) : 13 - 21(c) Society for Glycative Stress Research_ 13 _

Stop the “Vicious Cycle” induced by Glycative Stressthat these vicious cycles cause glycative stress to be further
intensified through these disorders. In this report, we will
explain the mechanism of these cycles caused by glycative
stress.

Vicious Cycles through Pancreas
Insulin is synthesized in pancreatic β-cells in thefollowing process (Fig. 1): Initially, it is biosynthesized as
pre-proinsulin in the rough endoplasmic reticulum (ER). The“pre” is signal-peptide, and after polypeptide is synthesized
and moves to the ER, it is cleaved off and becomesproinsulin. Proinsulin is a peptide combined with chains in
the order of B chain, C chain and A chain.
After being carried to Golgi body, proinsulin is cleaved
from protease, C-chain (C peptide) is removed and insulin
is produced. The structure of human insulin (molecularweight: 5,807) is that where A chain with 21 amino-acidresidues and B chain with 30 peptide chains are combinedby disulfide bonds. There is one disulfide bond also in the
A chain. Synthesized insulin is accumulated in cells andsecreted from cells by secretion stimulation.
Glycative stress also has an effect on β-cells and reduces
the synthesis and secretion of insulin 13 -15). Open-chain
glucose, open-chain fructose, aldehydes coming from outside
the cell and free fatty acids (FFA) are pointed out as factorsof glycative stress within cells.
What most often causes small amounts of aldehydes isthe formation of various aldehydes (aldehyde spark) that
occurs in chain reactions following postprandial hyperglycemia(glucose spike). When this occurs, glyceraldehyde (GA),glycolaldehyde, 3-deoxyglucosome (3-DG), glyoxal (GO) andmethylglyoxal (MGO) are synthesized 16).
While FFA is excessively accumulated in adipocytes as
triglycerides in a process leading to obesity, its level in blood ismaintained mainly under the lipase control and utilized by eachcell and tissue. The phenomenon where excessive FFA impairs
the secretion of insulin is called β-cell lipotoxicity 17, 18).
Actually, keto group (C= O) and aldehyde group (-CHO)
substances with aggressive-reactivity are synthesized from
FFA, which may be protein modification by carbonylation.
Carbonylated protein is metabolized furthermore and finallyforms AGEs.
Arginine and lysine are susceptible to carbonyl
modification among amino acid sequences of insulin, bothof which are dibasic amino acids. This is because dibasic
amino acids can retain another amino group (-NH 2) evenafter an amino group was used for peptide bonds. We havea 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 andinsulin synthesis decreases.
In the case of patients with type 2 diabetes mellitus(T2DM), because 9 % of insulin in the serum changes toglycated insulin, insulin resistance becomes elevated 19).
Glycated insulin has no function of uptaking glucose into
cells and cannot exert insulin function 20).
Furthermore, it is reported that in the conditions
where glycative stress is strong because of hyperglycemia
or otherwise, a TCA cycle disorder within mitochondria
tends to occur. If NAD (nicotinamide adenine dinucleotide)is depleted, the TCA cycle becomes unable to work wellFig. 1. The structure of insulin, proinsulin and pre-proinsulin.

_ 14 _Glycative Stress Research

H

S-

COOH

C

CH2

C
HOOC

H2N

H

CH

COOH

CH2COOHCHCOOHS
CH2
H2N CH COOH
Fig. 2. TCA cycle disorder induced by glycative stress and cysteine succination.
2SC, S-(2-succinyl)cysteine.

becomes strong, the produced amount of glycative insulin
increases, insulin resistance becomes more elevated anddiabetic stage further proceeds. Glycative stress develops andcomplicates T2DM through the cycles described above. It isvery important to inhibit these cycles with countermeasuresagainst glycative stress.

120

**

100

% Ratiosand fumarate is accumulated. Figure 2 shows the forming
process of cysteine succination (2SC) 1, 21, 22). If cysteine,
which is supposed to form a physiological disulfide bond, is
modified, the protein’s three-dimensional structure greatlychanges. The reason why fumarate becomes excessive inmitochondria is unknown; it may be because it is moreresistant to metabolization than citrate, ketoglutarate,
succinate, malate and oxaloacetate.
The protein becomes able to maintain normal threedimensional structure immediately after translation andbecomes a mature protein with physiological function by
being folded and modified in the ER. However, due to theincrease of glycative stress and decrease of chaperone
function, abnormal protein increases and synthesis of normal
protein is impaired. This is the condition where ER stressadvances. It is said that 30% of insulin synthesized in β-cells
is produced as ill-folded protein. Chaperone is a generic term
used to refer to proteins that combine with unfolded andimmature proteins to help them reach a normal condition(physiological condition) where they are appropriately folded.
In the experiment in this research, it was also confirmedthat when pancreatic β-cells were given the load of glycative
Fig. 3stress, insulin mRNA began decreasing and the syntheses
23)
of proinsulin and insulin protein decrease (Fig. 3 ) . If theadditive amount of AGEs is larger, it causes apoptosis in
β-cells.
Figure 4 shows the mechanism of these cycles throughthe pancreas. If glycative stress becomes strong, theproduction of AGEs increases, the secretion of insulin
decreases, diabetic stage further proceeds and glycative stressbecomes stronger. Another cycle shows that if glycative stress

**

80
60
40
20
0

Insulin mRNA
CTR
insulin
(+)
(−)
mRNA
Glycated HSA

Proinsulin
proinsulin

InsulininsulinWestern blot

Fig. 3. Influence of glycative stress on insulin synthesis in
the pancreatic β-cells.

_ 15 _

RIN-m5F cells are incubated with glycated HSA for 48 hours.
Insulin mRNA measured by the real-time PCR method.
Results are expressed as mean ± SD, n = 3. HSA, human serum
albumin; PCR, polymerase chain reaction; SD, standard
deviation. Data quoted from Reference 23).

Stop the “Vicious Cycle” induced by Glycative Stress

ER stress↑in Pancreas β cell

AGEs↑

Insulin secretion↓
Stages proceed

T2DM stage↑

Glucose↑
Aldehydes↑

Insulin resistance↑

Glycative stress↑

Glycated insulin↑

Fig. 4

Fig. 4. Vicious cycles induced by glycative stress in the pancreas.

AGEs, advanced glycation end products; ER, endoplasmic reticulum; T2DM, type diabetes mellitus.

A vicious Cycle through Visceral Fat Cells
Adiponectin is one of the beneficial substances among
biologically active substances (adipocytokine) secreted fromthe visceral adipose tissue, and it is a protein consisting of
244 amino acids. It exhibits actions including enhancementof fatty acid oxidation, inhibition of hepatic gluconeogenesis
and reduction of insulin resistance, performs preventive action
against diabetes and prevents arterial sclerosis 24). Adiponectinconsists of three monomers and forms the structure of threechain helices (trimers) by interaction and is stabilized bydisulfide bond of cysteine. The free cysteine of the trimer
formed in this way by being disulfide bonded forms hexamersor polymers 25). When stress increases, fumarate increased

by TCA cycle disorder causes 2SC modification to trimer
adiponectin and inhibits the formation of hexamer 21, 22). As aresult, it becomes difficult for adiponectin to pass through thecell membrane, so its secretion decreases (Fig. 5 ).
Figure 6 shows another vicious cycle through visceraladipose tissue. TCA cycle disorder is caused by glycative
stress enhancement within mitochondria, so fumarate isaccumulated. As a result, the formation of hexamer is inhibitedby 2SC modification, adiponectin secretion decreases andinsulin resistance increases, and as a result, glycative stressfurther increases. The inhibition of the vicious cycle bycountermeasures against glycative stress is important forthe prevention of the onset and development of metabolic
syndrome and T2DM.

Insulin resistance↑

High Glucose

Serum Adiponectin↓
2SC-Adiponectin(trimer)

TCA cycle
disorderHexamers passthrough membrane

2SC

Reaction tocysteine

Fumarate↑

Fig. 5

Fig. 5. Succination of adiponectin.

2SC-Adiponectin (trimer)
cannot pass

Adipocyte

2SC, S-(2-succinyl)cysteine. The figure quoted and modified from Reference 21, 22)_ 16 _Glycative Stress Research

TCA cycle disorder↑

Fumarate↑

Adipocytes

2SC-Adiponectin↑

Mitochondria
dysfunction ↑Glucose↑Secretion↓

Serum
Adiponectin↓

Glucose↑Glycative stress↑

Insulinresistance↑
Fig. 6
Fig. 6. A vicious cycle induced by glycative stress in the visceral adipose tissue.
2SC, S-(2-succinyl)cysteine.

Vicious Cycles through Kidney
The kidney is the most important organ for the clearanceof AGEs by playing the role in decomposition and excretionof AGEs. In the process of development of chronic kidneydisease (CKD) leading to kidney failure, AGEs increase
remarkably in body fluid, cells and tissues, and degenerativechanges caused by glycative stress are observed in the
body. In the case of dialysis patients, arterial sclerosis
mainly comprising ectopic calcification develops, leading toosteoporosis. AGEs remarkably affect skin and muscles, andthey present with hardening and pigmentation of skin andskeletal muscle atrophy (sarcopenia) 26 -28).
Recently, the relationship between kidney function
decline and cognitive function decline has been clarified 29 - 31).
The disease rate of cognitive function decline among thosewith even mild to moderate CKD before dialysis is high.
The cognitive function decline of the patients with CKD isoften caused by vascular risk factors. Its relationship withneurodegenerative diseases such as Alzheimer’s is also
becoming clear.
Diabetic kidney disease, among other diabetic
complications, interferes with urinary excretion of waste
matter from the body, and eventually leads to kidney failure.
The essence of the clinical condition is the glycation ofproteins forming kidney glomerular basement membrane 32, 33).
The basement membrane includes IV-type collagen and partly
consists of proteoglycan. The filtering function deterioration
is caused by glycation of basement membrane proteins andthe excretion of AGEs lowers as well as waste products, so theaccumulation of AGEs in the body increases remarkably. Thisis also the condition where glycative stress is strong.
The kidney is rich in GAPDH (glyceraldehyde -3phosphate dehydrogenase) and glyoxalase and they play arole as biological defense against glycative stress.
GAPDH exists in large amounts accounting for
10% ~20 % of the total amount of proteins within cytoplasm,
and it is positioned as the most important defense mechanism

for the organism metabolizing GA34, 35). The kidney is the mostimportant for GA metabolism. Triokinase plentifully exists inkidney phosphorylates GA coming into cells, transforms it toglyceraldehyde-3-phosphatge and keeps it within the cell anddoes not let it leak out of the cell, so the kidney’s capability ofretaining GA is very strong compared to other cells (Fig. 7 ) 36).
GA in cells is changed to 1-3-bisphosphoglycerate by GAPDH,
and it becomes lactate through pyruvate following the stepsof glycolysis and is then excreted from the cell. However,if the TCA cycle is disrupted by hyperglycemia, fumarate
increases and cysteine succination of GAPDH (formationof 2SC-GAPDH) occurs 37, 38). As 2SC-GAPDH has no GA
metabolic activity, it cannot make GA decomposition, so GA
concentrations inside and outside of the cell increase.
Glyoxalase plays the role of MGO metabolism. MGO is
non-enzymatically conjugated to reduced glutathione (GSH),
transformed to lactate by glyoxalase I & II and disconnectedfrom GSH. Glyoxalase exists in abundance in the kidney
and is involved in aldehyde metabolism and excretion suchas MGO 39, 40). Glyoxalase activity is lowered along with thedevelopment of CKD and the remaining unmetabolized
aldehydes accumulate 41). As a result, glycative stress is further
increased.
Figure 8 shows the vicious cycles through the kidney.
If the condition of strong glycative stress continues, theglycation of glomerular basement membrane protein occurs
and AGEs are accumulated, leading to the onset of diabetic
nephropathy. If kidney function declines, AGEs clearance
also reduces, and as a result, the amount of AGEs in the bodyfurther increases. Due to glyoxalase activity reduction causedby the decline of kidney function and 2SC modificationof GAPDH, the aldehydes in blood and tissue fluid such as
MGO and GA increase and glycative stress further develops.
It will be clarified that the cycles of glycative stress throughthe kidney becomes a great threat against homeostasis
maintenance of the body.

_ 17 _

Stop the “Vicious Cycle” induced by Glycative Stress

GlucoseHigh Glucose

Glucolysis

TCA cycle
disorderActivity ↓GAP

GlucosePolyol pathway

Glucose-6 phosphate

Fructose

Fructose-6-phosphate

Fructosemonophosphate

GAP

Sorbitol

GAPDH

GA

×

Triokinase

3-PG
Reaction tocysteine

GA

Normal

3-PG
1,3-Bisphosphoglycerate

Acetyl-CoA
Citrateα-Ketoglutariate

Oxaloacetate
Succinate
Fumarate

Mitochondria

Phosphoenolpyruvate

Fumarate↑

O2

Pyruvate

GA

LactateFig. 7

Renal cells(i.e. podocyte)

Fig. 7. The defense system against glyceraldehyde in the kidney.

GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GA, glyceraldehyde ; GAP, glyceraldehyde-3phosphate ; 3-PG, 3-Phosphoglycerate; 2SC, S-(2-succinyl)cysteine.

Stages proceed
Glycation of glomerular basement membrane↑

AGEs↑

Diabetic nephropathy↑
Renal function↓
GA↑

GAPDH
activity↓

AGEs
clearance↓

Aldehydes↑

Glycative stress↑

MGO↑

Glyoxalase
activity↓

Fig. 8Fig. 8. Vicious cycles induced by glycative stress in the kidney.

AGEs, advanced glycation end products; GAPDH, glyceraldehyde-3-phosphate dehydrogenase;GA, glyceraldehyde; MGO, methylglyoxal.

_ 18 _Glycative Stress ResearchVicious Cycles through Skeletal Muscles

consumption to further decrease. As a result, insulin resistanceincreases, glucose consumption decreases, spare glucose
increases, hyperglycemia is promoted and glycative stress isfurther strengthened. If skeletal muscle mass decreases due
to aging, this vicious cycle is further promoted. In order toreduce glycative stress for health promotion, it is important
to maintain muscle mass by muscle load training.

The homeostasis of human blood glucose level ismaintained within a certain definite range. As blood glucose
regulators, gluconeogenesis in the liver, glycogen degradation,
glucose uptake in skeletal muscles and adipose tissues andhormonal regulation are identified. Abilities of carbohydrate
metabolism and lipid oxidation in skeletal muscles arepromoted by continued physical exercise and it becomes
possible to flexibly utilize various energy sources on demand.
Energy consumption of skeletal muscle is approximately
22% (in the case of a man whose body weight is 70 kg andbody fat percentage is 20%) 42). Glucose utilization rate inskeletal muscles accounts for 70% of that of healthy people;
but it decreases by half in the case of patients with T2DM 43).
Sarcopenia means qualitative and quantitative declineof skeletal muscle caused by aging, and abnormal glucose
metabolism is caused by glucose metabolic capacity loweredby quantitative decline 44, 45). Aged diabetic patients tend tobe susceptible to sarcopenia, and if they have sarcopenia,
vascular management of diabetes becomes difficult 46). In
animal experiments also, the accumulation of AGEs inconnection with aging of skeletal muscles is recognized 47),so that it is estimated that glycated actin and glycated myosin
are accumulated in skeletal muscles of sarcopenia patients. It
is known that the increase of the skin autofluorescence (SAF)
has the relationship with the decrease of muscular power by
the reports of animal experiments, patients with diabetes andthose with sarcopenia 48-51), which shows that glycative stressis a great risk for muscle weakness.
Figure 9 shows the vicious cycles through skeletal
muscles. Glycation of muscle protein is caused by glycative
stress, which cause muscle volume, muscular power and energy

Aging

Conclusion
Glycative stress causes modification of proteins andincreases the risks of various disorders relating to aging
including diabetic complications. As a result, the reduced
insulin secretion from β-cells is caused and insulin
resistance increases due to glycative insulin formation. Itshows that glycative stress is deeply involved not only in thepathogenesis of diabetic complications, but also the onset
and development of T2DM, and the existence of vicious
cycles impairing health have been clarified. The casesof these cycles in the pancreas, visceral fat, kidney andskeletal muscles are stated in this paper. It is important totake preventative countermeasures against glycative stressand inhibit these cycles in order to prevent the onset anddevelopment of age- or T2DM-associated disorders.

Conflict of interest statement
The authors claim no conflict of interest in this study.

Glycated myosin/actin↑

Muscle volume↓

AGEs↑

Power↓
Energy↓Glucose↑
Aldehydes↑

Glucoseconsumption↓
Fig. 9Insulinresistance↑

Spare glucose ↑Glycative stress↑
Hyperglycemia↑

Fig. 9. Vicious cycles induced by glycative stress in the skeletal muscle.
AGEs, advanced glycation end products.

_ 19 _

Stop the “Vicious Cycle” induced by Glycative Stress

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