**8. AGEs and intrauterine hyperglycaemia**

In pregnant women or those with gestational diabetes during pregnancy, hyperglycaemia can create a hyperglycaemic environment in the uterus through the placenta. However, few studies have evaluated the molecular mechanisms by which the intrauterine hyperglycaemic environment affects foetal development and future illnesses in offspring. One study evaluated the hearts of infants born from diabetic pregnancy model rats with hyperglycaemia during pregnancy [123]. Additionally, a gestational diabetes rat model was created by administration of streptozotocin via the tail vein immediately after pregnancy. Akt-related insulin signalling was abnormal in the hearts of offspring born to mothers of these gestational diabetes model rats [124]. We investigated the expression of the insulin signalling system, ROS, AGEs, and related genes in the hearts of infants and in primary myocardial cultured cells (cardiomyocytes) isolated from the heart [125]. In primary cardiomyocytes isolated from the hearts of infants born to mothers with diabetes, insulin stimulation inhibited the translocation of GLUT4 to the cell membrane, indicating that insulin resistance was induced. Moreover, various proteins were excessively AGE-ised in the hearts and cardiomyocytes of offspring born from diabetic mother rats [125]. Intracellular ROS levels and *NF-*κ*B*, tumour necrosis factor (*TNF*α), and *IL-6* gene expression levels in isolated cardiomyocytes were significantly increased compared with those in offspring of normal mother rats [125]. Thus, in offspring who spent the foetal period in an intrauterine hyperglycaemic environment, maternal hyperglycaemia may have caused abnormal insulin signalling due to the chronic inflammation induced by intracellular ROS and excessive AGE formation, thereby leading to cardiac hypertrophy [125]. Interestingly, daily oral administration of the n-3 unsaturated fatty acid eicosapentaenoic acid by gastric sonde to mother rats ameliorated this abnormal signal transduction in the

#### **Figure 6.**

*The risk of future illness in children born to diabetic mothers. In diabetic mothers, maternal hyperglycaemia creates a hyperglycaemic environment in the womb through the placenta. During this time, the foetus is exposed to hyperglycaemia, and excessive hyperglycaemia activates AGE/RAGE signalling. This can cause the foetus to be exposed to an inflammatory cytokine storm. In addition, many proteins and enzymes are denatured by oxidative stress, which can also affect foetal development, and these effects may lead to the onset of disease after birth. Therefore, glycaemic control during pregnancy is critical.*

heart. Based on these findings, the intrauterine hyperglycaemic environment of pregnant women may have major effects on various organs other than the heart in children through oxidative stress caused by excessive AGEs, including AGE/RAGE signalling. In addition, the intrauterine hyperglycaemic environment may affect offspring through epigenetics [125, 126].

The concept that malnutrition in the womb may affect the future development of lifestyle-related diseases in children was first proposed by David Barker of Southampton University in the 1980s [127]. Barker and colleagues used birth weight as an indicator of foetal nutrition and examined its association with various causes of death; their results showed that children born with a low birth weight were at high risk of dying from heart disease in the future [128]. Birth cohort studies have reported a series of epidemiological studies supporting the theory of adult disease foetal onset, including the fact that foetuses exposed to malnutrition may develop lifestyle-related diseases in adulthood [129] by inducing an adaptive response that predicts the future environment by regulating gene expression [130]. Peter Gluckman, Mark Hanson, and others further developed this theory of adult disease foetal onset into a generalised theory on the developmental origins of health and disease [131]. However, in modern society, eating habits have changed dramatically, and overnutrition, including obesity and diabetes, has become a challenge. Importantly, oxidative stress caused by exposure to the maternal hyperglycaemic environment may also have major effects on the future onset of illness in offspring (**Figure 6**).

### **9. Development of therapeutic agents targeting the AGEs-RAGE system**

As described above, in a hyperglycaemic environment, oxidative stress induced by AGEs and RAGE can induce the onset and progression of various diabetic complications; hence targeting the AGEs-RAGE system, using AGEs formation inhibitors, AGEs degrading agents, AGEs-RAGE inhibitors and signal transduction inhibitors, may be an effective treatment strategy.

The first reported AGEs formation inhibitors are aminoguanidine and OPB-9195 (2-isopropylidenehydrazono-4-oxo-thiazolidine-5-ylacetanilide) which can capture

#### *Advanced Glycation End Products and Oxidative Stress in a Hyperglycaemic Environment DOI: http://dx.doi.org/10.5772/intechopen.97234*

reactive carbonyl compounds such as methylglyoxal and 3-DG and inactivate metal ions that catalyse radical formation such as chelating agents [132–134]. OPB-9195 has a stronger AGEs formation inhibitory activity than aminoguanidine [135], however, these compounds are associated with side effects such as vitamin B6 deficiency due to the capture of pyridoxal phosphate, anaemia, and liver damage, therefore, their clinical application has been discontinued. LR-90 (methylene bis [4,4-(2 chlorophenylureido phenoxyisobutyric acid)]) and ALT946 (N-(2-acetamidoethyl) hydrozinecarboximidamide hydrochlolide) are more potent AGEs inhibitors than aminoguanidine and OPB-9195 [136, 137], and are associated with fewer side effects; in particular, ALT946 has no NO synthase inhibitory activity, which is a side effect of aminoguanidine [137].

Pyridoxamine, a vitamin B6, has been reported to have renal damage-suppressing effects as well as carbonyl compound capturing and antioxidant effects [138–140]. Benfophothiamine, a vitamin B1 derivative, has various effects such as inhibiting AGEs formation, suppressing PKC activity and oxidative stress, activating transketolase, and inhibiting the polyol pathway [141]. Furthermore, sorbinin inhibits AGEs formation by blocking the polyol pathway [41, 42]. The renal protective effect of the renin-angiotensin system targeting drugs is attributed to the inhibition of pentosidine production [142]. The oral hypoglycaemic agent metformin inhibits AGEs formation via carbonyl compound capturing, metal chelate formation, and antioxidant activity [143].

N-phenacylthiazolium bromide (PTB) can cleave protein cross-linked by AGEs [144]. PTB water solubility increases when it is in the form of 3-phenacyl-4,5-dimethylthiazorium chloride (ALT-711). ALT-711 has been reported to suppress the accumulation of AGEs and improve vascular hardening and systolic blood pressure [145]. PTB and ALT-711 are therefore referred to as AGEs breaker agents. Certain plant extracts have been reported to exhibit this anti-AGEs effect. For example, terpinen-4-ol of citron (*Citrus junos*) has also been reported to decompose AGEs [146]. In addition, RAGE antagonists that block the interaction between AGEs and RAGE have been extensively studied [147].

Drugs targeting the AGEs-RAGE system primarily include AGEs formation inhibitors, AGEs breakers, and AGEs-RAGE signal inhibitors, which are investigated in non-clinical studies. Presently, the agents used for targeting AGEs-RAGE system in clinical settings include aldose reductase inhibitors, renin-angiotensinbased active drugs, and metformin. The reason behind using such diverse drugs and difficulty in discovering a specific drug is attributed to the structural diversity of AGEs, the multi-ligand receptor characteristics of RAGE, and the limited underdamping of the condition in which oxidative stress is generated in cells. However, oxidative stress induced by AGEs in a hyperglycaemic environment significantly influences the onset and progression of several lifestyle-related diseases. Therefore, advance translational research is essential to tackle challenges that basic research cannot.

### **10. Conclusions**

As discussed in this chapter, glycation is a random, nonenzymatic reaction that differs significantly from enzymatically catalysed glycosylation. AGEs formed by saccharification consist of a wide variety of molecular species, many of which have not been structurally characterised, and these species vary from harmful to harmless. Oxidative stress, including ROS, is induced by AGEs during normal metabolism but is mitigated physiologically by antioxidant enzymes in the body. However, in a hyperglycaemic environment, as is typically observed in patients with diabetes,

### *Fundamentals of Glycosylation*

oxidative stress that cannot be removed via the antioxidant system of the body causes various diabetic complications such as organ stress. As the population of patients with diabetes continues to increase, the number of pregnant women with diabetes is also increasing due to late marriage and an older age of primigravida. Research results have strongly supported that the maternal hyperglycaemic state creates an intrauterine hyperglycaemic environment through the placenta that is involved in the development of various diseases in the offspring. Further studies are needed to clarify the molecular mechanism involved in oxidative stress and disease caused by glycation and to link these mechanisms with the diagnosis and prevention of lifestyle-related diseases.
