CHAPTER FIVE

Advanced glycation end products

and insulin resistance in diabetic
nephropathy
⁎
Kirti Parwani and Palash Mandal
Department of Biological Sciences, P. D. Patel Institute of Applied Sciences, Charotar University of Science &
Technology, Gujarat, India
⁎
Corresponding author. e-mail address: palashmandal.bio@charusat.ac.in

Contents
1. Introduction 118
2. Advanced glycation end products 119
3. Receptors for AGEs 123
3.1 Membrane bound full length receptor for AGEs 123
3.2 Other receptors for AGEs 124
4. Role of AGEs in insulin resistance 125
4.1 Evidence from animal and in vitro studies 125
4.2 Evidences from in vivo studies 127
4.3 Evidence from studies on human subjects 128
5. AGEs and their involvement in diabetic nephropathy 129
6. Mechanisms of insulin resistance and its impact on the kidney 131
7. Inhibition of the AGE-RAGE axis: Treatments for diabetic nephropathy 134
8. Conclusion and future perspectives 138
References 139

Abstract
Insulin resistance is a central hallmark that connects the metabolic syndrome and
diabetes to the resultant formation of advanced glycation end products (AGEs), which
further results in the complications of diabetes, including diabetic nephropathy.
Several factors play an important role as an inducer to diabetic nephropathy, and
AGEs elicit their harmful effects via interacting with the receptor for AGEs Receptor for
AGEs, by induction of pro-inflammatory cytokines, oxidative stress, endoplasmic
reticulum stress and fibrosis in the kidney tissues leading to the loss of renal function.
Insulin resistance results in the activation of other alternate pathways governed by
insulin, which results in the hypertrophy of the renal cells and tissue remodeling.
Apart from the glucose uptake and disposal, insulin dependent PI3K and Akt also
upregulate the expression of endothelial nitric oxide synthase, that results in
increasing the bioavailability of nitric oxide in the vascular endothelium, which further
results in tissue fibrosis. Considering the global prevalence of diabetic nephropathy,

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118 Kirti Parwani and Palash Mandal

and the impact of protein glycation, various inhibitors and treatment avenues are
being developed, to prevent the progression of diabetic complications. In this
chapter, we discuss the role of glycation in insulin resistance and further its impact on
the kidney.

1. Introduction
Diabetes mellitus (DM) can be explained as a group of multiple
abnormalities characterized by hyperglycemia either due to insulin defi-
ciency or insulin resistance (IR) or in some cases both. The resulting
hyperglycemia induces several metabolic and physiological changes
including formation of advanced glycation end products (AGEs) (Vlassara
& Uribarri, 2014) and IR (Yki-Järvinen & Koivisto, 1984). Diabetes is also
one of the leading and most common causes of end stage renal disease
(ESRD), and is associated with increased mortality and morbidity,
responsible for more than 47% of new ESRD cases in the US (Caramori &
Rossing, 2022).
Diabetic Nephropathy (DN) is one of the most common complications
found in T2DM patients. 40% of patients with T2DM and 30% of IDDM
patients develop DN (Hussain et al., 2021). DN is thought to be one of the
major causes leading to chronic kidney disease (CKD) and ESRD (Alicic,
Rooney, & Tuttle, 2017). In a study done incorporating 4006 T2DM
patients in the United Kingdom, 28% of patients developed renal failure
after the average follow up of 15 years (Retnakaran et al., 2006). In India,
34.4% prevalence of DN (Hussain, Habib, & Najmi, 2019) and a com-
posite prevalence of 62.3% of diabetic-CKD (Dash, Agarwal, Panigrahi,
Mishra, & Dash, 2018) have been reported, suggesting the higher pre-
valence of DN in India. As per a report of American diabetes association
(ADA) (2014), more than 40% of diabetic patients are estimated to develop
CKD, comprising a significant number of patients further developing
ESRD requiring either dialysis or renal transplantation. IR is one of the
common attributes observed in patients with moderate to severe chronic
renal failure (DeFronzo & Alvestrand, 1980; Eidemak et al., 1995). There
are various reports suggesting a strong association of IR and hyper-
insulinemia with CKD through stage I to IV, independent of diabetes
(Chen et al., 2004; Soltani, Washco, Morse, & Reisin, 2015; Yamagata
et al., 2007). There are multiple biochemical and signal transduction
pathways that result in IR under diabetic condition. One of the major
Advanced glycation end products and insulin resistance in diabetic nephropathy 119

contributors to IR is post-translational glycation of insulin, which renders it

inefficient to function leading to hyperinsulinemia and hyperglycaemia
(Song & Schmidt, 2012).

2. Advanced glycation end products

AGEs are a heterogenous and complex group of proteins, nucleic
acid and lipids that are formed endogenously as well as during the cooking
of food via the Maillard reaction. During the Maillard reaction, the
reducing sugars like glucose and/or fructose non-enzymatically react with
amino groups present in the proteins, lipids, and nucleic acid to form Schiff
bases. Schiff base is an imine, a double bond between carbon atom of the
sugar molecule and nitrogen atom of the amino acid. Amadori products are
formed by the re-arrangement of the Schiff bases, where the hydrogen of
the hydroxyl group in the Schiff base, bonds with the nitrogen of the
C]N (imine group), resulting in the formation of a ketone, further
resulting in the formation of AGEs. Apart from this, Amadori products can
further breakdown via oxidation to form reactive dicarbonyls such as
glyoxal, methylglyoxal (MG), which form intermediate glycation products
by reacting with free amino groups of proteins. After a series of reactions
like condensation, dehydration, Amadori products and intermediate gly-
cation products, form irreversible intra- or inter-protein cross linked AGEs
(Brownlee, Cerami, & Vlassara, 1988; Grandhee & Monnier, 1991). Their
role in the development of various diseases like diabetes, secondary com-
plications arising due to diabetes like diabetic nephropathy, diabetic neu-
ropathy, cardiovascular complications has already been established, apart
from being recently recognized as a role player in obesity (Gao et al., 2017).
AGEs, which otherwise are found naturally in the body as a part of
metabolism of various sugars, have their formation rate increased under
diabetic conditions (Horie et al., 1997; Schleicher, Wagner, & Nerlich,
1997). Although the formation of AGEs was first described in 1912
(Maillard, 1912), its detailed role in pathophysiology of various diseases is
still being extensively researched.
Glycolysis is the pathway which is responsible for making energy out of
glucose catabolism. The glucose in the cells under normoglycemia would
get metabolized via glycolysis, however, under hyperglycemic conditions,
as observed in diabetics, intermediates of glycolysis get shunted into various
pathways due to the inhibition of enzyme glyceraldehyde-3-phosphate
120 Kirti Parwani and Palash Mandal

dehydrogenase (GAPDH) because of hyperglycemia induced excessive

superoxide radicals. These glycolytic intermediates are the prime intra-
cellular source for the formation of three classes of dicarbonyls compounds
such as glyoxal, MG, and 3-deoxyglucosone, which are the major glycating
agents. GAPDH and dihydroxy acetone phosphate gets converted to MG,
which further principally reacts with basic arginine groups to form arg-
pyrimidine, a fluorescent AGE, and 5-hydro-5-methylimidazolone
(Westwood & Thornalley, 1995). Lipid peroxidation in addition to glu-
cose, can also result in the formation of carbonyl species that can interact
with proteins which, further results in the formation of advanced lipox-
idation end products like Nε-(carboxymethyl)lysine (CML). Also, when
MG interacts with lysine in the protein, it results in the formation of Nε-
(carboxyethyl) lysine (CEL), which is a homolog of CML (Miyata,
Sugiyama, Suzuki, Inagi, & Kurokawa, 1999).
AGEs are also formed via alternate pathways which include polyol
pathway. Under diabetic conditions, higher glucose levels lead to activation
of the polyol pathway, where glucose is first converted to sorbitol by aldose
reductase. The sorbitol is then acted upon by sorbitol dehydrogenase to
form fructose (Gabbay, 1973; Henning, Liehr, Girndt, Ulrich, & Glomb,
2014; Singh, Bali, Singh, & Jaggi, 2014). The activation of the polyol
pathway serves two advantages for the formation and accumulation of
AGEs by increasing the intracellular NADH: NAD+ ratio. Firstly, the
fructose formed via the polyol pathway increases the rate of formation of
intracellular AGEs as it has got 7.5-fold faster rate than glucose in forming
the AGEs (Bunn & Higgins, 1981). Secondly, activation of the polyol
pathway inhibits the activity of glycolytic enzymes like glyceraldehyde
triphosphate dehydrogenase, thereby leading to accumulation of fruc-
tose and triose phosphates, further leading to the formation of highly
reactive molecules like glyoxal, MG, 3-deoxyglucosone, which as
mentioned earlier can interact and crosslink with proteins to form AGEs
(Gabbay, 1973; Henning et al., 2014; Singh et al., 2014). The formation
of AGEs and various physiological impacts caused by AGEs are shown in
Fig. 1. Different amino acid and the type of carbohydrate reacted, results
in the generation of different types of AGEs and Table 1 lists the car-
bohydrate sources for different AGEs and the chemical structures of
various AGEs are shown in Fig. 2.
Apart from being formed endogenously, AGEs are formed during
cooking via Maillard reaction as explained earlier, leading to non-enzy-
matic browning. It is known that cooking techniques like frying, baking,
Advanced glycation end products and insulin resistance in diabetic nephropathy 121

Fig. 1 The formation of AGEs via Maillard reaction leads to the activation of RAGE,
which along with inhibiting the glyoxalase I that can clear AGEs, activates oxidative
stress and inflammatory pathways.

Table 1 Carbohydrate sources and the corresponding AGEs.

Carbohydrate source AGEs formed
Ribose Pentosidine
Glucose, threose CML
Methylglyoxal when reacts with arginine Argypyrimidine
Methylglyoxal when reacts with lysine Carboxyethyl lysine, MOLD
3-Deoxyglucosone when reacts with arginine Imidazolone
3-Deoxyglucosone when reacts with lysine DOLD
Glyoxal GOLD
122 Kirti Parwani and Palash Mandal

Fig. 2 Chemical structure of various AGEs (A) dicarbonyls; (B) fluorescent AGEs
Pentosidine, Vesperlysine A, Argypyrimidine; and non-fluorescent AGEs like CML, N-
carboxymethyllysine; CEL, N-carboxyethyllysine; GOLD, glyoxal-lysine dimer: MOLD,
methylglyoxal-lysine dimer; GLAP, glyceraldehyde-derived pyridinium compound.

or roasting which usually happen at higher temperature, lead to increased

production of AGEs in the food (Lund & Ray, 2017; Scheijen et al., 2016).
Environmental factors like diet, smoking, alcohol consumption, etc. can
also exert impact on the rate with which AGEs accumulate endogenously
(Kumar Pasupulati, Chitra, & Reddy, 2016). Fly ash induced air-pollution
has been associated with the formation of AGEs in the fibroblasts exposed
to fly ash for longer time (Gursinsky et al., 2006). Factors affecting the AGE
formation in the food relies much on the composition of nutrients like
sugar, protein, and fat along with the techniques like temperature and
duration of preparation (Lund et al., 2017; Scheijen et al., 2016). Fat rich
food and the foods cooked at high temperatures are mostly rich in AGE
precursor MG and AGE like CML (Koschinsky et al., 1997; McCarty,
2005). The Western diet uses fructose (Bray, Nielsen, & Popkin, 2004) and
it has been known to be more reactive than glucose to form AGEs as
described earlier. Also, the processed food consumed is rich in AGEs as
processing of food requires treatment of food at higher temperatures for
longer time, therefore leading to the formation of AGEs (Uribarri et al.,
2010). These dietary AGEs when formed are absorbed by the gastro-
intestinal tract and play a role in accumulation of AGEs in the cells.
Advanced glycation end products and insulin resistance in diabetic nephropathy 123

The understanding of the role of dietary AGEs playing a significant role

in biological accumulation of AGEs came from a study in which 60% of
free form of pentosidine and 2% of its peptide bound form was recovered
in the urine samples of individuals fed with coffee brew and bakery pro-
ducts respectively (Förster, Kühne, & Henle, 2005). Also, oral intake of
diet rich in AGEs in rodents led to increased levels of CML in tissues
(Li et al., 2015), with higher deposition (81–320 μg CML/g dry matter) in
kidneys (Tessier et al., 2016). This was also further validated by clinical
trials in which higher consumption of diet rich in CML and CEL showed
higher levels of their free forms in urine and plasma (Scheijen et al., 2018).
Together, these studies suggest that although the endogenous AGEs are
related to increased glucose levels as in case of diabetic conditions, dietary
AGEs may also lead to detrimental effects as they tend to deposit in tissues.

3. Receptors for AGEs

Multiple receptors that interact with AGEs exist. Various receptors
have different effects upon interacting with AGEs, some have a preventive
one while some have a pathogenic effect. One of the mechanisms involved
in transducing inflammatory and pathogenic effects involves the interaction
of AGEs with full length Receptor for AGEs (RAGE).

3.1 Membrane bound full length receptor for AGEs

RAGE is a full length, membrane bound receptor present on numerous
cell types in the body, which include peripheral immune cells, endothelial
cells, smooth muscle cells, microglia, and neurons (Gao et al., 2017;
Litwinoff, Hurtado Del Pozo, Ramasamy, & Schmidt, 2015; Ramasamy,
Yan, & Schmidt, 2011). The other type of receptor that is endogenous
secretory RAGE (esRAGE) is produced by alternative splicing and lacks
the transmembrane domain. It is found majorly in the circulation. Ecto-
domain—shed RAGE (ecRAGE) results from the action of metallopro-
teases on full length RAGE (Lue, Walker, Jacobson, & Sabbagh, 2009).
AGEs being the ligand for all three types of receptors, is only able to
transduce the inflammatory signals via RAGE. The other receptors,
endogenous secretory RAGE (esRAGE) and ecRAGE can prevent the
activation of inflammatory response elicited via AGE-RAGE axis by
competitively binding with AGEs, thereby preventing the binding of AGEs
to RAGE (Maillard-Lefebvre et al., 2009; Yamagishi et al., 2006). The
124 Kirti Parwani and Palash Mandal

AGE-RAGE axis primarily acts by generation of ROS and oxidative stress,

mainly through the NADPH oxidase channel (Wautier et al., 2001).
Oxidative stress thus further increases the formation of more AGEs. This
was explained by an experiment showing that mice lacking RAGE had
lower AGEs and levels of oxidative stress as compared to RAGE-expressing
mice (Reiniger et al., 2010). Also, the RAGE knockout mice had lower
levels of MG and AGEs in the circulation than wild type mice, although
the levels of hyperglycemia were equal in both the mice (Reiniger et al.,
2010). AGEs on binding to RAGE can trigger the activation of extra-
cellular-signal-regulated kinase 1/2 and p38 mitogen-activated protein
kinase (MAPK), rho-GTPases, Janus kinase, c-Jun N-terminal kinase and
the transcription factor NF-kB (Grimm et al., 2012; Hirose, Tanikawa,
Mori, Okada, & Tanaka, 2010; Li et al., 2004; Ott et al., 2014; Tanikawa,
Okada, Tanikawa, & Tanaka, 2009). Further, ROS which is primarily
formed due to AGE-RAGE interaction, can also induce inflammation via
NF-kB activation, which further leads to upregulation of RAGE, leading
to a cause-and-effect mechanism (Bongarzone, Savickas, Luzi, & Gee,
2017; Ramasamy et al., 2011).
RAGE, being a multi-ligand receptor of the immunoglobulin class of
receptors, is not restricted to interact with AGEs only. It also interacts with
pro-inflammatory signals obtained from high mobility group box 1
(HMGB1) (Taguchi et al., 2000), and through S100/calgranulin (Hofmann
et al., 1999). They are known to upregulate the expression of matrix
metalloproteinases, pro-inflammatory cytokines, and program the change
in their expression in macrophages to amplify tissue damage (Schmidt et al.,
2007). Hence, AGE-RAGE axis may provoke oxidative stress and
inflammation; and upon recruitment of HMGB1-addressed inflammatory
cells at the site of tissue stress, may exacerbate oxidative stress and trigger
the formation of more AGEs.

3.2 Other receptors for AGEs

Other receptors than RAGE are found for AGEs, such as cluster of
differentiation 36 (Ohgami et al., 2001), and lectin like-oxidized low-
density lipoprotein 1 (Rudijanto, 2007). RAGE, type 1 and 2 macro-
phage scavenger receptors, oligosaccaharyl transferase–48 (AGE-R1),
80K-H phosphoprotein (AGE-R2) and galectin (AGE-R3) have been
identified to be present on a wide range of cells including macrophages,
endothelial cells, podocytes, monocytes, smooth muscle cells and
microglia (Stitt, Bucala, & Vlassara, 1997; Thornalley, 1998). They are
Advanced glycation end products and insulin resistance in diabetic nephropathy 125

also reported to interact with macrophage scavenger receptors (Araki

et al., 1995) or Advanced Glycation End Product Receptor (AGERs)-
1–2–3 (Lai et al., 2004). These receptors are responsible for maintaining
the homeostasis of AGEs by degrading the AGEs via endocytosis. AGEs
can upregulate AGER1 found in almost all cells and tissues which can
increase uptake and removal of AGEs (Nowotny, Jung, Höhn, Weber,
& Grune, 2015). AGER1 can diminish AGE-induced oxidative stress
(Cai et al., 2010 and Torreggiani et al., 2009) and can promote a sir-
tuin1-dependent deacetylation, thereby suppressing NF-κB (Cai et al.,
2012; Uribarri et al., 2011). This receptor is mainly localized in the
caveolin-rich membrane domain and, by taking up AGEs, promotes
their degradation and prevents AGE-damaging effects (Stitt, Burke,
Chen, McMullen, & Vlassara, 2000). AGE-R1 was the first discovered
and the most expressed of these components. Its level increases in
parallel with AGEs, but it is downregulated by persistently high levels of
AGEs (Thornalley, 2003). AGE-R1 promotes AGE turnover by
mesangial cells and contributes to counter regulation of AGE-induced
inflammation (Lu et al., 2004). AGE-R2 is a membrane protein without
binding activities. It is involved in stabilization of the receptor complex
in combination with AGE-R3, a carbohydrate-binding protein that
shows strong affinity for a wide variety of AGEs and regulates different
functions, from the cell cycle to inflammation (Ribau, Hadcock, Teoh,
DeReske, & Richardson, 1999; Vlassara et al., 1995). Prolonged
exposure to AGEs has been associated with increased AGE-R3
expression (Iacobini et al., 2003).

4. Role of AGEs in insulin resistance

Growing evidence suggests the interesting role and association of
AGE with IR, independently of diabetes mellitus. Tahara et al. (2012)
reported on 322 nondiabetic Japanese subjects; serum AGE levels corre-
lated with HOMA-IR in these subjects, and after multiple regression
analysis, AGEs, along with waist circumference, glycosylated hemoglobin,
and TGs, were correlated with the degree of IR.

4.1 Evidence from animal and in vitro studies

Various studies have been done on in vitro models, that suggest a probable
link between AGEs and IR. Recent developments show decreased action
126 Kirti Parwani and Palash Mandal

of insulin as an impact of glycation of insulin (Boyd et al., 2000). As insulin

is a very short-lived protein, with a half-life of 5–10 min, it has been
reported that insulin and pro-insulin may be getting modified by glycation
in the pancreas during its formation and storage. Boyd et al. (2000) pre-
pared mono-glycated insulin which resembles the glycated insulin in vivo,
that is, single glycation of phenylalanine residues in the amino terminus of
the B chain of insulin. The mice under a glucose tolerance test when
subjected to the modified mono-glycated insulin, showed a 20% reduced
glucose lowering potency as compared to the mice treated with non-gly-
cated insulin. Further, the mono-glycated insulin treated isolated abdom-
inal muscles showed 20% lesser efficiency in glucose uptake, oxidation of
glucose and glycogen synthesis as compared to non-glycated insulin (Boyd
et al., 2000). Hunter et al. studied the IR induced by glycated insulin with
the help of clamp techniques in human subjects. When mono-glycated
insulin was put to test under hyper insulinemic euglycemic clamp studies, it
resulted in lesser supply of exogenous glucose infusion to maintain nor-
moglycemia and 70% more supply of glycated insulin was required to
induce a similar response of control insulin-dependent uptake of glucose
(Hunter et al., 2003), suggesting that glycation of insulin results in impaired
insulin action.
Jia et al. (2006) showed that the arginine residue of the B chain of
insulin was modified by MG, which led to reduced insulin mediated
uptake of glucose in adipocytes and skeletal muscle cells compared to
unmodified insulin. MG has been shown to affect insulin signaling at
the molecular level by blocking tyrosine phosphorylation of insulin-
receptor substrate-1 (IRS-1) and blocking PI3 Kinase activation in INS-1
cells (pancreatic β-cells) (Fiory et al., 2011). MG modification of insulin
resulted in reduced insulin fibril formation and resulted in the formation of
insulin native like aggregates, speculating the reduced insulin action (Oliveira
et al., 2011). Apart from the direct effects of glycation on IR, there exist
multiple reports that suggest the mechanisms of glycation of protein other
than insulin and its impact of insulin sensitivity. TNF-α has been linked
to suppress insulin activity via induction of the pro-inflammatory
mechanisms involved in IR, and reports suggest that glycation of albumin
results in the increased production of TNF-α, which further may result in
IR (Naitoh, Kitahara, & Tsuruzoe, 2001; Miele et al., 2003). Human
albumin glycation in the L6 skeletal muscle myocytes resulted in the
RAGE dependent activation of PKC- α and suppression of IRS-1 action
(Cassese et al., 2008).
Advanced glycation end products and insulin resistance in diabetic nephropathy 127

4.2 Evidences from in vivo studies

The role of AGEs in IR has also been evaluated in animal models by
studying whether inhibition of AGEs can be used as a therapy to improve
insulin sensitivity. In one such study (Guo et al., 2009), Sprague-Dawley
rats were treated with MG alone in drinking water to check the induction
of IR. The animals in a second group received MG along with an anti-
oxidant N-acetyl cysteine (NAC) and in a third group received MG along
with TM20002, an inhibitor for AGEs. After four weeks of treatment, IR
was checked by hyper insulinemic euglycemic clamp, which showed better
sensitivity of insulin in the MG + NAC treated and MG + TM2002
treated groups as compared to MG alone. This shows that prevention and
treatment to control AGEs can help improve IR in tissues. The same
authors also showed that MG and salt co-treatment compared to MG or
salt alone showed increased systolic blood pressure, increased levels of
thiobarbituric acid reactive substances and albumin in urine (Guo et al.,
2009). It is also important to note that in this study, AGEs derived from
MG were higher in the groups treated with MG in comparison to the
group which was deprived of MG. In a study done on C57BL/6 mice, diet
rich in AGE MG-H1 induced IR and diabetes in non-obese animals by
depleting AGE-R1 receptor and sirtuin-1 (Cai et al., 2012) both of which
are known to be suppressed in chronic oxidative stress and diabetes.
In an in vivo study with KK-A(y) mice, a model often used to study obesity
and type 2 diabetes, Unoki-Kubota, Yamagishi, Takeuchi, Bujo, and Saito
(2010) observed that serum levels of AGEs were positively correlated with the
levels of insulin. This showed an IR phenotype in the animals. To understand if
glycation products were responsible for IR, they treated the animals with
pyridoxamine which is an inhibitor of AGE formation. They observed that
pyridoxamine was helpful in decreasing fasting insulin levels in a dose depen-
dent manner, which improved the insulin sensitivity.
In yet another study, Kooptiwut et al. (2005), addressed the direct role
of AGEs on the pancreatic β cells. They isolated islets from pancreas of two
metabolically different animals DBA/2 and C57BL/6 mice. DBA/2 mice
show pancreatic islet dysfunction when exposed to high glucose envir-
onment. Islets isolated from both strains were exposed to 11.1 or 40 mM of
glucose in presence and absence of AGE-inhibitor, aminoguanidine. Up to
10 days, the basal insulin release was observed in islets isolated from both
strains. But, as the chronic exposure to glucose continued, a decreased
secretion of insulin was observed in the islets from DBA/2 mice, which in
128 Kirti Parwani and Palash Mandal

the presence of aminoguanidine was significantly higher under the same

conditions. This could be due to improved islet glucokinase activity in
presence of aminoguanidine. Hence, it was proven that AGEs can lead to
pancreatic islet dysfunction with reduced glucokinase activity in islets.
With different in vitro and in vivo findings, there is evidence that suggests
that AGEs may contribute partially to the pathophysiology of IR, and
hence results in obesity and type 2 diabetes mellitus.

4.3 Evidence from studies on human subjects

Several pieces of evidence suggest the existence of intriguing links between
serum AGE levels and IR, even in non-diabetic human subjects. In a study of
207 healthy, non-diabetic subjects, Tan, Shiu, Wong, and Tam (2011) mea-
sured AGE levels, inflammatory markers, and homeostatic model assessment
index (HOMA-IR) as a measure of IR. The serum levels of AGEs were
significantly associated with IR, independently of gender. Tahara et al. (2012)
also demonstrated a positive correlation of serum AGEs with IR after multiple
regression analysis, as well as with glycosylated hemoglobin (HbA1C), trigly-
cerides (TGs) and waist circumference. The authors found the trends in all 322
non-diabetic Japanese subjects irrespective of gender.
In a study of diabetic human subjects (Sarkar, Kar, Mondal,
Chakraborty, & Kar, 2010), a plausible association between total carbonyl
compound levels in serum with HOMA-IR levels was tested. The authors
reported a significant correlation of carbonyl levels with IR. However,
they did not find any significance in the role of lipid peroxidation end
products with IR, conceivably suggesting a role of AGEs more than oxi-
dative stress in having an impact on insulin sensitivity.
Several reports associate AGEs levels and its effect on IR in PCOS
human subjects also, as PCOS subjects often show IR in comparison to
controls. Serum levels of AGEs were higher in females with PCOS as
compared to females with isolated components of the syndrome, proving the
role of AGEs in ovarian dysfunction along with other metabolic abnorm-
alities (Diamanti‐Kandarakis et al., 2008). In line with this, the same group
explained the role of anti-mullerian hormone (AMH), a hormone produced
by granulosa cells of primary follicles in PCOS. AMH is found to be elevated
in PCOS and is considered as an indicator of disturbed ovulation. The
authors found a positive correlation between circulating levels of AGEs and
AMH in women with PCOS, thereby suggesting a plausible link between
AGEs and AMH in PCOS (Diamanti‐Kandarakis et al., 2009). The effects of
AGEs on the development of IR are shown in Fig. 3.
Advanced glycation end products and insulin resistance in diabetic nephropathy 129

Fig. 3 Hyperglycaemia induced AGEs and its effects on insulin resistance: Activation
of AGE-RAGE axis results in the activation of TNF-α and PKC-α, resulting in inflam-
mation. Also, AGEs further upregulate RAGE by downregulating SIRT 1 and AGER1,
known to improve sensitivity and AGE clearance respectively.

5. AGEs and their involvement in diabetic nephropathy

As discussed earlier, AGEs can lead to various pathophysiological
effects on different organs leading to a variety of complications associated
with diabetes, including DN. It is characterized as a chronic complication
in diabetes, with raised albumin excretion of reduced GFR or both. Over
the past years, various studies have aided in the differentiation of stages of
DN in view of renal modifications.
Stage 1 marks the increase in the size of the kidney by up to 20% along
with elevated renal flow. The GFR remains normal or slightly elevated
without the signs of hypertension and albuminuria. DN progresses to stage
2 after two years of onset of DM, with the characteristics of thickening of
basement membrane and mesangial matrix expansion, with a normalized
GFR and no clinical signs. The first clinical sign of DN like micro-
albuminuria (30–300 mg/day) is observed in stage 3 of DN, which is
manifested within 5–15 years of onset of DM. However, there are no signs
of hypertension observed in patients at this stage, which is usually observed
in stage 4, which also shows irreversible proteinuria and GFR below
60 ml/min/1.73 m2. Stage 5 marks the stage of ESRD with GFR lower
than 60 ml/min/1.73 m2 and patients requiring replacement therapies like
130 Kirti Parwani and Palash Mandal

dialysis or transplantation. The involvement of AGEs with DN and CKD is

important to be understood as the kidney plays a pivotal role in the
metabolism and excretion of AGEs. The accumulation of AGEs increases
with declined renal function independently of DM (Oberg et al., 2004).
Therefore, higher levels of AGEs observed in DN are attributed to reduced
kidney filtration and tubular metabolism along with elevated synthesis of
AGEs. Excessive AGE accumulation can lead to glomerular and tubular
damage in the kidney by inducing oxidative stress, lipid peroxidation and
inflammation in the kidney tubules (Haraguchi, Kohara, Matsubayashi,
Kitazawa, & Kitazawa, 2020; Kaifu et al., 2018; Sun, Chen, Hua, Zhang, &
Liu, 2022). DN is associated or characterized by various histological
changes in renal tissue which result in decreased organ function. Changes
in the glomerulus basement membrane (GBM) reflects one of the initial
signs of DN. The thickening of GBM occurs due to deposition of extra-
cellular matrix components such as collagen and laminins. As discussed
earlier, AGEs can deposit in kidneys and therefore may be one of the
reasons to the change in the renal architecture. With no surprise, studies
with patients and rodents have shown that AGEs crosslink with matrix
proteins in the GBM (Beisswenger et al., 1995; Bohlender, Franke, Stein,
& Wolf, 2005; Soulis-Liparota, Cooper, Papazoglou, Clarke, & Jerums,
1991; Bouma et al., 2003). Studies with murine models have shown that
AGE-injected animals have prominent renal damage due to thickening of
GBM and expansion of mesangial matrix, further confirming the detri-
mental role of AGEs in the development of renal damage (Nogueira, Pires,
& Oliveira, 2017). Normal rodents when infused with AGEs showed
widening of basement membrane, mesangial matrix expansion, and glo-
merulosclerosis, possibly due to increased TGF-β and/or reduced nitric
oxide (NO) in the kidneys (Vlassara et al., 1994). The proximal tubules in
the kidney are characterized by a good number of lysosomes and mito-
chondria required for protein absorption or degradation, as most of the
glomerular filtrate is reabsorbed here through endocytosis. This endosomal
activity of lysosomes in the tubular cells is at large felicitated by megalin, an
endocytic receptor. The uptake of AGEs by the reabsorption through
tubular cells leads to glucotoxicity and proximal dysfunction of the tubular
lysosomes, further developing DN. This AGE-RAGE pathway results in a
positive feedback loop in the proximal renal tubules, further increasing the
tubular injury in DN patients with severe hyperglycaemia (Liu et al., 2022).
Further clarity on the role of AGEs in DN is discussed in reports which
suggest that the accumulation of AGEs in plasma is a measure of reduced
Advanced glycation end products and insulin resistance in diabetic nephropathy 131

renal function (Cooper, 2001). Diabetic patients suffering from ESRD

have been reported to have deposition of double the quantity of AGEs in
contrast to diabetic patients without renal disease (Makita et al., 1991). The
concept that AGEs cause DN is supported by the fact that inhibition of
AGEs in diabetic rodents prevents albuminuria and glomerulosclerosis
(Busch, Franke, Rüster, & Wolf, 2010). Non enzymatic glycation of
extracellular matrix proteins like collagen and laminin renders them less
reactive towards proteoglycans thereby increasing the permeability of the
membrane leading to leakiness and increased permeability to albumin
(Silbiger et al., 1993). This leads to loss of albumin in the urine leading to
albuminuria, which is also one of the hallmarks of DN.
AGEs induce apoptosis, expression of vascular endothelial growth factor
and, also stimulate the expression of MCP-1 in mesangial cells (Yamagishi
et al., 2002). AGEs lead to overexpression of TGF-β, which leads to
glomerulosclerosis and tubulointerstitial fibrosis in diabetic nephropathy
(Yamagishi et al., 2002; Raj, Choudhury, Welbourne, & Levi, 2000). The
expression of RAGE is found to be increased in podocytes of diabetic
patients with DN (Tanji et al., 2000; Suzuki et al., 2006), suggesting the
involvement of the AGE–RAGE axis in DN pathophysiology. AGEs upon
binding to RAGE leads to the production of ROS which further stimulates
the production of TGF- β, MAPK and NF-kB pathways in mesangial and
tubular cells (Brownlee, 2001; Chuang, Yu, Fang, Uribarri, & He, 2007;
Ha, Hwang, Park, & Lee, 2008; Yamagishi et al., 2002; Yamagishi et al.,
2003) reported that podocytes which are terminally differentiated cells in
kidney undergo apoptosis mediated by AGEs during the early stage of DN.

6. Mechanisms of insulin resistance and its impact on

the kidney
IR is defined as a decreased responsiveness of insulin receptor sig-
nalling to insulin, which in turn results in hyperglycemia. IR plays a very
important role in the disorders associated with metabolic and hemody-
namic abnormalities and is also associated with higher risk of cardiovascular
and CKD. Conventionally, tissue IR is understood as an underlying
impairment in the response of skeletal muscle, to the metabolic and phy-
siological actions of insulin (Muniyappa & Sowers, 2013; Shepherd &
Kahn, 1999), although other organs like pancreas, adipose tissues, liver
along with kidneys and heart are also insulin-dependent and insulin-
132 Kirti Parwani and Palash Mandal

sensitive. Insulin affects blood pressure by modulating the renin-angio-

tensin-aldosterone (RAA) system and through its effects on the sympathetic
nervous system. To understand how insulin affects renal tissue and its
remodelling, it is important to discuss the action of insulin. In a normo-
glycemic state, insulin binding to its receptor (a tyrosine-kinase receptor
containing two extracellular α subunits and two trans-membrane β sub-
units) auto-phosphorylates the β subunits which further interact with
IRS-1 and 2 and activate phosphoinositide-dependent kinase 1 via phos-
phoinositide-3 kinase (PI3K). This activates Akt which results in the
physiological effects of insulin on glucose uptake and utilization. The
disruption of this signalling pathway results in hyperinsulinemia and
the excess insulin may trigger insulin-dependent growth pathways in other
tissues, like the kidney (Bhandari et al., 2001; Coward et al., 2005; Nistala
& Whaley-Connell, 2013).
Insulin can activate growth signalling pathways like redox sensitive
serine kinase, other kinases like Rho kinase, JUN-NH2 terminal kinase,
mammalian target of rapamycin/serine kinase 1 pathways, that along with
growth regulate hypertrophy and fibrosis (Whaley-Connell & Sowers,
2017). Under IR, these pathways are alternatively regulated by the
RAA system and the sympathetic nervous system (Oroszlán et al., 2010;
Yamakawa, Tanaka, Kamei, Kadonosono, & Okuda, 2003). The activation
of these pathways promotes the activation of kinases like serine kinases,
which results in renal tissue remodelling by inducing growth and hyper-
trophy (Chen, Chen, Thomas, Kozma, & Harris, 2009; Nistala, & Whaley-
Connell, 2013; Whaley-Connell et al., 2011; Whaley-Connell et al.,
2012). Other than uptake and glucose disposal in normal insulinemia state,
PI3K and Akt also upregulate the expression of endothelial NO synthase,
that results in increasing the bioavailability of NO in the vascular endo-
thelium (Aziz & Chaudhary, 2016; Jia, Aroor, & Sowers, 2014). Therefore,
IR also leads to impaired NO dependent vascular activities, and induces
tissue inflammation and fibrosis, along with concurrent reduced glucose
disposal. The above findings suggest that IR regulates renal metabolic and
growth pathways and influences renal plasma flow, glomerular filtration,
inflammation, and fibrosis (Whaley-Connell & Sowers, 2017). One of the
earlier signs observed in DN is albuminuria, that is, excessive urinary
protein secretion can predict the extent and progression of the renal
damage. Albuminuria results from altered permeability of the filtration
barrier formed by glomerular epithelial cells and podocytes at the GBM.
This renal architecture is maintained by various cytoskeleton proteins and
Advanced glycation end products and insulin resistance in diabetic nephropathy 133

Fig. 4 The role of insulin resistance and the defective fat metabolism in the regulation
of kidney functions.

other signalling proteins, thus maintaining is permeability for proper renal

functions. Many in vivo and studies with human subjects have shown that
diabetes associated metabolic changes alter the ultrastructure of the kidney,
resulting in thickening of GBM, expansion of the mesangium, podocyte
detachment, reduction in endothelial cell glycocalyx, resulting in the
sclerosis of the glomerulus, that correlates with increased albuminuria
(Gnudi, Coward, & Long, 2016). IR interestingly associates with the
development of microalbuminuria in diabetic patients with T1DM and
T2DM. IR also contributes to increased sensitivity to salt, closely associated
with increased blood pressure, and albuminuria resulting in declining renal
function (Vedovato et al., 2004). Fig. 4 describes how IR through its
various roles impacts the kidneys, which may contribute to ESRD.
Various cells present in the kidneys are insulin sensitive with expression
of functional insulin receptors, and IR in different compartments can result
in different renal phenotypes. For instance, the deletion of podocyte spe-
cific insulin receptor in the glomerulus in knockout mice, developed
several hallmarks of DN including albuminuria, mesangial matrix expan-
sion, thickening of the GBM and glomerulosclerosis, in normoglycemic
134 Kirti Parwani and Palash Mandal

conditions, suggesting the role of IR independent of hyperglycaemia

(Welsh et al., 2010). Deletion of the insulin receptor in tubules resulted in
gluconeogenesis (Tiwari et al., 2013), while deletion in the collecting ducts
resulted in lower blood pressure (Li et al., 2013), and while the deletion in
the tubular epithelial cells resulted in hypertension (Tiwari et al., 2013). Of
late, the role of epigenetic modulation in IR has been documented, in
which fatty acid induced IR was associated with increased H3K36me2 and
reduced H3K27me3 in the FOXO1 promoter region, promoting gluco-
neogenesis in the human urinary podocyte cell line (Kumar, Pamulapati, &
Tikoo, 2016).

7. Inhibition of the AGE-RAGE axis: Treatments for

diabetic nephropathy
The key aim in inhibiting the AGE-RAGE axis is strict control of
hyperglycemia which would prevent the formation of AGEs and therefore
would inhibit the induction of the AGE-RAGE axis. However, when such
dietary intervention sometimes get difficult or ineffective, pharmacological
interventions are used as an alternative strategy to reduce AGEs and inhibit
RAGE. The body has endogenous mechanisms like α-ketogluteraldehyde
dehydrogenase, glyoxalase, and scavengers to inhibit glycation and for-
mation of AGEs, but hyperglycemia and activation of RAGE are reported
to downregulate the production and the activity of glyoxalase I. Therefore,
an urge to develop and adopt other pharmacological approaches becomes
the need of the hour.
Several approaches have been explored.
(1) Antioxidants: They can prevent the generation of the free radicals due
to auto-oxidation of glucose and formation of AGEs. Benfotiamine is
synthesized by S-acyl derivation of thiamine and has been shown to
have anti-oxidant and anti-AGE properties (Stirban et al., 2006).
(2) Amadorins: This class of Amadorins are the molecules that can pre-
vent the conversion of Amadori products to AGEs. Vitamin B6 was
identified to be the first Amadorin, which was used in the treatment of
DN (Voziyan & Hudson, 2005).
(3) Dicarbonyls Scavengers: Molecules like Aminoguanidine (±)-2-iso-
propylidenehydrazono-4-oxo-thiazolidin-5-yl acetanilide (OPB-
9195) are examples of dicarbonyls scavengers (Miyata et al., 1999).
Aminoguanidine inhibits the formation of AGEs by scavenging the
Advanced glycation end products and insulin resistance in diabetic nephropathy 135

precursors of AGEs. Its two crucial functional groups called hydrazine

and guanidino facilitate an irreversible interaction with dicarbonyls,
which further inhibit the formation of AGEs. Aminoguanidine has
been shown to be effective in DN by reducing albuminuria and renal
injury (Thornalley, 2003).
(4) AGE-crosslink breakers: ALT-711 (algebrium) (Peppa et al., 2006)
and N-phenylthiazolium bromide (Cooper et al., 2000) could confer
protection against DN and accumulation of AGEs, however the
mechanism of action of the drug is not yet fully elucidated.
(5) Anti-hyperglycemic drugs: Different classes of anti-hyperglycemic
drugs like biguanides (Beisswenger, Howell, Touchette, Lal, &
Szwergold, 1999), sulfonylureas (Tan et al., 2007), and dipeptidyl
peptidase 4 inhibitor (Sakata et al., 2013), have been tested and shown
to reduce the AGEs in clinical samples. As these drugs reduce glucose
levels, they can help in reversing the glycation and the formation of
AGEs.
(6) Angiotensin converting enzyme (ACE) inhibitors and angiotensin
receptor blockers (ARBs): ACE inhibitors like ramipril, temocaprilat,
enlaprilat, captopril and perindoprilat and ARBs like valsartan,
olmesartan, candesartan can prevent the ROS by metal chelation and
thereby block the formation of AGEs. ARBs are also known to inhibit
the expression of RAGE via peroxisome proliferator activated
receptor-ϒ (Yamagishi & Takeuchi, 2004).
(7) Statins: Statin like atorvastatin has been shown to prevent AGE induced
RAGE expression angiotensin converting enzyme in healthy rats (Feng
et al., 2011), while pravastatin prevented AGE induced tubular damage
and cell death in diabetic nephropathy (Ishibashi et al., 2012).
(8) RAGE antagonist: TTP488 and low molecular weight heparin
(LMWH) have been used as RAGE antagonists. LMWH has been also
shown to have preventive and therapeutic effects against albuminuria
and glomerulosclerosis in a DN mouse model (Myint et al., 2006).
Very recently, a search for RAGE inhibitors has been undertaken, in
which a RAGE aptamer was evaluated for its effects against strepto-
zotocin-induced diabetes in rats after treatment for 4 weeks. It could
successfully abrogate diabetes induced macrophage infiltration, renal
dysfunction, and AGE-RAGE oxidative stress axis (Matsui et al.,
2017). A specific AGE-inhibitor called FPS-ZM1 ameliorated urinary
albumin excretion and renal fibrosis in AGE-treated diabetic CD1
mice (Sharma, Tupe, Wallner, & Kanwar, 2018).
136 Kirti Parwani and Palash Mandal

(9) Decoy receptors: soluble RAGE (sRAGE) is a decoy type receptor,

used as a treatment of DN. sRAGE is just an extracellular domain of
membrane bound RAGE, but it lacks the transmembrane domain of
the full-length RAGE receptor. Since it has the same binding domain
as full-length RAGE, it can act as a decoy receptor by clearing the
AGEs and prevent its binding with RAGE. In a db/db mouse model,
treatment with sRAGE has been shown to decrease GBM thickening,
albuminuria and glomerulosclerosis (Wendt et al., 2003).
(10) Vitamins and Polyphenols: Vitamin C and E along with combination
of N-acetylcysteine with taurine and oxerutin were shown to be
potential anti-glycative agents (Odetti et al., 2003). Polyphenols such
as catechin have been recently identified as AGE inhibitors. In a study
by Zhu et al. (2014) Catechin inhibited AGE formation and reduced
the MG trapping along with expression of pro-inflammatory cyto-
kines. A patented Chinese drug, Jiangtang decoction drug reduces
accumulation of AGE and RAGE, increases phosphorylation of AKT
and phosphoinositide 3-kinase (PI3K), thereby ameliorating DN by
reducing the renal proinflammatory markers (Hong et al., 2017).
Other class of molecules like Mangiferin, a xanthonoid improved DN
in streptozotocin treated rats by decreasing the formation of AGEs,
reducing oxidative stress induced MAPK and PKC signaling and
inhibiting apoptotic markers (Pal, Sinha, & Sil, 2014). Resveratrol was
recently found to reduce the formation of AGEs by trapping MG and
forming resveratrol-MGO adducts (Shen et al., 2017). Of late,
chrysin, present in herbs and bee propolis, was proven to be inhibiting
AGEs induced renal fibrosis in mesangial cells in db/db mice by
inhibiting the accumulation of matrix proteins in AGEs treated dia-
betic glomeruli (Lee et al., 2018). Recently, swertiamarin was shown
to have prevented the progression of DN, in in vitro and in vivo
models by preventing the RAGE/ MAPK/ TGF- β pathway.
Through in silico analysis, it was also shown to block the binding of
AGEs to their receptor RAGE, thereby acting as a plausible RAGE
antagonist (Parwani et al., 2021).
(11) Glyoxalase 1 and Nrf-2 activators: The glyoxalase is the endogenously
present AGE-detoxification enzyme which detoxifies dicarbonyls, and
nrf- 2 plays a very important role in combating the oxidative stress
generated by dicarbonyls and free radicals. Hence compounds that can
enhance the expression of glyoxalase 1 and nrf-2 could be beneficial in
preventing RAGE activation. A formulation of trans-resveratrol and
Table 2 Clinical evidences of AGE-RAGE inhibition.
Drug Mechanism of action Results References
Benfotiamine Inhibits the formation of 41 patients with T2DM, but without any Contreras, Guzman‐Rosiles,
endogenously formed AGEs secondary complications when administered Del Castillo, Gomez‐Ojeda,
either 900 mg/day of Benfotiamine showed and Garay‐Sevilla (2017)
significant decreased CML levels as compared to
those on placebo.
Alagebrium AGE-breaking mechanism 57 healthy subjects above age 60 were randomly Fujimoto et al. (2013)
divided in 4 groups as follows: sedentary with
placebo; sedentary with 200 mg/day Alagebrium;
exercise with placebo and exercise with
200 mg/day Alagebrium. The subjects treated with
Alagebrium showed improved function of left
ventricle, which was further improved in subjects
of exercise with 200 mg/day Alagebrium group.
Sevelamer Inhibition of absorption of In a randomised single-blinded trial, 117 patients Yubero-Serrano,
carbonate exogenously taken AGEs with T2DM and stages 2 to 4 of DN, were given Woodward, Poretsky,
1600 mg/day of sevelamer carbonate or Vlassara, and Striker (2015)
1200 mg/day of calcium carbonate thrice a day.
Patients in sevelamer carbonate treatment group
showed significantly reduced circulating and
intracellular levels of AGEs like CML and MG
along with improved anti-oxidant status.
138 Kirti Parwani and Palash Mandal

hesperidin was shown to improve insulin sensitivity, reduce MG and

MG derived AGEs and improve vascular functions by activating
glyoxalase via nrf-2 dependent activation (Xue et al., 2016).
(12) Gut Microbiota and Prebiotics: Very recently for the first time, the
role of E. coli strains to degrade CML into defined metabolites with
the biogenic amine like carboxymethyl cadaverine as the main pro-
duct has been identified, proving the role of gut microbiota in
breaking down the AGEs (Hellwig et al., 2019). A study with a 12
weeks treatment of prebiotic inulin/oligofructose could prevent
AGE-related outcomes in adults with pre-diabetes, by improving
insulin sensitivity and reducing AGEs like MG and CML (Kellow,
Coughlan, Savige, & Reid, 2014).
Apart from the above-mentioned inhibitors, several AGE inhibitors
have been tested clinically for their efficacy, as mentioned in Table 2.

8. Conclusion and future perspectives

IR, and the hyperglycemia resulting from inefficient insulin action
results in the generation of the AGEs, which upon interacting with their
receptor RAGE elicit the inflammatory pathways that result in structural
and functional defects in the kidney. The literature review from the in vitro
and in vivo studies show that AGEs are also linked to the pathophysiology
of IR. The IR also contributes to the disturbance in the kidney functions
by promoting glomerular hypertrophy, albuminuria, increased tubular
retention of sodium, hypertension, which together promote the loss of
kidney functions and ESRD. Taking together the above findings, glycemic
control, and the prevention of the formation of AGEs seems to be the best
way to limit the progression of kidney diseases. Therefore, apart from the
current therapeutic approaches discussed in this chapter, newer preventive
and treatment strategies need to be designed along with getting a better
insight into the cellular mechanisms, focusing on the physiology of the
nephron, are needed to develop future targets for the treatment and pre-
vention of DN. The role of AGEs and their receptors have been shown to
play a pivotal role in development of IR, and since the incidences of
obesity and IR are increasing at an alarming rate in younger individuals,
improving the lifestyle along with development of preventive measures to
augment the formation of AGEs is challenging and highly warranted.
Advanced glycation end products and insulin resistance in diabetic nephropathy 139

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