




































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: naser_elsawy@ymail.com; 
 
 
 

Asian Journal of Immunology 
 
2(1): 34-44, 2019; Article no.AJI.53258 
 

 
 

 

 

Therapeutic Potential of the Dual Peroxisome 
Proliferator Activated Receptor (PPAR)/ Agonist 

Aleglitazar in Attenuating TNF-mediated 
Inflammation and Insulin Resistance in Human 

Adipocytes: A Review 
 

Naser A. ElSawy1* 
 

1
Department of Anatomy and Embryology, Faculty of Medicine, Zagazig University, Egypt. 

 
Author’s contribution 

 
The sole author designed, analysed, interpreted and prepared the manuscript. 

 
Article Information 

 
Editor(s): 

(1) Dr. Cynthia Aracely Alvizo Báez, Professor, Laboratory Immunology and Virology, Faculty of Biological Sciences, 
Autonomous University of Nuevo Leon, Mexico. 

Reviewers: 
(1) Umezurike Benedict Chidozie, Nigeria. 

(2) Gayatri C. Gawade, Bharati Vidyapeeth Dental College and Hospital, India. 
Complete Peer review History: http://www.sdiarticle4.com/review-history/53258 

 
 
 
 

Received 01 October 2019 
Accepted 05 December 2019 
Published 10 December 2019 

 
 

ABSTRACT 
 

Aleglitazar, is a novel promising drug, that related to peroxisome proliferator-activated receptor 
(PPARα&γ) agonists which shows an ant-diabetic and anti-inflammatory characteristics. The goal 
of this study is to evaluate anti-inflammatory and anti-arthritic properties of Aleglitazar in arthritis 
models induced in experimental animals and to conclude the comparative ulcerogenic potential of 
diclofenac in type 2 diabetes animals. The anti-inflammatory characteristics of Aleglitazar will be 
investigated in Carrageenan-induced hind paw edema as acute inflammation. 
The Aim of the review: This study aims to assess anti-inflammatory and anti-arthritic activities of 
aleglitazar in arthritis models induced in experimental animals. It is to determine comparative 
ulcerogenic potential diclofenac in type 2 diabetic animals on gastric mucosa in rats. 
 

 
Keywords: PPAR; Aleglitazar; TNF; inflammation insulin resistance; adipocytes. 

Review Article 



 
 
 
 

ElSawy; AJI, 2(1): 34-44, 2019; Article no.AJI.53258 
 

 

 
35 

 

ABBREVIATIONS 
 

ANG :  Angiotensin 
BMI :  Body mass index 
COX1 :  Cyclooxygenase-1 enzyme 
COX2 :  Cyclooxygenase-2 enzyme 
CRP :  C-reactive protein 
FFA :  Free fatty acids 
GCF :  Gingival crevicular fluid 
GDM :  Gestational diabetes mellitus 
GFR :  Glomerular filtration rate 
1GIR :  Glucose-insulin rate 
HbA1c :  Glycated haemoglobin 
HDL :  High-density lipoprotein 

cholesterol 
IL-1β :  Interleukin 1β 
LDL :  Low-density lipoprotein 

cholesterol 
NO :  Nitric oxide 
NO/ONOO :  Nitric oxide/peroxynitrite ratio 
NSAIDS :  Nonsteroidal anti-

inflammatory class of drugs 
PGE2 :  Prostaglandin E2 
PGs :  Prostaglandins 
PAI-1 :  Plasminogen activator 

inhibitor-1 
PPAR α & γ :  Peroxisome proliferator 

activated receptor α & γ 
SC :  Serum creatinine 
STZ :  Streptozotocin 
TG :  Triglycerides 
TNF- α :  Tumor necrosis factor alpha 
T2DM :  Type 2 diabetes mellitus 

 

1. INTRODUCTION 
 

Obesity is frequently associated with insulin 
resistance, and highly responsible for developing 
type 2 diabetes (T2D) [1,2], T2D is a metabolic 
disease that causes sugar to increase in blood 
circulation results from insulin resistance and the 
primary risk factor of T2D is inflammation [3]. 

Diclofenac is a proven, commonly used non-
steroidal anti-inflammatory and anti-pyritic drug. 
Diclofenac exerts its activity by inhibiting 
cyclooxygenase-1 (COX1) and cyclooxygenase-
2 (COX2) leading to inhibit prostaglandin 
synthases [4]. 
 
Aleglitazar is a new drug that used as an anti-
inflammatory drug that improved insulin 
sensitivity, and dyslipidemia. Aleglitazar is a 
single novel molecule that contains the both 
active synthetic peroxisome proliferator activated 
receptors (PPARs α&γ) has potent and dual 
agonist action on PPARs α&γ [5]. 
 

2. OBESITY 
 
Is a pathological condition result from an 
accumulation of excesses adipose tissue in a 
different site of the body including liver and 
skeletal muscle, and it's considered as a 
neurochemical imbalance can be measured by 
the body mass index (BMI), which is a ratio of 
weight to high. Normal range of BMI (18.5-24.9 
kg/m

2
), overweight range (25-29.9 kg/m

2
), 

obesity BMI 30 kg/m
2
 and more [6] (Fig. 1). 

 
Weight gain and increased adipocyte, result in 
hypertrophic and loss of function of adipocyte [8]. 
Free fatty acid (FFA) in this condition released in 
blood circulation, pro-inflammatory cytokines as 
tumor necrosis factor alpha (TNF-α), 
Plasminogen activator inhibitor (PAI)-1, and 
angiotensin (ANG)), and adiponectin which is a 
specific protein in adipocyte that play a role in 
insulin resistance and atherosclerosis [9]. 
 

Increased level of FFA and pro-inflammatory 
cytokines will lead to deposition in non-adipose 
tissues and decrease systemic inflammatory 
grade, resulting in activating the mechanism of 
insulin resistance in tissues (Fig. 2) [8]. 

 

 
 

Fig. 1. BMI: It is a method use for determination if a person weight within the normal range or 
at high risk for obesity [7] 

 



 
 
 
 

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36 

 

 
 

Fig. 2. Adipose tissue expansion, insulin resistance, and the metabolic syndrome. 
Macrophages are conducted, infiltrate and contributing further to pro-inflammatory M1 

phenotype in the hypertrophic adipose tissue [8] 
 

3. DIABETES MELLITUS 
 
Is a silent metabolic syndrome characteristic by 
hyperglycemia resulting from lowering or 
impaired insulin secretion or increase insulin 
resistance by the body tissue [6]. 
 

3.1 Types of Diabetes 
 
Insulin treatment is required at any type. Most 
important types are: 
 

1- Gestational diabetes mellitus (GDM) is 
known as any degree of glucose 
intolerance with onset or first recognition 
during pregnancy. Diet modification is 
applied or insulin for treatment, this 
condition may not persistence after 
pregnancy [10]. 

2- Type 1 diabetes (Autoimmune diabetes 
mellitus): Is an absolute insulin deficiency 
resulting from absolute destruction of β 
cells [11]. 

3- Type 2 Diabetes mellitus: Is a relative 
insulin reduction that resists the action of 

insulin [11]. People suffers from obesity 
are more threatened to develop T2D, and 
metabolic syndrome [6]. 

 

3.2 Complications 
 
Patients with T2D may present with characteristic 
symptoms such as thirst, polyuria, a defect of 
vision, and weight loss. In sever form, 
ketoacidosis or a non-ketotic hyperosmolar state 
may lead to loss of conscious. T2D can cause 
pathological and functional changes in the organ 
may be present for a long time before the 
diagnosis is made. The long-term effects of T2D 
lead to a gradual increase of the specific 
complications of retinopathy with a loss of vision, 
and nephropathy that may lead to renal failure 
[12]. 
 

3.3 Induction of T2D Mellitus in 
Experimental Animals 

 

T2D induced by streptozotocin (STZ), which is a 
molecule that produces a selective toxic effect in 
experimental animal [13]. Doses should be 

 

 
 

Fig. 3. Induction of STZ. Intraperitoneally in rat model to induce T2DM [17] 



 
 
 
 

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37 

 

calculated to perform a partial destruction of β 
cell mass to produce a non-ketotic and a mild 
insulin deficient state of T2D [14]. Animals will be 
injected with a single dose of streptozotocin 65 
mg/kg intraperitoneally (Fig. 3) [15]. 

 
Here are other ways to induce diabetes in a 
model rat by consuming of unbalanced high-fat 
diets that result in accumulation of fat in adipose 
tissue and increase body weight. The 
accumulation of fat will affect the releasing of 
deferent protein from the adipose tissue called 
adipokines, that plays an important role in insulin 
sensitivity and inflammation, which can be 
developed into some obesity-related disorder like 
type 2 diabetes [16]. 

 
4. INFLAMMATION 
 
Is a host response reflection to tissue injury,   
and indicates the occurrence by four signs 
(Cardinal signs): redness, swelling, heat, and 
pain [18]. 
 

4.1 Carrageenan-induced Hind Paw 
Edema in the Mouse 

 
Carrageenan induced inflammation by 
subcutaneous injunction in the right hind paw 
100 μL (suspended in 1.5% vichele) of 
carrageenan that results in acute, non-immune, 
well reached, and highly reproducible 
inflammation, the action of pro-inflammatory 
agents, histamine, complement, and reactive 
oxygen will produce cardinal signs of 
inflammation develop subsequently to the 
injection. The traditional method to measure 

inflammatory response is quantified by 
increasing the size of paw oedema [18], which 
represent the magnitude of inflammation 
response effectively [19]. 
 
Hind paw size can be measured either by 
plethysmometer's caliper which is a rough 
method (Fig. 4) or by new The new technology to 
asses induced acute paw inflammation in the rats 
by epifluorescence imaging, a Fluorescence 
intensity in the saline and carrageenan-treated 
hindpaw (Fig. 5). 
 

Carrageenan-induced hind paw edema as acute 
inflammation model in mice [18]. In addition, 
cotton pellet-induced granuloma as chronic 
inflammation model in rats [20]. 
 

100 µl of l carrageenan suspended in normal 
saline 1.5% concentration will be subcutaneously 
injected into a hind paw of the animals on one 
side. 100 µl of saline will be injected into the 
contralateral hind paw and used as a control. 
Using plethysmometer, the hind paw volumes will 
be measured before and after six hours of 
carrageenan injection. Oedema is expressed as 
the variation between the change in 
carrageenan-treated hind paw volume and the 
control saline-treated (Fig. 6) [18]. 
 
The results will be expressed as percentage                 
of puffiness calculated as following the     
formula: 
 

Alteration = (width of the hind paw at the end 
day of experiment− width of the hind paw 
prior carrageenan/width of the hind paw prior 
carrageenan × 100% ) [21]. 

 

 
 

Fig. 4. Hind paw measurement by caliper. The paw measure by placing the paw in the caliper 
paw touch either side of the caliper, measurements read in mm [19]



 
 
 
 

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38 

 

 
 

Fig. 5. Carrageenan-induced acute paw inflammation in the rat (Fluorescence intensity in the 
saline and carrageenan) measured after injection by epifluorescence imaging 60 and 120 min 

[22] 
 

 
 

Fig. 6. Carrageenan control and injected hind paw (A) control hind paw, (B) injected hind paw 
by carrageenan 100 μL suspended in 1.5% vichele, show an edema and redness [23] 

 

5. ANTI-INFLAMMATORY DRUGS 
 

5.1 Diclofenac 
 
Diclofenac sodium is a nonsteroidal anti-
inflammatory class of drugs (NSAIDS), that used 
as anti-inflammatory and painkiller drug. 
Diclofenac interposed by inhibiting the release 
ofcyclooxygenase-1 (COX1) and 
cyclooxygenase-2 (COX2), that convert 
arachidonic acid into prostaglandins (PGs). 
Diclofenac should be used in minimal dose due 
to its toxicity. Diclofenac at 5 mg/kg dose started 
to show an inhibition in hind paw edema after 2 
hours [24]. Diclofenac can increase the risk of 
heart attack, strokes, blood clots and 
gastroduodenal ulceration [25]. Gastroduodenal 
ulceration and bleeding are the major limitations 
to the use of NSAIDs. It's lead to damage to the 
gastroduodenal mucosa via several 

mechanisms, including the topical irritant effect of 
these drugs on the epithelium, weakness of the 
barrier properties of the mucosa, inhibition 
synthesis of the gastric prostaglandin, decrees 
blood flow through the gastric mucosa and 
interference with the repair of superficial injury. 
The presence of acid in the lumen of the 
stomach also help in increase rate of the 
pathogenesis of NSAIDs induced ulcers and 
bleeding, through impairing the restitution 
process, interfering with haemostasis and 
inactivating several growth factors that are 
important in mucosal defence and repair [26] 
(Fig. 7). 
 

5.2 Aleglitazar 
 
Aleglitazar is a combination of PPARα and γ 
agonist and designed to stimulate both α and γ 
receptors at minimum concentrations. PPARs



 
 
 
 

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39 

 

 
 

Fig. 7. Morphological and histological examination of rats gastric mucosa in diclofenac-
induced ulcer model (section was stained with Haematoxylin and Eosin and magnified by 20×). 
A. Stomach of control rat; B. Stomach of diclofenac-induced ulcer rat at a dose of (100 mg/kg) 

[27] 
 

are one of nuclear receptor superfamily, which 
participated in the transcriptional control of genes 
contributing in lipid and carbohydrate 
metabolism, and inflammation, especially in the 
setting of obesity, hypercholesterolemia, insulin 
resistance, and atherosclerosis. PPARs are 
divided into 3 subtypes: PPARα, PPARγ, and 
PPAR δ. PPAR α found at high concentration in 
liver, kidney and the skeletal muscle and PPAR γ 
found at high concentration in adipocytes, 
muscle cells, the liver and the kidney [5]. The 
synthetic agonists of PPAR α e.g. fibrate used for 
lowering triglycerides (TG) and raising high-
density lipoprotein cholesterol (HDL) in plasma, 
while the synthetic PPAR γ agonists e.g. 
thiazolidinediones pioglitazone used as 
antidiabetics [1]. 
 

5.3 Mechanism of Action 
 
Aleglitazar prepared to be an agonist for both 
PPAR α&γ.PPARα the agonistic action is 
controlled lipid levels, thus improving 
dyslipidemia. In addition, PPARγ controls 
glucose level and resulting in reduce insulin 
resistance in diabetic patients [28]. 
 

5.4 Optimal Dose 
 
Aleglitazar (150 ug/kg/day) for 16 weeks was 
selected to explore any potential association of 
this dual PPAR α/γ agonist with anti-arthritic and 
anti-inflammatory properties [29]. 
 
Supratherapeutic dose (600 μg) of aleglitazar for 
26 weeks in patients with normal to borderline 

impaired renal function with glomerular filtration 
rate (eGFR 60 mL/min per 1.73 m2), raised 
serum creatinine by a mean 22% to a plateau 
after 4 weeks. Then, serum creatinine resumed 
to baseline after 4 to 8 weeks of drug cessation 
[29]. 
 

5.5 Side Effect 
 
In increase the incidence of the expected dose, 
will lead to increase in serum creatinine, 
decrease glomerular filtration rate, progressive 
nephropathy and bilateral oedema [29]. 
 

5.6 Ulcergenic Effect 
 
Aaleglitazar with a dose of (150 µg/kg) shows 
pharmacological effects on the 8

th
 day after 

pellets. The day before scarification, all rats 
prevented from food and liquid for 12 hours. 
Gastric tissue will be removed and taken out, 
after cut open to the stomach the inner surface 
will be cleansed with saline 0.9% to clean any 
remains inside the stomach and hold it by bins to 
exposed its mucosa and stomach ulcer will 
examined under magnifying land lens to 
calculate ulcer index by the number and depth of 
the ulcers (gastric ulcer scoring), [30]. Part of the 
stomach (fundus) fixed in formalin and exposed 
to histopathological study to compare it with 
diclofenac [27]. 
 

5.7 Drug-drug Interaction 
 
Aleglitazar used in combination with warfarin 
which used as an anticoagulant drug, it affects 



 
 
 
 

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40 

 

the efficacy and safety by affecting the viscosity 
of the blood through angiotensin-2 receptor 
blocker so the blood vessels dilated that lead to 
decrease the velocity of the blood stream and 
increase the susceptibility of thrombosis [31]. 
 
In patients with normal to borderline impaired 
renal function and impaired glomerular filtration 
rate using aleglitazar in supratherapeutic dose 
will increase serum creatinine and decrease 
glomerular filtration rate that leads to progressive 
nephropathy and bilateral oedema so it interacts 
with diuretics [31]. 
 

6 BIOCHEMICAL TESTS 
 

6.1 Fasting Blood Glucose 
 
A daily dose of aleglitazar150 μg observed to 
modulate the fasting plasma glucose (FBG) [5]. 
 

6.2 Insulin 
 
Aleglitazar treatment helped to increase body's 
sensitivity to insulin significantly compared to 
placebo. 
 

6.3 HbA1c 
 
Clinical trials of aleglitazar in patients with type 2 
diabetes were conducted for 26 weeks 
(150 µg/day). The primary endpoint was 
significant reduction in glycated hemoglobin 
(HbA1c) concentration from baseline to week 26 
[32] (Fig. 8). 
 

6.4 Serum Creatinine 
 
Serum creatinine (SC) is a routine test for kidney 
function assessment [33]. Serum creatinine 

showed to increase and show to be reversible 
after cessation of aleglitazar within a follow-up 
period from 4 to 8 weeks [29]. 
 

6.5 Immuno-inflammatory Reactions in 
Obesity-Related Disorders 

 
C-reactive protein (CRP) is a crucial 
inflammatory biomarker [34]. High sensitivity to 
aleglitazar shows a significant reduction in CRP 
[35]. 
 

6.6 Free Fatty Acids (FFA) and 
Triglycerides and – HDL 

 
PPARα and PPARδ enhance the movement of 
lipid out of circulation by increase uptake of free 
fatty acid and oxidation in tissue, while PPAR 
γwill stimulate the process of lipid storage in 
adipose tissue. [36]. 
 
It has the most effective improvement in high-
density lipoprotein cholesterol, low-density 
lipoprotein cholesterol (LDL), and triglycerides. 
The result of lowering lipid profile reduce the risk 
of cardiovascular disease and particularly 
atherosclerosis [5]. 
 

6.7 Detection and Estimation of Serum 
Level of Tumor Necrosis Factor Alpha 
(TNF-α) 

 

In the patient with diabetes the inflammatory 
mediators levels of gingival crevicular fluid 
(GCF), interleukin 1 beta (IL-1beta) and 
monocytic secretion of prostaglandin E2 (PGE2) 
are increased more than the non-diabetic patient 
[37]. Tumor necrosis factor-alpha (TNF-α) 
synthesis in adipose tissue, the degree of 
adipose tissue related to the level of synthetase

 

 
 

Fig. 8. Gradually reduction inHbA1c. Significant reduction in HbA1c by aleglitazar was 
apparent by week [32] 



 
 
 
 

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41 

 

 
 

Fig. 9. TNF-α concentration in T2DM. (4.4+/-0.2 pg/ml) [41] 
 
of TNF-α, this is the bond between obesity and 
T2DM [38]. Serum level of TNF- α in obese 
patients with T2DM increased than normal or 
non-obese patient with T2DM, serum level of 
TNF- α show positive correlation to degree of 
adipose tissue and negative correlation with 
glucose-insulin rate (GIR),increase TNF- α highly 
associated with increased insulin resistance (Fig. 
9) [39]. 
 

6.8 Nitric Oxide (NO) Concentrations in 
Serum 

 
Obese rats were assigned to treatment by 
aleglitazar, the treatment was administered for 
nine weeks. Nitric oxide (NO) was measured. 
Aleglitazar increased NO release by 25% as the 
nitric oxide/peroxynitrite ratio (NO/ONOO-) which 
is an indicator of NO synthase uncoupling 
increased by 33% with aleglitazar treatment   
[40]. 
 

7. CONCLUSION 
 
Aleglitazar is a new promising drug, used as an 
anti-inflammatory, anti-diabetic, and anti-
hyperlipidemic drug. In comparison with 
diclofenac the standard anti-inflammatory drug. 
Inthe field of pharmacokinetics the AUC of 
aleglitazar. Increased with dose with values of 
(8.66 - 402) ng.h/ml while in diclofenac the AUC 
is between (72.6 - 177.5) ng.h/ml. Aleglitazar has 
more potent and has less side effect than 
diclofenac. But in some cases aleglitazar must 
be monitored under the supervision of a 
physician because it affects the safety and 
efficacy of warfarin and diuretics. 
 

CONSENT 
 
It is not applicable. 

ETHICAL APPROVAL 
 
As per international standard or university 
standard ethical approval has been collected and 
preserved by the authors. 
 

COMPETING INTERESTS 
 
Author has declared that no competing interests 
exist. 
 

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