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Open Access 
F u l l  L e n g t h  A r t i c l e  

 Effect of Losartan in Comparison with Pioglitazone on Lipid Profile 

in a Rat Model of Type 2 Diabetes Mellitus 

Muhammad Nauman Shad1, Muhammad Sair2, Amir Jalal3, Sadia Chiragh4, Zeeshan Ahmad5 
1 Associate Professor of Pharmacology, Sahara Medical College, Narowal 

2 Assistant Professor of Pharmacology, Islam Medical College, Sialkot 
3 Assistant Professor of Pharmacology, Sahara Medical College, Narowal 

4 Retired Professor of Department of Pharmacology, PGMI, Lahore 
5 PhD Research Scholar, Faculty of Pharmacy, University of Sargodha 

A B S T R A C T  

Objective: To evaluate the effect of losartan in comparison with pioglitazone on lipid profile in a type 2 diabetic rat 

mode. 

Materials and Methods: This case control study was conducted in Postgraduate Medical Institute (PGMI), Lahore from 

June to August 2011. Forty-five Sprague-Dawley rats of 5 weeks of age were randomized into three groups. All the rats 

were fed a high fat and sucrose diet. Pioglitazone or Losartan were given along with this diet to the rats in groups HFD-

PIO and HFD-LOS respectively, while group HFD was kept as control. At the end of 12 weeks, serum samples were 

obtained from all the animals and total cholesterol, HDL-cholesterol and triglyceride levels were obtained using kit 

method. LDL-cholesterol was determined using the Friedewald formula. 

Results: At the end of study period, lipid profile parameters were statistically improved between HFD-PIO and the 

control HFD group. The difference in the lipid profile parameters between the HFD-LOS and the control HFD group as 

well as between the HFD-PIO and HFD-LOS groups was not significant. 

Conclusion: The ARB losartan has a small but insignificant effect on lipid profile. 

Key words: Lipid Profile, Losartan, Pioglitazone, Type-2 Diabetes Mellitus 

Author`s Contribution 
1,2

Conception, synthesis, planning of 
research and manuscript writing 
Interpretation and discussion 
3,4 

Data analysis, interpretation and 
manuscript writing, 

5  
Active participation in 

data collection. 

Address of Correspondence 
Muhammad Nauman SHad 
Email: mnauman2002saj@yahoo.com 

Article info. 
Received:  September 20, 2017 
Accepted:  January 11, 2017 

Cite this article. Shad MN, Sair M, Jalal A, Chiraghi S, Ahmad Z. Effect of Losartan in 
comparison with Pioglitazone on Lipid Profile in a Rat Model of Type 2 Diabetes Mellitus. 
JIMDC.2018; 7(1):36-40 

 

Funding Source: Nil 
Conflict of Interest: Nil 

I n t r o d u c t i o n  
 

Diabetes mellitus is one of the leading chronic diseases in 

almost every country1, is characterized by increased 

blood glucose levels. Its associated complications 

including dyslipidemia lead to increased morbidity and 

mortality. Patients with adverse lipid profile including 

hypertriglycedemia, high levels of low density lipoproteins 

(LDL) and low levels of high density lipoproteins (HDL) 

are at high risk of cardiovascular disease.2 Many patients 

with type 2 diabetes have an abnormal lipid profile 

characterized by increased triglycerides and decreased 

high density lipoproteins HDL-C.3 Studies have shown 

that a high fat plus high carbohydrate diet play a major 

role in the pathogenesis of type 2 diabetes mellitus and 

dyslipidemia.4 A diet that contains a high percentage of 

saturated fatty acids and refined carbohydrates in 

combination is an unhealthy diet that may lead to insulin 

resistance, type 2 diabetes mellitus, dyslipidemia and 

various other features of the metabolic syndrome. Such 

O R I G I N A L  A R T I C L E  



 

                           37 J I M D C   2 0 1 8  37 

diets have been used to induce diabetes and dyslipidemia 

in animal models.5 

It is well known that cholesterol homeostasis is 

fundamental for appropriate insulin secretory function of β 

cells. Excessive cholesterol accumulation in β cells, when 

exposed to chronically increased levels of free fatty acids 

(for example in obesity or due to high fat diet), may cause 

lipotoxicity and reduce insulin secretion, causing β cell 

dysfunction & decreased β cell mass.6 

Dyslipidemia has been seen to be associated with 

dysfunction of pancreatic β cells and this is particularly 

evident in people with elevated total cholesterol (TC) and 

LDL-C levels.7 Thiazolidinediones (Glitazones) are a 

group of drugs used for treatment of type 2 diabetes 

which have shown to preserve beta cell function by 

protecting beta-cell from lipotoxicity.8 Glitazones are 

selective agonists of peroxisome proliferator activated 

receptor gamma (PPAR𝛾), a nuclear receptor which is 

most highly expressed in adipose tissue and controls the 

transcription and translation of a variety of genes involved 

in glucose and lipid metabolism.9 PPAR-γ is currently 

regarded as a therapeutic target in the metabolic 

syndrome.10 Pioglitazone, one of the major glitazones 

being used in the treatment in T2DM has shown to 

improve lipid profile including decrease in triglycerides 

and low-density lipoprotein (LDL), increase in high-density 

lipoprotein (HDL) and decrease in serum fatty acids.11 

Renin-angiotensin-aldosterone system has been linked 

with obesity-related hypertension and it is also involved in 

the association among obesity, metabolic syndrome, 

dyslipidemia, insulin resistance, chronic kidney disease, 

and hypertension.12 ACE Inhibitors have shown positive 

effects on the lipid profiles in children with the metabolic 

syndrome. Results in the study showed statistically 

significant decrease in LDL & triglyceride levels and 

significant increase in HDL levels.13 Now several ARBs 

(Angiotensin Receptor Blockers) including Telmisartan, 

Irbesartan and Losartan have shown to possess PPAR-γ 

agonist activity. Beneficial effects of PPAR-γ agonist 

activity on improving insulin sensitivity have been 

mentioned. This provides a strategic rationale and 

pharmacological platform for the use of dual ARB/PPAR-γ 

agonists to target the metabolic syndrome and its 

cardiovascular sequelae.10 

This provides the basis for the present study to observe 

effects, if any, of a dual ARB/PPAR-γ agonist losartan on 

lipid profile in a rat model of type 2 diabetes mellitus. 

M a t e r i a l s  a n d  M e t h o d s  

This randomized control trial was conducted at 

Postgraduate Medical Institute (PGMI), Lahore from June 

2018 to August 2018. The sample size was estimated by 

using 5% level of significance and 80% power of test with 

expected frequency of diabetes mellitus; 36, 57 and 94 

percent in glitazones, angiotensin receptor blockers and 

control groups respectively.15,16 The estimated sample 

size was 13 in each group (total 39). It was increased to 

15 in each group (total 45) to increase the accuracy of the 

results and to decrease the margin of error. Sprague-

Dawley rats of 4 weeks of age were purchased from the 

University of Veterinary & Animal Sciences, Lahore and 

kept in the animal house of PGMI in iron cages under 

hygienic conditions. Room temperature was maintained at 

25 + 2C under natural day/night cycle with free access to 

rat chow and water. They were allowed one week to 

acclimatize. From 5 weeks of age rats were fed on high 

fat diet containing 30% beef fat and 10% sucrose.14 

Animals were divided randomly into 3 groups of 15 

animals each. All three groups were fed high fat and 

sucrose diet throughout study period of 12 weeks. First 

group was given distilled water daily orally as a single 

morning dose and labeled as HFD (high fat diet) group. 

Second group was given pioglitazone in dose of 10mg/kg 

body weigh daily orally as a single morning dose for 12 

weeks and labeled as HFD-PIO group.15 Third group was 

given losartan in dose of 10mg/kg body weight daily orally 

as a single morning dose for 12 weeks and labeled as 

HFD-LOS group.1 Drugs Pioglitazone and losartan were 

obtained from Mass Pharmaceuticals. Each rat was 

weighed initially and after every week. Fasting blood 

glucose level was measured every week using a 

glucometer (AccuChek) using a drop of blood obtained 

from the tail vein. After 12 weeks rats were kept on 12 

hour fast and blood was collected by cardiac puncture. 

Samples were then centrifuged at room temperature at 

3000-4000 rpm for 5 minutes. Serum was stored at –20°C 

until analyzed for lipid profile. Total cholesterol, HDL-

cholesterol and triglyceride levels were obtained using 



 

                           38 J I M D C   2 0 1 8  38 

calorimetric kit methods. LDL-cholesterol was determined 

using the Friedewald formula:17 

 LDL = Total Cholesterol – HDL Cholesterol – 

Triglycerides/5.  

The data was entered and analyzed using SPSS 17.0. 

Mean ± SD was analyzed for quantitative variables like 

body weight, fasting blood glucose levels and lipid profile. 

One-way ANOVA was applied to compare the variables 

among the groups. Bonferroni’s post-test was applied to 

see whether variances were significantly different.  

R e s u l t s  

Mean fasting blood glucose level of animals at the start of 

study was 92±9, 87±7 and 91±7 mg/dl in group HFD, 

HFD-PIO and HFD-LOS respectively. Fasting blood 

glucose level increased in all groups over the study 

period. At 12 week fasting blood glucose level was 

significantly less in HFD-PIO and HFD-LOS group as 

compared to that of HFD group. Difference between HFD-

PIO and HFD-LOS group was not significant (Table 1). At 

12 weeks, mean serum cholesterol, LDL and triglyceride 

levels were higher and mean HDL level was lower in the 

control HFD group as compared to the HFD-PIO and 

HFD-LOS groups (Table 2). The mean serum cholesterol, 

LDL and triglyceride levels were higher and mean HDL 

level was lower in the HFD-LOS group as compared to 

the HFD-PIO group (Table 2). Total cholesterol and LDL 

levels were found to be significantly less in the HFD-PIO 

group as compared to that of HFD group. Triglyceride 

levels were also significantly less. HDL levels showed no 

significance between HFD-PIO and the control HFD group 

(Table 2). There was no statistical difference in any of the 

lipid parameters between HFD-LOS and the control HFD 

group as well as between the HFD-PIO and HFD-LOS 

groups (Table 2). 

D i s c u s s i o n  

In the present study, the effect of losartan on lipid profile 

was evaluated on rats fed a high fat plus sucrose diet, in 

comparison with pioglitazone. For this purpose, 45 

Sprague-Dawley rats of 5 weeks of age were randomized 

into three groups. All the rats in each group were fed a 

high fat and sucrose diet. Such an animal model is the 

best model to study the human metabolic syndrome. 

Numerous studies have shown that a diet rich in saturated 

fatty acids and refined carbohydrates increases the risk of 

developing the metabolic syndrome characterized by 

dyslipidemia, impaired glucose tolerance, insulin 

resistance and hypertension.5 

Pioglitazone and losartan were given along with this diet 

to the rats in group HFD-PIO and HFD-LOS respectively, 

while group HFD was kept as control. At the end of 12 

weeks, serum samples were obtained from all the animals 

and total cholesterol, HDL-cholesterol and triglyceride 

levels were obtained using kit method. LDL-cholesterol 

was determined using the Friedewald formula. At 12 

weeks, mean serum cholesterol, LDL and triglyceride 

levels were higher and mean HDL level was lower in the 

control HFD group as compared to the HFD-PIO and 

HFD-LOS groups. Total cholesterol, triglyceride and LDL 

levels were found to be significantly less in the group of 

rats fed pioglitazone along with the high fat diet (HFD-

PIO), as compared to the rats fed high fat diet alone 

(HFD).The rise in serum cholesterol, LDL & triglyceride 

levels and decrease in HDL cholesterol in rats fed on a 

high fat diet are consistent with effects of development of 

the metabolic syndrome in such animals.5 Similarly, 

findings are also seen in humans fed a high fed diet.18 

The decrease in triglycerides, total cholesterol and LDL 

cholesterol by pioglitazone is also consistent with several 

studies on this drug. Thiazolidinediones, especially 

pioglitazone, have shown to have favorable effects on 

plasma lipids. Pioglitazone has shown in several studies 

to reduce triglyceride levels, total cholesterol and LDL 

cholesterol.19  

Increase in HDL cholesterol however was not significant 

in the present study. The mechanisms by which 

pioglitazone produces these effects are highly complex 

and may involve anti-oxidant, anti-thrombotic, anti-

inflammatory, anti-apoptotic and anti-infective properties, 

as well as effects on endothelial function and repair. 

These may be associated with their effects on peroxisome 

proliferator-activated receptor-gamma (PPARγ) 

receptors.20 The present study showed a small but 

insignificant decrease in triglycerides, total cholesterol 

and LDL in rats fed a high fat diet plus losartan as 

compared to the rats fed on a high fat diet alone. HDL 

cholesterol also showed no significant change. Studies 

have shown variation in effects by different ARBs on lipid 

profile.21 It may also have been because the present 



 

                           39 J I M D C   2 0 1 8  39 

study was a preventive study in which some of the rats 

developed diabetes and some did not when fed on a high 

fat diet alone (HFD) or with pioglitazone (HFD-PIO) or 

losartan (HFD-LOS). 

 

Table 1: Body weight, fasting blood glucose and insulin levels of HFD fed rats at end of 12 week study period 
(n=45) 

Groups Body Weight  
(g) 

p-value* Fasting Blood 
Glucose (mg/dl) 

p-value* Serum Insulin 
(µIU/ml) 

p-value* 

HFD (mean±SD) 382 ± 48 --- 152 ± 12 ---- 23.20 ± 5.52 ---- 

HFD-PIO (mean±SD) 345 ± 45 ≤ 0.05 123 ± 17 ≤ 0.001 12.07 ± 6.82 ≤ 0.001 

HFD-LOS (mean±SD) 342 ± 38 ≤ 0.05 132±17 ≤ 0.001 14.13 ± 8.83 ≤ 0.01 

Table 2:  Lipid profile of HFD fed rats at end of 12 week study period (n=45) 

Groups Total 
Cholesterol 

p-value* Triglycerides p-
value* 

LDL p-
value* 

HDL p-
value* 

HFD  (mean 
± SD) 

138.5±7.97 ___ 169.2±9.93 ____ 84.1 ± 
7.17 

____ 20.6 ± 3.22 _____ 

HFD-PIO 
(mean ± SD) 

125.1±14.25  < 0.01 157.1 ± 16.35  <0.05 69.3 ± 
13.94 

< 0.01 24.4 ± 3.60 > 0.05 

HFD-LOS 
(mean ± SD) 

131.3±15.18 > 0.05 162.3 ± 17.44 >0.05 76.3 ± 
14.59 

> 0.05 22.6 ± 3.94 >0.05 

There was also no significant difference in effects on lipid 

profile parameters between rats fed on a high fat diet plus 

losartan and rats fed a high diet plus pioglitazone. 

C o n c l u s i o n  

The topical Nifedipine is more effective in relieving the 

pain and healing as compared to oral form in CAF. 

Further research work on large scale is recommended to 

evaluate the oral and topical forms of Nifedipine for the 

treatment of CAF. 

R e f e r e n c e s  

1. Shaw J, Sicree R, Zimmet P. Global estimates of the 

prevalence of diabetes for 2010 and 2030. Diabetes 

Res ClinPract. 2010; 87 (1): 4-14. 

2. Kyvelou SM, Vyssoulis GP, Karpanou EA, 

Adamopoulos DN, Zervoudaki AI, Pietri PG, 

Stefanadis CI. Effects of antihypertensive treatment 

with angiotensin II receptor blockers on lipid profile: 

an open multi-drug comparison trial. Hellenic J 

Cardiol. 2006; 47(1):21-8. 

3. Mahboob A, Taqweem A, Alam I, Ahmad I, Ali Z, Bilal 

M. Effect of Pioglitazone on Lipid Profile in Type 2 

Diabetic Patients. J Postgrad Med Inst. 2013; 27(1): 

13-9. 

4. Gastaldelli, A. Abdominal Fat: does it predict the 

development of type 2 diabetes? Am J Clin Nutr. 

2008. 87 (5): 1118-1119. 

5. Panchal, S., and Brown, L. Rodent models for 

metabolic syndrome research. J Biomed Biotechnol, 

2012.Article ID 351982. 

6. Giacca, A., Xiao, C., Oprescu, A., Carpentier, A. and 

Lewis, G. Lipid-induced pancreatic -cell function: 

focus on in vivo studies. Am J Physiol Endocrinol 

Metab. 2011. 300 (2): E255-E262. 

7. Zheng T, Gao Y and Tian H. Relationship between 

blood lipid profiles and pancreatic islet β cell function 

in Chinese men and women with normal glucose 

tolerance: a cross-sectional study. BMC Public 

Health. 2012. 12(1):634. 

8. Hanefeld, M. Pioglitazone and sulfonylureas: 

effectively treating type 2 diabetes. Int J Clin Pract. 

2007. 61 (s153): 20-27. 

9. Abdelrahman, M., Sivarajah, A. and Thiermermann C. 

Beneficial effects of PPAR-γ ligands in ischemia, 

reperfusion injury, inflammation and shock.  

Cardiovasc Res. 2005. 65 (4): 772-781. 

10. Rossi, G. Losartan metabolite exp3179: an AT1-

receptor–independent treatment strategy for patients 

with the metabolic syndrome? Hypertension. 2010. 

54(4): 710-712. 



 

                           40 J I M D C   2 0 1 8  40 

11. Nasser A, Niafar M, Dalir E, Najafipour F, 

Mohamadzadeh S, Adabi K, et al. The effect of 

pioglitazone on weight, lipid profile and liver enzymes 

in type 2 diabetic patients. Ther Adv Endocrinol 

Metab. 2015; 6(2) :56–60. 

12. Steifel, P., Vallejo-Vaz, J., Morillo, S., and Villar, J. 

Role of the renin-angiotensin system and aldosterone 

on cardiometabolic syndrome. Int J Hypertens. 2011; 

2011: Article ID: 685238 

13. Bitkin E, Boyraz M, Taşkın N, Akçay A, Ulucan K, 

Bedir M et al. Effects of ACE Inhibitors on Insulin 

Resistance and Lipid Profile in Children with 

Metabolic Syndrome.  J Clin Res Pediatr Endocrinol. 

2013. 5(3):164-169 

14. Panchal SK, Brown L, 2011. Rodent models for 

metabolic syndrome research. J Biomed Biotechnol, 

2011:351982. 

15. Koufany, M., Moulin, D., Bianchi, A., Muresan, M., 

Sebillaud, S., Netter, P., Weryha G., Jouzeau, J. Anti-

inflammatory effect of antidiabetic thiazolidinediones 

prevents bone resorption rather than cartilage 

changes in experimental polyarthritis. Arthritis Res 

Ther, 2008; 10 (1): R6. 

16. Chu, K., Lau, T., Carlsson, P. and Leung, P., 2006. 

Angiotensin II type 1 receptor blockade improves 

beta-cell function and glucose tolerance in a mouse 

model of type 2 diabetes. Diabetes.2006; 55 (2): 367-

74. 

17. Friedewald WT, Levi RI, Fredrickson DS. Estimation 

of the concentration of low density lipoproteins 

cholesterol in plasma without use of the 

ultracentrifuge. Clin Chem. 1972; 18(6): 499–502  

18. Chiu S, Williams PT, Krauss RM. Effects of a very 

high saturated fat diet on LDL particles in adults with 

atherogenic dyslipidemia: A randomized controlled 

trial. PloS one. 2017; 12(2): e0170664. 

19. Betteridge DJ. Effects of pioglitazone on lipid and 

lipoprotein metabolism. Diabetes Obes Metab. 2007; 

9(5):640-7. 

20. Deeg MA and Tan MH. Pioglitazone versus 

Rosiglitazone: Effects on Lipids, Lipoproteins, and 

Apolipoproteins in Head-to-Head Randomized Clinical 

Studies. PPAR Research. 2008. 

21. Derosa G, Ragonesi PD, Mugellini A, Ciccarelli L and 

Fogari R. Effects of Telmisartan Compared with 

Eprosartan on Blood Pressure Control, Glucose 

Metabolism and Lipid Profile in Hypertensive, Type 2 

Diabetic Patients: a Randomized, Double-Blind, 

Placebo-Controlled 12-Month Study. Hypertens Res. 

2004. 27(7): 457–464.