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INTERNATIONAL JOURNAL OF AGRICULTURE & BIOLOGY ISSN Print: 1560–8530; ISSN Online: 1814–9596 09–333/ZIP/2010/12–1–133–136 http://www.fspublishers.org Full Length Article
Effect of Pioglitazone on Glucose and Glycation Level in Type 2
Diabetic Patients

MUHAMMAD ALIM1, RAKHSHANDA NAWAZ, MUHAMMAD RAFIQUE ASI†, FAROOQ ANWAR AND TAHIRA IQBAL
Department of Chemistry and Biochemistry, University of Agriculture, Faisalabad-38040, Pakistan
†Nuclear Institute for Agriculture and Biology (NIAB), Faisalabad, Pakistan
Corresponding author’s e-mail: prof_alim68@yahoo.com

ABSTRACT
To elucidate the effects of pioglitazone treatment on glucose and glycation level in patients with type 2 diabetes, a total of 8
patients were treated with pioglitazone (30 mg day-1) for 12 weeks. After this period, there was a significant decrease in fasting
plasma glucose and glycation level. The fasting plasma glucose was decreased from 195 to 159 mg per dL and glycation level
decreased from 0.140 to 0.113 moles of glucose per moles of protein. These results suggest that pioglitazone decreases fasting
plasma glucose in type 2 diabetic patients and acts as an inhibitor of glycation in-vivo. 2010 Friends Science Publishers

Key Words: Pioglitazone; Glycation; Diabetic; Inhibitor

INTRODUCTION
increases transcription of insulin responsive genes and thus increases insulin sensitivity (Scholz et al., 2001). Diabetes mellitus commonly referred to as “diabetes” Most of the drugs metabolizing genes show different is a group of metabolic diseases characterized by activities in different populations, which are often major abnormalities at multiple organ sites. These defects include determinants of variable drug exposure and response insulin secretion, insulin action or both (Barnett, 2007). (Flockhart & Desta, 2009). Moreover individuals can differ There are different forms of diabetes mellitus but type 2 greatly in their inherent capacity to absorb, distribute, diabetes is the most common. It is also known as the non- excrete and metabolize drugs (Vesell, 1974). To accomplish insulin dependent diabetes mellitus (NIDDM) and occurs as the clinical benefits, safe and effective drug therapy is a result of progressive insulin secretory defect on the difficult due to large inter-patient variability in response to background of insulin resistance (American Diabetes many drugs (Flockhart & Desta, 2009). The values of Association, 2009). About 90 to 95% of people suffering biochemical and physiological parameters present in the from this disease have type 2 diabetes (DeFronzo, 1997). literature are not inline with the values calculated under our Without proper management many complications arise own environmental conditions. Therefore for the welfare of under hyperglycemic conditions. A high glucose humanity it is very necessary to generate information in our concentration increases protein glycation, also known as population to develop our own therapeutic standards under non-enzymatic glycosylation in blood and various organs (Krishmanurti & Steffes, 2001). These non-enzymatic Pioglitazone has been studied rarely and its effect on reactions between reducing sugars and free amino groups of glycation level has been reported only from few countries. proteins can alter the structure and function of proteins Moreover glycation research remains an area of outstanding (Hartog et al., 2007) and result in the formation of advanced interest, fascination and innovation in chemistry, biology, glycation end products (Ulrich & Cerami, 2001). medicine, food, nutrition and applied sciences. Therefore Pioglitazone (±) 5-{[4-[2-(5-ethyl-2-pyridinyl) ethoxy] the present project was designed to widen our knowledge phenyl] methyl}-2, 4-thiazolidinedione is an oral anti- about pioglitazone (an anti-diabetic) in Pakistani patients hyperglycemic agent, which is used in the treatment of type 2 diabetes (Gillies & Dunn, 2000). It belongs to a class Study Design and Methods
“thiazolidinediones", represent a potentially important group Subjects: A total of eight type 2 diabetic patients, clinically
of drugs with a mechanism of action differing from the diagnosed by physicians, were recruited from the outpatient existing therapies (Yki-Jarvinen, 2004). It acts primarily by medicine clinic of the General Hospital Faisalabad, decreasing insulin resistance in the treatment of type 2 Pakistan. They were recommended diet and exercise at diabetes (Radhakrishna et al., 2002). It is a peroxisome initial stage to control the diabetes. Patients who had proliferator activated receptor (PPARγ) agonist that previously received insulin, metformin, thiazolidinedione or To cite this paper: Alim, M., R. Nawaz, M.R. Asi, F. Anwar and T. Iqbal, 2010. Effect of pioglitazone on glucose and glycation level in type 2 diabetic
patients. Int. J. Agric. Biol., 12: 133–136
ALIM et al. / Int. J. Agric. Biol., Vol. 12, No. 1, 2010 any other medicine related to diabetes were excluded. Entry Table I: Demographic data of diabetic patients
criteria included age (35-55) years and weight (55-85 kg). Patients were in good general health without cardiac, Subject Age Weight
Height Blood
Pressure Body BMI*
hepatic, renal or other chronic diseases. The demographic No. ID Years Kg
Inches Systolic Diastolic °F
and clinical data of the patients is presented in Tables I and Study design: The study was conducted for 12 weeks by
keeping in view the ethical principles laid down in the Declaration of Helsinki (World Medical Association, 2004). Initially subject’s education was updated and their ability to comply with the protocol was checked. The subjects were instructed to take balanced diet during study period. All subjects gave signed, informed consent before participation Subscript ‘P’ stands for patient, *BMI is Body Mass Index Plasma collection: Blood samples from each patient after
Fig. 1: Change in concentration of glucose in diabetic
every 15 days, up to 12 weeks were collected by using patients
sterilize disposable syringes by venopuncture in pre- heparinised centrifuge tubes 10 mL Vacuette® Griener Bio-
one, Austria. These samples were mixed gently and were
then centrifuge at 4000 rpm and plasma was stored at –
20°C.
Analysis techniques: In plasma samples amount of glucose
was estimated by Kit method, protein concentration by
Biuret method and glycation level by Thiobarbituric acid
(TBA) method as described by Furth (1988),
spectrophotometrically.
Statistical analysis: For computation and the graphics, the
Microsoft Excel 7.0 was used. All data are reported as the
mean±SE (Steel et al., 1997).
Fig. 2: Change in concentration of plasma proteins in
diabetic patients
The results illustrating the effect of pioglitazone on glucose concentration, proteins concentration and glycation level in diabetic patients are presented in the Figs. 1–5. In patients, there is regular decrease in the concentration of fasting plasma glucose (FPG). After 8th week, minimum concentration (159.0±3.30 mg dL-1) was obtained in comparison to 195.5±8.65 mg per dL detected at the start of the study. This level slightly increased to 163.0±4.64 mg per dL after 10th week and then declined to 159.38±4.65 mg per dL (Fig. 1). There is not gradual increase or decrease in the concentration of plasma proteins. These values changed randomly and maximum concentration 67.96±1.77 mg per mL was achieved after 6th week and minimum value DISCUSSION
65.83±1.93 mg per mL after 10th week (Fig. 2). In patients, long term therapy with pioglitazone Results indicate that long term therapy with significantly decreased the glycation level. This level pioglitazone have significant effect on FPG level in type 2 reduced gradually up to 12th week, but in last weeks value of diabetic patients. This effect is more pronounced up to 8th glycation level become consistent. Maximum glycation week then concentration become almost constant. These level (0.144±0.014 mole mole-1) was observed after 2nd results are similar to the results reported in the literature. week and minimum value 0.113±0.010 mole per mole was Pioglitazone decrease blood glucose in diabetic animal obtained after 12th week (Fig. 3). The trends between the models (Saltiel & Olefsky, 1996) and in patients with type 2 change in fasting plasma glucose and glycation level and the diabetes (Suter et al., 1992). In general decrease in plasma change in concentration of proteins and glycation level are glucose or improvement of insulin resistance by pioglitazone requires several days in diabetic animals EFFECT OF PIOGLITAZONE ON GLUCOSE/GLYCATION LEVEL IN DIABETIC PATIENTS / Int. J. Agric. Biol., Vol. 12, No. 1, 2010 Table II: Clinical data of diabetic patients in the fasting state
Subject
Serum creatinine Triglycerides Hb
Cholestrol SGPT Total protein TLC
Neutrophils Lymphocytes
dL-1 /cmm
Subscript ‘P’ stands for patient, Hb: hemoglobin, SGPT: Serum Glutamic-Pyruvic Transaminase, TLC: Total leucocyte count
(Saltiel & Olefsky, 1996) or several weeks in patients with Fig. 3: Change in Glycation level in diabetic patients
type 2 diabetes (Iwamoto et al., 1991; Suter et al., 1992). Aronoff et al. (2000) mentioned that the blood glucose lowering effect of pioglitazone developed gradually over weeks and maximum decrease was observed after 10-14 weeks. Pioglitazone have the ability to reduce both fasting and postprandial glucose levels (Suter et al., 1992; Ravikumar et al., 2008). After pioglitazone treatment, fasting and postprandial endogenous glucose production (EGP) decreased (16.6±1.0 vs. 12.2±0.7 µmol kg-1 min-1) and (2.58±0.25 vs. 1.26±0.30 µmol/Kg/min), respectively (Ravikumar et al., 2008). Rubin et al. (1999) also observed a decrease in FBG levels of up to 60 mg/dL in a combination therapy. The results about the analysis of plasma proteins illustrate that there is not regular increase or Fig 4: Pattern between glycation level and
decrease in the concentration of proteins. These values concentration of glucose in diabetic Patients
remain within the normal limits. This indicate that long term treatment with pioglitazone have no effect on plasma proteins in type 2 diabetic patients. The decrease in the glycation level after 12 weeks treatment with pioglitazone is not surprising, because similar results are available in previous literature. As the pioglitazone significantly improves the glycemic control (Pavo et al., 2003; Umpierrez et al., 2006), therefore its inhibitory effect on glycation process can be explained in this scenario. As monotherapy, it improves the fasting blood glucose and glycosylated hemoglobin (Stratton et al., 2000; Pavo et al., 2003). On average, fasting blood glucose and glycosylated hemoglobin can be improved by approximately 40 mg per dL and almost 1%, respectively (Stumvoll & Fig. 5: Pattern between glycation level and
Haring, 2002). It was effective in reducing plasma glucose concentration of proteins in diabetic patients
from the baseline levels from week 4 and this decrease continued up to the last measurement at week 12 (Abe et al., 2007). In Wistar fatty rats, GHb levels declined gradually over 5 weeks administration of pioglitazone (Nagisa et al., 2003). It also acts as an important inhibitor of glycation and potent antioxidant (Rahbar et al., 2000; Gumieniczek, 2005). Moreover the pattern between the change in FPG and glycation level is quite similar, they show almost similar trends during the study. The pattern between change in concentration of proteins and glycation level in patients demonstrate that trend in the concentration change of plasma proteins is not similar to change in glycation level. ALIM et al. / Int. J. Agric. Biol., Vol. 12, No. 1, 2010 CONCLUSION
Pavo, I., G. Jermendy, T.T. Varkonyi, Z. Kerenyi, A. Gyimesi, S. Shoustov, M. Shestakova, M. Herz, D. Johns, B.J. Schluchter, A. Festa and M. Pioglitazone decreases the fasting plasma glucose Tan, 2003. Effect of pioglitazone compared with metformin on glycemic control and indicators of insulin sensitivity in recently level and acts as an inhibitor of glycation in type 2 diabetes diagnosed patients with type 2 diabetes. J. Clin. Endocrinol. Metab., Acknowledgement: We acknowledge the support provided
Radhakrishna, T., D.R. Sreenivas and G.O. Reddy, 2002. Determination of by the University of Agriculture, Faisalabad, Pakistan, in pioglitazone hydrochloride in bulk and pharmaceutical formulations by HPLC and MEKC methods. terms of equipment and laboratory facilities. Moreover we J. Pharm. Biomed. Anal., 29: 593– are grateful to the Higher Education Commission (HEC), Rahbar, S., R. Natarajana, K.K. Yernenia, S. Scott, N. Gonzales and J.L. Islamabad, Pakistan for finance of this research. Nadler, 2000. Evidence that pioglitazone, metformin and pentoxifylline are inhibitors of glycation. REFERENCES
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