Microsoft word - 25f ijab-09-333, 133-136

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 e
t 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.
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