Management of Diabetic with
Combined Therapy of Reducdyn and Metformin
in Streptozotocin induced Diabetic Male Rats.
Nwauche
Kelechi T., Monago Comfort C.* and Onwuka Franscis.
Department of Biochemistry, Faculty of
Chemical Sciences, College of Natural and Applied Sciences, University of Port
Harcourt, Choba, Rivers State, Nigeria.
ABSTRACT:
Metformin is a known antidiabetic
drug, while reducdyn is a known liver drug. Diabetes
mellitus is always associated with liver problem. The present study was
designed to investigate the effects of metformin and reducdyn in management of diabetes mellitus and its liver
associated problems in male rats. Metformin was
administered at a dose of 1.4mg/kg body weight per day for the period of the
treatment. This fixed dose of metformin was
co-administered differently with reducdyn at
different doses of 0.25mg/kg and 0.5mg/kg body weight to groups IV and V rats
respectively for 3, 6 and 9 weeks. The statistical analysis was carried out
using one way ANOVA followed by post hoc LSD multiple comparison on SPSS 19. Metformin, when administered alone and its
co-administration with the different doses of reducdyn
showed significant decrease in blood glucose concentration for 3, 6 and 9 weeks
of treatment when compared with the diabetic control group. There was no
significant (P>0.05) difference in the plasma AST and ALT activities for the
first 3, 6 and 9 weeks of treatment in all the groups when compared with the
diabetic control group. There was a significant (P˂0.05) decrease in AST
activities of groups III and IV (DCR on metformin
(1.4mg/kg) and DCR on metformin (1.4mg/kg) + reducdyn (0.25mg/kg) body weight) after 6 weeks of
treatment when compared with the Normal control (Group I). After the 9th week
of treatment, it was observed that only group III had a significant
(P˂0.05) decrease in the plasma AST and ALT activity when compared with
the normal control group. It is also noticed that groups III and IV had an
appreciable reduction rate in the plasma AST activities when compared with the
diabetic and normal control groups. There was a significant (P˂0.05)
decrease in the plasma ALP activities in all the groups treated for the first 3
weeks when compared with the normal and diabetic control groups (groups I and II)
except for groups III. However, there was no significant (P>0.05) difference
in the enzyme activities between the two control groups after 3 weeks of
treatment. After 6 weeks groups IV and V had a significant decrease in the
plasma ALP activities when compared with the normal and diabetic control groups
(groups I and II). Group III had no significant (P˂0.05) difference in the
plasma ALP activities when compared with the two control groups. As the
treatment progressed to the 9th week, there was no significant (P˂0.05)
difference in the plasma ALP activities between the normal and diabetic control
groups. Only group V had a significant (P˂0.05) decrease in the plasma ALP
activities when compared with the normal control group. Groups III and IV, had
no significant (P˂0.05) difference in the plasma ALP activities when
compared with the normal control group and diabetic control group (groups I and
II).
In histological evaluation of the pancreas andhepatic
tissue, the islet cells of the Langerhan of the
pancreas were repopulated and preserved in all the groups treated with the
drugs against the diabetic control group whose islet cells were reduced, while
mild inflammation of the hepatic tissue was observed in all the groups
throughout the period of treatment, except for those treated with metformin alone whose hepatic tissues were seen to have periportal inflammation after 3 and 6 weeks of treatment.
KEY
WORDS: Diabetes
Mellitus, Liver enzymes. Strepzotocin, Metformin, Reducdyn
INTRODUCTION:
The liver helps maintain normal blood glucose concentration in the
fasting and postprandial states. Loss of insulin effect on the liver leads to glycogenolysis and an increase in hepatic glucose
production. Abnormalities of triglyceride storage and lipolysis
in insulin-sensitive tissues such as the liver are an
early manifestation of conditions characterized by insulin resistance and are
detectable earlier than fasting hyperglycemia. The precise genetic,
environmental, metabolic factors and sequence of events that lead to the
underlying insulin resistance, however, is not fully understood (Lewis et
al., 2002)
In animal models, chronic hyperinsulinemia
is found to predispose the liver to relative resistance to insulin. This is
characterized by a failure of insulin to signal an increase in insulin receptor
substrate-2. Upregulation of sterol regulatory
element-binding protein 1c (SREBP-1c) also occurs, leading to increased lipogenesis (Shimomura et al., 2000). Despite
down-regulation of the insulin receptor substrate-2-mediated insulin signaling
pathway in insulin-resistant states, the up-regulation of SREBP-1c and
subsequent simulation of de novo lipogenesis in the
liver leads to increased intracellular availability of triglycerides, promoting
fatty liver. This also increases VLDL assembly and secretion (Lewis et al.,
2002). Thus, hyperinsulinemia might directly lead to
hepatic insulin resistance with associated fatty changes.
The excess in free fatty acids found in the insulin-resistant
state is known to be directly toxic to hepatocytes.
Putative mechanisms include cell membrane disruption at high concentration,
mitochondrial dysfunction, toxin formation, and activation and inhibition of
key steps in the regulation of metabolism (Neuschwander-Tetri
and Caldwell 2003). Other
potential explanations for elevated transaminases in
insulin-resistant states include oxidant stress from reactive lipid peroxidation, peroxisomal
beta-oxidation, and recruited inflammatory cells. The insulin-resistant state
is also characterized by an increase in proinflammatory
cytokines such as tumor necrosis factor-α (TNF-α), which may also
contribute to hepatocellular injury. In preliminary
studies, an increased frequency of specific TNF-α-promoter polymorphism
was found in nonalcoholic steatohepatitis (NASH)
patients, suggesting a possible genetic link or predisposition to fatty liver
found in insulin-resistant states (Grove, 1997)
The above theories all attribute elevated transaminitis
to direct hepatocyte injury. It is also hypothesized
that elevation in ALT, a gluconeogenic enzyme whose
gene transcription is suppressed by insulin, could indicate impairment in
insulin signaling rather than purely hepatocyte
injury (O'Brien and Granner 1991).
Individuals with type 2 diabetes have a higher incidence of liver
function test abnormalities than individuals who do not have diabetes. Mild
chronic elevations of transaminases often reflect
underlying insulin resistance. Elevation of transaminases
within three times the upper limits of normal is not a contraindication for
starting oral antidiabetic or lipid-modifying
therapy. In contrast, antidiabetic agents have
generally been shown to decrease alanine aminotransferase levels as tighter blood glucose levels are
achieved.
Liver function tests (LFTs) are commonly used in clinical practice
to screen for liver disease, monitor the progression of known disease, and
monitor the effects of potentially hepatotoxic drugs.
The most common LFTs include the serum aminotransferases
and alkaline phosphatase. Aminotransferases,
such as alanine aminotransferase
(ALT) and aspartate aminotransferase
(AST), measure the concentration of intracellular hepatic enzymes that have
leaked into the circulation and serve as a marker of hepatocyte
injury. Alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), act as markers of biliary function and cholestasis.
Chronic mild elevation of transaminases
are frequently found in type 2 diabetic patients.
This study is designed to evaluate the effect of the combined
therapy of metformin and reducdyn
on diabetic induced liver problems in male rats.
MATERIALS AND METHOD:
Drugs and Equipment.
Glucophage (metformin),
and reducdyn were obtained from Dooka
Pharmarcy, Ltd opposite the main gate of University
of Port Harcourt teaching hospital, Alakahia, Port
Harcourt while Streptozotocin was obtained from glaxosmithline ltd Ibadan. All other reagents were of
analytical grade. Optical densities were measured using digital
spectrophotometer (model 752S).
Animals
Adult male wistar albino rats weighing
170-200g were obtained from the animal House of the Department of Biochemistry,
University of Port Harcourt, Port Harcourt, Nigeria.
The rats were randomly sorted into five groups of nine animals each (these nine
animals were subdivided into three groups of three animals each for the 3, 6
and 9 weeks of treatment) so that the average difference was ± 2.0g. The
animals were housed in plastic cages. The animals were allowed normal feed i.e guinea growers mash (Port Harcourt Flour Mills, Port
Harcourt, Nigeria) and water ad libitum.
Experimental Design
The rats were divided into five groups of nine rats each after,
the induction of streptozotocin diabetes.
Group-I--Normal control rats
Group-II --Diabetic control rats
Group-III-- Diabetic rats received a
standard drug, GlucophageTM Metformin (1.4mg/kg)
Group-IV-- Diabetic rats received 1.4mg/kg
of GlucophageTM (metformin) and 0.25mg/kg of Reducdyn.
Group-V--Diabetic rats received 1.4mg/kg of GlucophageTM
(metformin) and 0.5mg/kg of Reducdyn.
Anti-Diabetic Study/Drug Administration
The rats were randomly sorted into five groups of nine animals
each (these nine animals were subdivided into three groups of three animals
each for the 3, 6 and 9 weeks of treatment) so that the average difference was
± 2.0g. The animals were housed in plastic cages. After a one week
acclimatization period on guinea growers mash (Port Harcourt Flour Mills, Port
Harcourt, Nigeria), the animals were fasted overnight and diabetes was induced
by intraperitoneal injection of freshly prepared
solution of streptozotocin (160mg/kg body weight) in
distilled water, while the normal control rats (NCR) were injected with
distilled water alone. Seven days after administration of streptozotocin,
the animals were again fasted and blood collected via tail cutting (Burcelin et al., 1995), for the determination of
their fasting glucose levels. Then the rats were kept for 3 days to stabilize
the diabetic condition (Jyoty et al., 2002)
before commencing treatment, which lasted for 9 weeks.
The first and second groups (normal control rats (NCR) and
diabetic control rats (DCR) received appropriate volume of water using a gavage via intubation. The third group i.e
the first treatment group received daily by intra-gastric gavages, 1.4mg/kg
body weight of GlucophageTM (metformin); the fourth group received 1.4mg/kg body weight of GlucophageTM
(metformin)
and 0.25mg/kg body weight of Reducdyn TM via the same route and the fifth group
received 1.4mg/kg body weight of GlucophageTM (metformin) and
0.5mg/kg body weight of ReducdynTM via the same route.
The animals were allowed normal feed and water ad libitum. At the end of each treatment period, i.e., 3
week, 6 week, and 9 week, the rats were weighed, fasted overnight and their
fasting glucose level estimated by an automatic one touch glucometer.
They were anaesthetized by exposure to chloroform. While under anesthesia, they
were painlessly sacrificed and blood was collected from each rat into heparin
sample bottles. The heparin anti-coagulated blood samples were centrifuged at
1000 x g for 10 min, after which their plasma was collected and stored for subsequent
analysis.
Liver Function Tests
Aspartate aminotransferase (AST), Alanine aminotransferase (ALT) and Alkaline phosphatase
(ALP) activities were determined by enzymatic methods with commercial test kits
(Randox Laboratories, Crumlin,
England).
Histopathology of the pancreas and
liver.
On the last day of each of the study period, i.e
3, 6 and 9 weeks, the animals were sacrificed and quickly dissected. Slices of pancreas and liver of the rats were
fixed in 10 % formalin and used for histopathological
studies.
Statistical Analysis of Data
Dataobtained were
analyzed statistically by means of one-way ANOVA and post hoc LSD, on SPSS 19.
In all, p<0.05 was considered significant. Data were presented as means.d (standard deviation).
RESULTS:
Table 1. below
shows the results of the effect of co-administration of metformin
and reducdyn onplasma
glucose level of normal rats and streptozotocin
induced diabetic male rats.
Table 1: Effect of co-administration of metformin and reducdyn on plasma
glucose level of normal and streptozotocin induced
diabetic male rats.
Group |
Treatment |
Serum glucose
level (mmol/l) |
||
3 weeks |
6 weeks |
9 weeks |
||
I |
Normal
Control Rats (NCR) |
4.2±0.26a,b |
3.9±0.85a,b |
4.8±0.91a,b |
II |
Diabetic
Control Rats (DCR) |
8.1±0.32a,b |
7.0±0.40a,b |
6.3±0.43a,b |
III |
DCR on Metformin (1.4mg/kg) |
4.6±0.97b |
4.2±0.80b |
4.5±0.20b |
IV |
DCR on Metformin (1.4mg/kg)
+ Reducdyn (0.25mg/kg) |
5.6±0.41a,b |
3.8±0.20b |
4.2±0.05b |
V |
DCR on Metformin (1.4mg)
+ Reducdyn (0.5mg/kg) |
6.3±0.77a,b |
4.9±0.98b |
4.4±0.98b |
Values are expressed as Mean ±SD; n=3, per group/week. Values in
the same column with common superscript letters (a,b,…) are significantly different at P>0.05.
Superscript A(a) represents significant difference when group I
(normal control rats) are compared with other groups at P˂0.05.
Superscript B(b) represents significant difference when group
II (diabetic control rats) are compared with other groups at P˂0.05.
Values without superscripts indicates no significant difference
when compared with the normal and diabetic control groups (groups I and II)
Table 2: Effect of co-administration of metformin and reducdyn on plasma Aspartate transaminase (AST)
activities of normal and streptozotocin induced
diabetic male rats.
Group |
Treatment |
Enzyme Activity (Iu/L) (mean
±S.D) |
||
3 weeks |
6 weeks |
9 weeks |
||
I |
Normal
Control Rats (NCR) |
21.6±2.30 |
25.6±6.11a |
27.0±4.00a |
II |
Diabetic
Control Rats (DCR) |
19.0±0.00 |
21.6±2.30b |
23.0±4.00b |
III |
DCR on Metformin (1.4mg/kg) |
20.3±2.30 |
19.3±2.51a |
18.3±5.03a |
IV |
DCR on Metformin (1.4mg/kg)
+ Reducdyn (0.25mg/kg) |
17.0±3.46 |
18.3±5.03a |
19.3±3.51 |
V |
DCR on Metformin (1.4mg/kg)
+ Reducdyn (0.5mg/kg) |
20.0±9.64 |
23.0±4.00 |
27.0±4.00 |
Values are expressed as Mean ±SD; n=3, per group/week. Values in
the same column with common superscript letters (a,b,…) are significantly different at P>0.05.
Superscript A(a) represents significant difference when group I
(normal control rats) are compared with other groups at P˂0.05.
Superscript B(b) represents significant difference when group
II (diabetic control rats) are compared with other groups at P˂0.05.
Values without superscripts indicates no significant difference
when compared with the normal and diabetic control groups (groups I and II)
Table 3: Effect of co-administration of metformin and reducdyn on plasma Alanine transaminase (ALT)
activities of normal and streptozotocin induced
diabetic male rats.
Group |
Treatment |
Enzyme
Activity (Iu/L) (mean ±S.D) |
||
3 weeks |
6 weeks |
9 weeks |
||
I |
Normal Control Rats (NCR) |
10.0±2.00 |
11.0±1.73 |
12.3±0.57a |
II |
Diabetic Control Rats (DCR) |
8.0±2.00 |
10.0±3.00 |
11.6±1.52b |
III |
DCR on Metformin (1.4mg/kg) |
7.3±2.30 |
8.0±1.00 |
8.6±1.15a |
IV |
DCR on Metformin
(1.4mg/kg) + Reducdyn
(0.25mg/kg) |
8.6±1.15 |
9.0±2.00 |
9.6±2.51 |
V |
DCR on Metformin
(1.4mg/kg) + Reducdyn
(0.5mg/kg) |
7.6±4.04 |
8.6±1.15 |
9.6±2.08 |
Values are expressed as Mean ±SD; n=3, per group/week. Values in
the same column with common superscript letters (a,b,…) are significantly different at P>0.05.
Superscript A(a) represents significant difference when group I
(normal control rats) are compared with other groups at P˂0.05.
Superscript B(b) represents significant difference when group
II (diabetic control rats) are compared with other groups at P˂0.05.
Values without superscripts indicates no significant difference
when compared with the normal and diabetic control groups (groups I and II)
Table 4: Effect of co-administration of metformin and reducdyn on plasma Alkaline phosphatase (ALP)
activities of normal and streptozotocin induced
diabetic male rats.
Group |
Treatment |
Enzyme Activity (Iu/L) (mean
±S.D) |
||
3 weeks |
6 weeks |
9 weeks |
||
I |
Normal
Control Rats (NCR) |
40.0±6.00a |
66.0±10.00a |
79.3±1.15a |
II |
Diabetic
Control Rats (DCR) |
40.0±2.00b |
64.0±7.21b |
76.6±4.16b |
III |
DCR on Metformin (1.4mg/kg) |
32.6±2.08 |
56.6±5.03 |
69.3±4.61 |
IV |
DCR on Metformin (1.4mg/kg)
+ Reducdyn (0.25mg/kg) |
28.3±4.61a,b |
42.6±3.05a,b |
64.0±7.21 |
V |
DCR on Metformin (1.4mg/kg)
+ Reducdyn (0.5mg/kg) |
30.3±6.42a,b |
45.3±1.15a,b |
61.3±13.61a |
Values are expressed as Mean ±SD; n=3, per group/week. Values in
the same column with common superscript letters (a,b,…) are significantly different at P>0.05.
Superscript A(a) represents significant difference when group I
(normal control rats) are compared with other groups at P˂0.05.
Superscript B(b) represents significant difference when group
II (diabetic control rats) are compared with other groups at P˂0.05.
Values without superscripts indicates no significant difference
when compared with the normal and diabetic control groups (groups I and II)
Fig. 1 Histopathological
studies of the pancreas of normal and diabetic control rats after 3 weeks of
treatment.
Fig. 2 Histopathological studies of the pancreas after 3
weeks of treatment with metformin alone and its combination with reducdyn.
|
|
Normal Control
Rats after 6 weeks of treatment |
Diabetic Control Rats After 6 Weeks of
treatment SLID Slide Shows
Reduced Islet |
|
|
DCR treated with
Metformin 1.4mg for 6 weeks Slide shows
repopulation of islet cell |
DCR treated with
Metformin 1.4mg/kg and Reducdyn
0.25mg/kg for 6 weeks Slide shows increased islet cell mass |
|
|
DCR treated with
Metformin 1.4mg/kg and Reducdyn
0.5mg/kg for 6 weeksSlide
shows repopulation of islet cells |
Fig. 3: Histopathological studies of the pancreas after 6
weeks of treatment with metformin alone and its combination with reducdyn.
After 9 weeks of treatment
|
|
Normal control
Rats after 9 weeks of treatment No Histologic
change seen |
Diabetic Control
Rats After 9 Weeks of treatment SLID Slide Shows Reduced Islet cell mass |
|
|
DCR treated with
Metformin 1.4mg for 9 weeks Slide shows no change
in islet cell mass |
DCR treated with
Metformin 1.4mg/kg and Reducdyn
0.25mg/kg for 9 weeks Slide shows no histologic
change in the islet cell mass |
|
|
DCR treated with
Metformin 1.4mg/kg and Reducdyn
0.5mg/kg for 9 weeks Slide shows normal islet cells |
Fig. 4 Histopathological studies of the pancreas after 9
weeks of treatment with metformin alone and its combination with reducdyn.
|
|
Normal Control
Rats after 3 weeks of treatment |
|
|
|
DCR after 3
weeks of treatment Slide shows mild inflammatory changes of the hepatocytes |
DCR treated with
Metformin 1.4mg for 3 weeks Slide shows
inflammatory change. |
|
|
DCR treated with
Metformin 1.4mg and reducdyn
0.25mg for 3 weeks Slide shows mild inflammatory change. |
DCR treated with
Metformin 1.4mg and reducdyn
0.5mg for 3 weeks Slide shows mild inflammatory change. |
Fig. 5
Histopathological studies of the liver of normal and diabetic control
rats after 3 weeks of treatment with metformin alone and its
combination with reducdyn.
.
After 6 weeks of treatment.
|
|
|
|
DCR after 6
weeks of treatment Slide shows mild inflammatory changes of the hepatocytes |
DCR treated with
Metformin 1.4mg for 6 weeks Slide shows
inflammatory change. |
|
|
DCR treated with
Metformin 1.4mg and reducdyn
0.25mg for 6 weeks Slide shows mild inflammatory change |
DCR treated with
Metformin 1.4mg and reducdyn
0.5mg for 6 weeks Slide shows mild inflammatory change. |
Fig. 6: Histopathological
studies of the liver of normal and diabetic control rats after 6 weeks of treatment with metformin alone and
its combination with reducdyn
After 9 weeks of treatment
|
|
Normal Control
Rats after 9 weeks of treatment Slide shows periportal
inflammation |
Diabetic Control
Rats after 9 weeks of treatment Slide shows inflammatory changes |
|
|
DCR treated with
Metformin 1.4mg for 9 weeks Slide shows
inflammatory change. |
DCR treated with
Metformin 1.4mg and reducdyn
0.25mg for 9 weeksSlide shows mild inflammatory
change. |
|
|
DCR treated with
Metformin 1.4mg and reducdyn
0.5mg for 9 weeks Slide shows mild inflammatory change. |
|
Fig. 7: Histopathological
studies of the liver of normal and diabetic control rats after 9 weeks of treatment with metformin alone and
its combination with reducdyn
DISCUSSION:
The success recorded in the use of streptozotocin
(STZ) for the induction of diabetes mellitus through the administration of
160mg/kg body weight can be attributed to the work of Ferreira et al.,
2002. This achievement was confirmed by evaluation of fasting blood glucose
concentration.
Normal control rats maintained a fairly stable level of glucose
throughout the study period with the values 4.2±0.26, 3.9±0.85 and 4.8±0.91 for
3, 6 and 9 weeks of treatment respectively. There was however significant (P˂0.05)
increase in the level of glucose concentration for the diabetic control rats
reaching a hyperglycemic level of 8.1±0.32, 7.0±0.40 and 6.3±0.43 for 3, 6 and
9 weeks of treatment respectively (see table 1).
Group III treated with standard drug (metformin
1.4mg/kg) showed a significant (P˂0.05) decrease in serum glucose
levels on the 3rd, 6th and 9th week of
treatment when compared with the diabetic control group (group II) as shown in
table 1.
When metformin 1.4mg/kg was
co-administered with different doses of reducdyn,
there was a significant (P˂0.05) decrease in the level of glucose
at the 6th and 9th week of treatment than the first 3
weeks of treatment.
Aspartate amino transferase (AST), an enzyme involved in the transfer of
amino group from aspartate to alpha keto acid is an established marker of hepatic function (Varley et al., 1980). Elevated level of this enzyme
is usually interpreted as indicative of hepatic damage/destruction (Varley et al., 1980). From table 2 above, it will be
observed that there was no significant (P˂0.05) difference in the
plasma AST activities in the first 3 weeks of treatment in all the groups when
compared with the normal and diabetic control groups (group I and II). As the
treatment continued to the 6th week, there was a significant (P˂0.05)
decrease of the AST activities of groups III and IV (DCR on metformin
(1.4mg/kg) and DCR on metformin (1.4mg/kg) + reducdyn
(0.25mg/kg) body weight) when compared with the normal control group (group I).
After the 9th week of treatment, it was observed that only group III
had a significant (P˂0.05) decrease in the plasma AST activity when
compared with the normal control group. It is also noticed that groups III and
IV had an appreciable reduction rate in the plasma AST activities when compared
with the diabetic and normal control groups.
Alanine amino transferase (ALT), another enzyme used as marker of hepatic
function had no significant (P˂0.05) difference in its activity
among the groups treated for 3 and 6 weeks respectively. As the treatment
continued to the 9th week, it was observed that group III (DCR on metformin, 1.4mg/kg) decreased significantly (P˂0.05)
in plasma ALT activity when compared with the normal control group. From the
above discussion, it will be observed that Glucophage
(metformin), 1.4mg/kg body weight was observed to significantly
lower the plasma enzyme activities of AST and ALT, an effect that appear quite
confusing apparently. This is due to the fact that some oral hypoglycemic
drugs, in addition to their established therapeutic effects, also possibly
elicit some deleterious effects on the hepatocytes.
This is in line with the suggestion of Katzung (1982)
“that drugs in addition to their desired clinical effects also elicit some
other effects, deleterious or otherwise on some metabolic/physiological system
of the host.
However, it is possible that the drug, Glucophage
may have possed these effects on the enzyme activity
by having direct competitive effect on the enzyme.
Alkaline phosphatase (ALP), a hydrolase enzyme responsible for removing phosphate group
from many types of molecules including nucleotides, proteins and alkaloids is
another specific enzyme used as a marker of hepatic function. Elevation of the
plasma level of this enzyme is also indicative or confirmatory of hepatic
damage (Varley et al., 1980). There was a
significant (P˂0.05) decrease in the plasma ALP activities in all
the groups treated for the first 3 weeks when compared with the normal and
diabetic control groups (groups I and II) except for groups III. However, there
was no significant (P˂0.05) difference in the enzyme activities
between the two control groups after 3 weeks of treatment. After 6 weeks groups
IV and V had a significant decrease in the plasma ALP activities when compared
with the normal and diabetic control groups (groups I and II). Group III had no
significant (P˂0.05) difference in the plasma ALP activities when
compared with the two control groups. As the treatment progressed to the 9th
week, there was no significant (P˂0.05) difference in the plasma
ALP activities between the normal and diabetic control groups. Only group V had
a significant (P˂0.05) decrease in the plasma ALP activities when
compared with the normal control group. Groups III and IV, had no significant (P˂0.05)
difference in the plasma ALP activities when compared with the normal control
group and diabetic control group (groups I and II).
From table 3, 4 above, it will be observed that the reference drug
Glucophage (metformin,
1.4mg/kg) increased the plasma enzyme activities of ALP significantly (P˂0.05)
when compared with other groups throughout the period of treatment and this may
be due to the adverse effect elicited by the drug on the liver.
Histological evaluation of the pancreas (fig.1-7) revealed a
remarkable reduction in the islet cell mass of Langerhan
of the streptozotocin induced diabetic rats
throughout the period of treatment. As they were treated with metformin and its co-administration with reducdyn, the islet cells were repopulated and preserved
throughout the period of treatment. Evaluation of the hepatic tissue after 3, 6
and 9 weeks of treatment revealed normal histology, mild inflammation and periportal inflammation of the normal control rat liver
after 3, 6 and weeks of treatment respectively. The liver of the diabetic
control rats was seen to have mild inflammation and tissue fragmentation after
3, 6 and 9 weeks of treatment. The administration of metformin
alone induced periportal inflammation after 3 and 6
weeks and mild inflammation after the 9th week of treatment. Mild
inflammatory change was observed on the liver of those treated with the
combination of metformin and different doses of reducdyn throughout the period of treatment except for the
9th week where mild periportal and intraparenchymal inflammation was observed on the liver of
those treated with metformin and the higher dose of redudyn (0.5mg/kg).
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Received on 25.08.2013
Modified on 10.09.2013
Accepted on 15.09.2013
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Research Journal of
Pharmacognosy and Phytochemistry. 5(5): September – October 2013, 224-235