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The present study was aimed to evaluate the anti-diabetic potential of Terminalia chebula (T. chebula) fruits on streptozotocin (STZ)-induced experimental diabetes in rats. Oral administration of ethanolic extract of the fruits (200 mg/kg body weight/rat/day) for 30 days significantly reduced the levels of blood glucose and glycosylated hemoglobin in diabetic rats. Determination of plasma insulin levels revealed the insulin stimulating action of the fruit extract. Also, the alterations observed in the activities of carbohydrate and glycogen metabolising enzymes were reverted back to near normal after 30 days of treatment with the extract. Electron microscopic studies showed significant morphological changes in the mitochondria and endoplasmic reticulum of pancreatic β cells of STZ-induced diabetic rats. Also, a decrease in the number of secretory granules of β-cells was observed in the STZ-induced diabetic rats and a these pathological abnormalities were normalized after treatment with T. chebula extract. The efficacy of the fruit extract was comparable with glibenclamide, a well known hypoglycemic drug.
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283
Journal of Health Science, 52(3) 283–291 (2006)
INTRODUCTION
Diabetes mellitus (DM) is considered as one of
the five leading causes of death in the world. About
150 million people are suffering from diabetes
worldwide, which is almost five times more than
the estimates ten years ago and this may double by
the year 2030. India leads the way with its largest
number of diabetic subjects in any given country. It
has been estimated the number of diabetes in India
is expected to increase 57.2 million by the year
2025.1) Diabetes is a complex multisystemic disor-
der characterized by a relative or absolute insuffi-
ciency of insulin secretion insulin dependent diabe-
tes mellitus (IDDM) or concomitant resistance of
the metabolic action of insulin on target tissues2) non
insulin dependent diabetes mellitus (NIDDM).
Insulin therapy affords glycemic control in
IDDM yet its short comings include ineffectiveness
on oral administration, short shelf life, need for pres-
ervation in refrigeration, fatal hypoglycemia in the
event of excess dosage, reluctance to take injection
and above all, the resistance due to prolonged ad-
ministration, limits its usage. Similarly treatment of
NIDDM patients with sulfonylureas and biguanides
is always associated with side effects.3) Hence, search
for a drug with low cost, more potentials, and with-
out adverse side effects is being pursued in several
laboratories around the world.
Throughout the world many traditional plants
have been found successful for antidiabetic activity.
Further, most of the marketed medicines are distil-
lations, combinations, reproductions or variations of
substances that are found in nature. Our forefathers
recommended some of the substances, which are
abundantly found in nature long before their value
was demonstrated and understood by scientific meth-
ods. However, few have received scientific or medi-
cal scrutiny and the World Health Organization
(WHO) has recommended the traditional plant treat-
ments for diabetes warrant further evaluation.4)
Moreover, today it is necessary to provide scientific
proof as to whether it is justified to use a plant or its
active principles for treatment.5)
Terminalia chebula (T. chebula) Retz
(Combretaceae), a native plant in India and South-
east Asia, is extensively cultivated in Taiwan. Its
dried ripe fruit, has traditionally been used to treat
various ailments in Asia.6) It is a popular folk medi-
Anti-Diabetic Activity of Fruits of
Terminalia
chebula
on Streptozotocin Induced Diabetic Rats
Gandhipuram Periasamy Senthil Kumar, Palanisamy Arulselvan, Durairaj Sathish Kumar,
and Sorimuthu Pillai Subramanian*
Department of Biochemistry and Molecular Biology, University of Madras, Guindy Campus, Chennai-600 025, Tamil Nadu, India
(Received February 10, 2006; Accepted March 21, 2006)
The present study was aimed to evaluate the anti-diabetic potential of Terminalia chebula (T. chebula) fruits on
streptozotocin (STZ)-induced experimental diabetes in rats. Oral administration of ethanolic extract of the fruits
(200 mg/kg body weight/rat/day) for 30 days significantly reduced the levels of blood glucose and glycosylated
hemoglobin in diabetic rats. Determination of plasma insulin levels revealed the insulin stimulating action of the
fruit extract. Also, the alterations observed in the activities of carbohydrate and glycogen metabolising enzymes
were reverted back to near normal after 30 days of treatment with the extract. Electron microscopic studies showed
significant morphological changes in the mitochondria and endoplasmic reticulum of pancreatic
β
cells of STZ-
induced diabetic rats. Also, a decrease in the number of secretory granules of
β
-cells was observed in the STZ-
induced diabetic rats and a these pathological abnormalities were normalized after treatment with T. chebula extract.
The efficacy of the fruit extract was comparable with glibenclamide, a well known hypoglycemic drug.
Key words diabetes, Terminalia chebula, ethanolic extract, carbohydrate metabolism, electron microscope
*To whom correspondence should be addressed: Department of
Biochemistry and Molecular Biology, University of Madras,
Guindy Campus, Chennai-600 025, Tamil Nadu, India. Tel. &
Fax: +91-44-22300488; E-mail: subbus2020@yahoo.co.in
284 Vol. 52 (2006)
cine and has been studied for its homeostatic laxa-
tive, diuretic and cardiotonic activities.7,8)
T. chebula has been reported to exhibit a variety
of biological activities, including antidiabetic,9) an-
ticancer,10) antimutagenic11,12) and antiviral13) activ-
ity. However, no systematic work on its anti-diabe-
togenic activity has been reported in the literature.
Hence, the present study was aimed to evaluate the
pharmacological effect of ethanolic extract of T.
chebula on carbohydrate and glycogen metabolism
in both normal and streptozotocin (STZ)-induced
diabetic rats. The effects of T. chebula are compared
to glibenclamide that is often used as a standard drug.
MATERIALS AND METHODS
Chemicals Streptozotocin was purchased from
Sigma Chemical Co., St. Louis, MO, U.S.A. Radio-
immunoassay kit for insulin assay was obtained from
Linco Research Inc., U.S.A. All the other chemicals
used were of analytical grade.
Plant Material Fresh mature T. chebula fruits
were collected from a tree in Kolli Hills, Namakkal
District, Tamil Nadu, India. The plant was identi-
fied and authenticated by Dr. K. Kaviyarasan, CAS
in Botany, University of Madras, and a voucher
specimen was deposited at the herbarium of Botany.
Preparation of T. chebula Fruit Extract Dried
fruits were powdered in an electrical grinder and
stored at 5°C until further use. 100 g of the powder
was extracted with petroleum ether (60–80°C) to
remove lipids. It was then filtered and the filtrate
was discarded. The residue was extracted with 95%
ethanol by Soxhlet extraction. The ethanol was
evaporated in a rotary evaporator at 40–50°C under
reduced pressure. The yield of the extract was 8.5 g/
100 g.
Animals —–— Adult male albino rats of Wistar strain
weighing approximately 150 to 180 g were procured
from Tamil Nadu Veterinary and Animal Sciences
University, Chennai, India. They were acclamatized
to animal house conditions, fed with standard rat feed
supplied by Hindustan Lever Ltd., Bangalore, In-
dia. All the animal experiments were conducted ac-
cording to the ethical norms approved by Ministry
of Social Justices and Empowerment, Government
of India and Institutional Animal Ethics Committee
guidelines (Approval No. 01/030/04).
Toxicity Studies To study any possible toxic
effects and/or changes in behavioural pattern, rats
were treated with graded dose of T. chebula extract
(100–500 mg/kg body weight/rat/day) and kept un-
der close observation for 8 hr daily for 30 days. All
symptoms including changes in awareness, mood,
motor activity, posture, motor-co-ordination, muscle
tone and reflexes were recorded for 30 days.
Induction of Experimental Diabetes —–— T h e
animals were fasted overnight and diabetes was
induced by a single intraperitoneal injection
of a freshly prepared solution of Streptozotocin
(55 mg/kg body weight) in 0.1 M cold citrate buffer
(pH 4.5).14) The animals were allowed to drink 5%
glucose solution overnight to overcome the drug-
induced hypoglycemia. Control rats were injected
with citrate buffer alone. After a week time for the
development of diabetes, the rats with moderate dia-
betes having glycosuria and hyperglycemia (blood
glucose range above 250 mg/dl) were considered as
diabetic and used for the drug treatment. The fruit
extract in aqueous solution was administered orally
through a gavage at a concentration of 200 mg/kg
body weight/rat/day for 30 days.
Experimental Design The animals were di-
vided into two sets, one for the evaluation of a glu-
cose tolerance test and a second one for the analysis
of biochemical parameters. Each set was further di-
vided into four groups; each comprising a minimum
of six animals in each group as detailed below:
Group I: Normal control rats.
Group II: Diabetic control rats.
Group III: Diabetic rats given T. chebula fruit
extract (200 mg/kg body weight/day/rat) in aqueous
solution orally for 30 days.
Group IV: Diabetic rats administered with
glibenclamide (600
µ
g/kg body weight/day/rat) in
aqueous solution orally for 30 days.15)
The body weight gain and fasting blood glucose
levels of all the rats were recorded at regular inter-
vals during the experimental period.
Glucose Tolerance Test After 30 days of treat-
ment, a fasting blood sample was collected from all
the groups in heparinized tubes. Blood samples were
also collected at the time intervals of 30, 60, 90 and
120 min after administration of glucose at a concen-
tration of 2 g/kg of body weight.16)
Biochemical Assays After 30 days of treat-
ment, the fasted rats of various groups were sacri-
ficed by cervical decapitation. Fasting blood glucose
was estimated by the O-toluidine method of Sasaki
et al.17) The levels of hemoglobin and glycosylated
hemoglobin were estimated according to methods
of Drabkin et al.18) and Nayak et al.19) respectively.
Plasma insulin was estimated by using a radioim-
285
No. 3
munoassay kit.
A portion of the liver tissue was dissected,
washed with ice cold saline and homogenized in
0.1 M Tris–HCl buffer, pH 7.4. The supernatant was
used for the assay of enzyme activity. The hexoki-
nase activity was assayed by the method of
Brandstrup et al.20) The activities of glucose-6-phos-
phatase and fructose-1,6-bisphosphatase were as-
sayed according to the method of Koide and Oda21)
and Gancedo and Gancedo,22) respectively. The
King23) method was adopted for the assay of lactate
dehydrogenase (LDH) activity. Glycogen synthase
and phosphorylase activities were assayed by the
method of Leloir and Goldenberg24) and Cornblath
et al.,25) respectively. Another portion of wet liver
tissue was used for the estimation of glycogen by
the method of Morales et al.26)
Electron Microscopy Studies For electron
microscopic examination of pancreas, primer fixa-
tion was made in 3% glutaraldehyde in sodium phos-
phate buffer (200 mM, pH 7.4) for 3 hr at 4°C. Ma-
terials were washed with same buffer and postfixed
in 1% osmium tetroxide and in sodium phosphate
buffer (pH 7.4) for 1 hr at 4°C. Tissue samples were
washed with same buffer for 3 hr at 4°C, and were
dehydrated in graded ethanol series and were em-
bedded in Araldite. 60–90 nm sections (60–90 nm)
were cut on an LKBUM4 ultramicrotome using a
diamond knife and sections were mounted on a cop-
per grid and stained with uranyl acetate and Reynolds
lead citrate.27) The grids were examined under a
Phillips electron microscope model 201C (EM201C)
transmission electron microscope.
Statistical Analysis All the grouped data were
statistically evaluated with statistical package for
social sciences (SPSS)/10 software. Hypothesis test-
ing methods included one-way analysis of variance
(ANOVA) followed by least significant difference
(LSD) test; P values of less than 0.05 were consid-
ered to indicate statistical significance. All the re-
sults were expressed as the mean ± standard devia-
tion (S.D.) for six animals in each group.
RESULTS
Acute toxicity studies conducted by us (data not
shown) revealed that the administration of graded
doses of T. chebula fruit extract (up to a dosage of
500 mg/kg body weight/day) for 30 days produced
no effect on the general behaviour or appearance of
the animals and all the rats survived the test period.
There were no signs and symptoms such as restless-
ness, respiratory distress, diarrhea, convulsions,
coma. Assay of pathophysiological enzymes such
as alkaline phosphatase (ALP), aspartate transami-
nase (AST) and alanine transaminase (ALT) in
plasma revealed the nontoxic nature of fruit extract.
Figure 1 shows the change in body weight gain
of control and experimental groups of rats. There
was a significant decrease in the body weight of dia-
betic rats compared with control rats. Upon treat-
ment with T. chebula and glibenclamide, the body
weight gain was improved but the effect was
more pronounced in T. chebula treated rats than
glibenclamide.
Fig. 1. Changes in Body Weight of Control and Experimental Groups of Rats
Values are given as mean + S.D. for groups of six rats each. Values are statistically significant at *p< 0.05, Diabetic control rats were compared with
control rats. Diabetic + T. chebula and diabetic + glibenclamide treated rats were compared with diabetic control rats.
286 Vol. 52 (2006)
The levels of blood glucose in control and ex-
perimental groups of rats after oral administration
of glucose is shown in Fig. 2. The blood glucose
value in the control rats rose to a peak value 60 min
after glucose load and decreased to near normal lev-
els at 120 min. In diabetic control rats, the peak in-
crease in blood glucose concentration was observed
after 60 min and remained high over the next 60 min.
T. chebula and glibenclamide treated diabetic rats
showed significant decrease in blood glucose con-
centration at 60 and 120 min compared with diabetic
group of rats.
Table 1 shows the level of blood glucose, plasma
insulin, total hemoglobin, glycosylated hemoglobin
and urine sugar in normal and experimental groups
of rats. There was a significant elevation in blood
glucose, urine sugar and glycosylated hemoglobin,
while the level of plasma insulin and total hemoglo-
bin decreased during diabetes when compared to
control group. Administration of T. chebula brought
back to near normal values as that of standard drug
glibenclamide treatment.
Table 2 depicts a significant decrease in the ac-
tivity of hepatic hexokinase, a significant increase
in the activities of lactate dehydrogenase, glucose-
6-phosphatase and fructose-1,6-bisphosphatase in
STZ-induced diabetic rats when compared to con-
trol rats. Treatment with T. chebula extracts (group
III) and glibenclamide (group IV) significantly con-
trolled the alterations and restored the altered levels
to near normalcy. T. chebula treatment exerted more
effect than glibenclamide in diabetic rats.
Table 3 presents the changes in hepatic glyco-
gen content and in the activities of glycogen syn-
thase and glycogen phosphorylase in the hepatic tis-
sue of control and experimental group of rats. A sig-
Fig. 2. Glucose Tolerance Test Curve of Control and Experimental Groups of Rats
Blood sample collected at 0, 30, 60, 90 and 120 min intervals after administration of glucose (2 kg/body weight) were assayed for glucose content.
Values are given as mean ± S.D. for groups of six animals each; Values are statistically significant at *p< 0.05; Diabetic control rats were compared with
control rats; diabetic + T. chebula and diabetic + glibenclamide treated rats were compared with diabetic control rats.
Table 1. Changes in the Level of Blood Glucose, Plasma Insulin, Hemoglobin, Glycosylated Hemoglobin and Urine Sugar in Control
and Experimental Groups of Rats
Groups Blood glucose Plasma insulin Hemoglobin Glycosylated Urine sugar
milligram/deciliter microunit/milliliter (g/dl) hemoglobin
(mg/dl) ( U/ml) (% HbA
1
c)
Control 85.43 5.72 16.54 1.07 13.52 0.81 6.24 0.38 Nil
Diabetic control 265.08 20.14* 5.27 0.76* 9.25 0.67* 12.36 0.91* +++
Diabetic + T. chebula 92.30 6.09* 15.26 0.71* 12.93 0.82* 6.72 0.42* Nil
Diabetic + Glibenclamide 102.40 6.45* 13.86 0.62* 12.46 0.77* 6.95 0.42* +
Values are given as mean S.D. for groups of six animals in each group. Values are statistically signicant at *p005. Diabetic control
rats were compared with control rats. Diabetic + T. chebula and diabetic + glibenclamide treated rats were compared with diabetic control rats. (+)
indicate 0.25% sugar and (+++) indicates more than 2% sugar.
287
No. 3
nificant decrease in liver glycogen content and gly-
cogen synthase activity and concomitant increase in
the activity of glycogen phosphorylase was observed
in the diabetic group of rats and it was normalized
after treatment.
A decrease in the number of secretory granules
of
β
-cells was observed in diabetic group (Fig. 3)
when compared to the control group (Fig. 4). Also
severely decreased secretory granules, severe de-
struction of nuclear membrane and degenerative
changes in the core of islet cells and nucleus were
observed in STZ-induced diabetic rats. However,
diabetic rats treated with T. chebula extract showed
apparently normal cell architecture (Fig. 5). It simi-
lar observations have also been observed in diabet-
ics rats treated with glibenclamide (Fig. 6).
DISCUSSION
Streptozotocin is well known for its selective
pancreatic islet
β
-cell cytotoxicity and has been ex-
tensively used to induce Type-1 diabetes in experi-
mental rat model. It interferes with cellular meta-
bolic oxidative mechanisms.28) Increasing evidence
in both experimental and clinical studies suggests
that oxidative stress plays a major role in the devel-
opment and progression of both types of diabetes
mellitus. Free radicals are formed disproportionately
in diabetes by glucose oxidation, non enzymatic
glycation of proteins and subsequent oxidative deg-
radation of glycation proteins. Diabetes is usually
accompanied by impaired antioxidant defenses.
Fig. 3. Swelling of Mitochondria (M), Decreased Secretory
Granules (G), Clear Vesicles () in Electron Micrograph
from of the Diabetic Rat
Magnification: × 15000.
Table 3. Level of Glycogen, Activities of Glycogen Synthase and Glycogen Phosphorylase in the Liver Tissue of Control and Experi-
mental Groups of Rats
Groups Glycogen Glycogen synthase (micromole Glycogen phosphorylase
(mg of glucose/g of uridine diphosphate (micromole of phosphate
of wet tissue) formed/hr/mg protein) liberate/hr/mg protein)
Control 58.23 3.55 845.62 69.34 612.18 50.19
Diabetic control 26.80 1.95* 567.43 50.50* 870.64 80.09*
Diabetic + T. chebul a 56.28 3.54* 812.12 68.21* 653.23 54.87*
Diabetic + Glibenclamide 50.95 3.20* 786.56 66.85* 713.51 57.79*
Values are given as mean S.D. for groups of six animals in each group. Values are statistically signicant at *p005. Diabetic control
rats were compared with control rats. Diabetic + T. chebula and diabetic + glibenclamide treated rats were compared with diabetic control rats.
Table 2. Changes in the Activities of Hepatic Hexokinase, Lactate Dehydrogenase, Glucose-6-phosphatase and Fructose 1,6-
Bisphosphatase of Control and Experimental Groups of Rats
Groups Hexokinase Lactate dehydrogenase Glucose-6-phosphatase Fructose 1,6-
(micromole Glucose- (micromole pyruvate (micromole phosphate bisphosphatase (micromole
6-phosphate formed formed/hr/mg liberated/hr/mg protein) phosphate liberated/
hr/mg protein) protein) hr/mg protein)
Control 273.6 16.68 248.23 15.88 1042 84.40 482 29.88
Diabetic control 139.3 10.58* 356.45 27.09* 1968 184.99* 749 55.42*
Diabetic + T. chebul a 270.1 17.28* 253.92 16.00* 1061 88.06* 502 31.62*
Diabetic + Glibenclamide 257.4 17.50* 268.37 16.90* 1216 103.36* 531 33.98*
Values are given as mean S.D. for groups of six animals in each group. Values are statistically signicant at *p005. Diabetic control
rats were compared with control rats. Diabetic + T. chebula and diabetic + glibenclamide treated rats were compared with diabetic control rats.
288 Vol. 52 (2006)
Glibenclamide is often used as a standard antidia-
betic drug in STZ-induced moderate diabetes to com-
pare the efficacy of variety of hypoglycemic com-
pounds.29) The present study was conducted to as-
sess the hypoglycemic activity T. chebula fruits in
STZ-induced diabetic rats. The ability of T. chebula
fruit extract in significantly increasing the body
weight and effectively controlling the increase in
blood glucose levels in diabetic group of rats may
be attributed to its antihyperglycemic effects. Fur-
ther, the antihyperglycemic activity of T. chebula was
associated with an increase in plasma insulin level,
suggesting an insulinogenic activity of the fruit ex-
tract. The observed increase in the level of plasma
insulin indicates that T. chebula fruit extract stimu-
lates insulin secretion from the remnant
β
-cells or
from regenerated
β
-cells. In this context, a number
of other plants have also been reported to exert hy-
poglycemic activity through insulin release stimu-
latory effect.30,31)
The observed increase in the levels of
glycosylated hemoglobin (HbA1c) in diabetic con-
trol group of rats is due to the presence of excessive
amounts of blood glucose. During diabetes the ex-
cess of glucose present in blood react with hemo-
globin to form glycosylated haemoglobin.32,33)
Mechanisms by which increased oxidative stress is
involved in the diabetic complications are partially
known, including activation of transcription factors,
advanced glycated end products (AGEs), and pro-
tein kinase C. Glycosylated hemoglobin has been
found to be increased over a long period of time in
the diabetic mellitus.34) There is an evidence that
glycation may itself induce the generation of oxy-
gen-derived free radicals in diabetic condition.35)
Treatment with T. chebula extract showed a decrease
in the glycosylated hemoglobin with a concomitant
increase in the level of total hemoglobin in the dia-
betic rats standard drug glibenclamide also showed
the same results.
Liver plays an important role in the maintenance
of blood glucose level by regulating its metabolism.
Hexokinase, which brings about the first phospho-
rylation step of glucose metabolism, is reduced sig-
nificantly in the diabetic group of rats.36) This may
be the reason for the diminished consumption of glu-
cose in the system and increased blood sugar level.
In STZ-induced diabetic rats, the hexokinase syn-
thesis is decreased due to low levels of mRNA cod-
ing for the hexokinase and insulin administration
stimulated transcription of hexokinase mRNA syn-
thesis and thus enhanced the rate of synthesis and
Fig. 4. Electron Micrograph of a Normal
β
-Cell in the Control
Rat
Magnification: × 15000.
Fig. 6. Normal Mitochondria (M), Normal Nucleus (N) and
Increased Secretory Granules (G) in the Diabetic Group
Given Glibenclamide
Magnification: × 15000.
Fig. 5. Apparently Normal Mitochondria (M), Normal Nucleus
(N) and Increased Secretory Granules (G) in the Dia-
betic Group Given T. chebula
Magnification: × 15000.
289
No. 3
activity of the enzyme.37) The mechanism played by
T. chebula extract in enhancing the hexokinase ac-
tivity could be due to the activation of mRNA cod-
ing for hexokinase in diabetic rats.
Lactate dehydrogenase in anaerobic glycolysis,
catalyses the conversion of pyruvate to lactate which
subsequently is converted to glucose in gluconeo-
genic flux. In diabetic condition, an increased activ-
ity of lactate dehydrogenase was observed.38,39) The
LDH system reflects the Nicotinamide adenine di-
nucleotide/reduced nicotinamide adenine dinucle-
otide (NAD+/NADH) ratio indicated by the lactate/
pyruvate ratio of hepatocyte cytosol.40) In T. chebula
extract and glibenclamide treated group of rats, the
reduction in the LDH activity is probably due to the
regulation of NAD+/NADH ratio by oxidation of
NADH.
The hepatic gluconeogenic enzymes, glucose-
6-phosphatase and fructose-1,6-bisphosphatase were
increased significantly in diabetic rats. The increased
activities of these two gluconeogenic enzymes in
liver may be due to the activation or increased syn-
thesis of the enzymes contributing to the increased
glucose production during diabetes by the liver.41)
The therapeutic role of T. chebula and glibenclamide
may be due to its primarily modulating and regulat-
ing
δ
activities of the two gluconeogenic enzymes,
either through the regulation by 3,5-cyclic adenos-
ine monophosphate (cyclic AMP) and any other
metabolic activation or inhibition of glycolysis and
gluconeogenesis.
The conversion of glucose to glycogen in the
liver cells is dependent on the extracellular glucose
concentration and on the availability of insulin which
stimulates glycogen synthesis over a wide range of
glucose concentration.42) The regulation of glycogen
metabolism in vivo occurs by the multifunctional
enzyme glycogen synthase and glycogen phospho-
rylase that play a major role in the glycogen me-
tabolism.43) The reduced glycogen store in diabetic
rats has been attributed to reduced activity of glyco-
gen synthase44) and increased activity of glycogen
phosphorylase.45) In the present study the experimen-
tal diabetic rats treated with T. chebula extract and
glibenclamide treated groups restored the level of
hepatic glycogen by means of decreasing the activ-
ity of glycogen phosphorylase and increasing the
activity of glycogen synthase. This coincides with
the previous work in our laboratory.46)
In the diabetic group of rats treated with T.
chebula extract, an increase in the number of
β
-cells
in the islets shows that they were regenerated. Also,
the increase in secretory granules in the cells indi-
cates that the cells were stimulated for insulin syn-
thesis. A decrease in the number of secretory gran-
ules, nuclear shrinkage and pycnosis, swelling of
mitochondria and endoplasmic reticulum, round-
shaped mitochondria, hypertrophied cytoplasmic
organelles such as golgi and endoplasmic reticulum
have been reported in the
β
cells of STZ-induced
diabetic rats.47,48) Our results are also inline with the
previous report.
In conclusion, the present study shows that the
ethanolic extract of T. chebula fruit has potential
hypoglycemic action in STZ-induced diabetic rats
and the effect was found to be more effective than
glibenclamide Further, studies are in progress at
molecular level to explicitly explain more about the
mechanism of the antidiabetic activity of T. chebula
and compounds responsible for its antidiabetic ef-
fect.
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... Scientists were striving to evaluate antidiabetic activities of such natural products and its scientific validation (Florence et al., 2014). The ethanolic extract of T.chebula fruit showed potent hypoglycemic activity in streptozotocin-induced diabetic rats and was found more efficacious than glibenclamide, a standard hypoglycemic drug in commercial use (Kumar et al., 2006). Ethanolic extract of W. somnifera root have potent anti-inflammatory as well as anti-diabetic activity (Udayakumar et al., 2009). ...
... The work was carried out at Division of Medicine, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, Uttar Pradesh during 2015-2016. Subclinically diabetic dogs were identified based on preliminary screening of random blood glucose, fasting blood glucose and Benedict's test for the presence of sugar in urine (Kaneko et al. 2008). Animals selected via preliminary tests were further confirmed through glycated haemoglobin estimation by ion exchange chromatography using commercial kit (Coral clinical systems, India) as per Trivelli et al. (1971), serum fructosamine estimation by nitrobluetetrazolium reduction method (Sahu and Sarkar, 2008) and serum insulin estimation by ELISA (Bioassay technology laboratory, China). ...
... The study is approved by Institutional Animal Ethics Committee (IAEC) under institute project IVRI/MED/12-15/ 008. Thirty subclinically diabetic dogs were selected based on the diabetic biomarkers (Kaneko et al. 2008) and were divided into five groups of six animals each; Group I was positive control without any treatment, Group II fed with T. chebula extract @ 100 mg/kg body weight, Group III fed with W. somnifera extract @ 100 mg/kg body weight, Group IV fed with both T. chebula extract, and W. somnifera extract @ 100mg/kg body weight each and Group V fed with standard antioxidant N-acetyl cysteine @ 10 mg/kg body weight. The antioxidants were administered for 30 days at the above mentioned daily dosages. ...
... Another study by Kumar et al. [39] reported the potential anti-diabetic activity of T. chebula fruit extract against STZ-induced diabetes in rats. Studies have shown that oral administration of the extract at a dose of 200 mg/kg body weight/rat/day reduced glucose levels, stimulates insulin action and ameliorates β-cells pathological abnormalities caused by STZ induction. ...
... Kumar et al. [39] In STZ-induced diabetic rats, T. chebula fruit extract significantly reduced the levels of blood glucose. This antihyperglycemic activity of T. chebula was associated with an increase in plasma insulin level, suggesting an insulinogenic activity of the T. chebula. ...
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Terminalia chebula Retz. (Fam. Combretaceae), commonly called black or chebulic myrobalan, is a species of Terminalia. In Tibet, T. chebula is called the “King of Medicine”. It is well known as ‘Haritaki’ since it can be used to cure all kinds of diseases and is considered sacred to God Siva (Hara). The whole plant possesses high medicinal value. The aim of this article is to review the available scientific information regarding traditional uses, bioactive chemical constituents, and pharmacological activities of T. chebula based on in vitro and in vivo studies. First, in this paper, the studies published on T. chebula from 1980 to 2022 were reviewed, and the biological activity and mechanisms of action of T. chebula were evaluated based on in vitro and in vivo studies. T. chebula presented anti-diabetic, anti-hyperlipidemic, antioxidant, hepatoprotective, neuroprotective, anti-inflammatory, anti-arthritic, gastroprotective, anti-microbial, antiparasitic, wound healing, and anti-aging activities. Thus, this review suggests potential applications of T. chebula in nutraceuticals, functional foods, and pharmaceutical industries.
... The dried immature fruit of T. chebula displayed a considerable α-glucosidase inhibitory effect. It also stimulates glucose-mediated insulin secretion and intestinal glucose transport [10,60]. Ethanol extract of T. chebula fruit significantly reduced blood glucose and glycosylated haemoglobin level and enhanced the activity of carbohydrate and glycogen metabolising enzymes. ...
... At doses of 250mg and 500mg twice a day, the T. chebula extract was administered for 84 days, which helped to improve modified-Knee Injury & Osteoarthritis Outcomes Score (mKOOS) of the knee and joint mobility, as well as total joint health in mostly healthy populations with exercise/activity-induced knee discomfort, including knee soreness. The findings of the trial imply that the advantages may further increase from knee health to total joint and spine health [60]. ...
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Terminalia chebula Retz, commonly known as 'Haritaki/Myrobalan,' has been utilised as a traditional medicine for a long time. It has been extensively exercised in various indigenous medicine practices like Unani, Tibb, Ayur-veda, and Siddha to remedy human ailments such as bleeding, carminative, dysentery, liver tonic, digestive, antidiarrheal, analgesic, anthelmintic, antibacterial and helpful in skin disorders. Studies on the pharmacological effects of T. chebula and its phytoconstituents documented between January, 1996 and December, 2021 were explored using various electronic databases. During the time mentioned above, several laboratory approaches revealed the biological properties of T. chebula, including antioxidative, antiproliferative, anti-microbial, proap-optotic, anti-diabetic, anti-ageing, hepatoprotective, anti-inflammatory, and antiepileptic. It is also beneficial in glucose and lipid metabolism and prevents atherogenesis and endothelial dysfunction. Different parts of T. chebula such as fruits, seeds, galls, barks extracted with various solvent systems (aqueous, ethanol, methanol, chloroform, ethyl-acetate) revealed major bioactive compounds like chebulic acid, chebulinic acid, and chebulaginic acid, which in turn proved to have valuable pharmacological properties through broad scientific investigations. There is a common link between chebulagic acid and chebulanin with its antioxidant property, antiaging activity, antiinflammatory, antidiabetic activity, and cardioprotective activity. The actions may be through neutralizing the free radicals responsible for producing tissue damage alongside interconnecting many other diseases. The current review summarises the scientifically documented literature on pharmacological potentials and chemical compositions of T. chebula, which is expected to investigate further studies on this subject.
... The ethanolic extract of TC fruit may have hypoglycemic properties [69]. TC is a vital herbal plant in both Tibetan and Ayurvedic medicine, and its active principles, gallic acid (GA) and chebulagic acid (CA), are powerful antioxidants and free radical scavengers with the capability to regulate oxidative stress, apoptosis, and inflammation. ...
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Hyperglycemia is the hallmark of diabetes, which is a collection of related metabolic disorders. Over time, diabetes can cause a variety of problems, including cardiovascular disease, nephropathy, neuropathy, and retinopathy. Ethanolic novel polyherbal extract (PHE) was prepared by mixing equal amounts of the following ingredients: Terminalia chebula Retz. (TC), Terminalia bellerica Roxb. (TB), Berberis aristata DC. (BA), Nyctanthes arbostratis L. (NA), Premna integrifolia L. (PI), and Andrographis paniculata Nees. (AP). Analysis of PHE results revealed phytochemicals like glycosides, flavonoids, alkaloids, tannins, phytosterols, and saponins. The aim of the study was to prepare an ethanolic extract of PHE using the cold maceration technique, and identify bioactive molecules from gas chromatography-mass spectrometry (GC-MS) analysis, and evaluate biological responses by using in vitro studies like antioxidant and anti-inflammatory activity. PHE was found to contain a total of 35 phytochemicals in GC-MS of which 22 bioactive compounds were obtained in good proportion. There are a few new ones, including 2-Buten-1-ol, 2-ethyl-4-(2, 2, 3-trimethyl-3-cyclopenten-1-yl (17.22%), 1, 2, 5, 6-Tetrahydrobenzonitrile (4.26%), 4-Piperidinamine, 2, 2, 6, 6-tetramethyl-(0.07%), Undecanoic acid, 5-chloro-, chloromethyl ester (0.41%) are identified. Antioxidant activity was estimated using EC 50 values of 392.143µg/ml, which were comparable to the standard value of EC 50 310.513µg/ml obtained using DPPH. Antioxidant activity was estimated with EC 50 392.143µg/ml, comparable to standard EC 50 310.513µg/ml using DPPH. In vitro anti-inflammatory potential was found with IC 50 of 91.449µg/ml, comparable to standard IC 50 89.451 µg/ml for membrane stabilisation and IC 50 of 36.940µg/ml, comparable to standard IC 50 35.723µg/ml for protein denaturation assays. As a result, the findings of this study show an enrichment of bioactive phytochemicals that can be used to investigate biological activity. To better understand how diabetes receptors work, in silico studies like docking could be carried out.
... The hyperglycemia associated with diabetes causes the production of free radicals either due to glucose degradation, the non-enzymatic glycation of proteins or subsequent oxidative degradation [37]. Several reports suggested that oxygen-derived free radicals were produced during the process of glycation [38], and these generated free radicals cause lipid peroxidation and damage to cell membranes in diabetes [37]. The changes in lipid peroxidation associated with diabetic animals showed a decrease in the activity of several antioxidant enzymes viz. ...
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Background: Globally, diabetes mellitus is the most common cause of premature mortality after cardiovascular diseases and tobacco chewing. It is a heterogeneous metabolic disorder characterised by the faulty metabolism of carbohydrates, fats and proteins as a result of defects in insulin secretion or resistance. It was estimated that approximately 463 million of the adult population are suffering from diabetes mellitus, which may grow up to 700 million by 2045. Solanum indicum is distributed all over India and all of the tropical and subtropical regions of the world. The different parts of the plant such as the roots, leaves and fruits were used traditionally in the treatment of cough, asthma and rhinitis. However, the hypoglycaemic activity of the plant is not scientifically validated. Purpose: The present study aimed to evaluate the antioxidant, antidiabetic and anti-hyperlipidaemic activity of methanolic fruit extract of Solanum indicum (SIE) in streptozotocin (STZ) induced diabetic rats. Method: Experimentally, type II diabetes was induced in rats by an i.p. injection of STZ at a dose of 60 mg/kg. The effect of the fruit extract was evaluated at doses of 100 and 200 mg/kg body weight in STZ-induced diabetic rats for 30 days. Result: The oral administration of fruit extract caused a significant (p < 0.05) reduction in the blood glucose level with a more prominent effect at 200 mg/kg. The fruit extract showed dose-dependent �-amylase and �-glycosidase inhibitory activity. It reduced the serum cholesterol and triglyceride levels remarkably in diabetic rats compared to normal. The extract showed the reduced activity of endogenous antioxidants, superoxide dismutase, glutathione peroxidase and catalase in the liver of STZ diabetic rats. Conclusion: The result confirmed that the fruit extract of Solanum indicum showed a dose-dependent blood glucose lowering effect and significantly reduced elevated blood cholesterol and triglycerides. It prevented oxidative stress associated with type II diabetes in STZ rats. Keywords: Solanum indicum; streptozotocin; antioxidants; lipid profile; antidiabetic
... Herbal medicine has gained popularity in the past decade, and there has been a growing demand for herbal products among diabetic patients because of its low cost, perceived effectiveness, and little or no side effects (Kumar et al., 2006). ...
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Background Hippocratea velutina (HV) is a novel plant folklorically used for lowering blood glucose, hence a potential source of new antidiabetic medication. Objective The study evaluated the anti-diabetic potentials of the methanol extract of Hippocratea velutina leaf and its toxicity profile in mice and rats. Methods Acute and subacute toxicity tests of the plant extract were carried out using a modified OECD guideline. Its antidiabetic activity in streptozotocin-induced diabetic rats at 50, 150, and 300 mg/kg for 28 days was assayed, while glibenclamide (5 mg/kg) and distilled water were the positive and negative controls, respectively. Histopathological examination of vital organs was also carried out. Results Preliminary phytochemical screening of the leaf extract showed the presence of tannins, flavonoids, saponins, alkaloids, terpenoids, deoxy-sugars, and anthraquinones in HV. The extract had LD50 greater than 2000 mg/kg in mice. It had no toxic effects on the haematological and biochemical components from blood samples collected but caused significant blood glucose level reduction in normal rats at 150 and 300 mg/kg. In streptozotocin-induced diabetic rats, the extract elicited a non–dose-dependent antidiabetic effect on day seven at all the tested doses, significantly higher than glibenclamide (10 mg/kg). However, on days 14, 21, and 28, the extract activity at all the tested doses and glibenclamide were comparable. The extract did not affect the liver, brain, kidney, and pancreas histology at 200 mg/kg but caused slight and severe effects on these organs at 400 and 800 mg/kg, respectively. Conclusion The study concluded that Hippocratea velutina possessed antihyperglycaemic activity and is non-toxic at low doses but could have deleterious effects to the liver and kidney at high concentrations.
... Mortality was observed after 72 hours. Acute toxicity was determined according to the method of Litchfield and Wilcoxon [6]. Experimental Design (Table 1 Whole plant extracts and standard drug glibenclamide (5 mg/kg) and saline were administered with the help of feeding cannula. ...
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The present research study was carried out to evaluate the evaluation of anti-diabetic activity of Vinca rosea ethanolic extraction of whole plant extracts in insulin induced diabetic mice for 14 days. The ethanolic whole plant extract at high dose (500 mg/kg500 mg/kg) exhibited significant anti-hyperglycemic activity than whole plant extract with at low dose (300 mg/kg) in diabetic rats. The plant ethanolic extracts also expressed improvement in parameters such as, body weight and lipid profile as well as regeneration of-cells of pancreas in diabetic rats. Histopathological studies reveal the healing of pancreas, by Vinca rosea extracts, as a possible mechanism of their anti-diabetic activity.
... Currently, available therapy for diabetes include insulin and various oral hypoglycaemic agents such as sulfonylureas, biguanides, thiazolidinediones, glinides, and a-glucosidase inhibitors. These are known to produce prominent adverse effects and they have failed to significantly alter or amend diabetes complications in long term (Bahmani et al., 2014;Kumar et al., 2006;Mohammady et al., 2012). According to the World Health Organization (WHO), diabetes affects about 3% of the world's population, with the prevalence anticipated to double to 6.3% by 2025 (Andrade-Cetto and Heinrich, 2005). ...
... Diabetes mellitus was induced by administering 150 mg/kg of alloxan intraperitoneally. At the end of the 48 th hour of induction, rats which manifested over 120 mg/dl of glucose were selected and used for the study [10]. ...
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The aim of this study was to determine the ameliorative effect of aqueous leaf extract of Moringa oleifera on diabetes induced appetite and testicular weight loss in wistar rats. Freshly harvested leaves of Moringa oleifera was processed into powder and subsequently extract. Thirty (30) adult male wistar rats were divided into six groups of five rats each. Group 1 was the normal control which was only fed with rat chow and water ad libitum. Group II was induced with diabetes without treatment, Group III-V were induced with diabetes prior to treatment with 100, 200, and 400 mg/kg bw respectively, while Group VI was induced with diabetes and subsequently treated with standard drug. Animal feed intake and weight of the harvested testicle from the rats were determined using standard procedures. The testicular weight as well as feed intake of the untreated diabetic rats were significantly (P<0.05) low compared to that reported for the control (Group I). However, this observation was significantly (P<0.05) reversed in treated diabetic rats in a dose dependent manner. This study reveals that Moringa oleifera can promote testicular health through its anti-diabetic potential.
... Stevia rebaudiana, which was reported to be more than hundred times sweeter than the sugar, possesses hypoglycemic action in diabetic patients (Shivanna et al. 2013). Likewise, many more plants such as Aegle marmelos, Acacia arabica, Andrographis paniculata, Aloe barbadensis, Juglans regia, Momordica charantia, Terminalia chebula, Tinospora cordifolia, and Withania somnifera were reported to show antidiabetic action either due to dowregulation of the blood glucose level by improving the action of insulin or by some other metabolic functioning (Stanely et al. 2000;, Kumar et al. 2006;Udayakumar et al. 2009; Tripathi and Chandra 2010; Naveen and Baskaran 2018). ...
Article
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The mechanism for glycogen synthesis stimulation produced by adenosine, fructose, and glutamine has been investigated. We have analyzed the relationship between adenine nucleotides and glycogen metabolism rate-limiting enzymes upon hepatocyte incubation with these three compounds. In isolated hepatocytes, inhibition of AMP deaminase with erythro-9-(2-hydroxyl-3nonyl)adenine further increases the accumulation of AMP and the activation of glycogen synthase and phosphorylase by fructose. This ketose does not increase cyclic AMP or the activity of cyclic AMP-dependent protein kinase. Adenosine raises AMP and ATP concentration. This nucleotide also activates glycogen synthase and phosphorylase by covalent modification. The correlation coefficient between AMP and glycogen synthase activity is 0.974. Nitrobenzylthioinosine, a transport inhibitor of adenosine, blocks (by 50%) the effect of the nucleoside on AMP formation and glycogen synthase but not on phosphorylase. 2-Chloroadenosine and N6-phenylisopropyladenosine, nonmetabolizable analogues of adenosine, activate phosphorylase (6-fold) without increasing the concentration of adenine nucleotides or the activity of glycogen synthase. Cyclic AMP is not increased by adenosine in hepatocytes from starved rats but is in cells from fed animals. [Ethylenebis (oxyethylenenitrilo)]tetraacetic acid (EGTA) blocks by 60% the activation of phosphorylase by adenosine but not that of glycogen synthase. Glutamine also increases AMP concentration and glycogen synthase and phosphorylase activities, and these effects are blocked by 6-mercaptopurine, a purine synthesis inhibitor. Neither adenosine nor glutamine increases glucose 6-phosphate. It is proposed that the observed efficient glycogen synthesis from fructose, adenosine, and glutamine is due to the generation of AMP that activates glycogen synthase probably through increases in synthase phosphatase activity. It is also concluded that the activation of phosphorylase by the above-mentioned compounds can be triggered by metabolic changes.
Article
This chapter describes the assay method, purification procedure, and properties of glycogen synthetase from rat liver. Activity is measured by the amount of UDP formed from UDPG in the presence of glycogen and G-6-P. The UDP estimation is carried out by using a preparation of pyruvate kinase which catalyzes the transfer of phosphate from phosphopyruvate to UDP. The pyruvate liberated is estimated colorimetrically. The assay is applicable to purified preparations and to crude extracts. ctivity of glycogen synthetase is expressed in micromoles of UDP formed per milliliter of enzyme per minute. Within certain limits (up to about 0.06 micromoles of UDP), the relationship between UDP formation and time or enzyme concentration is linear. G-6-P gives a four- to fifteenfold increase in activity. Protein is estimated after TCA precipitation, because large amounts of glycogen produce turbidity which interferes in direct determinations. Plasma albumin precipitated in the same way is used as a standard. A smaller activating effect has been observed with glucosamine- 6-phosphate and Gal-6-P.
Article
1. Levels of phosphofructokinase, glucose-6-phosphate dehydrogenase and fructose-1,6-diphosphatase activities have been compared in different yeasts belonging to glucose fermenting and non-fermenting groups grown in different conditions. 2. Phosphofructokinase was present in all the fermentative species tested. On the contrary its level was not measurable in any of the aerobic yeasts tested with the exception of Pichia species. 3. No significant variations were observed in the values of glucose-6-phosphate dehydrogenase from the two groups of yeasts. 4. The synthesis of fructose-1,6-diphosphatase was repressed in both groups, by growth in sugar carbon sources. However, a remarkable difference in the sensitivity of the fructose-1,6-diphosphatase from both groups towards inhibition by AMP was observed. The enzyme from all fermentative yeasts tested showed a strong inhibition by AMP (1 mM producing about 80% inhibition) while the enzyme from aerobic yeasts showed different responses, inhibition ranging from 10% in Rhodotorula and Sporobolomyces, to 90% in Pichia.
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A new triterpene, 2α-hydroxymicromeric acid, and two known compounds, maslinic acid and 2α-hydroxyursolic acid have been isolated from Terminalia chebula leaves.
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S-allyl cysteine sulphoxide (SACS), a sulphur containing amino acid of garlic which is the precursor of allicin and garlic oil, has been found to show significant antidiabetic effects in alloxan diabetic rats. Administration of it at a dose of 200 mg/kg body weight decreased significantly the concentration of serum lipids, blood glucose and activities of serum enzymes like alkaline phosphatase, acid phosphatase and lactate dehydrogenase and liver glucose-6-phosphatase. It increased significantly liver and intestinal HMG CoA reductase activity and liver hexokinase activity.
Article
Activities of hexokinase and glucose-6-phosphate dehydrogenase have been measured in red blood cells from control, diabetic and insulin treated rats. After an initial decrease, the enzyme activities increased, but remained lower than control levels. A reversal of the diabetes effect was seen with insulin administration. Insulin induced hypoglycemia increased both enzymes. An overall control of glucose metabolism by insulin in red blood cells was observed.
Article
Phosphorylase and glycogen synthase protein were measured in normal and genetically diabetic (C57BL/KsJ db/db) mice liver extracts using rocket immunoelectrophoresis, and these data correlated with measurements of total phosphorylase and total glycogen synthase activities, respectively. Phosphorylase protein in 5-week-old normal mice was about 5 micrograms/mg protein and reached 8 micrograms/mg protein by 9 weeks. In comparison, the diabetic mice had elevated levels of phosphorylase protein (11-13 micrograms/mg protein) which correlated with an increased total phosphorylase activity compared to normals. The correlation coefficient for the phosphorylase activity vs protein plot was highly significant (r = 0.73, P less than 0.001). The molar concentration of phosphorylase subunit in normal mouse liver was calculated to be 11 microM and up to 23 microM in the diabetic mice. The liver concentration of glycogen synthase was relatively constant in normal mice at 400 ng/mg protein (corresponding to approximately 1.4 microM) but varied from 230 to 441 ng/mg protein (0.9 to 1.8 microM) in diabetic mice. There was little correlation between glycogen synthase activity and enzymatic protein (r = 0.15). These results indicate (1) that phosphorylase is present at concentrations approximately 10 times that of glycogen synthase, and (2) that glycogen synthase activity is relatively more dependent upon factors other than the amount of enzymatic protein.
Article
1. The concentrations of the oxidized and reduced substrates of the lactate-, beta-hydroxybutyrate- and glutamate-dehydrogenase systems were measured in rat livers freeze-clamped as soon as possible after death. The substrates of these dehydrogenases are likely to be in equilibrium with free NAD(+) and NADH, and the ratio of the free dinucleotides can be calculated from the measured concentrations of the substrates and the equilibrium constants (Holzer, Schultz & Lynen, 1956; Bücher & Klingenberg, 1958). The lactate-dehydrogenase system reflects the [NAD(+)]/[NADH] ratio in the cytoplasm, the beta-hydroxybutyrate dehydrogenase that in the mitochondrial cristae and the glutamate dehydrogenase that in the mitochondrial matrix. 2. The equilibrium constants of lactate dehydrogenase (EC 1.1.1.27), beta-hydroxybutyrate dehydrogenase (EC 1.1.1.30) and malate dehydrogenase (EC 1.1.1.37) were redetermined for near-physiological conditions (38 degrees ; I0.25). 3. The mean [NAD(+)]/[NADH] ratio of rat-liver cytoplasm was calculated as 725 (pH7.0) in well-fed rats, 528 in starved rats and 208 in alloxan-diabetic rats. 4. The [NAD(+)]/[NADH] ratio for the mitochondrial matrix and cristae gave virtually identical values in the same metabolic state. This indicates that beta-hydroxybutyrate dehydrogenase and glutamate dehydrogenase share a common pool of dinucleotide. 5. The mean [NAD(+)]/[NADH] ratio within the liver mitochondria of well-fed rats was about 8. It fell to about 5 in starvation and rose to about 10 in alloxan-diabetes. 6. The [NAD(+)]/[NADH] ratios of cytoplasm and mitochondria are thus greatly different and do not necessarily move in parallel when the metabolic state of the liver changes. 7. The ratios found for the free dinucleotides differ greatly from those recorded for the total dinucleotides because much more NADH than NAD(+) is protein-bound. 8. The bearing of these findings on various problems, including the following, is discussed: the number of NAD(+)-NADH pools in liver cells; the applicability of the method to tissues other than liver; the transhydrogenase activity of glutamate dehydrogenase; the physiological significance of the difference of the redox states of mitochondria and cytoplasm; aspects of the regulation of the redox state of cell compartments; the steady-state concentration of mitochondrial oxaloacetate; the relations between the redox state of cell compartments and ketosis.