Vol.2, No.1, 27-34 (2012) Journal of Diabetes Mellitus
Islet protection and amelioration of diabetes type 2
in Psammomys obesus by treatment with
Ziv Ehud1, Weiss Lola1, Raz Itamar1, Patlas Natan1, Yekhtin Zhanna2, Gallily Ruth2#
1Diabetes Unit, Hadassah University Hospital, Jerusalem, Israel
2Lautenberg Center for Immunology, Institute Medical Research Israel Canada (IMRIC), Medical Faculty, Hebrew University, Jeru-
salem, Israel; #Corresponding Author: ruthg@ekmd.huji.ac.il
Received 19 December 2011; revised 18 January 2012; accepted 31 January 2012
Background and Purpose: Cannabidiol (CBD), a
non-psychoactive component of Cannabis sa-
tiva, has been shown by us, to have an anti-in-
flammatory effect in collagen-induced arthri tis in
DBA mice and in type 1 diabetes in NOD mice.
As inflammation is a process involved in diabe-
tes type 2, we administered CBD to Psammomys
obesus (sand rats), a species which develops
diabetes type 2 when fed high-energy (HE) diet,
to investigate whether we can hinder the devel-
opment of the disease. Experimental Approach:
Male Psammomys obesus were kept on a high
energy diet during the experiments. They were
treated with CBD (i.p injection, 5 mg/kg, 5 times/
week) for 4 weeks and kept (without CBD) for
another 29 - 39 days. The weights of the animals
as well as blood glucose and plasma insulin
levels were determined and the morphology of
the p ancreatic islet s was examined. Key Result s:
CBD significantly reduced blood glucose levels
in Psammomys obesus, without effecting body
weight. Plasma insulin levels were significantly
higher in the CBD-treated group. The most strik-
ing effect noted was the marked decrease of the
destruction of pancreatic islets and beta cells.
Conclusions and Implications: CBD partially
protects pancreatic islets and beta cells from
destruction. CBD lowers significantly the blood
glucose level and increases insulin level in
Psammomys obesus with diabetes type 2, but
does not lead to obesity. As CBD already has
been administered to patients for other medical
indications we propose its use as a therapeutic
agent in diabetes type 2.
Keywords: Cannabidiol; Type 2 Diabetes; Islet
Protection; Psammomys obesus
Obesity and type 2 diabetes (T2D) have reached epi-
demic proportions in the Western world. T2D is a par-
ticularly heterogeneous disorder, despite the many clini-
cal similarities seen in diabetic patients, including hyper-
glycemia, hypeinsulinemia hyperlipidemia, hypertension
and obesity. There is crosstalk between the various tis-
sues involved in the diabetes syndromes: adipose tissue,
muscle and liver via signals that include free fatty acids
and adipokines. Several investigators have shown sig-
nificant increased in pro-inflammation cytokines such as
IL6, TNF-α and glucose intolerance [1-3].
Cannabidiol (CBD) is a constituent of the Cannabis
sativa plant, which does not cause psychoactive effects
due to its low affinity binding to the CB1 receptor. CBD
potential therapeutic activity was documented in several
reviews [4-6]. CBD has been shown to posses immuno-
modulation [7] and anti-inflammation properties [8,9] It
also inhibited the release of the pro-inflammatory cyto-
kines IL-1, TNF-α and IFN-γ by peripheral blood mono-
nuclear cells [10]. We have reported that CBD signifi-
cantly inhibited insulitis, beta cell destruction and the
occurrence of overt type 1 diabetes in NOD female mice
[11,12]. We have also found that CBD treatment sup-
pressed the production of the Th1-associated cytokines,
IL-12, IFN-γ and TNF-α and enhanced production of the
Th2-associated cytokines, IL-4 and IL-10, suggesting a
possible gradual progression from destructive Th1 im-
munity to protective Th2 immunity [11,12].
We previously demonstrated that CBD was effective in
suppressing the progression of autoimmune joint de-
struction in the collagen-induced arthritis animal model
of rheumatoid arthritis, a Th1-mediated disease [13]. The
anti-autoimmune effects of CBD were associated with
reduction in synovial cell TNF-α production, inhibition
of reactive oxygen release from zymosan-stimulated
*Conflict of interest: The authors declare no conflict of interest.
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Z. Ehud et al. / Journal of Diabetes Mellitus 2 (2012) 27-34
neutrophils and suppression of joint-specific T-cell pro-
liferation and IFN-γ production. Although diabetes type 1
differs from diabetes type 2, there are many similar
manifestations, such as enhancement of the levels of
proinflammation cytokines and free radicals.
We decided to examine the effects of CBD in the Psam-
momys obesus, a model of type 2 diabetes, since CBD
inhibits the production of IL-1b, TNF-α and IFN-γ, cyto-
kines that are involved in the beta cells destruction lead-
ing to diabetes. The Psammomys obesus in nature feeds
on salt bush, which supply most of its nutrients and water.
When they are fed a high-energy (HE) diet, they develop
diabetes. The Jerusalem colony of Psammomys obesus
was established from animals from the Dead Sea region.
Generally four stages of consecutive progression to dia-
betes in this species are defined, namely Stage A: Basal
normoglycemia and normoinsulinemia. Stage B: Hyper-
insulinemia (ranging from 120 to 300 mU/L), while ani-
mals remain normoglycemic and gain weight. Stage C:
Documentation which entails a marked hyperglycemia
together with both hyperinsulinemia and hyperproinsu-
linemia and further obesity. Stage D: (6 - 12 weeks after
stage C) Low plasma insulin, increase of blood glucose,
hyperlipidemia, and body weight loss [14].
In this study we examined the effect of CBD on the
development of diabetes in male sand rats feeding on
high diet, by assaying glucose and insulin levels in blood
and analyzing the islets and beta cell integrity in histo-
logical sections of the pancreta
2.1. CBD
CBD was extracted from cannabis resin (hashish) as
previously reported [15].
For in vivo injection, CBD was first dissolved in etha-
nol and then Cremophor EL (Sigma) was added up to a
1:1 ratio. This solution was further diluted in saline so
that the final solution was ethanol/Cremophor/saline
2.2. Psammomys obesus
Psammomys, 4.5 month old, male (Hebrew University
Colony, Harlan, Jerusalem, Israel) were fed by a low
energy (LE) diet, normoglycemia maintaining diet (2.38
kcal/g; Koffolk, Petach-Tikva, Israel). Diabetes was in-
duced by feeding the animals a high-energy (HE) diet
(2.92 kcal/g; cat #2018, Teklad Global Diets, Boston,
MA) [14,16]. All experiments were authorized by the
Institutional Animal Care Committee.
2.3. Experimental Protocols
In the first experiment, 30 Psammomys were divided
into two groups: 15 were treated with CBD and the other
15 with the vehicle (Ctr). To determine the ability of
CBD to suppress the diabetic manifestations in Psam-
momys, the animals were injected intraperitoneally (i.p.)
with 5 mg/kg CBD, or with the vehicle alone five times/
week. The injections continued for 4 weeks, starting 3
days before feeding with the HE diet. Thereafter, the
Psammomys were kept on High Diet without CBD treat-
ment, for another 29 days (total-60 days from the begin-
ning of CBD treatment). The additional period without
treatment was chosen to establish the sustainable effect
of the CBD on the beta cells integrity as was found in
NOD mice [11,12]. Body weight and tail-blood glucose
(Accutrend Sensor; Roche Diagnostics, Mannheim,
Germany) were monitored twice a week for one month
and once a week thereafter.
Twenty nine days after the end of CBD treatment, the
animals were anesthetized with Ketalar (Parke-Davis,
Gwent, UK) and the blood was collected in 10% EDTA,
by cardiac puncture. The pancreata were fixed in 10%
formalin in buffer, for histological analysis. Serum was
stored at 20˚C for analysis of insulin.
In the second experiment, 20 animals were used, 10
animals for the vehicle-treated and 10 for the CBD-
treated group (5 mg/kg CBD, five times/week, for 4
weeks). The animals were monitored as in the first ex-
periment. The experiment was ended, 39 days after the
end of CBD treatment, total of 70 days, from the begin-
ning of CBD treatment.
2.4. Histology
Pancreatic tissue was fixed in 10% buffered formalin
and was embedded in paraffin. The 5-micron sections
were stained with hematoxylin and eosin. Sections were
screened and scored by two independent observers.
2.5. Statistical Analysis
Data were expressed, as means ± SEM. Statistical
analysis was carried on, as specified in the results.
P value was considered significant when P 0.05.
3.1. Weight of CBD-Treated Psammomys
The weights of the CBD-treated Psammomys, in the
two experiments, were not significantly different be-
tween the treated and control animals, as determined by
the Fisher Exact Test (see Figu res 1(a), (b)).
3.2. Glucose Levels of CBD-Treated
It has been observed previously that Psammomys be-
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Z. Ehud et al. / Journal of Diabetes Mellitus 2 (2012) 27-34 29
0510 1520 25 3035 4045 5055 60
weight (gr)
0510 1520 25 30 35 40 45 5055 60 65 70
weight (gr)
Figure 1. Weight of the Psammomys following CBD treatment.
(a) Experiment 1, observation for 60 days; (b) Experiment 2,
observation for 70 days. CBD was injected ip 5 mg/kg (5 times/
week) from day 3 to day 31. Controls were injected with the
vehicle: Non significant-treated vs. control p > 0.05.
come diabetics (glucose >200 mg/dl) when they are
transferred to HE diet. Within 7 days81% of the ani-
mals reach blood glucose level over 200 mg/dl and over
90% of themwithin 14 days [16].
In our first experiment (60 days observation) 13 rats
(86%), out of 15 control Psammomys, developed diabe-
tes (glucose > 200 mg/dl) within 30 days (Figure 2(a))).
In contrast, only 4 animals (25%), out of 15, in the
CBD-treated group (5 mg/kg, 5 times/week) developed
hyperglycemia (over 200 mg/dl). The CBD-treated Psam-
momys had significantly lower mean glucose levels com-
pared to the vehicle-treated Psammomys (P 0.05)
(Figure 2).
In the second experiment (70 days observation, Figure
2(b)), in the control group, 6 out of the total 7 (86%)
Psammomys developed diabetes (3 died). Whereas only 4
of 10 (40%) of the CBD-treated Psammomys had hyper-
glycemia and all these animals survived (Figures 2(a),
051015 202530 3540 45 505560
blood glucose (mg/dl)
0510 1520253035404550556065 70
blood glucose (mg/dl)
Figure 2. Levels of blood glucose in plasma of
Psammomys following CBD treatment. (a) Exp. 1;
(b) Exp. 2. See details in Figure 1. Non-significant-
Treated vs. Control P 0.05.
Least-squares linear regression was used to fit the
level of glucose as a function of time, separately for each
animal. The regression coefficients (slopes) were then
employed in Mann-Whitney test on the combined sample.
The CBD lowered the rate of a glucose increase signifi-
cantly (P 0.05) as determined by a Mann-Whitney test
on the combined sample).
3.3. CBD Prevents Insulin Depletion in
Diabetes-Prone Psammomys
The most prominent characteristic of diabetic Psam-
momys is the rapid depletion of pancreatic insulin stores
[17] which probably result from prolonged β-cell stimu-
lation by the HE diet. This mechanism plays an impor-
tant role in the development and progression of diabetes
in the Psammomys model. In the present study in both
experiments the plasma levels of insulin in the vehicle-
treated control (median at 118 - 142 μU/ml) were sig-
nificantly lower than the CBD-treated groups (153 - 210
μU/ml) (Figure 3) Also the CBD-treated animals, tended
to maintain their insulin at the pre-HE levels, probably as
a result of cyto-protection conferred to the pancreatic
β-cells by CBD.
Copyright © 2012 SciRes. OPEN ACCESS
Z. Ehud et al. / Journal of Diabetes Mellitus 2 (2012) 27-34
plasma insuli n (U/ml)
pl asma insulin (U/ml)
Figure 3. Insulin levels (μU/ml) in Psammomys plasma at the
end of the CBD treatment experiments. (a) Exp.1, mean insulin
in CBD-treated group was 209.8 μU/ml, in the control 142
μU/ml (non significant); (b) Exp.2, mean insulin in CBD-
treated group was 153 μU/ml, in the control group 118 μU/ml
Significant-treated vs. control P 0.05.
In order to increase the statistical power, the data from
the two experiments were combined. A Mann-Whitney
test was then used to compare insulin levels in the ex-
perimental animals with those in the controls.
3.4. Animal Survival
CBD-treatment increased, although not significantly,
the Psammomys survival as seen in Ta b l e 1 . In the two
experiments, 13/25 (52%) of the controls survived,
whereas in the CBD-treated animals, 18/25 (72%) sur-
vived at the end of the two experiments.
There is no statistical difference in survival between
the treated and untreated animals (P = 0.20, as deter-
mined by the Fisher Exact Test).
3.5. CBD Protects β-Cells from Destruction
The morphological evaluation of the pancreata histo-
logical sections of the control group showed abnormal
islet morphology. About 20% of the islets were without
regular borders and were destroyed, also a high percent-
age of the islets (75%) were with many vacuoles (Table
2 and Figures 4(b ), (c)).
On the other hand, in CBD- treated animals, no dam-
aged islets were observed and most of them were normal.
Also, only 26% of the islets had numerous vacuoles. The
quantitative morphological results of Langerhans islets
are given in Ta bl e 2 and the morphology of the islets is
demonstrated in Figure 4. The control islets (Figures
4(b), (c)), show giant cells with vacuoles as well as de-
stroyed islets, with no islet border and only few beta in-
tact cells, whereas the islets from the CBD-treated ani-
mals, were normal (Figure 4(a)). Thus, the histological
assessment is in line with the results of blood glucose
and plasma insulin levels. These findings demonstrate
that the treatment with CBD protects the pancreatic β-
cells integrity against the excessive release of insulin into
Table 1. Psammomys survival following CBD treatment.
after 30 days after 57 - 66 days
Control CBD Control CBD
Exp. 1 7/15 11/15 7/15 8/15
Exp. 2 7/10 10/10 6/10 10/ 10
Exp. 1 and Exp. 214/25 21/25 13/25 18/25
% survival 56 84 52 72
Table 2. Morphological study of Psammomys langerhans islets*.
Morphology CBD Treatment Control
Normal + very few small vacuales 79 (62%) 30 (38%)
Many Vacuoles 51 (26%) 147 (74%)
Damaged Islets 0 (0% ) 19 (100%)
Data of 2 experiments.
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Z. Ehud et al. / Journal of Diabetes Mellitus 2 (2012) 27-34
Copyright © 2012 SciRes.
Figure 4. Photomicrographs of Langerhans islets of Psammomys obesus. (a) Normal Islets of CBD-treated Psammomy; (b) Giant
Islets with vacuoles from vehicle-treated Psammomys (control); (c) Damaged/destroyed islets from vehicle-treated Psammomys
the blood and preserves the islet’s normal morphology. immunological course very similar to human type 2 dia-
betes. Diabetes in the Psammomys is characterized by
hyperglycemia, hyperinsulinemia followed by depleted
pancreatic insulin. Normoglycemic diabetes-prone Psam-
momys obesus which were fed HE diet, developed hy-
perglycemia within 4 - 14 days, together with a progres-
sive decline of pancreatic insulin content, increased rate
of beta-cell death and damage to the islets. Indeed, ex-
posure of islets from diabetes-prone Psammomys obesus
to high glucose levels, in vitro, results in increase in
apoptosis of beta-cells [17,19].
In this study we show that CBD treatment prevents the
damage to the islet structure, preserves islet insulin con-
tent and prevents the destruction of beta cells which is
induced by the HE diet.
We demonstrate that four weeks of CBD treatment (5
mg/kg) is effective in preserving normoglycaemia in the
majority of the Psammomys keeping on a HE diet,
whereas the vehicle-treated animals became hypergly-
cemic. Generation of reactive oxygen species may represent
an alternative mechanism for both glucotoxicity and li-
potoxicity. Hence CBD, a non-psychoactive component
of marijuana, which possesses antioxidant, anti-inflam-
matory and immunosuppressive properties can be ex-
The Psammomys obesus exhibits normally insulin re-
sistance in its native environment, which is seen both in
muscle and liver [18]. On transfer to HE diet they de-
velop nutrition-dependent diabetes with a clinical and
Z. Ehud et al. / Journal of Diabetes Mellitus 2 (2012) 27-34
pected to have positive effects. Indeed, Patane et al. [20]
showed that treatment of islets with metformin, which
also has antioxidant properties, protects the islets from
the harmful effect of free fatty acids and restores the in-
sulin secretion after chronic exposure to free fatty acids
or high glucose. In our study we demonstrate the ability
of CBD to significantly reduce the incident of diabetes in
male Psammomys and to protect the pancreas islets from
destruction. Our previous results [11,12] indicate that
CBD can decrease both the incidence of autoimmune
type 1 diabetes, as well as the destruction of the islets in
NOD female mice.
It has been argued that inflammation is involved in the
pathogenesis of diabetes type 2 [21,22]. As in all in-
flammatory Th1-associated diseases, the reduction of
proinflammatory cytokine production, with an increase
in IL-4 and IL-10, as demonstrated in the NOD mice,
suggests that a mechanism of immunomodulation is in-
volved, namely an immune shift from Th1 to Th2. An-
other mechanism that might be involved in our study is
based on the anti-oxidative activity of CBD [13,23], that
very likely prevents beta cell destruction in the HE fed
Psammomys. Vanadyl sulfate and rosiglitazone have also
been found to be effective in preventing hyperglycemia
and hyperinsulinemia [24,25], while nicotine treatment
[26] caused decrease in food intake and body weight. An
antidiabetic effect was also obtained by G protein kinase
analogs [27] and electroacupuncture [28].
CBD administration did not cause obesity in Psam-
momys, therefore, it may be assumed that CBD does not
enhance muscle or liver insulin sensitivity or improve
lipid metabolism in this species.
It is known that HE diet which induces glucotoxicity,
causes damage to Psammomys beta cells. Several studies
[29,30] have reported changes of islets morphology of
Psammomys maintained on a HE diet, namely a gradual
destruction of beta-cell, loss of insulin, apoptosis and
necrosis. Our study clearly demonstrates that CBD has a
beneficial effect on the integrity of Psammom ys pancre-
atic islets. It was reported [31] that CBD attenuated high
glucose-induced endothelial cell inflammatory response
by inhibiting NF-kb nuclear translocation.
Irreversibility of nutritionally induced type 2 diabetes
in Psammomys is related to beta cell apoptosis [17,32,33]
although this aspect was not explored in our study.
The significant increased insulin availability in CBD
treated animals counteracts insulin resistance, which is
essential for reducing glucose concentrations in the
plasma during HE diet and for preservation of pancreatic
beta cell function.
One can assume that the normoglycemia in Psammo-
mys will be associated with normal level of serum insulin
concentrations; however CBD treatment did not reduce,
but rather increased these concentrations. Also the hy-
perinsulinemia fallowing CBD administration did not
cause obesity. We can assume that CBD does not change
insulin sensitivity in Psammomys.
The cytokines level could not be assayed in our ex-
periments, due to lack of available cytokines tests for
Psammomys. However, one can speculate that the reduc-
tion of inflammatory cytokines following CBD treatment
in mice [11,12] might also play a role in the outcome of
CBD treatment in Psammomys.
Plasma TNF-α is associated with insulin resistance.
This supports the claim that TNF-α plays a significant
role in the pathogenesis of chronic insulin resistance in
humans [34] It has been shown that visfatin, TNF-α, and
IL-6 mRNA expressions are increased in peripheral
mononuclear-monocytic cells from women with type 2
diabetes, independent of their BMI [35].
Since CBD is known to inhibit production of IL-1b,
TNF-α and IFN-γ in mice [11,12] and that these factors
are known to be involved in the pathway of autoimmune
islet cell destruction leading to diabetes, it may represent
one of the mechanisms involved in the lack of islets de-
struction and preservation of normal glucose levels in the
Several mechanisms of action of CBD were proposed
[4], among them FAAH inhibition, adenosine uptake
inhibition and PPAR gamma activation as well as at-
tenuation of oxidative/nitrosative stress. Moreover, CBD
has been applied in various clinical conditions to human
patients [5] without any observed toxic effects.
As CBD already has been administered to patients for
other medical indications [4,6] and proved to be ex-
tremely safe, we propose its use as a therapeutic agent in
diabetes type 2.
We are grateful to Professor Raphael Mechoulam for providing us
the Cannabidiol (CBD).
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