Introduction
Diabetes mellitus is in a group of metabolic disorders having hyperglycemia as a common
manifestation. It is a syndrome with both hereditary and environmental factors. Glycemia and
diabetes are rising globally, driven both by population growth and ageing. The number of people
with diabetes increased from 153 million in 1980 to 347 million in 2008 [1 ]. The greatest relative increase is expected to occur in Africa, followed by the
Eastern Mediterranean and the Middle East [2 ]. The global health
expenditure on diabetes has been expected to total at least USD 376 billion in 2010, rising to
USD 490 billion in 3030 [3 ]. Diabetes is projected to become one of
the worldʼs main disablers and killers within the next 25 years [4 ].
Experimental diabetes in animals has provided considerable insight into the physiological and
biochemical derangement of the diabetic state. Significant changes in lipid metabolism occur in
diabetes as well as a profound alteration in the concentration and composition of lipids. In
these cases, the lipid structural changes are clearly oxidative in nature [5 ]. In diabetes, increased lipid peroxidation is associated with hyperlipidemia [6 ]. Oxidative stress is, thus, produced under diabetic condition and is
likely involved in the progression of pancreatic damage [7 ]. Despite
the great strides made in the understanding and management of diabetes, the disease and its
complications are increasingly unabated.
The role of oxidative stress and altered antioxidant levels in the pathogenesis of diabetic
complications is well established [8 ]. Oxidative stress may have a
common pathway linking diverse mechanisms for diabetes complications, such as vascular
dysfunctions, nephropathy, neuropathy, and retinopathy. Apart from the initiation of lipid
peroxidation, oxygen free radicals stimulate glycation of protein, inactivate enzymes and change
the structure and function of collagen and other membranes, thereby playing a role in the
long-term complications of diabetes [9 ]. Oxidative stress in
diabetes coexists with a reduction in the antioxidant status and increase of the deleterious
effects of free radicals [10 ]. Studies indicated that antioxidant
intake may reduce the risk of developing type 2 diabetes [11 ].
Antioxidants were shown to reduce the risk of diabetes onset and improve glucose disposal and
associated complications [12 ].
Phenolic compounds (e.g., phenolic acids, flavonoids, quinones, and tannins) are natural
antioxidants abundant in many desert and steppic plants. They function as terminators of free
radical chains or as chelators of redox-active metal ions capable of catalyzing lipid
peroxidation [13 ]. A positive linear correlation was found between
the antioxidant activity (the capability to scavenge oxygen reactive species) and the total
phenolic content in plants [14 ], [15 ],
suggesting that phenolic compounds contribute significantly to the antioxidant capacity of the
investigated plant species. Direct correlation between the antioxidant property of medicinal
plants and the latterʼs antidiabetic activity was found [16 ], and
the relationship between the molecular structure of flavonoids and their radical-scavenging
capability was shown [17 ].
Overproduction of reactive oxygen species (ROS) has been implicated in the causation of
several acute diseases, such as liver cirrhosis, atherosclerosis, cancer, degenerative diseases,
diabetes, and ageing. Therefore, compounds that can scavenge ROS have great potential in
ameliorating or even stopping the processes leading to these diseases [18 ]. Antioxidants – ROS scavengers – thus play important roles in protecting the human
body against the damage they cause.
Ethnic medicine uses mostly plants to fight diseases. The antidiabetic effects of medicinal
mushrooms and their hypoglycemic mechanism have been reviewed [19 ].
Sugar control is thought to be linked to the action of substances like glycosides, alkaloids,
terpenoids, tannins, and flavonoids contained in medicinal plants [4 ], [19 ]. Generally, plant-based ethnic drugs and herbal
formulations are less toxic and freer from side effects than their synthetic counterparts [20 ].
Being exposed to harsh environmental stress conditions, desert and steppic plants have
developed unique survival systems based on phytochemicals of remarkable properties. Many of them
not only protect the plant against the enhanced environmental oxidative stress conditions but
are thought also to be capable of diminishing, or even preventing, deleterious oxidative
processes in the human body, which are involved in the development of cancer, diabetes, and
neurodegenerative diseases [21 ].
The high potential of desert and steppic plants in treating and preventing diabetes is
reflected in Bedouin ethnic medicine. Although a systematic comparison between the antidiabetic
attributes of desert and semidesert plants to those of plants growing under milder conditions
has not yet been documented, those of the former could still be evaluated while observing the
deleterious health effects due to the changes in the lifestyle of the Israeli Negev Bedouins in
the last few decades. The transition has primarily been from traditional diet (local herbs, milk
from sheep, goats, and camels nourished on natural pasture) to westernized food and has resulted
in a dramatic increase in diabetes morbidity and mortality among the Bedouins [22 ], [23 ]. Indeed, consumption of camel
milk has traditionally been regarded by the Israeli Negev Bedouins as a sure remedy against
diabetes, and its ethnic use, based on experience, has recently also been scientifically
validated [24 ], [25 ], [26 ].
This review highlights the antidiabetic effects of extracts and pure components derived from
desert and steppic (semidesert) plants in ethnic medicine and in research. [Table 1 ] summarizes the plantsʼ antidiabetic bioactivities. [Fig. 1 ] exhibits the chemical structures of antidiabetic active
components included in some of them.
Fig. 1 Several antidiabetic compounds contained in desert and steppic plants.
Table 1 Antidiabetic effects of desert and steppic plants.
Plant
Part of plant used/type of extract
Target & antidiabetic effect
Administration route/dosage
Reference
b. w. = body weight; s. c. i.= subcutaneous injection; i. p. i. = intraperitoneal
injection; alc. = alcohol
Achillea santolina
whole plant water-ethanol extract
Reduced activities of superoxide dismutase, catalase, and levels of pancreatic
glutathione in STZ diabetic male Wistar albino rats; reduced blood glucose level and
exhibited hypoglycemic activity in STZ diabetic rats.
oral/mL/rat/day (equivalent to 0.1 g plant powder per kg b. w. per day)
Yazdanparast et al., 2007 [61 ]
Aloe barbadensis (Aloe vera)
dried sap from leaf
Reduced fasting serum glucose levels in patients with non-insulin-dependent diabetes;
induced hypoglycemia in alloxan-diabetic Swiss albino mice.
oral/humans: half a teaspoonful; mice: 0.5 g · kg−1 b. w.
Ghannam et al., 1986 [76 ]
bitter principle from leaf extract
Produced hypoglycemic effect in alloxan-diabetic mice.
oral/5 mg · kg−1 b. w.
Ghannam et al., 1986 [76 ]; Ajabnoor, 1990 [77 ]
Aloe arbores- cence
polysaccharide fraction isolated from leaves
Lowered glucose levels in normal mice, and in alloxan-induced hyperglycemic mice.
oral/ad libitum
Hikino et al., 1986 [78 ]
Anabasis articulata
butyl alcohol extract of β -sitoglucoside saponin from aerial parts
Decreased glycemia in diabetic and non-diabetic mice.
oral/10 mg (dried butanolic extract) kg−1 b. w.
Kambouche et al., 2011 [68 ]
Artemisia herba-alba
plantʼs aqueous extract
Produced initial hyperglycemia, followed by hypoglycemia in normoglycemic and in
alloxan-treated rabbits and mice.
oral/0.39 g (dry extract) kg−1 b. w.
Marrif et al., 1995 [30 ]
aerial parts
Produced hypoglycemic activity to normoglycemic and to alloxan-diabetic rabbits.
oral/0.39 g (dry extract) kg−1 b. w.
Twaij, 1988 [31 ]
hydro-alcoholic extract
Reduced mean fasting blood glucose, serum insulin concentrations, and insulin resistance
in high-fat diet-induced diabetic rats.
oral/2 g (dry extract) kg−1 b. w.
Hamza et al., 2011 [32 ]
aqueous extract of aerial parts
Reduced blood glucose level, prevented elevation of glycosylated hemoglobin level,
exhibited hypoliposis effect and protected against body weight loss of diabetic rats and
rabbits.
oral/0.39 g (dry extract) kg−1 b. w.
Al-Shamaony et al., 1994 [33 ]
Lowered elevated blood sugar in patients with diabetes mellitus.
Al-Waili, 1986 [34 ]
volatile oil from aerial parts
Decreased the high blood glucose level of alloxan-diabetic rats.
s. c. i./1350–1950 mg · kg−1 b. w.
Essway et al., 1995 [35 ]
Artemisia judaica
Reduced blood glucose level in experimentally diabetic rats but negligibly affected
normal rats.
oral/0.25 g · kg−1 and 0.5 g · kg−1 b. w. for the water ext. and
0.5 g · kg−1 and 1 g · kg−1 b. w. for the alc. ext.
Nofal et al., 2009 [27 ]
Atriplex halimus
pressed juice, or water extract, or dialysate of the green leaves
Induced hypoglycemic effect in alloxan-diabetic albino rats.
oral
Aharonson et al., 1969 [70 ]
Balanites aegyptiaca
water extract of fruits
Decreased plasma glucose levels in diabetic male rats.
oral/3.6–9 g/week/rat
Morsy et al., 2010 [59 ]
Calotropis procera
dry latex from aerial parts
Caused dose-dependent decrease in blood glucose and an increase in the hepatic glycogen
content in alloxan-induced diabetic rats; prevented loss of body weight in diabetic rats
and brought down their daily water consumption to values comparable to normal rats.
oral/100–400 mg · g−1 b. w.
Roy et al., 2005 [62 ]
water, petroleum ether, and ethanol extracts of leaves
Reduced blood glucose level, total cholesterol, phospholipids, low-density lipoprotein
and very low-density lipoprotein and increased high-density lipoprotein in STZ-induced
diabetic male Wister albino rats.
oral/250 mg (dry extract) kg−1 b. w.
Bhaskar and Sumant, 2009 [63 ]
Capparis spinosa
fruit
Decreased blood glucose level in STZ- and HFD- diabetic rats, normalizing it
within 2 weeks of daily oral administration.
oral/20 mg (dry extract) kg−1 b. w.
Eddouks et al., 2004 [38 ]; Lemhadri et al., 2007 [39 ]
Caralluma sinaica
ethanol extract of aerial parts
Induced dose-dependent reduction in blood glucose levels in normal male albino rabbits,
and brought to normal plasma glucose in STZ-induced diabetic rabbits.
oral/50–200 mg/kg b. w.
Habibuddin et al., 2008 [74 ]
Chiliadenus iphionoides
ethanol extract of aerial parts
Increased insulin secretion in β cells and glucose uptake in adipocytes and
skeletal myotubes. Displayed hypoglycemic activity in diabetic sand rats. (Psammomys
obesus )
oral
Gorelick et al., 2011 [52 ]
aqueous extract of aerial parts
Decreased blood glucose levels in diabetic and in nondiabetic rats.
oral
Afifi et al., 2011 [54 ]
Larrea tridentate (Creosote bush)
nordihydro-guaiaretic acid
Decreased concentration in plasma glucose of male mice without change in plasma insulin
concentration, improved oral glucose tolerance and enhanced the ability of insulin to lower
plasma glucose concentrations.
Luo et al., 1998 [82 ]
Moringa peregrina
aqueous and ethanol extracts of aerial parts
Induced antihyperglycemic effect on streptozotocin-induced diabetes in rats.
oral/25 mg · kg−1 b. w.−1 b. w.
El-Alfy et al., 2011 [64 ]
Ochradenus baccatus
Initiated slow hypoglycemic activity in alloxanized rats.
Shabana et al., 1990 [51 ]
Opuntia strepta-
broiled nopal stems
Induced hypoglycemic effect in patients with non-insulin-dependent diabetes mellitus
(NIDDM)
oral/500 g per person
Frati-Munari et al., 1988 [73 ]
Peganum harmala
essential oil
Ameliorated hyperglycemia-induced stress oxidative and hepatic dysfunction in diabetic
rats.
Hamden et al., 2009 [60 ]
Plantago ovata
husk hot water extract
Suppressed rise in blood glucose after sucrose loading in control and diabetic rats;
improved glucose tolerance in normal, type 1 and type 2 diabetic rats. Antihyperglycemic
activity due to increased motility of the gastrointestinal tract.
oral/0.5 g · kg−1 b. w.
Hannan et al., 2006 [67 ]
Retama raetam
fruits methanol extract
Lowered blood glucose levels in STZ-diabetic rats.
oral/250 mg · kg−1 b. w.
Algandaby et al., 2010 [56 ]
water extract of aerial parts
Induced hypoglycemic effect in STZ-diabetic rats.
oral/20 mg · kg−1 b. w.
Maghrani et al., 2003 [57 ]
water extract of aerial parts
Displayed hypoglycemic activity in both normal and STZ-diabetic rats.
oral/10 mg · kg−1 b. w.
Maghrani et al., 2005 [58 ]
Terminalia chebula, Terminalia helerica, Emblica officinalis
methanol extract of aerial parts
Reduced blood sugar level in normal and in alloxan-treated diabetic rats.
oral/100 mg · kg−1 b. w. normal rats. 120 mg · g−1 b. w.
alloxinated rats
Sabu and Kuttan, 2002 [16 ]
Teucrium polium
water – ethanol extract
Induced a decrease in glucose level and an increase in blood insulin level in
STZ-diabetic rats.
oral/0.5 g (dry extract) kg−1 b.w
Yazdanparast et al., 2005 [43 ]
water extract
Suppressed blood glucose levels; induced higher GSH levels along with enhanced CAT and
SOD activities in pancreatic tissue; lowered serum NO, pancreatic MDA, PCO, and AOPP
levels.
oral/0.5 g (dry extract) kg−1 b. w.
Ardestani et al., 2008 [45 ]
ethanol extract
Demonstrated insulinotropic effect on INS-1E cells and a reduction of blood glucose
levels in both normo- and hyperglycemic rats.
intragastric/125 mg (dry extract) kg−1 b. w.
Stefkov et al., 2011 [46 ]
Ziziphus spina-christi
leaf butyl alcohol extract
Reduced serum glucose level, liver phosphorylase, and glucose-6-phosphatase (G-6-pase)
activities; increased serum pyruvate level and liver glycogen content and improved glucose
utilization in STZ-diabetic rats.
oral/100 mg · kg−1 b. w.
Glombitza et al., 1994 [47 ]
leaf water extract
Reduced blood glucose level, increased serum insulin and C-peptide levels, reduced
elevated blood lactate level and elevated the reduced blood pyruvate content in
STZ-diabetic rats.
oral/200 mg · kg−1 b. w.
Michel et al., 2011 [49 ]
leaf butyl alcohol extract or pure christinin-A
Reduced serum glucose level and increased serum insulin level in nondiabetic control and
in type 2, but not in type 1 diabetic rats.
oral/100 mg · kg−1 b. w.
Abdel-Zaher et al., 2005 [50 ]
Exploring the Antidiabetic Attributes of Desert and Steppic Plants
Artemisia judaica L. (Compositae) is an evergreen perennial shrub growing in the
Israeli arid southern Arava and the southern Sinai desert and is commonly used in traditional
Bedouin medicine. It was found that both water and alcoholic extracts of this plant
significantly reduced blood glucose levels in experimentally diabetic rats, while no significant
effect was detected in normal rats [27 ]. Phytochemical analysis of
A. judaica revealed that it is a rich source of flavonoids, including apigenin
(4′,5,7-trihydroxyflavone) and cirsirmaritin ([Fig. 1 ]). Indeed,
the major bioactive compounds of defatted alcohol and water extracts of A. judaica were
found to be flavonoids, compounds exhibiting strong antioxidant activities [28 ], [29 ].
Artemisia herba-alba Asso. (also called “white wormwood”; Compositae) is a dwarf
perennial shrub growing in semiarid zones and in favorable niches in hot deserts of the Middle
East, but also in semiarid zones of southern Europe and Asia. The aqueous extract of
A. herba-alba was found to produce initial hyperglycemia, followed by hypoglycemia in
normal and alloxan-treated rabbits and mice [30 ]. This plant has
been widely used in Iraqi folk medicine for the treatment of diabetes mellitus. Oral
administration of an aqueous extract of its aerial parts to normoglycemic and to
alloxan-diabetic rabbits produced significant hypoglycemic activity, which proved to be
consistent and time dependent [31 ].
Hydro-alcoholic extracts of Centaurium erythraea Rafn (Gentianaceae) and
A. herba-alba , used in the traditional treatment of diabetes in north-eastern Algeria,
were tested in mice with established type 2 diabetes induced with a standardized high-fat diet
[32 ]. At 35 weeks, groups treated with A. herba-alba or
with C. erythraea when compared to the high-fat diet control showed a significant
reduction in mean fasting blood glucose concentration, triglyceride, total cholesterol, and
serum insulin concentrations. The plant extracts also markedly reduced insulin resistance as
compared to high-fat diet controls. Although A. herba-alba has already been shown to have
antihyperglycemic and antihyperlipidemic effects, this research demonstrated for the first time
the effect of this plant on established high-fat diet-induced diabetes.
A study assessed the efficacy and toxicity of A. herba-alba
[33 ]. Feeding diabetic rats and rabbits with 0.39 g/kg body weight
of the aqueous extract of the aerial parts of the plant for 2–4 weeks resulted in a significant
reduction in blood glucose levels, prevented elevation of glycosylated hemoglobin levels, led to
hypoliposis and protected against body weight loss of the diabetic animals.
Fifteen patients with diabetes mellitus treated with A. herba-alba extract showed a
considerable lowering of elevated blood sugar, while 14 out of the 15 patients had good
remission of diabetic symptoms. No side effects were recorded during or after treatment with the
plant extract [34 ].
Mice treated with the volatile oil of A. herba-alba showed significant hypoglycemia,
and the high blood glucose levels of alloxan-treated diabetic rats significantly decreased
subsequent to injecting the oily extract [35 ].
The genus Capparis (Capparidaceae or Capparaceae) includes more than 250 species and
has a wide distribution, particularly covering the Atlantic coasts from the Canary Islands and
Morocco to the Black Sea and Armenia [36 ]. The species Capparis
spinosa L. is a semiarid, drought tolerant perennial shrub, largely distributed throughout
the Mediterranean Sea basin. In Israel, a variant, Capparis spinosa L. var.
arvensis Zohary, is found throughout the arid part of the country, the southern Jordan
Valley, Judean Desert, Negev, and Arava, growing on poor stony lands in wadies and canyons [37 ]. In Arab and Bedouin traditional medicine different parts of the
plant have been used for treating rheumatism, women infertility, open wounds, respiratory
diseases, and diabetes. The aqueous extract of the fruit of this plant was found to produce a
significant decrease in blood glucose level in streptozotocin (STZ)-diabetic rats [38 ] and in high-fat diet (HFD) diabetic rats [39 ], normalizing blood glucose levels within 2 weeks of daily oral administration.
Treating nondiabetic rats with the plantʼs extract did not result in significant changes in
blood glucose levels. No changes were observed in basal plasma insulin concentrations following
treatment with this plant in either normal or STZ-diabetic rats, suggesting that the underlying
mechanism of its pharmacological activity is independent of insulin secretion.
Teucrium polium L. (syn. Teucrium capitatum L.; Lamiaceae) is a wild-growing
Mediterranean and West Irano-Turanian perennial, a plant belonging to the semiarid and arid
climates of the Middle East, North Africa, south-western Asia, and southern Europe [40 ]. As a medicinal plant, it has been used for more than 2000 years.
Traditionally, T. polium has been used for treating different pathological conditions,
such as gastrointestinal disorders, inflammations, diabetes, and rheumatism. In Arab and Bedouin
traditional medicine, T. polium has been primarily applied in treating abdominal pain,
indigestion, diabetes, liver diseases, and hypertension [41 ].
During the past 40 years, different classes of compounds have been isolated from various parts
of this plant, the main groups of which are terpenoids and flavonoids. These compounds possess a
broad spectrum of pharmacological effects, including antioxidant, anticancer, anti-inflammatory,
hypoglycemic, hepatoprotective, hypolipidemic, antibacterial, and antifungal activities [42 ].
The aqueous extract of the dried aerial parts of T. polium has traditionally been used
in southern Iran. The local claimed hypoglycemic effect of this plant was validated through
administering the crude extract to STZ-diabetic rats. Compared to untreated diabetic rats, the
glucose level in the treated rats was decreased by 64 %, and an increase of almost 160 % was
observed in the blood insulin level. In vitro investigation using isolated rat Langerhans
islets indicated that the crude aqueous extract of T. polium is capable of enhancing
insulin secretion by almost 135 % following a one dose treatment at a high glucose
concentration, suggesting that a regenerative process of the islets of Langerhans in the T.
polium -treated diabetic rats has occurred [43 ]. In another
study, Gharaibeh et al. suggested that the hypoglycemic activity of aqueous extracts derived
from T. polium is due to the enhancement of peripheral metabolism of glucose rather than
an increase in insulin release [44 ].
Rats treated with T. polium extract had significantly higher glutathione (GSH) levels,
along with enhanced catalase (CAT) and superoxide dismutase (SOD) activities in the pancreatic
tissue. In addition to suppressed blood glucose levels, serum nitric oxide (NO), pancreatic
malondialdehyde (MDA), protein carbonyl content (PCO), and advanced oxidation carbonyl products
(AOPP) levels were all lower in the diabetic rats treated with the T. polium extract as
compared with untreated counterparts [45 ].
The insulinotropic and antihyperglycemic effects of the ethanol extract of T. polium
from the Republic of Macedonia, a plant traditionally used in that country to treat diabetes,
were also investigated [46 ]. The dried extract showed a distinct
in vitro insulinotropic effect on INS-1E cells at 500 µg/mL. An oral administration of
the extract to both normal and hyperglycemic rats lowered blood glucose levels of both groups by
35 %.
Ziziphus spina-christi (L.) Willd. (Christʼs thorn jujube; Rhamnaceae) is an evergreen
tree of Sudanese origin native to northern and tropical Africa, and southern and western Asia.
In Israel it grows in valleys up to an elevation of 500 m. It is also found in moist wadies in
the Israeli hot Judean Desert and Arava. Z. spina-christi is a plant commonly used in
Egyptian and Middle East traditional medicine for the treatment of various ailments [47 ], [48 ]. A study investigated the effect
of the butyl alcohol extract of leaves of this plant and that of christinin-A ([Fig. 1 ]), its principal saponin glycoside, in normal and STZ-induced
diabetic rats [47 ]. In normal rats, treatment for one and four
weeks produced insignificant changes in all studied parameters. However, in diabetic rats, both
treatments significantly reduced serum glucose levels, liver phosphorylase, and
glucose-6-phosphatase (G-6-pase) activities and significantly increased serum pyruvate levels
and liver glycogen content after 4 weeks of treatment. A marked improvement was noticed in
glucose utilization in diabetic rats in both cases. Serum insulin and pancreatic cyclic
adenosine monophosphate (cAMP) levels showed a significant increase in diabetic rats treated
with the extract, suggesting an improvement of the pancreas function.
Additional study showed that the antihyperglycemic potencies of leaf extracts of Z.
spina-christi on STZ-induced diabetic rats depend on seasonal variation, and that leaves
should preferably be collected from June to October [49 ]. This
study showed that oral administration of Z. spina-christi leaf extract reduced the blood
glucose level with a significant increase in serum insulin and in C-peptide levels. The extracts
reduced the elevated blood lactate level and elevated the reduced blood pyruvate content of
diabetic rats. In line with the amelioration of the diabetic state, Z. spina-christi
extract, both plain and formulated, restored liver and muscle glycogen content, together with a
significant decrease of hepatic glucose-6-phosphatase and enhanced the activities of
glucose-6-phosphate dehydrogenase. In vitro tests marked a dose-dependent inhibitory
activity of Z. spina-christi extract against α -amylase enzyme with an
IC50 at 0.3 mg/mL. This work showed that Z. spina-christi leaf extract
improves glucose utilization in diabetic rats by increasing insulin secretion, which may be due
to both saponin and polyphenols contents, and controls hyperglycemia through the attenuation of
meal-derived glucose absorption, attributed to the total polyphenols content.
Abdel-Zaher et al. studied the effect of butyl alcohol extract of the leaves of Z.
spina-christi and its major saponin glycoside, christinin-A, on serum glucose and insulin
levels in nondiabetic controls, type 1 and type 2 diabetic rats [50 ]. They found that treatment either with 100 mg/kg extract, or with christinin-A
alone, reduced the serum glucose level and increased the serum insulin level of nondiabetic
control and in type 2 diabetic rats, but not of type 1 diabetic rats. Similar effects were
obtained with the butyl alcohol extract and with christinin-A. Pretreatment of nondiabetic
control and type 2 diabetic rats, either with butyl alcohol extract or with christinin-A,
enhanced the glucose lowering and insulinotropic effects of glibenclamide, a sulfonylurea
antidiabetic drug used for the treatment of type 2 diabetes. It was also found that treating
rats with 100 mg/kg butyl alcohol extract for 3 months produced no functional or structural
disturbances in the liver and kidney and no hematological changes. These results point to the
leaves of Z. spina-christi as a safe alternative to lower blood glucose. The safe
insulinotropic and subsequent hypoglycemic effects of Z. spina-christi leaves could be
due to a sulfonylurea-like activity.
The hypoglycemic effect of 31 plants from different Egyptian localities was tested [51 ]. Twenty-one plant extracts were given orally to normal rats, and
fifteen were tested on fasting and alloxanized rats. The results were compared with a standard
oral hypoglycemic drug [DAONIL® tablets; Daonil (INN), also known as glyburide (USAN), a
second-generation sulfonylurea antidiabetic agent] used as a positive control. Eight plants
exhibited persistent hypoglycemic effects, while transient hypoglycemic effects appeared in
response to the administration of four other plants. Among the fifteen plant extracts tested on
alloxanized diabetic rats, only four showed hypoglycemic effects more potent than those of the
administered dose of DAONIL® tablets. These were Matthiola livida (Delile) DC.
(Brassicaceae), Salvia aegyptiaca L. (Lamiaceae), and Arthrocnemum glaucum
Ung.-Sternb. (Chenopodiaceae). S. aegyptiaca also induced the hypoglycemic effect in
fasting alloxanized diabetic rats.
C. iphionoides (Boiss. & Blanche) Brullo (syn. Varthemia iphionoides Boiss.;
Compositae) is a small aromatic shrub, an herbaceous perennial hemicryptophyte distributed in
the Mediterranean woodlands and shrub-steppes, deserts and extreme deserts, and is used
traditionally in the treatment of diabetes mellitus. The ethanol extract of the aerial parts of
C. iphionoides increased insulin secretion in β cells as well as glucose uptake
in adipocytes and skeletal myotubes. The extract also displayed hypoglycemic activity in
diabetic sand rats (Psammomys obesus ) [52 ].
Various extracts of the aerial parts of C. iphionoides were investigated for their
radical scavenging, antioxidative, and porcine pancreas α -amylase inhibitory activities
[53 ]. Ethanol and water extracts showed a pronounced
1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity, with inhibition of about 90 %
at a concentration of 100 µg/mL, and α -amylase inhibitory activity of about 70 % at a
concentration of 200 µg/mL by the 2-chloro-4-nitrophenyl α -maltotrioside (CNP-G3)
degradation method.
Aqueous extract of the aerial parts of C. iphionoides decreased blood glucose by 70 %
after one hour in STZ-treated rats and also lowered blood glucose in normal rats 4 hours after
treatment [54 ].
The effect of C. iphionoides was evaluated in vitro and in vivo on
enzymatic starch digestion [55 ]. The results confirmed that
C. iphionoides could be considered a potential candidate for therapeutic modulation of
impaired fasting glycemia, impaired glucose tolerance, and type 2 diabetes.
Retama raetam (Forssk.) Webb & Berthel (Fabaceae) is a phanerophyte shrub
distributed in the Mediterranean woodlands and shrublands, semi-steppe shrublands,
shrub-steppes, deserts, and extreme deserts. The fruits of R. raetam are used in Saudi
traditional medicine for the treatment of diabetes. A study evaluating the potential and
mechanisms of the antidiabetic activity of R. raetam methanol extract in STZ-induced
diabetic rats showed that the extract neither altered glucose uptake by rat isolated psoas
muscle nor the activity of hepatic microsomal glucose-6-phosphatase [56 ]. The methanol extract of R. raetam improved STZ-induced diabetes in rats due
to stimulating pancreatic insulin release and the reduction of intestinal glucose
absorption.
The effect of the aqueous extract of the leaves of R. raetam on blood glucose levels
was investigated in fasting normal and streptozotocin-induced diabetic rats after single and
repeated oral administration [57 ]. The aqueous extract of
R. raetam at a dose of 20 mg/kg significantly reduced the blood glucose in normal rats 6
hours after a single oral administration and two weeks after repeated oral administration. This
hypoglycemic effect was more pronounced in STZ-diabetic rats. The extract had no effect on basal
plasma insulin levels, indicating an extra-pancreatic mechanism. The aqueous extract of
R. raetam thus possesses a significant hypoglycemic effect in both normal and
STZ-diabetic rats.
An additional study of the hypoglycemic activity of the aqueous extract of the aerial parts of
R. raetam in normal and in STZ-diabetic rats following intravenous injection indicated a
significant decrease in blood glucose levels in normal rats and an even more marked decrease in
diabetic rats [58 ]. The results suggested that the hypoglycemic
effect is due to an extra-pancreatic action of the extract since the basal plasma insulin
concentrations remained constant. The aqueous extract perfusion of R. raetam caused a
potent inhibition of renal glucose reabsorption. This effect indicated at least one mechanism
that could explain the observed hypoglycemic activity of this plant in both normal and diabetic
rats.
Balanites aegyptiaca (L.) Delile (Balanitaceae) is a multi-branched, spiny shrub or
tree up to l0 m high, native to Africa, the Arabian Peninsula, and adjacent parts of the Middle
East. Within Africa it ranges from Mauritania in the west to Somalia in the east and from Egypt
southwards to Zimbabwe. It is a highly drought-tolerant evergreen desert plant species, having a
wide ecological distribution, but prefers open woodlands and savannahs. The fruit of a B.
aegyptiaca species grown naturally at radioactive places in the Wadi El-Gemal area, Egypt,
exhibited potential antidiabetic and hypolipidemic capabilities [59 ].
Peganum harmala L. (Syrian rue; Nitrariaceae) is a perennial shrub with fleshy
spikey-looking leaves, growing up to 0.8 m tall. It is native to the eastern Mediterranean
region and extends up to India. It can be found in diverse climates, ranging from Mediterranean
to steppes and deserts. In Israel, it is distributed mainly throughout the arid and semiarid
northern Negev. Treatment of diabetic rats with the essential oil of P. harmala
ameliorated hyperglycemia-induced stress, and oxidative and hepatic dysfunction. Administration
of the oil to diabetic rats initiated antidiabetic and antioxidant activities through the
decrease in the plasmatic glucose level, an increase in hepatic SOD, CAT, and glutathione
peroxidase activities, and a concomitant reduction in glutathione and glycogen contents compared
to untreated diabetic rats [60 ].
Achillea santolina L. (Compositae) is a 0.3 m high perennial shrub, growing on loess
soils in the semiarid central northern Negev in Israel. This plant is used by Bedouin
traditional healers as a hypoglycemic agent. The protective effect against pancreatic damage of
the hydro-ethanol extract of the plantʼs aerial parts was tested on STZ-treated diabetic rats
[61 ]. Following oral administration of the extract, a significant
reduction in the activities of SOD, CAT, and pancreatic GSH levels was observed in the diabetic
rats, compared to control subjects. Extract of A. santolina reduced blood glucose level,
serum NO, pancreatic MDA, PCO, and AOPP. CAT and SOD activities decreased by diabetic conditions
were significantly increased in diabetic rats treated with the extract, manifesting the high
hypoglycemic activity of A. santolina , an attribute probably resulting from its
antioxidative potential [61 ].
A. santolina L., Pistacia atlantica Desf. (Anacardiaceae), Rheum ribes L.
(Polygonaceae), Sarcopoterium spinosum L. Spach (Rosaceae), and T. polium L. have
traditionally been used as herbal antidiabetic medicines. The in vitro and in vivo
effects of water extracts of these plants were tested [55 ].
Compared to acarbose (IC50 = 1.2 µg/mL), water extracts of P. atlantica,
R. ribes , and S. spinosum exerted significant dose-dependent dual inhibition of
α -amylase and α -glucosidase in the in vitro enzymatic starch digestion
bioassay, with IC50 values of 46.98, 58.9, and 49.9 mg/mL, respectively. Comparable
in vivo results were obtained for starch-fed rats exhibiting significant acute
postprandial anti-hyperglycemic efficacies. While the extracts of A. santolina and T.
polium lacked any favorable in vitro anti-α -amylase and
anti-α -glucosidase effect, other modes of action can possibly explain their substantial
acute anti-hyperglycemic activities in starch-treated rats. Except for P. atlantica
extracts, none of the investigated extracts qualified for improving the glucose intolerance in
fasting rats on glucose loading. P. atlantica, R. ribes , and S. spinosum are
potential candidates for amelioration/management of type 2 diabetes.
Calotropis procera (Aiton) W. T. Aiton (Asclepiadaceae), also called Sodom apple, is a
flowering plant growing in North Africa, tropical Africa, western Asia, south Asia, and
Indochina. It is a soft-wooded, evergreen perennial shrub found in the hot oasis around the Dead
Sea and in the Jordan Valley. It is a plant tolerant to drought and salt. The dry latex of C.
procera , collected from its aerial parts and mixed with normal saline, was evaluated for
its antioxidant and anti-hyperglycemic effects against alloxan-treated diabetic rats [62 ]. Daily oral administration of the dry latex produced a
dose-dependent decrease in the blood glucose and an increase in the hepatic glycogen content. It
also prevented the loss of body weight in diabetic rats and brought down the daily water
consumption to values comparable to normal rats. The latex also increased the hepatic level of
glutathione and the level of endogenous antioxidants, SOD and CAT, while bringing down the
levels of thiobarbituric acid-reactive substances (TBARS) in the alloxan-induced diabetic rats.
It was found that the efficacy of the dry latex as an antioxidant, and as an antidiabetic agent,
was comparable to the standard antidiabetic drug, glibenclamide.
Water, petroleum ether, and ethanol extracts of the leaves of C. procera were tested
for their anti-hyperglycemic effect on STZ-induced diabetic Wister albino rats [63 ]. The three extracts significantly reduced the blood glucose level,
total cholesterol, phospholipids, low-density (LDL), and very low-density lipoprotein (VLDL) in
the treated diabetic rats and concomitantly increased the high-density lipoprotein (HDL),
indicating the recovery of their lipid metabolism. This investigation established
pharmacological evidence supporting the folkloric claim of the antidiabetic attributes of this
plant.
Moringa peregrina (Forssk.) Fiori (Moringaceae Martinov) is a wild plant growing in the
eastern desert mountains of Egypt. The aqueous and ethanol extracts of this plant were found to
exert a significant anti-hyperglycemic effect on STZ-induced diabetic rats [64 ].
Plantago ovata Forssk. (Plantaginaceae) is a plant growing in semiarid regions of
India, Iran, northern Africa, and Pakistan. It has been traditionally used for constipation,
diarrhea, hemorrhoids, irritable bowel syndrome, weight loss, obesity, high cholesterol, and
diabetes [65 ]. A patent deals with a functional powdered beverage
containing the seed powder of this plant as the effective component, capable of preventing adult
diseases including diabetes [66 ].
Administration of the husk extract of P. ovata significantly improved glucose tolerance
in normal, type 1, and type 2 diabetic rats [67 ]. When orally
administered with sucrose solution, the extract suppressed postprandial blood glucose and
retarded the small intestinal absorption without inducing the influx of sucrose into the large
intestine. It significantly reduced glucose absorption in the gut during in situ
perfusion of the small intestine to nondiabetic rats. The extract did not stimulate insulin
secretion in perfused rat pancreas, isolated rat islets, or clonal β cells. Neither did
it affect glucose transport in 3 T3 adipocytes. The suggested mechanism for the reduction of
hyperglycemia is via the inhibition of intestinal glucose absorption and enhancement of
motility.
Anabasis articulata Moq. (Amaranthaceae) is a Saharo-Arabian shrub growing in wadies
and flat lands of the extreme deserts of Israel, Jordan, and Sinai. Water extracts of this plant
are used in traditional medicine for the treatment of diabetes. An oral administration of butyl
alcohol extract of β -sitoglucoside saponin obtained from A. articulata to diabetic
mice decreased glycemia to 20.09 % (p < 0.05) six hours after administration, practically
restoring to normal the blood glucose level of the diabetic mice. The results obtained indicated
an antidiabetic action like a reference compound, glibenclamide [68 ].
A. articulata is used in Algerian traditional medicine as a remedy for diabetes [67 ]. The administration of the aqueous extract of the aerial part of
this plant to alloxan-treated diabetic mice remarkably decreased glycemia (to nearly 30 %) 6
hours after administration. The aqueous extract contain alkaloid and saponin, but only the
latter furnish the active component responsible for restoring normal blood glucose levels [69 ].
Atriplex halimus L. (salt bush; Amaranthaceae) is a halophyte native to Europe and
Northern Africa, including the Sahara in Morocco. It grows in all parts of Israel on salty
lands, in the Judean Desert, Jordan Valley, and along the Mediterranean coast. The leaves of
this plant are the main feeding source for the sand rat. When these rats are fed with
high-caloric diets, they develop diabetes which can be reversed by the addition of
A. halimus leaves [70 ]. Alloxan-diabetic albino rats showed
a significant hypoglycemic effect when fed with either pressed juice or water extract, or
dialysate of the green leaves of this plant, but with no decrease in appetite [70 ]. A. halimus showed an insulin potentiating effect in an
animal model for diabetes and obesity [71 ]. Another study showed
the effectiveness of A. halimus extract against type 2 diabetic patients [72 ]. Indeed, tisane (herbal tea) prepared from the leaves of this plant
is traditionally used by Bedouins in Israel for treating diabetes [37 ].
Opuntia , also known as nopales or paddle cactus, is a genus in the cactus family,
Cactaceae. Currently, only prickly pears are included in this genus of about 200 species
distributed throughout most of the Americas. Prickly pear species are found in abundance in
Mexico, especially in the central and western regions. They are also found in the western United
States, in arid regions in the Northwest, throughout the mid- and lower elevations of the Rocky
Mountains, such as in the state of Colorado, where species such as Opuntia phaeacantha,
Opuntia polyacantha, and others, become dominant. The hypoglycemic effect of Opuntia
streptacantha Lemaire was tested, showing that the stems of this plant induce a
hypoglycemic effect in patients with non-insulin-dependent diabetes mellitus (NIDDM) [73 ].
Caralluma sinaica (Decne.) A. Berger (Apocynaceae) is a plant distributed in the
deserts and dry steppes of the Middle East. In Israel, it grows near the Dead Sea and in the
southern Negev. Native people in the Asir region in Saudi Arabia are reported to chew this plant
as a hypoglycemic herb [74 ]. The utility of C. sinaica in
diabetes mellitus was examined by testing its effect on an STZ-induced diabetic model and oral
glucose tolerance [74 ]. Administration of an ethanol/water extract
of the aerial part of C. sinaica to normal rabbits caused a significant decrease in
glucose level, while in diabetic rabbits, the plasma glucose was brought to almost normal.
Administration of either C. sinaica or glibenclamide blocked the rise of glucose caused
by the STZ. The STZ-induced lowering of glycogen content of the liver and muscle was reversed by
both C. sinaica and glibenclimide. STZ induced a significant increase in renal glycogen
content, which was brought almost back to normal by the C. sinaica extract. Compared with
the glibenclamide treatment, the blood glucose lowering effect was more pronounced for diabetic
rabbits given C. sinaica . The above effects could explain the basis for the ethnic use of
this plant in managing diabetes mellitus.
The genus Aloe comprises small to large evergreen perennials with fleshy, sword to
lance-shaped leaves. This genus contains about 400 species, native to sub-Saharan Africa, the
Saudi Arabian Peninsula, and to many islands of the western Indian Ocean. However, the majority
are desert plants inhabiting the deserts of South Africa. The dried sap of Aloe
barbadensis Mill. (syn. Aloe vera ; Xanthorrhoeaceae) is one of several traditional
remedies used for diabetes in the Arabian Peninsula [75 ]. It caused
a sustained lowering of blood sugar levels in patients [76 ], while
a similar effect was obtained in alloxan-induced diabetic mice, suggesting that the hypoglycemic
effect of plants of the Aloe genus may be mediated through stimulating synthesis and/or
the release of insulin from Langerhans beta-cells [77 ].
Polysaccharide fractions from water extracts of whole leaves of Aloe arborescence Mill.
reduced the glucose levels in normal mice. Two polysaccharides (glycans) were separated from the
water extract of the leaves of this plant and described as arboran A and arboran B. Both were
found to produce marked hypoglycemic effects in normal and in alloxan-induced hyperglycemic mice
[78 ].
Discussion
The review highlights the effects of extracts of desert and steppic plants on various
parameters of diabetes including unveiling potential biochemical pathways involved. Several
plant extracts influence the content of free radicals and antioxidants in treated animals,
suggesting that the levels of free radicals and antioxidants are associated with the diabetic
state. For example, the extract of A. santolina , in addition to reducing blood glucose
level in diabetic rats, lead to an increase of catalase (CAT) and superoxide dismutase (SOD),
whose activities used to be decreased by diabetic conditions [61 ].
Similarly, Calotropis procera extracts, in addition to reducing blood glucose and
increasing hepatic glycogen content, also lead to an increased hepatic level of glutathione, the
level of endogenous antioxidants, SOD and CAT in diabetic rats [62 ].
The involvement of glutathione and glutathione-related enzymes was suggested as the mechanism
of action of natural antioxidant compounds [85 ]. Recent studies
suggested that there are consistent structure–function relationships that affect
bioavailability, antioxidant capacity, and the ability to induce antioxidant/detoxifying enzymes
[86 ], [87 ], [88 ].
Flavonoids probably also function in reducing glucose levels in diabetic animals, as suggested
by the case of Artemisia judaica , known to be a rich source of flavonoids and very
effective in reducing blood glucose levels in experimentally diabetic rats [27 ]. Diabetic rats treated with extracts of T. polium , known to
contain terpenoids and flavonoids that possess hypoglycemic effects, showed changes in various
biochemical parameters related to diabetes apart from a reduced glucose level, such as serum
nitric oxide (NO), pancreatic malondialdehyde (MDA), protein carbonyl content (PCO), and
advanced oxidation carbonyl products (AOPP) levels [44 ]. The
hypoglycemic activity of C. iphionoides Boiss is accompanied by radical-scavenging
activity, suggesting that reducing radical levels contribute to better blood sugar levels [52 ].
The improvement of diabetes parameters by plant extracts is associated with an improvement in
the lipid state, as hyperlipidemia and the oxidised forms of glycated lipids enhance insulin
resistance. For example, treatment of diabetic rats with extracts of C. procera not only
improved sugar levels in the treated diabetic animals [62 ], [63 ], but also reduced total cholesterol, phospholipids, low-density
(LDL) and very low-density lipoprotein (VLDL), and increased the levels of high-density
lipoprotein (HDL). Extract of A. herba-alba produced significant hypoglycemic activity in
rabbits associated with reducing triglyceride, total cholesterol, and serum insulin
concentrations. In term of mechanism, it prevented the elevation of glycosylated hemoglobin
levels. Preclinical studies with patients with diabetes mellitus showed that treatment with
A. herba-alba extract caused considerable lowering of elevated blood sugar and remission
of diabetic symptoms [30 ], [34 ], [35 ].
Several studies presented in this review pointed to the possible mode of action of the plant
extract or its active moiety. For example, Z. spina-christi extract contains antidiabetes
activity in the form of its principal saponin glycoside christinin-A. Apart from reducing serum
glucose levels, liver phosphorylase, glucose-6-phosphatase (G-6-pase) activities, and elevated
blood lactate, it significantly increased serum pyruvate levels, liver glycogen content, serum
insulin, C-peptide levels, and pancreatic cyclic adenosine monophosphate (cAMP) levels in
diabetic rats [47 ], [48 ]. The
hypoglycemic activity of C. iphionoides Boiss extract in diabetic rats can be attributed
to its direct effect on insulin secretion from β cells, glucose uptake by adipocytes, and
skeletal myotubes [52 ]. Intravenous injection of R. raetam
extract, apart from leading to decreased blood glucose levels in diabetic rats, also inhibited
renal glucose reabsorption [57 ], and the administration of an
ethanol/water extract of the aerial part of C. sinaica improved renal glycogen content in
rat models [74 ]. One of the complications in diabetes patients is
deterioration in renal function; identification of plant materials that will inhibit/delay such
complications is very important.
It is important to mention that some of the plant extracts reviewed here were used
traditionally by local communities in the desert and were found to be effective in the treatment
of diabetes symptoms in human patients. Arab and Bedouin communities use herbal tea made of
C. spinosa to treat patients with diabetes, and this tradition can be supported by the
results of the experiment that showed that diabetic rats that consumed aqueous extract of the
fruit of C. spinosa presented reduced glucose levels in the blood. Interestingly, herbal
tea prepared from the leaves of A. halimus is used in folk medicine by Bedouins of the
desert in Israel for treating diabetes [70 ], [71 ]. Treatment of an animal model for diabetes and obesity with
A. halimus extract showed a significant hypoglycemic effect with no decrease in
appetite, supporting the beneficial ethnic use of this plant against diabetes in human
patients.
We suggest to perform preclinical studies with patients with diabetes with several of the
above-mentioned plants.
In summary, the ever increasing prevalence of the two types of diabetics in Western society
could be attributed to environmental factors and to lifestyle. Thus, targeting both, meaning
adopting the prevention approach, seems to be the preferred approach to cope with the problem.
Current research of diabetes, as also clearly reflected in this review, focuses mainly on curing
the disease.
The use of extracts of plant sources, and particularly those derived from desert and steppic
plants, to treat patients with diabetes, has been shown to achieve a positive outcome. However,
little efforts have as yet been directed to exploring toxicity and side effects in desert and
steppic plants. Also little work was performed to investigate the action of isolated pure
bioactive components derived from these plants, comparing their therapeutic activity, toxicity,
and side effects to those of the crude extracts from which they were derived. Not much effort
has yet been directed to clinical studies of these plants.
Owing to the accumulated traditional knowledge, desert and steppic plants used from time
immemorial to prevent and cure diabetes are natural candidates for in-depth exploration.
Prominent candidates mentioned in this review are A. judaica, A. herba-alba, Z.
spina-christi, C. iphionoides, T. polium , and C. spinosa (particularly the evergreen
var. aravensis growing on arid lands in the southern part of Israel, Jordan, and the
Sinai desert). However, we also suggest other plants, not known to be of traditional use but
still found to exhibit positive results in the laboratory, as candidates for in-depth
exploration. Investigating the therapeutic effects of extract mixtures derived from several
plants, each known to be endowed with antidiabetic properties, may become an interesting
challenge too.
Supporting information
High-resolution pictures of some Judean Desert plants used in ethnic anti-diabetes medicine
and in diabetes research are available as Supporting Information.
