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The National Ribat University
Faculty of Graduate Studies and Scientific Research
Hypoglycaemic Effect of Solenostemma argel in
Type II Diabetic patients in
Jaber Abo Aleiz Specialized Center for Diabetes Mellitus
A Thesis Submitted in Fulfillment of Partial Requirement of
Master Degree in Human Nutrition and Dietetics
By:
Hanadi Elyas Elawad Mohammed
Supervisor:
Professor Omer Musa Izzeldin Othman
Co-Supervisor:
Association Professor Khanssa Mohammed Elamin Osman
March, 2014
I
Dedication
It is with my deepest gratitude
and warmest affection that
I would like to dedicate this thesis
to my beloved husband
Mutasim Khidir Abdalla Kanon
and to my cherished children
Mohamed,
Rugiadan,
Rinad
and
Rubeen
II
Acknowledgement
I would like to express my deepest appreciation and thanks to my supervisor
Professor Omer Musa Izzeldin, for encouraging and guiding me to accomplish my
research. Special thanks to my co-supervisor Assn. Professor Khanssa Mohammed
Elamin for her brilliant comments and suggestions. Special gratitude to our master
program coordinator Professor Bahieldin Ibrahim Magboul for giving me
additional knowledge.
In addition, thanks to Jaber Abo Aleiz Specialized Center for Diabetes
Mellitus for giving me permission to organize my experimental study. Thanks to
Prof Mahdi Mohammed for guiding me. Furthermore, I acknowledge with
appreciation Dr. Nagwa Abdulrahman Fatout for her suggestions and help. Also
thanks to the patients who agreed and cooperates to be the subjects of my study.
Thanks to Ms. Salma Bakheet who has been there to assist me in recruiting patients
and gathering data. Special thanks to all of my friends for their support.
My deepest appreciation to Ms. Elena Dariagan who helped me to
coordinate my project especially in writing this research. My acknowledgement to
Ms. Sara Ahmed who extended her help in many ways.
A special thanks to my family. No words can express how grateful I am for
all the support. To my dearest father and mother, your prayers have sustained me
this far and gratitude for taking care of my kids. To my adorable children thank
you so much for the love and inspiration you have given me. Last but not the least,
my sincere appreciation to my beloved husband who has supported me all the way
to finish my M.Sc degree.
III
Abstract
The purpose of this study was to investigate the effects of Solenostemma
argel to reduce blood glucose level in type II diabetic patients in Jabir Abo Aleiz
Specialized Center for Diabetes Mellitus. A three months before-after study was
conducted in 56 uncontrolled type II diabetic patients on oral hypoglycaemic
agent. The patients selection was carried out following inclusion and exclusion
criteria. The patients received (2g) of S.argel once/day in the form of water extract.
Glycated haemoglobin (HbA1c) and fasting blood glucose (FBS) were determined
at the beginning and the end of the study. Blood samples were collected monthly
for measurement of fasting blood glucose levels. The results showed a significant
decrease in HbA1c and FBS levels. The mean level of HbA1c was reduced from
8.602 to 7.45 and mean level of FBS was reduced from 188.13 to 157.67mg/dl
after three months. On the basis of the results of this study, it is concluded that
S.argel has significant antidiabetic activity as it lowers the HbA1c and FBS in type
II Diabetic patients.
IV
خــــــالصة األطـــــزوحة
ذد .الدم خافضة لمستوى سكزنبات الحزجل العشبي كماده فعالية هدفث هذه الدراسة لتقييم
67عه عذد إشرهد .انذراسح ثالثح اشزيذج ,انذراسح تزكز جاتز أت انعز انرخصص نزظ انسكز
.يسرخذي انحثب انخفعح نهسكز ي نذو غيز يرظ سكز ا انثاي يزيط سكز ي انع
جى ف انيو ي انحزجم ف صرج ٢ذال كم يزيط إخريار انزظ ذثعا نعاييز يحذد,ذى
يذ يسر ذرحن نكم يزيط ذى فحص يسر سكز انذو قثم تعذ اراء انذراسحيسرخهص يائ .
عياخ دو شزيا نكم يزيط نرحذيذ سكز انذو صيا تاالظاف نسحةيذ يسر انيغهتي انسكز ذحذ
. يسر سكز انذو صيا
يرسط أظزخ ريجح انذراسح اخفاض يهحظ ف يسرياخ سكز انذو عذ انزظ .حيث اخفط
يرسط اخفط 2.76± 8.56 إن 2.66 ± 9.706ي نذ انزظ تي انسكزيسر انيغه
يهجزاو نكم ديس :70.21 ±268.78 إن 69.86±299.21ي نذ انزظ يسر سكز انذو صيا
تاءا عه ريجح ذ انذراسح خهص ان أ ثاخ انحزجم ن قذر عه خفط يسر سكز انذو. نيرز.
V
List of Contents
No Title
Page
No.
Dedication …………………………………………………. I
Acknowledgement …………………………………………. II
Abstract (English) ………………………………………….. III
Abstract (Arabic) …………………………………………... IV
List of Content ……………………………………………... V-VI
Appendices VII
List of Abbreviations ………………………………………. VIII
List of Table ……………………………………………….. IX
List of Figures ……………………………………………… X
Chapter One
1 Introduction ………………………………………………... 2-3
1.1 Justification ………………………………………………... 3
1.2 Objectives ………………………………………………… 4
1.2.1 General Objective ………………………………………….. 4
1.2.2 Specific Objective …………………………………………. 4
1.3 Hypothesis …………………………………………………. 4
Chapter Two
2 Literature Review 6
2.1 Classification of Diabetes Mellitus ………………………... 6
2.1.1 Type I Diabetes ……………………………………………. 6
2.1.2 Type II Diabetes …………………………………………... 6
2.1.3 Other Specific Types ………………………………………. 7
2.2 Gestational Hyperglycaemic & Diabetes ………………….. 7
VI
2.3 Management of Type II ……………………………………. 7-8
2.4 Anti-diabetic plants ………………………………………... 8-9
2.5 Solenostemma argel ………………………………………... 10
2.5.1 Active ingredients present in S.argel ………………………. 10-12
2.5.2 Effect of water extract of S.argel in the induced-diabetic
rats ………………………………………………………….
12
2.5.3 Traditional medicinal uses ………………………………… 13-14
2.5.4 Toxicity ………………………….………………………… 14-15
Chapter Three
3 Subjects and Methods 17
3.1 Study Design ………………………………………………. 17
3.2 Study Area …………………………………………………. 17
3.3 Study Duration …………………………………………….. 17
3.4 Subjects ……………………………………………………. 17
3.4.1 Sample Size ………………………………………………... 17-18
3.4.2 Criteria 18
3.4.2.1 Inclusion Criteria ………………………………………….. 18
3.4.2.2 Exclusion Criteria ………………………………………….. 18
3.5 Plant Example ……………………………………………... 19
3.6 Procedures …………………………………………………. 19
3.7 Statistical Analysis ………………………………………… 19
3.8 Ethical Clearance for research ...…………………………… 20
Chapter Four
4 Results ……………………………………………………... 22-35
Chapter Five
5 Discussion …………………………………………………. 37-39
Chapter Six
VII
6.1 Conclusion ………………………………………………… 41
6.2 Recommendation ………………………………………….. 41
References …………………………………………………. 43-52
Appendices
Appendix A Questionnaire ………………………………………………. 54-55
Appendix B Concept and Permission forms …………………………….. 56-59
Appendix C Figures and Tables …….……..…………………………... 60-66
Appendix D Images of Solenostemma argel …………………………….. 67
VIII
LIST OF ABBREVIATIONS
ADA - American Diabetes Association
ALP - Alkaline phosphate enzyme
AST - Aspartate aminotransferase
BMI - Body Mass Index
dl - decilitre
FBS - Fasting blood sugar
g - gram
GIT - Gastro Intestinal Tract
GOT - Glutamic-oxalacetic transaminase
GPT - Glutamic pyruvate transaminase
HbA1c - Glycated Haemoglobin
IDDM - Insulin dependent diabetes mellitus
kg - kilogram
mg - milligram
Mo. - Month
Mos. - Months
NIDDM - Non-insulin dependent diabetes mellitus
No.(s) - Number(s)
P Value - Probable Value
S.argel - Solenostemma argel
SD - Standard deviation
WHO - World Health Organization
β-cell - Beta-cell
IX
LIST OF TABLE
Table 1
The main characteristics of study population …… 23-24
Table 2 Effects of duration of disease on HbA1c and FBS
levels before and after treatment of S.argel………. 29
Table 3 Effect of number of drugs on HbA1c and FBS
levels before and after treatment of S. argel……… 30
Table 4 Effect of gender on HbA1c and FBS levels before
and after treatment of S. argel……………………. 32
Table 5 Effect of age group on HbA1c and FBS levels
before and after treatment of S. argel…………….. 33
Table 6 Effect of occupation on HbA1c and FBS levels
before and after treatment of S. argel………….…. 34
Table 7 Effect of education on HbA1c and FBS levels
before and after treatment of S. argel…………..… 35
Table 8 Effect of 3 months treatment with S.argel on
HbA1c levels of study group………………….…. 60
Table 9 Effect of 3 months treatment with S.argel on FBS
levels of study group…………………………….... 60
Table 10 Effect of BMI cut off points on HbA1c and FBS
levels before and after treatment of S.argel…….… 61
Table 11 Effect of comorbid conditions on HbA1c and FBS
levels before and after treatment of S.argel……….. 62
X
LIST OF FIGURES
Figure 1 Effect of 3 months treatment with S.argel on
HbA1c levels of study group…………………. 25
Figure 2 Effect of 3 months treatment with S.argel on FBS
levels of study group………………………….. 26
Figure 3 Effect of BMI cut off points on HbA1c levels
before and after treatment of S.argel…………. 28
Figure 4 Effect of comorbid condition on HbA1c levels
before and after treatment of S.argel…………. 31
Figure 5 The main characteristics of study population.. 63
Figure 5-1 Gender ………………………………………... 63
Figure 5-2 Age/Year ……………………………………… 63
Figure 5-3 Educational Level ……………………………. 64
Figure 5-4 Occupation …………………………………… 64
Figure 5-5 Duration of Disease ………………………….. 65
Figure 5-6 Number of Drugs …………………………….. 65
Figure 5-7 Comorbid Condition …………………………. 66
Figure 5-8 BMI cut off points ……………………………. 66
1
Chapter One
Introduction
2
1. Introduction
The term "diabetes mellitus" describes a metabolic disorder of multiple
etiology characterized by chronic hyperglycaemia with disturbances of
carbohydrate, fat and protein metabolism resulting from defects in insulin
secretion, insulin action, or both. The effects of diabetes mellitus include long-term
damage, dysfunction and failure of various organs (WHO, 1999).
The world prevalence of diabetes among adults (aged 20-79 years) will be
affecting 285 million adults in 2010 (6.4%), and will increase to 439 million adults
by 2030 (7.7%). Between 2010 and 2030, there will be a 69% increase in numbers
of adults with diabetes in developing countries and a 20% increase in developed
countries (Shaw et al., 2010).
More than 400 traditional plant treatments for diabetes mellitus have been
recorded, but only a small number of these have received scientific and medical
evaluation to assess their efficacy. Traditional treatments have mostly disappeared
in occidental societies, but some are prescribed by practitioners of alternative
medicine or taken by patients as supplements to conventional therapy. However,
plant remedies are the mainstay of treatment in under developed regions. A
hypoglycaemic action from some treatments has been confirmed in animal models
and non-insulin-dependent diabetic patients and various hypoglycaemic
compounds have been identified. A botanical substitute for insulin seems unlikely,
but traditional treatments may provide valuable clues for the (Bailey and Day,
1989).
3
Renewed attention to alternative medicines and natural therapies has
stimulated a new wave of research interest in traditional practices and the World
Health Organization expert committee on diabetes has listed as one of its
recommendations that traditional methods of treatment for diabetes should be
further investigated (Watt and Wood, 1988; WHO, 1980).
Solenostemma argel (Del) Hayne is known locally in Sudan as „hargal‟, and
belongs to the family Asclepiadaceae. Other members of the family include S.
Oleifolium (Nectoux) Bullocket Bruce and S. Triste (Nees) K. Muelli. It is an erect
shrub reaching a height of 60-100cm, with many velvety, pubescent branches from
the base. It is distributed in Saudi Arabia, Egypt, Libya, Chad and Palestine. In
Sudan, it is indigenous in the northern regions between Barbar and Abu Hamad
(ElKamali, 1991). Sudan is regarded now as the richest source of this plant
(Organgi, 1982; El-Ghazali, 1997 and Ahmed, 2003). S.argel leaves were at one
time, used to adulterate Khartoum Senna (Trease and Evans, 1989).
1.1 Justification:
A larger number of studies indicate a growing burden of diabetes,
particularly in developing countries. The traditional anti diabetic plants might
provide a useful source of new oral hypoglycaemic compounds for development as
pharmaceutical entities, compare to allopathic medicine which can cure a wide
range of diseases, but its high prices and occasional side-effects are causing many
people to return to herbal medicines.
4
1.2 Objectives
1.2.1 General objective:
To assess the Solenostemma argel effect to reduce blood glucose level in
type-2 diabetic patients.
1.2.2 Specific objective:
To evaluate the appropriate dose of S.argel.
To determine the side effect of S.argel.
To determine effect of comorbid condition HbA1c and FBS levels
before and after treatment of S.argel.
To determine effect of BMI cut off points on HbA1c and FBS levels
before and after treatment of S.argel.
1.3 Hypothesis:
S.argel acts as a hypoglycaemic medicinal plant that reduces blood glucose
level in type II diabetic patients. That based on experimental work which was
carried on albino rats affect blood glucose level.
5
Chapter Two
Literature
Review
6
2. Literature Review
2.1 Classification of Diabetes Mellitus:
2.1.1 Type 1 diabetes
(β-cell destruction usually leading to absolute insulin deficiency) Immune-
mediated diabetes. This form of diabetes, which accounts for only 5-10% of those
with diabetes previously encompassed by the terms insulin dependent diabetes
(IDDM), type I diabetes or juvenile-onset diabetes results from a cellular-mediated
autoimmune destruction of the β-cells of the pancreas (ADA, 2008). In which
“insulin is required for survival” to prevent the development of ketoacidosis, coma
and death (WHO, 1999). Again (Willis et al., 1996) stated that individual with this
form of type I diabetes often become dependent on insulin for survival eventually
and are at risk for ketoacidosis.
2.1.2 Type 2 diabetes
(Ranging from predominantly insulin resistance with relative insulin
deficiency to predominantly an insulin secretory defect with insulin resistance).
This form of diabetes which accounts for 90-95% of those with diabetes (ADA,
2008). Previously encompassed by the terms non-insulin dependent diabetes
(NIDDM), type II diabetes or adult-onset diabetes referred to individuals who have
insulin resistance and usually have relative (rather than absolute) insulin
deficiency. At least initially and often throughout their lifetime, these individuals
require insulin for control, i.e. metabolic control rather than for survival (WHO,
1999).
7
2.1.3 Other specific types:
Other specific types are currently less common causes of diabetes mellitus,
but are those in which the underlying defect or disease process can be identified in
a relatively specific manner. They include for example, fibrocalculous
pancreatopathy a form of diabetes which was formerly classified as one type of
malnutrition–related diabetes mellitus (WHO, 1999).
2.2 Gestational hyperglycaemia and diabetes
Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia
of variable severity with onset or first recognition during pregnancy. It does not
exclude the possibility that the glucose intolerance may antedate pregnancy but has
been previously unrecognized. The definition applies irrespective of whether or not
insulin is used for treatment or the condition persists after pregnancy (WHO,
1999).
2.3 Management of type II
Dietary control of diabetes is fundamental to the management and treatment
of NIDDM. In the last few decades, a number of studies have indicated the value
of plant fibre or complex carbohydrates including highly viscous soluble fibre such
as guar gum and B-glucan, for control of blood glucose concentrations (Edwards et
al., 1988; Groop et al., 1993; Japan and Pitts, 1985 and Jenkins et al., 1978).
(Clark, 1998) stated that while external insulin is necessary for control of
type I diabetes mellitus, the use of drug therapy in type 2 diabetes is initiated only
after dietary and lifestyle modifications. Similarly, (Zhang and Moller, 2000)
reported that the available therapies for diabetes include insulin and oral
8
antidiabetic agents such as sulfonylureas, biguanides and α-glycosidase inhibitors.
Many of these oral antidiabetic agents have a number of serious adverse effects.
In addition (Cristina et al., 2012) stated that type II diabetes is the most
commonly encountered type of diabetes. Current antidiabetic therapy is based on
synthetic drugs that very often have side effects. For this reason there is a
continuous need to develop new and better pharmaceuticals as alternatives for the
management and treatment of the disease. Natural hypoglycaemic compounds may
be attractive alternatives to synthetic drugs or reinforcements to currently used
treatments. Their huge advantage is that they can be ingested in everyday diet.
Recently, more attention is being paid to the study of natural products as potential
antidiabetics. Also (Bnouham et al., 2006) stated that uncontrolled diabetes leads
to many chronic complications such as blindness, heart failure and renal failure. In
order to prevent this alarming health problem the development of research into
new hypoglycaemic and potentially antidiabetic agents is of great interest.
2.4 Anti-diabetic plants:
In the last years there has been an increasing demand for natural products
with antidiabetic activity mainly due to the side effects associated with the use of
insulin and oral hypoglycaemic agents (Cunha et al., 2008). Moreover bioactive
drugs isolated from plants having hypoglycaemic effects showed antidiabetic
activity equal and sometimes even more potent than known oral hypoglycaemic
agents used in clinical therapy. (Bnouham et al., 2006)
Gallegaofficinalis is now well established that its hypoglycaemic and
insulin-sensitizing potential is associated with its guanide compound, galegine.
This plant is still of great importance today despite the fact that the guanide
9
compounds were discovered to be toxic for the human body. Related compounds
such as the biguanide metformin molecule were later developed and are still
widely used in antidiabetic therapy (Goldstein and Wieland, 2008).
The mode of action of the extracts from these plants is uncertain however,
many antidiabetic plants act at least in part through their fibre, vitamin or mineral
contents and some secondary metabolites (Day, 1998).
A large number of hypoglycaemic compounds have antioxidant properties.
(Goldstein and Wieland, 2008). While polyphenolic compounds especially
flavonoids are among the classes of compounds that have received the most
attention (Soumyanath, 2006) with regard to their antidiabetic properties.
Flavonoids are natural polyphenolic molecules of plant origin known for their
antioxidant, anti-inflammatory and anti-carcinogenic properties and dietary intake
of flavonoids might prove to be important for alternative diabetes treatments or
reduction of the risk of the disease (Pinent et al., 2008). Unfortunately, many of
these compounds are alkaloids, flavonoids and glycosides which do not lend
themselves readily to pharmaceutical development (Day, 1995).
In addition (Edwards et al., 1988) claimed that inclusion of viscous
polysaccharides in the diet decreased postprandial blood glucose concentrations in
subjects with type II diabetes.
10
2.5 Solenostemma argel:
2.5.1 Active ingredients present in S.argel
Solenostemma argel, belongs to the Asclepiadaceae family. This family
includes many wild growing medicinal plants (e.g. Calotropisprocera, S.argel,
Leptadineaspp) (El Tigani and Ahmed, 2009) similarly, (Ahmed, 2003) claims
that S.argel is considered to be medicinally important in the Sudan, Libya and
Chad. Also, S.argel is a plant or plant part of valued for its medicinal, aromatic or
savory qualities. Herb plants produce and contain a variety of chemical substances
that act upon the body (Shayoub, 2003).
In addition, it was found that tissue cultures have produced compounds
previously undescribed and cultures of higher plant cells may provide an important
source of new economically important compounds (Butcher, 1977; Constabel and
Tyler, 1994). Moreover, chemical investigations, chromatographic screening and
phytochemical as well as tissue culture studies of S.argel leaves, stems and flowers
revealed the presence of numerous biochemical ingredients such as pyrgene
glycosides, flavonoids, kaempferol, quercetin, rutin, flavonols, flavanones,
chalcones and alkaloids. (Eltigani and Ahmed, 2009; Shafek and Michael, 2012
and Plaza A et al., 2005). In their report on S.argel, (Khalid et al., 1974) showed
the presence of kaempferol and steroidal glycosides in leaves of hargel also they
found that the flavanoids can be detected at (_290-368 nm).
Again (Mohamed et al., 2012) argued that the solenostemma argel contain
flavonoids, kaempferol, quercetin, rutin, flavonols, flavanones, chalcones and
alkaloids in S.argel. Also they contain pregnane ester glycosides in S.argel
extracts. S.argel was found to include some flavanoids saponins alkaloids (Khalid
et al., 1974). Moreover there are 2000 flavonoid found in S.argel found in as
11
methoxil or hydroxile group, further studies were needed to investigate this
flavonoid. S.argel can be used medically in kidney disease, liver, respiratory
system. Leaves of S.argel can be used an anti-inflammatory, antiseptic,
vasodilatory and hypotensive (Koca et al., 2011).
Phytochemical studies of the leaves, stems and flowers revealed the presence
of -amyrin and -sitosterol, 7-methoxy-3-22-dihydroxy-stigmastene, ethoxy
derivative of vangurolic acid, an unidentified sterol. Moreover, they detected the
presence of flavonoids and saponins in the different organs and alkaloids and/or
nitrogenous bases in the leaves, stems and flowers (Khalid et al., 1974). Kamel
(2003) proved that it contained acylated phenolic glycosides.
While (Mahran and Saber, 1964), (Mahran et al., 1976) isolated -amyrin, -
sitosterol-containing rutin and quercetin from S.argel. In addition, ElTohami, MS
(1996) claimed that S.argel. Solenostemma argel contains an acidic resin,
glycoside, choline, phytosterols and amyrins.
Many previous studies have reported the presence of monoterpenes,
pregnane glycosides and acylated phenolic glycosides in the leaves. In addition,
there is an occurrence of four new pregnane glycosides from the pericarps of
S.argel (Plaza et al., 2003). Also Kamel (2003) proved that it contained acylated
phenolic glycosides. Another study in its chloroform extract showed that it had an
anti-inflammatory activity and it contained a new pregnene glycoside (solenoside
A) and a known one besides kaempferol 3-O-glucoside and 3-O-rutinoside
(Innocenti et al., 2005).
12
From the previous phytochemical studies, it was found that its leaves
characterized by high carbohydrates (64.8%) and low crude fiber (6.5%), 15 %
protein, 1.6% crude oil, 7.7% ash, and 4.4% moisture content. It contained high
potassium (0.54%), calcium (0.06%), magnesium (0.03%) and sodium (0.01%),
but it characterized by low cupper (0.0001%), ferrous (0.002%), manganese
(0.002%) and lead (0.001%). The protein fractionation of leaf characterized by
high Albumins (16.7%), Non-Nitrogenous Protein (15.3%), Prolamine (11.7) and
low Globulins (8.7 %) and Glutulin (6.2%). Leaf contained phytic acid (3.2 g/100g
and tannin content (0.4%) (Murwan et al., 2010).
While (Plaza, et al., 2003) reported that the protein, sugar, fiber and vitamins
are present with minerals Na+, K+, Ca+2, Mg+2, Ni+3, P+3.
On the other hand, the presence of biologically active components such as
phytates and phenolic compounds are found to have adverse effects on intrinsic
properties of protein (Khalid et al., 1974 and Yagoub, 2003). Similarly, Phytic acid
represents a complex class of naturally occurring organic form of phosphorus
compounds that can significantly influence the functional and nutritional properties
of foods (Goldstein and Swain 1963).
2.5.2 Effects of water extract of S.argel on the induced-diabetic rats
Albino rats were fasted for 12 hours, then they were given water extract
225mg/kg the reduced glucose was measured at initial time 0hr. then after 2hrs.
and then after 4hrs., the best results were obtained after 4hrs where the reduce
glucose was 82.40mg/dl while, the standard Dawnil was 83.28mg/dl the control
was 93.40 (Izzeldin et al.,2012).
13
2.5.3 Traditional medicinal uses of S.argel
Some uses Solenostemma argel in folkloric medicine as treatment of GIT
(Gastro Intestinal Tract) disturbances, hypercholesterolemia and diabetes mellitus;
and externally in poultice form as anti-inflammatory and anti-rheumatic and
inhalation of its smoke for the treatment of measles and cold. The stem is generally
used as antispasmodic and to treat cough. Moreover, „Hargal‟ infusion is used to
treat jaundice, urinary tract infection and the disturbance of the menstrual cycle
(ElKamali and Khalid, 1996).
It is also used to cure stomach ache, anti-colic, remedy for suppurating
wounds and anti-syphilitic when used for prolonged period of 40 to 80 days
(Boulos, 1983; Hammiche and Maiza, 2006). Also anti-inflammatory and anti-
rheumatic agent (Shayoub et al., 2013). Again leaves are used as an antispasmodic,
carminative and as an anti-diabetic (Kamel et al., 2000 and Hassan et al., 2001).
In addition, it is used in indigenous medicine as an effective remedy for
cough. The infusion of its leaves is used for gastro-intestinal cramps and infections
of the urinary tract (ElTohami, 1996). It is an effective remedy for bronchitis and
is used to treat neuralgia and sciatica (Tharib et al., 1986).
While (Mudawi, 2003) reported that the chloroform extract (600 – 800)
mg/kg induced a delayed and gradual decrease in amplitude of the spontaneous
contractions of pregnant or non-pregnant uterus. In a similar (ElTahir et al., 1987)
studied the pharmacological activities of S.argel, including spasmolytic and uterine
relaxant activities.
14
(Plaza et al., 2005) found that pregnane glycosides isolated from this plant
were reported to reduce cell proliferation. Also the plant has antimicrobial activity
(Mohamed et al., 2012). Again Ross and their co-workers (1980) illustrated the
presence of antibiotic substances in the ethanol extracts of Hargel plant. Similarly
it was reported to have antimicrobial properties as well as antibacterial and
antioxidant activity (Shafek and Michael, 2012; Mahalel, 2012).
Moreover many studies confirmed that the S.argel had remedial effect
against numerous diseases and health problems such as diabetes mellitus (Trojan,
et al., 2012) and cancer (Amr, et al., 2009; Hanafi and Mansour, 2010).
2.5.4 Toxicity
From (Osman et al., 2014) argued that S.argel had incurred hepatorenal
toxicity in the experimental animals. Also in a feeding test with chicken a diet
containing 10 leaves of solemenstomma argel caused a depression in growth and
hepatotoxicity (EL-sanusi and Adam, 2007).
In addition (Osman et al., 2014) finding that human use of S.argel, it could
be of significance to propose for those seeking S.argel for treatment, to use the
plant with the dose far below 600 mg/kg and to monitor closely the levels of
creatinine, urea, alkaline phosphatase (ALP) and aspartate aminotransferase (AST)
during the course of treatment.
On the other hand, (Shayoub et al., 2013) finding that the different types
(leaves, extracts or alkaloids) of Solenostemma argel tablets showed a very good
therapeutic effectiveness (71%-100%) and a great margin of safety (98%-100%).
No side effects or adverse reactions were recorded and the patients did not
15
complain of any undesirable or intolerable toxic or adverse effects of these
preparations of Solenostemma argel.
16
Chapter Three
Subjects and
Methods
17
3. Subjects and Methods
The methodology of this study is a modification of two studies that had used
of antidiabetic plants on human (Huseini et al., 2006; Bunyapraphatsara et
al.,1996).
3.1 Study design:
Before - after case study.
3.2 Study area:
Jabir Abo Aleiz Specialized Center for Diabetes Mellitus in Khartoum,
Sudan
3.3 Study duration:
From April to August, 2014
3.4 Subjects:
3.4.1. Sample size
Prevalence of antidiabetic plants is 50%.
n = z 2. p q / d
2
n = Sample size
z = Standard normal deviate = 1.96
p = Proportion of the characteristic under study estimated in the target
population
q = 1- p
d = Error allowed = 0.05
18
= = = 384
Due to limited time and budget a total of 46 patients with type 2 diabetes
enrolled in this study.
The patients had been selected from cases of type II diabetes mellitus at the
Jabir Abo Aleiz Centre, who are treated with oral hypoglycaemic agent using
the following inclusion and exclusion criteria.
3.4.2 Criteria
3.4.2.1 Inclusion criteria
Uncontrolled type-II diabetic patients.
HbA1c above 6.5.
Aged 40-70 years.
Freely consented to participate in the study.
3.4.2.2 Exclusion criteria
Liver disease patients.
One of the functions of liver is alkaline phosphates enzyme which
affect carbohydrate metabolism, therefore all liver disease patients
were not included.
Kidney disease.
Disfunctioning of kidney affected cholesterol level which reflected on
blood glucose level.
19
3.5 Plant Sample:
S. argel powdered leaves packed in tea bags (1g each) were obtained from
the local market. The dose calculation based on dose translation from animal
to human (Reagan-Shaw et al., 2007).
3.6 Procedures:
The study group received 2g of S.argel once/day in the form of water
extract (pour 100ml of boiling water over two bags) in the morning in
combination with oral hypoglycaemic agent for three months.
Blood samples withdrawn monthly for measurement of fasting blood
glucose levels.
HbA1c was measured two times, the first one at the beginning of the
study and the second one by the end of three months.
Every patient was well educated about how to use the S.argel tea
bags, besides receiving an advice about importance of using S.argel.
The patients follow ups was done in two ways:
Telephone call weekly.
Each patient was given a form to tick on the days which he/she use
the tea bags. This will confirm the follow up procedures.
3.7 Statistical analysis:
Data was recorded and analyzed using SPSS computer program.
Appropriate statistical methods were employed.
20
3.8 Ethical Clearance for Research:
Ethic Committee of Scientific Research of Ribat University gave the
permission and had been accepted by the administration of Jabir Abo Aleiz
Specialized Center for Diabetes Mellitus.
The researcher considers ethical clearance at both the application and
implementation stages.
21
Chapter Four
Results
22
4. Results
A total of 46 patients had been enrolled in this study. Table 1 shows the
main characteristics of the study population. Females were more than males, 31
compared to 15, a percentage of 67.4% and 32.6% respectively. The age group of
40-50 years old represents 43.5% (20 patients), which is the highest values;
followed by 51-60 years 41.3% (19 patients). The group of 61-70 years old
represents the lowest value 15.25% (7 patients). In case of education levels
secondary group was 30.4% (14 patients), followed by primary and high secondary
23.9% (11 patients). The illiterate group ranked last 21.70% (10 patients).
Unemployed represents 54.3% (25 patients) while the employed was 45.7% (21
patients).
The patients who have <10 years duration of disease correspond to 71.1%
(33 patients) the highest value, followed by 23.9% (11 patients) for 10-20 years
duration of disease and 4.3% (2 patients) for >20 years duration of disease (the
lowest percent). Monotherapy (received one hypoglycaemic agent) represents
lower than multiple therapy (received more than hypoglycaemic agent) 26.1% (12
patients) compared to 73.9% (34 patients).
Patients with diabetes only represents 58.7% (27 patients) compared to
41.3% (19 patients) for comorbid conditions.
For BMI cut off points, the overweight patients has the highest value of
43.5% (20 patients) followed by Normal BMI of 23.9% (11 patients). Obesity
grade 1 was 21.7% (10 patients), followed by obesity grade II 6.5% (3 patients)
23
and 2.2% (1 patient) for both underweight & morbid obesity.
Table 1 - The Main Characteristic of Study Population.
Patients No.(s) %
Gender:
Male
Female
15
31
32.6
67.4
Age/years:
40-50
51-60
61-70
20
19
7
43.5
41.3
15.2
Education Level
Illiterate
Primary
Secondary
High Secondary
10
11
14
11
21.7
23.9
30.4
23.9
Occupation
Employed
Unemployed
21
25
45.7
54.3
Duration of Disease:
<10
10-20
>20
33
11
2
71.7
23.9
4.3
Number of Drugs
*Mono Therapy
** Multiple Therapy
12
34
26.1
73.9
24
„cont.
***Other Diseases
Yes
No
19
27
41.3
58.7
****BMI cut off points:
Underweight (<18.5)
Normal (18.5-24.9)
Overweight (25-29.9)
Obesity grade I (30-34.5)
Obesity grade II (35-39.9)
Morbid Obesity >40
1
11
20
10
3
1
2.2
23.9
43.5
21.7
6.5
2.2
*Hypoglycaemic Agent one drug.
**Multiple drug hypoglycaemic agent
***Hypertension, Asthma, Hyper cholestramia, Others
****Cut off points of the BMI (Mahan and Escott-Stump, 2008)
25
After treatment of S.argel for three months there is statistically significant
difference in the main parameters, the mean level of HbA1c = 8.602± 1.52 and
after the treatment it was reduced to 7.45±1.62; the P value was (.000) Figure 1.
Figure 1 – Effect of 3 months treatment with S.argel on HbA1c levels of study
group.
26
Observed FBS (Figure 2) after one and three months (FBS2 & FBS4) from
the beginning of treatment: there is statistically significant difference (P value
<0.05) which is positive correlation to the HbA1c.
Before treatment the mean level of FBS was 188.13mg/dl and after three
months it was reduced to 157.67 mg/dl. After one month it was reduced to 163.48
mg/dl, after two months it was reduced to 165.89mg/dl but statistically
insignificant result was obtained (P value>0.05).
Figure 2 - Effect of 3 months treatment with S.argel on FBS levels of study
group.
27
28
Figure (3) shows that after treatment of S.argel for three months there is a
significant difference within the BMI cut off points, (P value < .05) the P value =
.008. The more response happened in obesity grade II they reduced HbA1c from
8.1 to 5.96, followed by overweight from 8.52 to 7.07, next obesity grade I from
8.64 to 7.67, lastly normal BMI group from 8.93 to 8.54. (The normal BMI
decrease of HbA1c was .39, the overweight 1.45, obesity grade I .97 and obesity
grade II 2.14). In FBS no significant difference within BMI cut off points.
Figure 3 - Effect of BMI points on HbA1c levels before and after treatment of
S.argel.
29
No significant difference within the duration of disease group concerning HbA1c before and after treatment
of S.argel (table 2). The same result regarding FBS excluding before treatment there was significant difference (P
value .004).
Table 2 - Effect of the duration of disease on HbA1c and FBS levels before and after treatment of S.argel.
Duration of the
Disease
Patients No.(s)
HbA1c 1st
HbA1c 2nd
FBS 1 FBS2 FBS3 FBS4
<10 33 8.49±1.16 7.33±1.63 189.64±55.28 156.88±33.65 157.97±65.38
151.21±46.51
10-20 11 8.77±2.28 7.51±1.47 162.18±46.34 176.9±49.85 186.18±53.18
172.36±90.59
>20 2 9.4±2.55 9.15 ±2.19 306±28.28 198.5±30.41 185.±41.01
183±79.09
Over All 46 8.6 7.45 188.13 163.48 165.89 157.67
P Value .664 .307 .004 .143 .397 .505
Values are given as mean ±SD from the number of patients in each group.
30
Table (3) shows no significance difference between monotherapy and multiple therapy regarding HbA1c
before and after treatment of S.argel. Looking into the first two months (FBS1 & FBS2) after treatment of
S.argel, there was significant difference (P value .015, .014) respectively. The highest response was in patients who
received only one hypo glycaemic agent (mono therapy), the FBS2 & FBS3 were decreased by (35.7, 48.3). While
the multiple therapy FBS2 & FBS3 decreased by (20.8 and 13.4). In the last month (FBS3) there was no
significant difference (P value =.721).
Table 3 - Effect of the number of drugs on HbA1c and FBS levels before and after treatment of S.argel.
Type of
Medication
Patients
No.(s)
HbA1c
1st
HbA1c
2nd FBS 1 FBS2 FBS3 FBS4
Mono Therapy
12 7.89±1.07 6.91±1.13 176±55.93 140.33±21.01 128.7±31.43 152.25±34.198
Multiple Therapy
34 8.85±1.59 7.64±1.73 192.41±60.15 171.65±40.57 179±65.32 159.59±67.29
Over All 46
P Value .059 .181 .412 .015 .014 .721
Values are given as mean ±SD from the number of patients in each group.
31
In case of patients with diabetes only and comorbid conditions figure (4),
regard with HbA1c there was a significance difference before and after treatment
of S.argel (p value < .05). The patients with diabetes only, were more controlled
than comorbid conditions before and after treatment. The decrease of HbA1c (by
1.15) was equal in patients with diabetes only compare to patients with comorbid
conditions. View the FSB there was no significance difference after three month
duration of treatment of S.argel.
Figure 4 - Effect of comorbid conditions on HbA1c levels before and after
treatment of S.argel.
32
Table (4) shows FBS. For HbA1c no significant difference after treatment only before there was significance
difference (P value <.05), males were more controlled than females (7.95 for males before and after treatment no
significant difference between males and females regarding compare to 8.92 for females).
Table 4 - Effect of the Gender on HbA1c and FBS levels before and after treatment of S.argel.
Gender Patients
No.(s)
HbA1c 1st
HbA1c 2nd
FBS 1 FBS2 FBS3 FBS4
Male 15 7.95±1.00 6.83±1.14 182.33±53.15 152.07±46.18 155.13±55.93 137.07±40.10
Female 31 8.92±1.64 7.75±1.74 190.94±61.92 169.0±34.21 171.10±65.24 167.65±66.02
Over All
46
P Value .043 .069 .647 .168 .421 .107
Values are given as mean ±SD from the number of patients in each group.
33
Table 5, 6 and 7 tells us that there was no significance difference (P value >.05) within the group of ages,
occupation and education levels consider HbA1c and FBS.
Table 5 - Effect of age group on HbA1c and FSB levels before and after treatment of S.argel.
Age/
Years
Patients
No.(s)
HbA1c
1st
HbA1c
2nd FBS 1 FBS2 FBS3 FBS4
40-50 20 8.54 ±1.23 7.45 ±1.92 187 ±50.05 173.65±32.57 172.15±71.461 180.55±60.18
51-60 19 8.97 ±1.86 7.52 ±1.48 195.95±67.65 154.42±38.57 163.47±62.55 147.42 ±58.89
61-70 7 7.77 ±1.01 7.13 ±1.16 170.14±60.41 159±53.12 154.57±28.39 120.14 ±39.12
Over
All 46 8.6 7.5 188.13 163.48 165.89 157.67
P Value .199 .855 .617 .293 .801 .042
Values are given as mean ±SD from the number of patients in each group.
34
Table 6 - Effect of the Occupation on HbA1c and FBS Levels before and after treatment of S.argel.
Occupation Patients
No.(s)
HbA1c
1st
HbA1c
2nd FBS 1 FBS2 FBS3 FBS4
Employed 21 8.69
±1.77
7.46
±1.73 191.14 ±59.37 157.81±38.46 168.33±63.17 151.86±60.11
Unemployed 25 8.52
±1.31 7.44 ±156 185.60±59.32 168.24±39.29 163.84±62 60 162.56±60.95
Over All 46
P Value .708 .979 .754 .370 .810 .554
Values are given as mean ±SD from the number of patients in each group.
35
Table 7 - Effect of Education level on HbA1c and FBS levels before and after treatment of S.argel.
Education
Level
Patients
No.(s) HbA1c
1st
HbA1c
2nd FBS 1 FBS2 FBS3 FBS4
Illiterate 10 8.13 ±8.7 7.17±1.64 170.8 ±64.44 161.2 ±46.63 173.7 ±76.26 149.40±78.30
Primary 11 9.3 ±2.25 7.37±1.80 175.27±71.55 156 ±42.74 168.09±60.19 145.55±64.12
Secondary 14 8.59 ±1.26 7.52 ±1.87 208.5 ±53.80 170.07±38.86 174.50±66.49 166.93±52.35
High Level 11 8.35 ±1.33 7.69 ±1.21 190.82±42.9 164.64±30.20 145.64±46.69 165.55±51.61
Over All 46 8.6 7.45 188.13 163.48 165.89 157.67
P Value .315 .905 .386 .846 .672 .775
Values are given as mean ±SD from the number of patients in each group.
36
Chapter Five
Discussion
37
5. Discussion
The present study investigated the effect of S.argel on the glucose profile in
patients with type II diabetes. The results show that statistically significant
differences in the main parameters between before treatment of S.argel the HbA1c
= 8.602± 1.52 and after the treatment of S.argel (duration of three months) the
HbA1c was reduced to 7.45±1.62; the P value was (.000).
There are not too many studies that have investigated the anti-diabetic
activity of S.argel, except for one study: Effects of water extract of S. argel. on
the induced-diabetic rats (Izzeldin et al., 2012). The result found in the present
study is in agreement with the finding from this study.
The mechanism underlying the glucose lowering effect of S.argel is not
clear. S.argel contains a wide number of active constituents including flavonoids
(Eltigani and Ahmed, 2009; Shafek and Michael, 2012; Plaza A et al., 2005;
Khalid et al. 1974; Mohamed et al., 2012 and Koca et al., 2011). Flavonoids are
natural polyphenolic molecules of plant origin known for their antioxidant, anti-
inflammatory and anti-carcinogenic properties and dietary intake of flavonoids
might prove to be important for alternative diabetes treatments or reduction of the
risk of the disease (Soumyanath, 2006; Pinent et al., 2008; Day, 1995). S.argel has
antioxidant properties (Shafek and Michael, 2012; Mahalel, 2012) and a large
number of hypoglycaemic compounds have antioxidant properties (Goldstein and
Wieland, 2008). Many antidiabetic plants act at least in part through their fiber,
vitamin or mineral contents (Day, 1998) and S.argel contain protein, sugar, fiber
and vitamins with minerals Na+, K+, Ca+2, Mg+2, Ni+3, P+3 (Plaza, et al. 2003
and Murwan et al., 2010) .
38
After treatment of S.argel for three months there is significant difference
within the BMI cut off points. The normal BMI decrease of HbA1c was .39, the
overweight 1.45, obesity grade I .97, obesity grade II 2.14, that means with
exceptional of obesity grade I, we found that the more response associated with
increasing of obesity. This mean there are good effect in this group may be due to
decrease weight; so the good response to their treatment plus the effect of S.argel.
Regarding the effect of number of medications we found that before and
after treatment of S.argel no significant difference in HbA1c and FBS4 between
mono therapy and multiple therapy, but on other hand there was significant
difference after treatment of S.argel in FBS2 and FBS3. The highest response was
in patients who received only one hypoglycaemic agent (mono therapy) because
their diabetes is not so bad from the beginning.
Duration of disease (>10, 10-20, <20) years there were no significant
difference before and after treatment of S.argel. We expect that group III (<20
years) has less response. This group must be more resistant to the plants extract
because diabetic patients must have had more complication in the long duration
of disease.
The age, educational level, occupation and gender table show no significant
differences regarding HbA1c and fasting blood glucose level before and after
treatment of S.argel with exception of gender in which there was significant
difference before treatment. We expect this result.
Usually hypertension and cardiovascular are the most common diseases
associated with diabetes in addition to others like asthma, intestinal diseases and
39
stomach diseases. Significant difference occurred in HbA1c before and after
treatment of S.argel. In comorbid conditions the decrease of HbA1c was equal to
patients with diabetes only. This contradicts our exception that more response will
occur in patients with diabetes only because the comorbid conditions have more
complications hence, the response to treatment of plant extract might not give good
result. This result is a good support to the claim that S.argel can remedy widely
diseases (ElKamali and Khalid, 1996; Boulos, 1983; he and Hammic Maiza, 2006;
Hassan et al., 2001; ElTohami, 1996 and Tharib et al., 1986).
40
Chapter 6
Conclusion
and
Recommendation
41
6.1 Conclusion
In this study, evidence is presented that the Solenostemma argel, a
traditional medicinal plant, can reduce blood glucose level in type II diabetic
patients. This significant positive result is due to active ingredient components
present in S.argel.Thus, the traditional medicine use of S.argel for the control of
diabetes may be supported by this study, which is the same result approved on
induced-diabetic rats.
Currently, there is a dramatically worldwide increase in the number of
people suffering from diabetes, particularly in developing countries. Beside high
prices and occasional side-effects of hypoglycaemic agents are causing many
people to return to herbal medicines.
6.2 Recommendation
More research must be carried on S.argel to find the active ingredients
which reduce blood glucose in diabetes type II.
Liver functions like (ALP) alkaline phosphate enzyme, (GPT)
glutamic pyruvate transaminase, (GOT) glutamic-oxalacetic
transaminase, Billirubin and kidney functions like (ammonia, urea,
creatinine, total protein), these tests must carried out to show there is
no any toxic effect for human body in case of treatment of diabetes
patient with active ingredient of S.argel.
Pharmaceutical and chemical formulation of the accurate doze of
S.argel active ingredient must be formulated and manufactured to give
it as prescription for these patients.
42
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Appendices
54
Appendix (A)
Questionnaire
Hypoglycaemic effect of Solenostemma argel in Type II diabetic patients in
Jaber Abo Aleiz Specialized Center for Diabetes Mellitus
Serial No:……………………………………………………
Name: ………………………………………………………
Address of use: ……………………………………………..
File No: ……………………………………………………..
1\General Information:-
1. Gender : male female
2. Age: 40-50 51-60 61-70
3. Education level:
Illiterate Primary Secondary
High level
4.Occupation:
Employee Unemployed
2\Medical History:
1. Duration of Disease: <10 10-20 >20
55
2. Number of Drugs: Mono Therapy
Multiple Therapy
1. Comorbid Conditions: Yes No
3\Nutrition Assessment:
1. Weight: …………………..
2. Height: ……………………
3. BMI: ………………………
4\ Investigation:
1. HbA1c 1st
2nd
2. F.B.S: 1st
2nd
3rd
4th
56
Appendix (B)
57
58
59
60
Appendix (C)
Table 8 – Effect of 3 months treatment with S.argel on the HbA1c levels of the
study group.
Beginning After 3 months P Value
HbA1c 8.602± 1.52 7.450 ±1.620 .000
Values are given as mean ±SD from the number of patients in the study group.
Table 9 - Effect of 3 months treatment with S.argel on the FBS levels of the
study group.
Beginning After 1 month After 2 months
After 3
months
FBS 188.13± 58.75 163.48±38.838 165.89 ±62.197 157.67± 60.139
P Value .009 .061 .009
Values are given as mean ±SD from the number of patients in the study group.
61
Table 10 - Effect of BMI cut off points on HbA1c and FBS levels before and after treatment of S.argel.
BMI cut off
points
Patients
No.(s)
HbA1c
1st
HbA1c
2nd FBS 1 FBS2 FBS3 FBS4
Normal
(18.5-24.9) 12 8.93 ±1.97 8.54 ±1.19 211.92 ±61.57 180.42±49.43 185.58 ±65.06 171.58 ±52.92
Overweight
(25-29.9) 20 8.52 ±1.33 7.07 ±1.14 186.55 ±52.82 158.4±30.46 156.75±56.27 155.8 ±63.73
Obesity
Grade I
(30-34.5)
9 8.64±1.47 7.67±2.39 179.33±75.15 154.44±36.93 167.9±81.99 154.22±78.45
Obesity
Grade II
(35-39.5)
5 8.1 ±1.34 5.96 ±0.93 153.2 ±21.16 159.4±43.85 151.6±39.36 138 ±16.98
Over all 46 8.6 7.49 188.13 163.48 165.89 157.67
P Value .775 .008 .272 .376 .606 .759
Values are given as mean ±SD from the number of patients in each group.
62
Table 11 - Effect of comorbid conditions on HbA1c and FBS levels before and after treatment of S.argel.
Other Diseases
Patients No.(s)
HbA1c 1st
Hb1c 2nd
FBS 1 FBS2 FBS3 FBS4
Yes 19 8.03±1.12 6.88±1.33 156.95±45.35 164.89±43.24 152.84±51.19 158.63±69.89
No 27 9.00±1.65 7.85±1.71 210.07±57.79 162.48±36.24 175.07±68.33 157±53.63
Over All 46
P Value .031 .046 .002 .838 .237 .929
Values are given as mean ±SD from the number of patients in each group.
63
Figure 5 - The main characters of study population
5-1 Gender:
5-2 Age/Years:
64
5-3 Education Level:
5-4 Occupation:
65
5-5 Duration of Disease:
5-6 Number of Drugs:
66
5-7 Comorbid Conditions:
5-8 BMI Cut Off Points:
67
Appendix (D)
Images of Solenostemma argel