thesis

1. Diabetes mellitus Diabetes mellitus is a metabolic disorder characterised by
hyperglycaemia arising as a consequence of a relative or absolute deficiency
of insulin secretion, resistance to insulin action or both. This is a major and
growing public health problem throughout the world, with an estimated
worldwide prevalence of 171 million in 2000, expected to increase to 380
million people by 2035. In particular, the number of people with diabetes in
India, currently around 40.9 million, is expected to rise to 69.9 million by
2030. India leads the world with largest number of diabetic subjects thus
earning the dubious distinction of being termed as “Diabetes capital of the
world”. Although the prevalence of diabetes is consistently increasing, an
effective treatment is still Chapter 1 Introduction 4 lacking. Current
pharmacotherapeutics insufficiently reverse hyperglycaemia, having limited
tolerability and induce side effects. Hence the identification of new
pharmacological approaches to effectively prevent, treat and cure this
metabolic disorder is of crucial importance. In recent times, many
traditionally used medicinally important plants have been tested for their
antidiabetic potential by various investigations in experimental animals
(Ramkumar et al. 2011) (Graham and Schuurman 2015). The pathogenic
mechanism of Diabetes mellitus is complex and the complicated networks
related to this disease involve distinct signalling pathways. Currently,
discovery of potential modulators targeting these pathway has become a
potent approach for antidiabetic drug lead compound development.
Compared with synthetic compounds, natural compounds provide inherent
larger-scale structural diversity and have been the major resource of bioactive
agents for new drug discovery. To date, more and more active components

2. from plants or marine organisms have been reported to regulate diabetic
pathophysiological signalling pathways and exhibit antidiabetic activity.
These pathways include insulin signalling pathway, carbohydrate metabolism
pathway, the pathways involving insulin secretion and PPAR regulation,
endoplasmic reticulum stress and inflammation related pathways and
chromatin modification pathways (Liu et al. 2010) Currently insulin and oral
hypoglycemic agents are used in the treatment of Diabetes mellitus. Many
undesirable side effects are associated with these therapies. In order to
overcome these problems it is essential to search new class of compounds
(Patil et al. 2011) 1.3. Plants as antidiabetic agent There is a growing trend
towards the use of herbal preparations in the treatment of D.mellitus. This
resulted in an interest to investigate the plant species with antihyperglycemic
effect, to isolate the active ingredients responsible and also to understand the
molecular mechanism that explains the antidiabetic activity (Roberto et al.
2011). Chapter 1 Introduction 5 In vitro experiments are often designed to
reflect the mechanisms of the existing drugs used in diabetic management.
Plants that possess alpha amylase or alpha glucosidase inhibitory effects
reflects the action of acarbose, PPARγ agonist activity reflect the
thiazolidinediones, while aldose reductase inhibitors are potential agents for
preventing diabetic complications, like the drug epalrestat (Liu et al. 2010).
Following figure describes the molecular mechanisms of some of the
antidiabetic plants whose mode of action have already been reported. Figure
1.1 Molecular mechanisms of hypoglycemic effects of selected plant species
(Ezuruike and Prieto 2014) Thus with this identified mechanisms, researchers
and healthcare professionals can immediately identify the potential

3. therapeutic benefit of the plant. This information could contribute to a more
rational therapeutic regimen for diabetes patients, possibly benefitting from a
synergistic effect with herbal remedies. Chapter 1 Introduction 6 Drugs of
plant origin contain many phytoconstituents and commercially available
preparation contain a combination of extracts of different plants and these
will act on different targets which could provide additive or synergistic effect.
One such formulation was ‘BGR 34’ tablets introduced by CSIR after an
extensive research in collaboration with National Botanical Research Institute
(NBRI) and Central Institute of Medicinal and Aromatic Plants (CIMAP). This
formulation was reported to contain extracts of six different plants. These
plants were found to contain 34 different phytoconstituents which exhibits
antidiabetic activity. The molecular mechanisms reported, demonstrates the
synergistic effect of these plant extracts. Table 1.3 BGR 34 constituents Sl No
Name of the plant Active phytoconstituent having antidiabetic activity 1
Berberis aristata Berberin, Berbamine, Palmatine, Dehydrocheilanthifoline,
6-Oxoberberine, Columbamine, Jatrorrhizine 2 Rubia cordifolia Rubiadin,
Purpurin, Xanthopurin, Manjistin, Pseudopurin 3 Trigonella foenum graecum
4-Hydroxy isoleucine, Galactomannan, Alphatocoferol, Fenugreekine,
Scopoletin, Trigonelline 4 Pterocarpus marsupium Pterostillbene, Marsupin,
Pterosupin, Liquirtigenin, Epicatechin, Quercetin, Myrcetin, Isoliquirtigenin 5
Tinospora cordifolia Palmatine, Jatrorrhizine, Magnoflorine 6 Gymnema
sylvestre Gymnemic acid, Gurmarin, Gymnemagenin, Dihydroxy gymnemic
triacetate, Isoquinoline 1.4. Plants as a source of antidiabetic leads There are
about 800 plants that may possess potential antidiabetic ingredients (Perla
and Jayanty 2013). So it is invaluable to utilize the generations of

4. accumulated traditional knowledge about medicinal plants as a basis for
discovering new antidiabetic lead compounds (Govil, Singh, and Arunachalam
2006). Plant derived Chapter 1 Introduction 7 natural products hold great
promise for discovery and development of new pharmaceuticals. Careful
consideration of the entire process of discovery and development will be
required to realise this great promise effectively. (McChesney, Venkataraman,
and Henri 2007) A number of alkaloidal and non-alkaloidal active principles
from plants used in diabetes management have been reported. Figure 1.2.
Nitrogen containing compounds with antidiabetic activity(Ezuruike and Prieto
2014) Similarly a wide range of terpenes and phenolic compounds have been
identified as active principles of many antidiabetic plants. Chapter 1
Introduction 8 Figure 1.3. Terpenoidal compounds showing antidiabetic
activity(Ezuruike and Prieto 2014) Several isolated flavonoids and
hydroxylated compounds have been identified as bioactive constituents in
traditionally used antidiabetic plants. Figure 1.4. Phenolic compounds with
beneficial effects in diabetes(Ezuruike and Prieto 2014) Chapter 1
Introduction 9 Figure 1.5. Other hydroxylated compounds with beneficial
effects in diabetes (Ezuruike and Prieto 2014). Isolation of pure active
ingredients always provides great zeal and enthusiasm among researchers to
continue such investigations. Exploration of the bioactivity of natural
products continues to provide novel chemical scaffolds for further drug
inventions (Harvey 2007). We believe that a very significant portion of these
leads will continue to be natural product derived. “It should be remembered
that Mother Nature had three billion years to refine her chemistry and we are
only now scratching the surface in exploring nature’s molecular diversity”

5. (Cragg and Newman 2013). 1.5. Modern strategies in natural product
research With the outstanding developments in the areas of separation
science, spectroscopic techniques and microplate-based ultrasensitive in vitro
assays, natural product research is enjoying renewed attention for providing
novel and interesting chemical scaffolds. The various available hyphenated
techniques, e.g., GC-MS, LCMS, LC-FTIR, LC-NMR, LC-NMR-MS, LC-MS-MS,
have made possible the pre isolation analyses of crude extracts or fractions
from different natural sources, isolation and on-line detection of natural
products, chemotaxonomic studies, chemical finger printing, quality control
of herbal products, dereplication of natural products, and metabolomic
studies. (Sarker, Latif, and Gray 1998) Chapter 1 Introduction 10 As natural
products continue to produce structurally diverse molecules with unique
biological functions, we decided to investigate the antidiabetic potentials of
Tinospora sinensis and Chonemorpha fragrans which are used traditionally
for antidiabetic activity and also to isolate the active constituents responsible
for the activity.