**3. Global impact of diabetic mellitus**

Diabetes mellitus is a disease common to all parts of the world [26]. It is a common and very prevalent disease affecting the citizens of both developed and developing countries. It has been estimated that 25% of the world population is affected by this disease [27]. Currently, India has got the largest number of diabetics and is being called as diabetic capital of the world. Diabetes has significant health consequences for individuals and communities. In fact, many countries face large increases in the number of people suffer‐ ing from diabetes. The World Health Organization estimated that about 30 million people suffered from diabetes in 1985 and the number increased to more than 171 million in 2000. Additionally, it has been estimated that the number will increase to over 366 million by 2030 and that large increases will occur in developing countries, especially in people aged between 45 and 64 years [28].

A large disparity in total health spending for diabetes among the top 80 most populous countries exists, varying from USD 1.3 million to USD 198.0 billion. The country with the highest total expenditure, the United States of America, will spend 52.7% of the global expenditure. India, the country with the largest population of people living with diabe‐ tes, will spend an estimated USD 2.8 billion or less than 1% of the world total. The total diabetes spending in the 18 countries in IDF's African Region will be only USD 1.2 billion, 0.3% of the global total [29]. The absolute level of health expenditure in developing countries appears to be quite low. The lowest 20 spending countries in the top 80 most populated countries will spend less than USD 50 per person per year for managing diabetes and diabetes-related complications. Expenditure at this level cannot even cover the annual wholesale cost of a generic oral agent capable of preventing acute, life-threatening hypergly‐ caemia [29]. Considering the health services and therapeutic treatments needed to man‐ age diabetes and diabetes-related complications, more health care resources are required to provide adequate diabetes care in the poor countries.

**Figure 2.** Mechanisms of cardiovascular dysfunction in diabetes: role of superoxide and peroxynitrite. Hyperglycaemia induces increased superoxide anion (O2•−) production via activation of multiple pathways including xanthine and NAD(P)H oxidases, cyclooxygenase, uncoupled nitric oxide synthase (NOS), glucose autoxidation, mitochondrial respi‐ ratory chain, polyol pathway, and formation of advanced glycation end products (AGE). Hyperglycaemia-induced in‐ creased superoxide generation may also favour an increased expression of nitric oxide synthases (NOS) through the activation of NFκB, which may increase the generation of nitric oxide (NO). Superoxide anion may quench NO, thereby reducing the efficacy of a potent endothelium-derived vasodilator system. Superoxide can also be converted to hydro‐ gen peroxide (H2O2) by superoxide dismutase (SOD) and interact with NO to form a reactive oxidant peroxynitrite (ONOO−), which induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and activation of matrix metalloproteinases (MMPs) among others. This figure was adapted from [34].

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Hyperglycaemia-induced oxidative stress also mediates endothelial dysfunction which plays a central role in the pathogenesis of micro- and macro-vascular diseases with resultant increase in pro-inflammatory cytokines and induction of apoptosis and impairment of nitric oxide release. Hyperglycaemia induces vascular damage probably through a single common pathway - increased intracellular oxidative stress- linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways [35]. However, synthetic drugs against diabetes mellitus have been reported with avalanche of side effects (Table 1) as reported

by Kavishankar *et al*. [36].

#### **4. Diabetic mellitus and oxidative stress**

Diabetes mellitus is associated with an increased risk of cardiovascular diseases mediated via oxidative stress. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression with irreversible oxidative modifications [30-31]. Hyperglycaemia-induced mitochondrial dysfunction and endoplasmic reticulum stress has been shown to promote reactive oxygen species (ROS) accumulation, accelerates cellular damage and significantly contributes to the diabetic complications development and progression [30, 32-33]. PA *et al*. [34] described the mechanism of cardiovascular dysfunction in diabetes mellitus (Figure 2).

**3. Global impact of diabetic mellitus**

98 Antioxidant-Antidiabetic Agents and Human Health

between 45 and 64 years [28].

provide adequate diabetes care in the poor countries.

**4. Diabetic mellitus and oxidative stress**

Diabetes mellitus is a disease common to all parts of the world [26]. It is a common and very prevalent disease affecting the citizens of both developed and developing countries. It has been estimated that 25% of the world population is affected by this disease [27]. Currently, India has got the largest number of diabetics and is being called as diabetic capital of the world. Diabetes has significant health consequences for individuals and communities. In fact, many countries face large increases in the number of people suffer‐ ing from diabetes. The World Health Organization estimated that about 30 million people suffered from diabetes in 1985 and the number increased to more than 171 million in 2000. Additionally, it has been estimated that the number will increase to over 366 million by 2030 and that large increases will occur in developing countries, especially in people aged

A large disparity in total health spending for diabetes among the top 80 most populous countries exists, varying from USD 1.3 million to USD 198.0 billion. The country with the highest total expenditure, the United States of America, will spend 52.7% of the global expenditure. India, the country with the largest population of people living with diabe‐ tes, will spend an estimated USD 2.8 billion or less than 1% of the world total. The total diabetes spending in the 18 countries in IDF's African Region will be only USD 1.2 billion, 0.3% of the global total [29]. The absolute level of health expenditure in developing countries appears to be quite low. The lowest 20 spending countries in the top 80 most populated countries will spend less than USD 50 per person per year for managing diabetes and diabetes-related complications. Expenditure at this level cannot even cover the annual wholesale cost of a generic oral agent capable of preventing acute, life-threatening hypergly‐ caemia [29]. Considering the health services and therapeutic treatments needed to man‐ age diabetes and diabetes-related complications, more health care resources are required to

Diabetes mellitus is associated with an increased risk of cardiovascular diseases mediated via oxidative stress. ROS can directly damage lipids, proteins or DNA and modulate intracellular signaling pathways, such as mitogen activated protein kinases and redox sensitive transcription factors causing changes in protein expression with irreversible oxidative modifications [30-31]. Hyperglycaemia-induced mitochondrial dysfunction and endoplasmic reticulum stress has been shown to promote reactive oxygen species (ROS) accumulation, accelerates cellular damage and significantly contributes to the diabetic complications development and progression [30, 32-33]. PA *et al*. [34] described the

mechanism of cardiovascular dysfunction in diabetes mellitus (Figure 2).

**Figure 2.** Mechanisms of cardiovascular dysfunction in diabetes: role of superoxide and peroxynitrite. Hyperglycaemia induces increased superoxide anion (O2•−) production via activation of multiple pathways including xanthine and NAD(P)H oxidases, cyclooxygenase, uncoupled nitric oxide synthase (NOS), glucose autoxidation, mitochondrial respi‐ ratory chain, polyol pathway, and formation of advanced glycation end products (AGE). Hyperglycaemia-induced in‐ creased superoxide generation may also favour an increased expression of nitric oxide synthases (NOS) through the activation of NFκB, which may increase the generation of nitric oxide (NO). Superoxide anion may quench NO, thereby reducing the efficacy of a potent endothelium-derived vasodilator system. Superoxide can also be converted to hydro‐ gen peroxide (H2O2) by superoxide dismutase (SOD) and interact with NO to form a reactive oxidant peroxynitrite (ONOO−), which induces cell damage via lipid peroxidation, inactivation of enzymes and other proteins by oxidation and nitration, and activation of matrix metalloproteinases (MMPs) among others. This figure was adapted from [34].

Hyperglycaemia-induced oxidative stress also mediates endothelial dysfunction which plays a central role in the pathogenesis of micro- and macro-vascular diseases with resultant increase in pro-inflammatory cytokines and induction of apoptosis and impairment of nitric oxide release. Hyperglycaemia induces vascular damage probably through a single common pathway - increased intracellular oxidative stress- linking four major mechanisms, namely the polyol pathway, advanced glycation end-products (AGEs) formation, the protein kinase C (PKC)-diacylglycerol (DAG) and the hexosamine pathways [35]. However, synthetic drugs against diabetes mellitus have been reported with avalanche of side effects (Table 1) as reported by Kavishankar *et al*. [36].


reactive oxygen species results in simultaneous massive increase in cytosolic calcium concen‐ tration causes rapid destruction of B cells. In the same vein, streptozotocin enters the B cell via a glucose transporter (GLUT2) and causes alkylation of DNA. DNA damage induces activation of poly ADP-ribosylation, a process that is more important for the diabetogenicity of strepto‐ zotocin than DNA damage itself. More so, Poly ADP-ribosylation leads to depletion of cellular NAD+ and ATP [41]. Enhanced ATP dephosphorylation after streptozotocin treatment supplies a substrate for xanthine oxidase resulting in the formation of superoxide radicals. Also, streptozotocin liberates toxic amounts of nitric oxide that inhibits aconitase activity and

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Recently, Etuk *et al.* [42] reported that the following medicinal plants have been validated scientifically as potent antidiabetic plants: *Acacia arabica* (Lam.) Muhl. ex Willd. (Family:

Mimosaceae), *Aegle marmelos* (L.) Correa ex Roxb. (Family: Rutaceae), *Allium cepa* L. (Family: Liliaceae), *Allium sativum* L. (Family: Alliaceae), *Aloe vera* (L.) Burm.f. (Family: Aloaceae), *Anthemis mobilis* Linn*.* (Family: Compositae), *Areca catechu* L. (Family: Arecaceae), *Artemisia pallens* Wall. ex DC. (Family: Compositae), *Annona squamosa* L. (Family: Annonaceae), *Andrographis paniculata* Nees (Family: Acanthaceae), *Aerva lanata* (L.) Juss. ex Schult. (Family: Amaranthaceae), *Asteracantha longifolia* Nees (Family: Acanthaceae), *Azadirachta indica* A. Juss. (Family: Meliaceae), *Biophytum sensitivum* (L.) DC. (Family: Oxalidaceae), *Bombax ceiba* L.

L. (Family: Chenopodiaceae), *Brassica juncea* (L.) Czern. (Family: Brassicaceae), *Barleria lupulina* Lindl. (Family: Acanthaceae), *Boerhavia diffusa* L. (Family: Nyctaginaceae), *Brickellia veronicaefolia* A. Gray (Family: Asteraceae), *Cassia auriculata* L. (Family: Leguminosae), *Caesalpinia bonducella* (L.) Roxb. (Family: Cesalpinaceae), *Capparis decidua* (Forsk.) Edgew. (Family: Capparidaceae) *Cajanus cajan* (L.) Millsp. (Family: Fabaceae), *Citrullus colocynthis* (L.) Schrad. (Family: Cucurbitaceae), *Coccinia indica* Wight & Arn. (Family: Cucurbitaceae), *Casearia esculenta* Roxb. (Family: Flacourtiaceae), *Catharanthus roseus* (L) G. Don. (Family: Apocyna‐ ceae), *Camellia sinensis* Kuntze (Family: Theaceae), *Coriandrum sativum* L. (Family: Apiaceae).

*Allium cepa L., Clerodendron phlomoides Linn., Cinnamomum tamala (Buch.-Ham.) T. Nees & Eberm., Coccinia indica Wight & Arn., Enicostemma littorale Blume, Ficus bengalensis L., Momordica charantia L., Pterocarpus marsupium Roxb., Cyamopsis tetragonolobus (L.) Taub., Cephalandra indica Naud., Casearia esculenta Roxb., Cannabis indica (Lam.) E. Small & Cronq., and Syzygium cumini L. when subjected to clinical trials, showed promising hypoglycaemic effects*[43]. *Other potent antidiabetic*

participates in DNA damage [41].

(Family: Bombacaceae), *Beta vulgaris*

**7. Antidiabetic plants in clinical trials**

The following antidiabetic plants are currently under clinical trials viz:

**6. Some scientifically validated antidiabetic plants**

**Table 1.** Synthetic drugs and their side effects
