Ebook Anti-diabetes mellitus plants - Active principles, mechanisms of action and sustainable utilization: Part 1

Anti-Diabetes Mellitus Plants

Subramoniam

Life Science | Healthcare

Active Principles, Mechanisms of Action and Sustainable Utilization

Anti-Diabetes Mellitus Plants: Active Principles, Mechanisms of Action and
Sustainable Utilization begins with a detailed introduction to diabetes mellitus
including current treatments in conventional medicine for this disease. It provides
an authoritative overview of available methods for studying the anti-diabetes mellitus activities of plant products. The book highlights the likely therapeutic superiority
of scientifically developed combinations of anti-diabetes mellitus phytochemicals
and polyherbal formulations. This unique reference covers the development of
polyherbal formulations and conventional combination drugs with desired targets of
action for diabetes mellitus patients. In this book, more than 300 anti-diabetes
phytochemical compounds are extensively covered and updated with their pharmacological properties. It will serve as a valuable source of information for researchers,
students, doctors, biotechnologists, diabetic patients, and other individuals wanting to learn more about plant-based treatments for diabetes mellitus.

Features
• Provides extensive coverage of anti-diabetes mellitus phytochemicals
with worldwide anti-diabetic potential
• Explores the possibility that polyherbal formulations, if developed
scientifically with respect to their mechanisms of actions and their efficacy,
could prove to be the best treatment for diabetes mellitus
• Presents mechanisms of action for approximately 400 plants, including
10 major mechanisms with illustrations
• Presents studies on in vitro propagation through tissue culture of
more than 100 anti-diabetes mellitus plants

Active Principles, Mechanisms of

Action and Sustainable Utilization

Appian Subramoniam

K27340
ISBN-13: 978-1-4987-5323-4

90000

9 781498 753234

Anti-Diabetes Mellitus Plants

The incidence and severity of diabetes mellitus are increasing worldwide, presenting a significant burden to society in both economic terms and overall well-being.
There is a growing demand for novel, safe and effective medicines due to the limited
efficacy and undesirable side effects of current conventional drugs. We now have a
great opportunity to develop plant-based therapies for diabetes mellitus with superior efficacy and safety utilizing modern science and technology.

Anti-Diabetes
Mellitus Plants


Anti-Diabetes
Mellitus Plants
Active Principles, Mechanisms of
Action and Sustainable Utilization



Anti-Diabetes

Mellitus Plants
Active Principles, Mechanisms of
Action and Sustainable Utilization

Appian Subramoniam

Boca Raton London New York

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Taylor & Francis Group, an informa business


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Library of Congress Cataloging‑in‑Publication Data
Names: Subramoniam, Appian, 1950- author.
Title: Anti-diabetes mellitus plants : active principles, mechanisms of
action and sustainable utilization / Appian Subramoniam.
Description: Boca Raton : Taylor & Francis, 2016. | Includes bibliographical
references and index.
Identifiers: LCCN 2016006662 | ISBN 9781498753234 (alk. paper)
Subjects: LCSH: Diabetes--Alternative treatment. | Materia medica, Vegetable.
Classification: LCC RC661.H4 S82 2016 | DDC 616.4/62--dc23
LC record available at />Visit the Taylor & Francis Web site at

and the CRC Press Web site at



To my loving parents

v



Contents
Preface.....................................................................................................................................................xiii
Acknowledgments..................................................................................................................................... xv
Author..................................................................................................................................................... xvii

1.Introduction....................................................................................................................................... 1
1.1 Diabetes Mellitus and Its Complications................................................................................. 1
1.1.1 Diabetes Mellitus....................................................................................................... 1
1.1.1.1 Diagnosis of DM........................................................................................ 1
1.1.1.2Prevalence.................................................................................................. 1
1.1.1.3 Effect on Economy and Well-Being.......................................................... 2
1.1.1.4 Different Types of DM.............................................................................. 2
1.1.2 Complications of DM................................................................................................. 5
1.2 Glucose Homeostasis............................................................................................................... 7
1.2.1 Insulin and Glucose Homeostasis.............................................................................. 7
1.2.2 Glucagon, Incretins, and Other Hormones in Glucose Homeostasis........................ 9
1.3 Treatment/Management of DM in Current Conventional Medicine....................................... 9
1.3.1 Insulin and Other Parenteral Therapy....................................................................... 9
1.3.2 Oral Hypoglycemic Agents...................................................................................... 10
1.3.2.1 Insulin Secretagogues.............................................................................. 10
1.3.2.2 AMPK Activators with Hypoglycemic and Hypolipidemic Effects........11
1.3.2.3PPAR-γ Agonists..................................................................................... 12
1.3.2.4 α-Glucosidase Inhibitors......................................................................... 12
1.3.2.5 Dipeptidyl Peptidase-4 Inhibitors........................................................... 12
1.3.2.6 Inhibitors of Sodium–Glucose Cotransporter-2...................................... 13
1.3.2.7 Dopamine Receptor Agonist................................................................... 13
1.3.2.8 Bile Acid Binding Resins........................................................................ 13
1.3.2.9 Other Therapies....................................................................................... 13
1.4 Herbal Therapies for DM....................................................................................................... 13
1.5Conclusion.............................................................................................................................. 15
2. Anti-Diabetes Mellitus Phytochemicals.........................................................................................17
2.1Background/Introduction........................................................................................................17
2.2Phytochemicals with Anti-DM Activities............................................................................. 36
2.3Isolation of Anti-Diabetic Phytochemicals.......................................................................... 130
2.4Proven Anti-DM Plants without Identified Active Principles..............................................131

2.5Conclusions...........................................................................................................................131
3. Mechanism of Action of Anti-Diabetes Mellitus Plants.............................................................133
3.1Introduction...........................................................................................................................133
3.2 Major Mechanism of Action of Anti-DM Molecules and Extracts......................................133
3.2.1 Stimulation of Insulin Secretion and/or Regeneration of the β-Cells....................133
3.2.2 Sensitization of Insulin Action (Decreasing Insulin Resistance)...........................163
3.2.3 Insulin-Like Action/Insulin Mimetic (Partial or Complete)................................. 164
3.2.4 Activation of PPAR-γ............................................................................................. 164
3.2.5 Increasing the Levels of GLP-1..............................................................................165
3.2.6 Activation of AMPK.............................................................................................. 166
3.2.7 Inhibition of Carbohydrate Digestion in the Intestine........................................... 166
vii


viii

Contents
3.2.8 Inhibition of Glucose Absorption from the Intestine.............................................167
3.2.9 Inhibition of Glucose Reabsorption in the Kidney.................................................168
3.2.10 Inhibition of Aldose Reductase Activity..................................................................168
3.2.11 Other Mechanisms..................................................................................................168
3.3 Plants with Multiple Mechanisms of Action........................................................................169
3.3.1 Cinnamomum verum J.S. Presl. .............................................................................169
3.3.2 Curcuma longa L. ..................................................................................................170
3.3.3 Glycyrrhiza uralensis Fisch. ..................................................................................170
3.3.4 Gymnema sylvestre R. Br.  .....................................................................................172
3.3.5 Ipomoea batatas L. ................................................................................................173
3.3.6 Mangifera indica L.  ...............................................................................................174
3.3.7 Momordica charantia L.  .......................................................................................175
3.3.8 Panax ginseng C.A. Meyer.....................................................................................176

3.3.9 Terminalia bellerica (Gaertn) Roxb.  .....................................................................178
3.3.10 Trigonella foenum-graecum L. ..............................................................................178
3.3.11 Vitis vinifera L.  ..................................................................................................... 180
3.3.12 Compound with Multiple Mechanisms.................................................................. 180
3.4 Anti-DM Plants without Known Mechanisms of Action.....................................................181
3.5Conclusions...........................................................................................................................182

4. Polyherbal and Combination Medicines for Diabetes Mellitus.................................................183
4.1Introduction...........................................................................................................................183
4.2Synergistic, Additive, Stimulatory, and Antagonistic Effects of
Phytochemicals.....................................................................................................................183
4.3 Dose Effects of Anti-DM Molecules/Extracts.....................................................................185
4.4 Development of Rational Polyherbal Formulations..............................................................185
4.5 Polyherbal Therapy for DM..................................................................................................188
4.5.1 Polyherbal Formulations (Ayurvedic Type) Used in India

and Elsewhere.........................................................................................................188
4.5.1.1 Aavaraiyathi churnum............................................................................188
4.5.1.2 Annoma squamosa and Nigella sativa Formulation..............................188
4.5.1.3APKJ-004...............................................................................................188
4.5.1.4 Cogent db................................................................................................188
4.5.1.5DIA-2......................................................................................................189
4.5.1.6Diabecon.................................................................................................189
4.5.1.7 Diabecon-400 (D-400)...........................................................................189
4.5.1.8Diabecure................................................................................................189
4.5.1.9Diabet.....................................................................................................189
4.5.1.10Diabeta................................................................................................... 190
4.5.1.11 Diabetes-Daily Care.............................................................................. 190
4.5.1.12Diabrid................................................................................................... 190
4.5.1.13Dia-Care................................................................................................ 190

4.5.1.14Diakyur.................................................................................................. 190
4.5.1.15Dianex.....................................................................................................191
4.5.1.16Diashis....................................................................................................191
4.5.1.17Diasol......................................................................................................191
4.5.1.18Diasulin..................................................................................................191
4.5.1.19Dihar...................................................................................................... 192
4.5.1.20DRF/AY/5001........................................................................................ 192
4.5.1.21EFPTT/09.............................................................................................. 192
4.5.1.22ESF/AY/500........................................................................................... 192
4.5.1.23Glucolevel.............................................................................................. 192
4.5.1.24Gluconorm-5.......................................................................................... 192


Contents

ix

4.5.1.25Glyoherb................................................................................................ 193
4.5.1.26 HAL or HA-lipids.................................................................................. 193
4.5.1.27Hyponidd............................................................................................... 193
4.5.1.28Jamboola................................................................................................ 193
4.5.1.29 Karnim Plus........................................................................................... 194
4.5.1.30 LI85008F or Adipromin........................................................................ 194
4.5.1.31MAC-ST/001......................................................................................... 194
4.5.1.32NIDDWIN............................................................................................. 194
4.5.1.33Okchun-San........................................................................................... 194
4.5.1.34Okudiabet.............................................................................................. 194
4.5.1.35PMO21................................................................................................... 195
4.5.1.36SMK001................................................................................................. 195
4.5.1.37SR10....................................................................................................... 195

4.5.1.38 Sugar Remedy........................................................................................ 195
4.5.1.39Ziabeen.................................................................................................. 195
4.5.1.405EPHF................................................................................................... 196
4.5.1.41 Other Formulations................................................................................ 196
4.5.2 Polyherbal Anti-DM Formulations Used in Chinese Medicine............................ 197
4.5.2.1 Gan Lu Xiao Ke Capsule....................................................................... 198
4.5.2.2 Yuquan Wan.......................................................................................... 198
4.5.2.3 Tangmaikang Jiaonang.......................................................................... 198
4.5.2.4 Xiaoke Wan........................................................................................... 198
4.5.2.5 Jinqi Jiangtang Pian............................................................................... 199
4.5.2.6 Jiangtangjia Pian and Kelening Jiaonang.............................................. 199
4.5.2.7 Xiaotangling Jiaonang........................................................................... 199
4.5.2.8 Shenqi Jiangtang Keli............................................................................ 200
4.5.2.9 Other Formulation in Chinese Traditional Medicine............................ 200
4.6Problems Associated with the Existing Polyherbal Formulations

Including Ayurvedic Formulations...................................................................................... 200
4.7 Combination Medicines with Pure (Chemical Entity) Phytochemicals.............................. 201
4.8Conclusion............................................................................................................................ 201
5. Methods to Assess Anti-Diabetes Mellitus Activity of Plants................................................... 203
5.1Introduction.......................................................................................................................... 203
5.2 Animal Models of DM......................................................................................................... 203
5.2.1 Chemical-Induced Models..................................................................................... 203
5.2.1.1 Alloxan-Induced DM............................................................................. 204
5.2.1.2 Streptozotocin-Induced DM.................................................................. 204
5.2.1.3 Goldthioglucose-Induced DM............................................................... 207
5.2.1.4 Other Chemical-Induced DM................................................................ 207
5.2.2 Surgical Models of DM.......................................................................................... 207
5.2.3 Spontaneous or Genetically Derived DM.............................................................. 208
5.2.3.1 Obese Models of Type 2 DM................................................................. 208

5.2.3.2 Nonobese Models of Type 2 DM............................................................210
5.2.3.3 Autoimmune Model of Type 1 DM........................................................210
5.2.3.4 Genetically Engineered DM...................................................................211
5.2.4 Diet /Nutrition-Induced Type 2 DM.......................................................................212
5.2.4.1 C57/BL6J Mouse....................................................................................212
5.2.4.2 Other Diet-Induced Rodent Models.......................................................212
5.2.5 Other Animal Models of DM.................................................................................212
5.2.5.1 Virus-Induced Model of DM..................................................................212
5.2.5.2 Intrauterine Growth Retardation–Induced Diabetic Rats......................212
5.2.5.3 Models for Diabetic Complications........................................................213


x

Contents
Assessment of Anti-DM Activity Using Animal Models.......................................213
5.2.6.1 Selection of an Appropriate Animal Model...........................................213
5.2.7 Nonmammalian Animal Models............................................................................215
5.2.7.1 Zebrafish Model of DM..........................................................................215
5.2.7.2 Silkworm Model of DM/Hyperglycemia...............................................215
5.3 In Vitro Methods...................................................................................................................216
5.3.1 Stimulation of Insulin Secretion.............................................................................216
5.3.1.1 Isolated Islet Cells..................................................................................217
5.3.1.2 Insulin Secreting Cell Lines...................................................................217
5.3.2 Stimulation of β-Cell Proliferation.........................................................................217
5.3.3 Glucose Uptake and Insulin Action........................................................................218
5.3.3.1 Alternative Glucose Substrate for In Vitro Uptake Studies...................218
5.3.3.2 Insulin Action in Liver...........................................................................218
5.3.3.3 Insulin Action in Muscle........................................................................219
5.3.3.4 Insulin Action in Adipose Tissue...........................................................219

5.3.3.5Phosphorylation and Dephosphorylation Kinetics

of Insulin Receptor and Insulin Receptor Substrates............................ 220
5.3.4 Adipocyte Differentiation...................................................................................... 220
5.3.5 Glucagon Receptor Antagonists............................................................................ 221
5.3.6PPAR-γ Ligand Activity Screening....................................................................... 221
5.3.7 Glucagon-Like Protein-1 Levels............................................................................ 221
5.3.7.1 Dipeptidyl Peptidase-4 Inhibitor Screening.......................................... 222
5.3.8 Inhibition of Carbohydrate Digestion.................................................................... 222
5.3.8.1 α-Amylase Assay................................................................................... 222
5.3.8.2 α-Glucosidase Assay............................................................................. 223
5.3.9 Inhibition of Glucose Absorption from the Intestine............................................ 223
5.3.10 Inhibition of Aldose Reductase Activity............................................................... 224
5.3.11 Activity and Expression of AMP-Activated Protein Kinase................................. 224
5.3.12 Interfering Phytochemicals in the In Vitro Assays................................................ 225
5.3.13 Solubilizing Plant Extracts for In Vitro Studies.................................................... 225
5.4 Clinical Evaluation.............................................................................................................. 225
5.4.1 Phase 1 Clinical Trial............................................................................................ 226
5.4.2 Phase 2 Clinical Trials........................................................................................... 227
5.4.3 Phase 3 and 4 Clinical Trials................................................................................. 227
5.4.4 Ethical Issues......................................................................................................... 228
5.5Conclusion............................................................................................................................ 229
5.2.6

6. Sustainable Utilization of Anti-Diabetes Mellitus Plants...........................................................231
6.1Introduction...........................................................................................................................231
6.2 In Vitro Propagation of Plants through Tissue Culture........................................................231
6.2.1 Shoot Multiplication In Vitro................................................................................. 237
6.2.2Callus..................................................................................................................... 237
6.2.3 Rooting of In Vitro Regenerated Shoots................................................................ 238

6.2.4 Hardening and Acclimatization of Plantlets in Soil.............................................. 238
6.2.5 Somatic Embryogenesis......................................................................................... 238
6.2.6 Suspension Culture................................................................................................ 238
6.2.7 Protoplast Cultures................................................................................................. 238
6.2.8 Hairy Root Cultures............................................................................................... 239
6.3 Conservation of Medicinal Plants........................................................................................ 239
6.3.1 In Situ Conservation............................................................................................... 239
6.3.2 Ex Situ Conservation of Plants.............................................................................. 239
6.3.2.1 Field Gene Banks and Seed Banks........................................................ 240
6.3.2.2 In Vitro Conservation (In Vitro Gene Banks)........................................ 240


Contents

xi

6.3.3 Slow Growth Conservation In Vitro...................................................................... 240
6.3.4Cryopreservation.................................................................................................... 241
6.4 Rare, Endangered, and Threatened Anti-DM Plants........................................................... 242
6.5 Micropropagation of Anti-DM Medicinal Plants................................................................ 242
6.5.1 Micropropagation on Rare, Endangered, and Threatened Anti-DM Plants.......... 243
6.5.2 Micropropagation Studies on Important Anti-DM Plants..................................... 253
6.6 Development of Cultivation Conditions/Agrotechniques for Anti-DM Plants.................... 297
6.6.1 Selection of Best Genotypes and Phenotypes........................................................ 298
6.7Conclusion............................................................................................................................ 298
References.............................................................................................................................................. 301
Index........................................................................................................................................................381

Preface
The worldwide prevalence of diabetes mellitus (one of the oldest diseases known to humans) in the adult
population is more than 8%. This is a huge burden to society in terms of quality of life, cost of treatment, and loss in productivity of patients. In traditional medicine all over the world, plant-based crude
drugs are used to treat diabetes mellitus from time immemorial. Even today, the majority of the world’s
population use plant products to control diabetes mellitus. Now, it is time to create new knowledge from
traditional knowledge with the help of modern science and technology. There is a necessity to develop
plant-based therapies for diabetes mellitus with superior efficacy and safety in light of modern science.
Although there are numerous polyherbal formulations to treat diabetes in traditional medicine, none
of them were developed rationally. The reasons for the presence of specific ingredients in the given
ratio in a polyherbal formulation and phytochemical interactions in the formulation, if any, are not
explained ­satisfactorily. It should be remembered that most of these formulations existed well before
the ­advancement of modern medical sciences. Polyherbal formulations, if developed scientifically
­considering the mechanisms of actions and efficacy as projected in Chapter 4, could prove to be the best
treatment for diabetes mellitus. Further, it is heartening to note that many vegetables, spices, and fruits
are endowed with anti-diabetes mellitus properties. Development of rational polyherbal formulations
with these plant products could be very safe and effective.
Other gap areas identified in this book to be filled by future research include the following: Active
molecules are not identified fully in a majority of known anti-diabetes mellitus plants including more
than 30 very important anti-diabetes mellitus plants. Mechanisms of action also remain to be elucidated
in more than 50 established anti-diabetes mellitus plants. Most of the in vivo experimental studies have
been carried out in alloxan- and streptozotocin-induced type 1 (to a large extent) diabetic animals only.
These models provide only limited information regarding mechanisms of action as well as the efficacy
in different types of type 2 diabetes mellitus of test drugs (plant products).
In the case of important anti-diabetes mellitus plants, cultivation conditions and elite genotypes
were not standardized keeping in view with anti-diabetes mellitus properties. Anti-diabetes mellitus
­properties of the plants have to be adequately considered while developing the agrotechniques. Although
­developing intercrops and utilizing unproductive lands are attractive alternatives for growing ­medicinal
plants, the quality of the medicinal plants in terms of their required pharmacological properties should
be ­considered. Micropropagation could aid in achieving uniform quality of the bulk amount of planting
­materials as per requirement. In many cases, this is essential in large-scale production of uniform ­quality

­plant-based medicines.
Type 2 diabetes mellitus is a heterogeneous disease, and tremendous advancement in our knowledge on
diabetes mellitus and its complications could enable us to get substantial information regarding s­ pecific
defect(s) in the metabolic syndrome in individual cases. Therefore, applying full knowledge of the mechanisms of action of anti-diabetes mellitus phytochemicals, tailor-made combination therapy, or single phytochemical entity therapy can even be developed in the future to provide individualized treatment.
There are more than 300 phytochemicals with varying levels and mechanisms of anti-diabetes
­mellitus activities. A number of such compounds are commonly occurring in many plants including certain edible plant parts. For example, compounds with promising anti-diabetes mellitus properties, such
as chlorogenic acid, oleanolic acid, quercetin, and β-sitosterol, are present in a variety of plant species
including many fruits, vegetables, and spices. These molecules have pharmacological properties other
than anti-diabetes mellitus activities. Plants containing a reasonably high level of one or more of such
compounds are considered only as anti-diabetes mellitus plants.
Literature on different animal models of diabetes mellitus show that a sedentary lifestyle coupled with
plenty of nutrition and/or fatty diet could lead to type 2 diabetes mellitus. This aspect could have an
important bearing in the prevention of type 2 diabetes mellitus in humans.
xiii


xiv

Preface

Another fact from the literature is that many of the anti-diabetes mellitus plants have more than one active
molecule and most of the promising active molecules possess more than one ­pharmacological property
and more than one target molecule in the body. Many anti-diabetes compounds show ­anti-inflammatory
and anticarcinogenesis properties as well; this may be partly due to their ­common ­antioxidant effect.
Besides, the metabolic network may be responsible, to some extent, for the ­several apparent pharmacological properties of some of the anti-diabetes mellitus compounds. Antioxidant, a­ nti-diabetes mellitus,
anticancer, anticardiovascular diseases, and anti-inflammatory activities are interlinked by cross talks
between the complex signaling pathways. This is one of the limitations in clearly understanding specific
mechanisms of actions of certain anti-diabetes mellitus compounds in the case of in vivo studies.
A decade of studies on anti-diabetes mellitus properties of plants has been updated in a recent book
(Plants with Anti-Diabetes Mellitus Properties [CRC Press, 2016]) by this author. This book is a follow-up

to that one. This book begins with a detailed introduction on diabetes mellitus including current treatments for this disease in conventional medicine (Chapter 1). Chapter 2 describes 303 anti-diabetes mellitus
­phytochemicals; the compounds are arranged alphabetically for easy reference and chemical structures
of 70 ­compounds are provided. In Chapter 3, mechanisms of action of about 400 plants, which include
10 major ­mechanisms, are presented; multiple mechanisms of action of 10 selected anti-diabetes ­mellitus
plants and berberine are illustrated. Chapter 4, among other things, highlights the likely therapeutic superiority of ­scientifically developed combinations of anti-diabetes mellitus phytochemicals and p­ olyherbal
formulations. An overview of available methods to study anti-diabetes mellitus activities of plant products
is provided in Chapter 5. These include in vitro assays, in vivo animal models including nonmammalian
animal ­models, and clinical trials. Seventeen RET (rare, endangered, and threatened) anti-diabetes mellitus
plant species are described in Chapter 6. Further, studies on in vitro propagation through tissue culture of
112 anti-diabetes mellitus plants are given.
Lower plant species such as fungi and algae as well as bacteria are not covered in this book.
This book provides new insights with adequate and updated background knowledge on anti-diabetes
mellitus phytochemicals, their mechanisms of action, and their combination therapy to promote research
and development toward the creation of plant-based superior therapies for diabetes mellitus. An added
attraction in this book is the light shed on sustainable and proper utilization of anti-diabetes mellitus
plant species. Such a book covering all the relevant areas of study, required for the development of plantbased superior anti-diabetes mellitus therapy, is not available at present. The author sincerely hopes that
this book will, certainly, be very useful to researchers, students, doctors, diabetic patients, plant biotechnologists, and others concerned with plant-based treatment of diabetes mellitus.


Acknowledgments
The book would not have come to the final form without timely help that I received from many friends,
colleagues, and well-wishers. I sincerely thank all of them.
I acknowledge with gratitude Dr. Usha Mukundan (principal and professor of Ramniranjan
Jhunjhunwala College, Mumbai, India) and her colleagues for providing pictures of tissue-cultured
plantlets of five anti-diabetes mellitus plants. These images are from their work carried out in the Plant
Biotechnology Research Laboratory of Ramniranjan Jhunjhunwala College, Mumbai. Dr. William
Decruse, senior scientist, Tropical Botanical Garden and Research Institute, Trivandrum, Kerala, India,
is acknowledged for providing the images of tissue-cultured plantlets of Coscinium fenestratum and
Piper longum. I thank Lalitha Ramakrishnan, Cambridge University, and her colleague Kelvin Takaki
for providing the image of zebrafish larva. Anil S. C. Das is acknowledged for his technical help in the

use of software in the preparation of the manuscript.
My deep appreciation is to my son-in-law, Dr. Subeesh, daughters Dr. Vanathi and Vini, and wife
Thankam for their support, enthusiasm, and encouragement during the preparation of this manuscript.
I gratefully acknowledge John Sulzycki (senior editor, CRC Press, Taylor & Francis Group) whose
positive involvement and high level of professionalism was instrumental in the initiation and completion of this book. I am very thankful to Jill Jurgensen (senior project coordinator, CRC Press,
Taylor & Francis Group) for her understanding and valuable professional efforts in the processing
of the manuscript for this book. I sincerely thank Iris Fahrer (project editor, CRC Press, Taylor &
Francis Group) and Ramya Gangadharan (project manager, diacriTech, Chennai) for ensuring an
extremely efficient and smooth production process of this book. Besides, I acknowledge the sincere
efforts put in by the copy editor. Cheryl Wolf (editorial assistant, CRC Press, Taylor & Francis
Group), and others involved in the promotion and marketing of this book are acknowledged sincerely.

xv



Author
Appian Subramoniam, PhD, is the former director of the Tropical Botanic
Garden and Research Institute in Kerala, India, and the author of the recent
book Plants with Anti-Diabetes Mellitus Properties (CRC Press, 2016).
He earned his master’s degree in zoology in 1974 from Annamalai University,
Tamil Nadu, India, and his doctoral degree in biochemistry in 1979 from the
Maharaja Sayajirao University of Baroda, India. Dr. Subramoniam carried out
his postdoctoral research in biochemical pharmacology at Howard University,
Washington, DC, and at Temple University, Philadelphia, Pennsylvania. He
has worked in a few reputed institutes in India (Central Food Technology
Research Institute, Mysore; Industrial Toxicology Research Centre, Lucknow;
and Bose Institute, Calcutta) and carried out original, very high-quality
­multidisciplinary research work in the broad areas of biomedical sciences and plant sciences. He is a
recognized PhD guide for a few universities in India in the fields of biochemistry, biotechnology, pharmacology, ­chemistry, and zoology. He has guided ten PhD scholars. Dr. Subramoniam is the author

of more than 170 scientific ­publications, which include original research publications in reputed international journals, book chapters, and review papers in journals. He has nine patents to his credit. He
served as a reviewer of ­scientific journals in the fields of ethnopharmacology, phytopharmacology,
­biochemistry, and ­toxicology. He joined Tropical Botanic Garden and Research Institute (TBGRI) as
a scientist in ethnopharmacology and ethnomedicine in 1994. He was the appointed director of TBGRI
in 2009. At TBGRI, he ­established advanced p­ hytopharmacological research. During his tenure there,
TBGRI earned national and i­nternational recognition in medicinal plant research for discovering many
­important leads from plants for the development of valuable medicines. For example, his research
group discovered a potent ­aphrodisiac principle, 2,7.7-trimethyl bicyclo [2.2.1] heptane, from an orchid,
Vanda tessellata, and his group discovered the promising anti-inflammatory property of chlorophyll-a
and its degradation ­products. Dr. Subramoniam has received several national awards for his excellent
scientific contributions, such as the Hari Om Ashram Award for research in Indian medicinal plants,
Swaminathan Research Endowment Award for outstanding contribution in the scientific evaluation of
medicinal plants for their therapeutic use (awarded by the Indian Association of Biomedical Scientists),
Jaipur Prize from the Indian Pharmacological Society, and Dr. B. Mukherjee Prize (2006) from Indian
Pharmacological Society. He served as president of Southern Regional Indian Pharmacological Society,
2009; vice p­ resident of Indian Association of Biomedical Scientists, 2007–2010, and vice president of
Kerala Academy of Sciences (2011–2013). He is currently a consultant in medicinal plant research.

xvii



1
Introduction

1.1  Diabetes Mellitus and Its Complications
1.1.1  Diabetes Mellitus
Diabetes mellitus (DM) is one of the oldest diseases known to humans. DM is characterized by hyperglycemia resulting mainly from defects in insulin production/secretion and/or insulin action. In DM,
varying degrees of failure of normal regulation of metabolism of carbohydrate, lipids, and protein occur.
Glucagon, a peptide hormone produced by α-cells of pancreas, and gut-derived hormones such as incretin and other agents, also have important roles in glucose homeostasis, including hepatic glucose production and insulin resistance (Mingrone and Gastagneto-Gissey 2014). Chronic hyperglycemia in DM

leads to secondary pathophysiological changes, including long-term life-threatening complications in
major organs.

1.1.1.1  Diagnosis of DM
The most reliable and convenient test for identifying DM in asymptomatic individuals is the determination of fasting plasma glucose (FPG) levels. FPG ≥ 7.0 mmol (126 mg/dL) warrants the diagnosis of DM.
A random plasma concentration ≥11.1 mmol/L (200 mg/dL) accompanied by polyurea, polydipsia, and
weight loss is sufficient for the diagnosis of DM. The impairment of glucose metabolism starts when the
fasting glucose concentrations exceed about 7.78 mmol/L (140 mg/dL). Oral glucose tolerance testing is
also a valid means for diagnosis of DM; however, it is not recommended as a part of routine care (Powers
2008). Glycohemoglobulin (HbA1c or A1C) values reflect average glycemic control over the previous
period of about 3 months. Normal range of HbA1c values is from 4.0% to 6.4%. HbA1c levels of 6.5%
or higher indicate diabetes.

1.1.1.2 Prevalence
According to the International Diabetes Federation (IDF), the worldwide prevalence of adults with DM
is about 8.3%, accounting for approximately 382 million people (IDF 2012). In 2010, in the People’s
Republic of China, the prevalence of DM in people aged 20 years or older was 9.7%, accounting for 92.4
million adults with DM (Yang et al. 2010c). Among DM patients, about 90% are affected with type 2
DM. Type 2 DM has become a major health problem in both developed and developing countries. There
are considerable geographical variations in the prevalence and severity of both type 1 and type 2 DM.
According to IDF (IDF 2011) the Western Pacific region has the most people with DM (132 million).
Most of these people have type 2 DM. In the United States, minority ethnic groups such as African
Americans and Native Americans have higher incidence of type 2 DM than the non-Hispanic white
population. The greatest increase in prevalence is predicted to occur in Africa and the Middle East.
Scandinavia has the highest incidence of type 1 DM. Japan and China have relatively low incidences of
type 1 DM. The prevalence of type 2 DM is the highest in certain Pacific islanders and relatively low in
Russia (Powers 2008). In Basrah, Iraq, one in five adults is affected by DM (Mansour et al. 2014).

1

2

Anti-Diabetes Mellitus Plants

1.1.1.3  Effect on Economy and Well-Being
The cost of health care involved in DM is increasing day by day; DM is a huge economic burden for the
patients and countries. In 2012, an estimated 22.3 million people in the United States were diagnosed
with diabetes; the estimated total economic cost of diagnosed diabetes in 2012 was US$245 billion, a
41% increase from the estimated total economic cost in 2007. This estimate highlights the substantial
burden that diabetes imposes on society (American Diabetes Association 2013). DM is a chronic disease; severe DM needs lifelong treatment in almost all cases. DM has tremendous adverse impacts on
the economy and happiness of the society and country in terms of quality of life, emotional and social
well-being, cost of the treatment, and loss in productivity of patients.

1.1.1.4  Different Types of DM
There are two major types of DM, which are designated type 1 and type 2. Type 1 DM is the result of near
total insulin deficiency or absence of insulin. Among the DM patients about 10% suffer from type 1 DM.
Type 2 DM is a heterogeneous group of disorders characterized by variable degrees of insulin resistance,
impaired insulin secretion, and increased glucose production from liver. Type 2 DM accounts for more
than 90% of cases of DM all over the world. Malnutrition-related diabetes is prevalent in Africa and certain
Asian countries. There are other causes of hyperglycemia, which include chronic pancreatitis or chronic
drug therapy with saquinavir (protease inhibitor), glucocorticoids, thiazids diuretics, diazoxide, and growth
hormone. Gestational DM (glucose intolerance during pregnancy) is another type of DM. It may be related
to the metabolic changes of late pregnancy and the increased insulin requirement. It occurs in about 4%
of pregnancies in the United States. Most women revert to normal glucose tolerance postpartum but have
a substantial risk of developing type 2 DM later in life. Maturity onset diabetes of the young is a subtype
of DM characterized by early onset of hyperglycemia and impairment in insulin secretion. It is inherited
(autosomal dominant inheritance). An extremely rare case of DM is pancreatic β-cell destruction by viral
infections (Powers 2008). Mutations in the insulin receptor (IR) may cause severe insulin resistance.

1.1.1.4.1  Type 1 DM and Its Causes
The major causes of type 1 DM are shown in a flowchart (Figure 1.1). Type 1 DM most commonly develops before the age of 30, but it can develop at any age. It is commonly caused by complete destruction of
β-cells in genetically susceptible individuals by chronic autoimmune disease believed to be triggered by
an infection or environmental factor (Kukreja and Maclaren 1999; Pietropaolo 2001). The presence of
islet cell antibodies in nondiabetic individuals predicts a risk of developing type 1 DM.
Genetic risk of type 1 DM is conferred by polymorphism in many genes that regulate innate and
adaptive immunity. The major susceptibility gene for type 1 DM is located in human leukocyte antigen
(HLA) class II gene located in chromosome 6 (Kelly et al. 2001). There are additional modifying factors
of genetic risk in determining the development of type 1 DM. Nongenetic factors such as viral infection
and vitamin D deficiency may increase risk (Lammi et al. 2005).
Environmental factors and their interaction with the immune system also give rise to the occurrence
of type 1 DM. Certain toxic chemicals may also cause type 1 DM. Although in most of the individuals,
type 1 DM is caused by autoimmune destruction of β-cells (type 1A), some individuals develop type 1
DM by unknown nonimmunological mechanisms (type 1 B) (Dejkhamron et al. 2007).

1.1.1.4.2  Type 2 DM and Its Causes
Major causes for the development of type 2 DM are shown in Figure 1.2. Type 2 DM typically develops
with increasing age (particularly after the age of 40 years). However, it occurs in obese adolescents as
well. Obesity is present in over 80% of type 2 diabetic patients (Powers 2008).
Genetic components are associated with insulin resistance. The contribution of the genes to an individual’s risk of type 2 DM is influenced by factors such as sedentary lifestyle, increased nutritional
intake, and obesity. The dramatic increase in type 2 DM in the present century is due to the changing environmental factors as well as sedentary lifestyle, dietary habits including pro-oxidant food, and
­mental stress.


3

Introduction
Genetic predisposition

Toxic chemicals

Infections

Death of β-cells
(Autoimmune
response mediated or
other types of cell
death)

Idiopathic
(primary autoimmunity)

Type 1
diabetes
mellitus
FIGURE 1.1  Major causes of type 1 diabetes mellitus.
Diet
(pro-oxidant rich diet:
very high fat, and excess
carbohydrate intake)

Obesity
Mental stress

Genetic predisposition
(defects in genes involved in insulin
action and/or prodction, etc.)

Insulin resistance,
defective insulin

secretion/insulin
deficiency,
excess glucagon
secretion

Sedentary (inactive)
life

Type 2
diabetes
mellitus
FIGURE 1.2  Major causes of type 2 diabetes mellitus.

The contribution of maternal environment and in utero factors to the risk of type 2 DM in subsequent generations via epigenetic modifications is now being recognized as potentially important
in explaining the very high rate of type 2 DM currently seen in many populations in the developing
world.
Insulin resistance has a central role in the development of type 2 DM. Induction of the resistance is
partly by the sustained activation of various serine/threonine protein kinases that phosphorylate insulin
receptor substrate (IRS) proteins and other components of the insulin-signaling pathway. This intense
signaling leads to activation of negative feedback mechanisms. Normally, these feedback mechanisms
are there to terminate excess insulin action. Phosphorylation of IRS proteins inhibits their function and
interferes with insulin signaling in a number of ways, leading to the development of an insulin-resistant
state (Cooper et al. 2012). In general, post-IR defects in insulin signaling lead to insulin resistance. In
rare cases, due to gene defects IR gets mutated at the site of adenosine triphosphate (ATP) binding or


4

Anti-Diabetes Mellitus Plants

replaces tyrosine residues at the major sites of phosphorylation. This leads to failure of insulin signaling
and cell response to insulin (Ellis et al. 1986).
Insulin resistance could develop in humans within an hour of acute increase in plasma nonesterified
fatty acids. The increased rates of nonesterified fatty acid delivery and decreased intracellular fatty acid
metabolism result in an increase in the levels of diacyl glycerols (DGs), fatty acyl coenzyme A, and
ceramides. These metabolites in turn activate serine/threonine phosphorylation of IRS-1 and IRS-2 and
reduce the ability of phosphatidyl inositol kinase-3 in proper downstream regulation of insulin signaling
(Khan et al. 2006).
An increase in visceral adipose tissue deposition leads to obesity and an increase in the production
of proinflammatory adipokines. Such individuals are at a high risk of type 2 DM and cardiovascular
diseases. Expansion of adipose tissue is associated with the accumulation of macrophages that expresses
several proinflammatory genes, including tumor necrotic factor (TNF) and interleukin-1 (IL-1), which
locally impair insulin signaling. Oxidative stress, endoplasmic reticulum stress, and inflammation could
promote both insulin resistance and β-cell dysfunction (Kahn et al. 2014).
Clock genes expressed in the brain are important in the establishment of circadian rhythmicity.
Changes in diurnal patterns and quality of sleep can have important effects on metabolic processes.
Hypothalamic inflammation might also contribute to central leptin (produced by adipose tissue that acts
at the level of hypothalamus to suppress appetite) resistance and weight gain (Kahn et al. 2014). Leptin in
normal physiological conditions causes accumulation of fat and reduces appetite through hypothalamic
effect, but in obese subjects leptin resistance is developed, which leads to excessive flux of free fatty
acids. This in turn leads to insulin resistance and β-cell dysfunction.
In addition to the secretion of incretin hormones, the gastrointestinal tract has crucial roles in
type 2 DM. The gut may have an important role in insulin resistance in obese type 2 DM (Mingrone
and Castagneto-Gissey 2014). Jejunal proteins secreted by type 2 obese diabetic mice or insulinresistant obese humans impair insulin signaling. These proteins induce insulin resistance in normal
mice and inhibit insulin signaling in vitro in rat skeletal muscle cells. Metabolic surgery has been
shown to be effective in inducing remission of type 2 DM prior to any significant weight reduction. In metabolic surgery, the secretion of these proteins may be drastically impaired or abolished
(Mingrone and Castagneto-Gissey 2014). Furthermore, in duodenal–jejunal bypass surgery, jejunal nutrient sensing is required to rapidly lower glucose concentration (Breen et al. 2012). In the
proximal jejunum, stimulation of a nutrient sensor by glucose and/or lipid reduces hepatic glucose
production. Recent studies suggest that microbes present in the gut also have a role in the development of insulin resistance.
The liver is a major source of glucose production through glycogenolysis and gluconeogenesis.

Excess accumulation of lipids in liver develops and causes insulin resistance and type 2 DM. Studies
in mice and humans have elucidated an important role for hepatic diacylglycerol activation of atypical
protein kinase C (PKCa) in triggering hepatic insulin resistance (Perry et al. 2014). Lipid accumulation is probably associated with the secretion of proinflammatory cytokines from Kupffer cells (resident macrophages) and the recruited macrophages that impair insulin signaling. Markers of systemic
inflammation, including C-reactive proteins and its upstream regulator IL-6, are associated with insulin
sensitivity and β-cell function. Decrease in inflammation improves β-cell function in patients with type
2 DM (Kahn et al. 2014).
1.1.1.4.2.1  Pathogenesis of Type 2 DM  During the early stage of type 2 DM, insulin resistance is
compensated by increased production of insulin; thus, normal glucose levels are preserved (DeFronzo
2004). Studies suggest that insulin resistance precedes defect in insulin secretion. Eventually, the defect
in insulin secretion progresses to a level where insulin secretion is grossly inadequate. The delicate balance between β-cell replication and apoptosis is interrupted in DM. Further, the replacement with new
β-cells appears to be limited in humans after 30 years of age (Kahn et al. 2014).
At the onset of the pathogenesis of type 2 DM, the peripheral insulin-responsive tissues such as muscle
and adipose exhibit a decreased rate of disposal of excess glucose and fatty acid from the circulatory
system. At the same time, due to reduced insulin sensitivity of the liver, hepatic glucose production
increases. In type 2 DM, pronounced insulin resistance is observed in muscle, liver, and adipocytes.


Introduction

5

Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased
peripheral glucose utilization results in postprandial hyperglycemia and impaired glucose tolerance.
The ectonucleotide pyrophosphatase, phosphodiesterase-1 (ENPP-1), known to hydrolyze
5ʹ-phosphodiester bond in nucleotides, is very important in insulin signaling. When ENPP-1 interacts
with IR, a decrease in insulin-dependent tyrosine phosphorylation of its α-subunit occurs. This leads
to the failure of the autophosphorylation of β-subunit and switching off of insulin signaling (Abate
and Chandalia 2007; Ohan et al. 2007). Inappropriate degradation of insulin receptor substrate 1 and
2 (IRS-1 and IRS-2) in the insulin-signaling pathway partly through the upregulation of suppressors of
cytokine signaling was reported in many cases (Balasubramanyam et al. 2005).

In obese subjects, retinol-binding protein-4 interacts with phosphatidyl inositol 3-kinase (PI3K)
and reduces its activity. This also leads to insulin resistance in muscles and enhances the expression
of phosphoenol pyruvate carboxylase in liver. The changes in the production of adipokines are also
reported in nonobese Asian Indians having a direct link with obesity-independent insulin resistance.
Obesity also reduces the phosphorylation of proteins involved in intracellular insulin signaling via
IRS-1 and PI3K. This results in the reduction of glucose transporter-4 (GLUT4)-mediated influx of glucose (Ishiki and Klip 2005). The decreased insulin signaling in the skeletal muscles contributes to lipid
accumulation and impairment in glycogen formation in the muscle cells. The excessive accumulation
of triglycerides in the skeletal muscle cells of obese subjects is observed due to the greater mobilization of free fatty acids from insulin-resistant adipocytes. Increased free fatty acid flux from adipocytes
leads to increased synthesis of very low density lipoprotein (VLDL) and triglycerides. This may lead
to fatty liver diseases. Lipid accumulation and impaired fatty acid accumulation may generate lipid
peroxides. In addition to the contribution of fatty acid and triglycerides in the pathogenesis of type 2
DM, leptin, resistin, adiponectin, and TNF-α produced by adipocytes have roles in the pathogenesis.
TNF-α, overexpressed in obese subjects, leads to impaired insulin signaling (Rosen and Spiegelman
2006). Syndromes associated with insulin resistance may include in certain cases acanthosis nigricans
(increased thickness of the prickle cell layer of the skin and hyperpigmentation) and ovarian hyperandrogenism and polycystic ovary.

1.1.2  Complications of DM
In both type 1 and type 2 DM, uncontrolled hyperglycemia and, to some extent, hyperlipidemia lead
to the development of both acute and long-term complications. The development of complications is
simplified and presented in a flowchart (Figure 1.3). Diabetes ketoacidosis (DKA) and hyperglycemic
hyperosmolar state (HHS) are the acute complications of DM. DKA is very common in type 1 DM
patients, but it also occurs in certain type 2 DM cases. Major symptoms include nausea, thirst/polyurea,
abdominal pain and shortness of breath; in children, cerebral edema is frequently associated with this.
Ketoacidosis results from a marked increase in fatty acid release from adipocytes with a shift toward
ketone body synthesis in the liver. Normally, these fatty acids are converted to triglycerides or VLDL
in the liver. But high levels of glucagon alter hepatic metabolism to favor ketone body formation. Both
insulin deficiency (absolute or relative deficiency) and glucagon excess are generally required for DKA to
develop. Excess catecholamines, cortisol, and/or growth hormone also contribute to the development of
DKA. HHS is primarily seen in individuals with type 2 DM with a history of polyurea, weight loss, and
diminished oral intake. Clinical features include profound dehydration, hyperosmolality, hyperglycemia,

tachycardia, and altered mental status. Hyperglycemia associated with DM and inadequate fluid intake
induces an osmotic diuresis that leads to intravascular volume depletion (Powers 2008).
Chronic complications of DM can be divided into vascular and nonvascular complications.
Microvascular complications lead to retinopathy, neuropathy, and nephropathy, whereas coronal arterial
disease, peripheral arterial disease, and cerebrovascular disease are due to macrovascular complications.
The microvascular complications of both type 1 and type 2 DM result from chronic hyperglycemia.
Coronary heart diseases and morbidity are two to four times greater in patients with DM. Dyslipidemia
and hypertension also play important roles in macrovascular complications. Nonvascular complications
include gastroparesis, diarrhea, uropathy, sexual dysfunction, infections, periodontal diseases, dermatological complications, and glaucoma. Foot ulcers and infections can lead to gangrene, which may require


6

Anti-Diabetes Mellitus Plants

Diabetes
mellitus

Diabetes ketoacidosis

(more common in type 1)

Acute
complications

Hyperglycemia,
hyperlipidemia
AGEs formation, sorbital accumulation,
Sustained PKC pathway activation,
Increased production of ROS,

Increased glucose flex (hexose amine pathway)

Hyperosmolar and
hyperglycemia state

(primarily seen in type 2)

Chronic
complications

Vascular
complications
Macrovascular
complications

Microvascular
complications

Coronary artery disease
Cerebrovascular disease

Retinopathy,
nephropathy,
neuropathy

Nonvascular
complications
Gastroparasis, diarrhea,
uropathy, glaucoma,
periodontal disease,

sexual dysfunction,
foot ulcer, gangrene,
dermatological problems

FIGURE 1.3  Complications of diabetes mellitus. AGEs, advanced glycation end products; PKC, protein kinase C; ROS,
reactive oxygen species.

amputation. Hyperglycemia facilitates the growth of pathogenic fungi and bacteria. Furthermore, abnormal cell-mediated immunity and phagocyte function and diminished vascularization lead to a greater
frequency and severity of infections in DM.
Diabetes nephropathy develops in 30%–40% of patients with both type 1 and type 2 DM within 20–25
years after the onset of DM (Powers 2008). Diabetic nephropathy is the leading cause of DM-related
morbidity and mortality (Lopes 2009; Wada and Makino 2009). DM is the leading cause of blindness in
the United States. Individuals with DM are 25 times more likely to become blind than normal individuals.
Blindness is primarily due to diabetic retinopathy and macular edema. Diabetic neuropathy occurs in about
50% of individuals with chronic type 1 or type 2 DM. Diabetic retinopathy is classified into two stages:
nonproliferative and proliferative. Nonproliferative retinopathy is marked by retinal vascular microaneurysms. In proliferative retinopathy, neovascularization appears in response to retinal hypoxia (Powers
2008). Neuropathy involving the autonomic nervous system may lead to genitourinary dysfunction.
The mechanisms wherein hyperglycemia leads to the aforementioned serious complications are not
fully understood. However, the suggested mechanisms include (1) formation of advanced glycosylation
end products (AGEs), (2) increased levels of sorbitol formation, (3) sustained activation of the PKC
pathway, and (4) increased glucose flux through the hexosamine pathway. Intracellular hyperglycemia
causes the formation of AGEs by nonenzymatic glycosylation of proteins. AGEs have been shown to
cross-link proteins and accelerate atherosclerosis, promote glomerular dysfunction, reduce nitric oxide
synthesis, and induce endothelial dysfunction. During hyperglycemia, a part of the glucose is converted
to sorbitol by the enzyme aldolase reductase; increased sorbitol concentration leads to increase in cellular osmolality, alterations in redox potential, and increase in reactive oxygen species (ROS) generation.
These may facilitate retinopathy, nephropathy, and neuropathy. Hyperglycemia increases the formation of DG, which activates PKC. This enzyme, among other actions, alters transcription of genes for
fibronectin, type IV collagen, contractile proteins, and extracellular matrix proteins in endothelial cells.
Hyperglycemia increases glucose flux through the hexose amine pathway, which generates fructose6-phosphate, a substrate for O-linked glycosylation and proteoglycan production. This pathway may