Natural Products and their Bioactives in Antidiabetic Drug Discovery E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 607

Veröffentlichungsjahr: 2023

Beschreibung

Natural Products and their Bioactives in Antidiabetic Drug Discovery Enables researchers to effectively understand and use bioactive compounds to target, prevent, and manage diabetes Natural Products and Their Bioactives in Antidiabetic Drug Discovery provides readers with an overview of recent research in new drug discovery against diabetic complications based on bioactives from NPs, bridging the gap between the public research institutes and private companies working to find drugs to treat diabetes. To aid in reader comprehension, the text includes case studies and illustrated examples in relevant chapters. Part one presents chapters on fundamental concepts of diabetes mellitus (DM) and recent drug discovery progress along with the various druggable targets and challenges. Part two covers bioactive compounds targeting Type-1 Diabetes. Part three focuses on Type-2 Diabetes. In Part four, the contributors address gestational DM prevention and management with natural compounds. Written by a global team of experts in the field, Natural Products and their Bioactives in Antidiabetic Drug Discovery covers sample topics such as: * Obesity risk factor in patients with T1DM and possible role of nutritional therapy in its management * Use of natural non-insulin drugs as a novel approach to enhance therapeutic outcomes against T1DM * Effectiveness of functional foods in intervening the diabetic complications and realistic results in clinical trials * Implementation of nanotechnology in improving the bioavailability and reducing the threshold dose of bioactive compounds * Various antidiabetic mechanisms of action of different polyphenols and immunomodulatory role of NPs bioactives relevance in T1DM therapy * Effects of natural products on genetics of gestational diabetes With comprehensive coverage of recent research in new drug discovery against diabetic complications based on bioactives from NPs, Natural Products and Their Bioactives in Antidiabetic Drug Discovery is an essential resource for researchers and professionals involved in drug discovery and development, health care, medicinal chemistry, phytochemistry, plant science, and toxicology.

Leseprobe

Natural Products and their Bioactives in Antidiabetic Drug Discovery

Edited by

Kanti Bhooshan Pandey CSIR-Central Salt & Marine Chemicals Research Institute, Bhavnagar, Gujarat, India

Maitree Suttajit University of Phayao, Phayao Province, Thailand

Pinar Atukeren Istanbul University-Cerrahpaşa, Istanbul, Turkey

This edition first published 2024

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Contents

Cover

Title Page

Copyright Page

List of Contributors

Preface

Part I Fundamental Concepts of Diabetes Mellitus and Drug Discovery Process

1 Diabetes Mellitus and Natural Product-Based Drug Discovery Novel Directions

2 Marine Natural Products in the Management of Diabetes Mellitus

3 Carbohydrate-Based Antidiabetic Agents from Natural Products

4 Functional Foods in Clinical Trials in the Intervention of Diabetes Complications

5 Role of Nanotechnology in Refining the Antidiabetic Activities of Plant Derived Bioactives

Part II Bioactive Compounds Against Type 1 Diabetes Mellitus

6 Epidemiology and Genetics of Type 1 Diabetes Mellitus the Effect of the Mediterranean Diet

7 the Emerging Role of Plant Polyphenols in the Management of Type 1 Diabetes Mellitus

8 Bioactives as Modulators of β-Cells and Immunity in Therapy of Type 1 Diabetes Mellitus

9 Obesity in Type 1 Diabetes Mellitus Clinical Impact and Nutritional Therapy

10 Protective Effects of Natural Non-Insulin Drugs Against Type 1 Diabetes Mellitus

Part III Bioactive Compounds Against Type 2 Diabetes Mellitus

11 Age-Induced Biomarkers of Oxidative Stress in Type 2 Diabetes Mellitus Role of Plant Polyphenols

12 Bioactives from Clove Oil for Antibacterial Wound Dressings for the Treatment and Management of Wounds in Type 2 Diabetes Mellitus

13 Nutritional Features and Bioactivities of Thymoquinone Against Type 2 Diabetes Mellitus

14 Effect of Resveratrol and Catechins in Maintaining Redox Homeostasis During Type 2 Diabetes Mellitus

15 Cannabis Action Mechanisms and Potential Roles in the Management of Type 2 Diabetes Mellitus

Part IV Gestational Diabetesprevention and Management by Natural Compounds

16 Epidemiology of Gestational Diabetes Mellitus Preventive Significance of Dietary Pattern

17 Biomarkers of Gestational Diabetes Mellitus, Dietary Polyphenols, and Drug Discovery

18 Medicinal and Aromatic Plants in the Prevention of Gestational Diabetes and Associated Consequences Current Insights

19 Enhancement of Insulin Sensitivity and Management of Lipid Disorders During Gestational Diabetes Mellitus Role of Capsaicin

20 Effects of Natural Products on the Genetics of Gestational Diabetes Mellitus

Index

End User License Agreement

List of Tables

CHAPTER 01

Table 1.1 Insulin preparations mainly...

Table 1.2 Symptoms leading to...

Table 1.3 Newman and Cragg...

Table 1.4 Antidiabetic agent sources...

Table 1.5 Agents approved 2021...

CHAPTER 02

Table 2.1 Diabetes types, major...

Table 2.2 Marine natural antidiabetic...

CHAPTER 04

Table 4.1 Selected functional foods...

CHAPTER 05

Table 5.1 A description of...

CHAPTER 07

Table 7.1 Anti-diabetic role...

CHAPTER 08

Table 8.1 Different classes of...

CHAPTER 09

Table 9.1 ISPAD clinical practice...

CHAPTER 10

Table 10.1 Traditional plants used...

Table 10.2 Phytochemicals used in...

CHAPTER 11

Table 11.1 Chemical structures of...

CHAPTER 12

Table 12.1 Comparison of clove...

Table 12.2 Antimicrobial properties of...

CHAPTER 17

Table 17.1 List of the...

Table 17.2 The potent biomarkers...

CHAPTER 19

Table 19.1 Clinical effects of...

List of Illustrations

CHAPTER 01

Figure 1.1 Different antidiabetic structures.

Figure 1.2 Different antidiabetic structures.

Figure 1.3 Different antidiabetic structures.

Figure 1.4 Different antidiabetic structures.

CHAPTER 02

Figure 2.1 Pie chart representing...

Figure 2.2 Regional projection of...

Figure 2.3 Regional-wise projection...

CHAPTER 03

Figure 3.1 Complications associated with...

Figure 3.2 Glucosidase inhibitor (A...

Figure 3.3 Flavanol glycoconjugates (glucosidase...

CHAPTER 04

Figure 4.1 Hyperglycemia-induced biochemical...

Figure 4.2 General antidiabetic effects...

CHAPTER 05

Figure 5.1 The diagram shows...

Figure 5.2 Different types of...

CHAPTER 06

Figure 6.1 Simplified scheme of...

CHAPTER 07

Figure 7.1 Factors involved in...

Figure 7.2 Major steps in...

Figure 7.3 Classification of natural...

Figure 7.4 Polyphenol-loaded nanodelivery...

CHAPTER 08

Figure 8.1 Schematic representation of...

CHAPTER 12

Figure 12.1 Different physiological pathways...

Figure 12.2 Pathophysiological processes involved...

CHAPTER 13

Figure 13.1 (a) Nigella sativa...

Figure 13.2 Schematic representation of...

CHAPTER 14

Figure 14.1 The chemical structure...

CHAPTER 17

Figure 17.1 Common and simple...

Figure 17.2 Predictive and diagnostic...

Figure 17.3 Descriptive illustration of...

CHAPTER 18

Figure 18.1 Diagrammatic representation of...

Guide

Cover

Title Page

Copyright

Table of Contents

List of Contributors

Preface

Begin Reading

Index

End User License Agreement

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List of Contributors

Muveddet Emel AlphanDepartment of Nutrition and Dietetics Faculty of Health Science Istanbul Atlas University Istanbul, Turkey

Bavani ArumugamDepartment of Biomedical Science Faculty of Medicine University of Malaya Kuala Lumpur Malaysia

Pınar Atukeren Department of Medical Biochemistry Cerrahpaşa Faculty of Medicine Istanbul University-Cerrahpaşa Istanbul, Turkey

Yasemin AydinDepartment of Biology Faculty of Science Istanbul University Istanbul, Turkey

Sahar BakhtDepartment of Pharmaceutical Chemistry Government College University Faisalabad Faisalabad, Pakistan

Onur BaykaraDepartment of Medical Biology Cerrahpaşa Medical Faculty Istanbul University-Cerrahpaşa Turkey

Bilge Nur ColDepartment of Nutrition and Dietetics Faculty of Health Science Istanbul Atlas University Istanbul, Turkey

S. Asha Devi Laboratory of Gerontology Department of Zoology Bangalore University Bangalore Karnataka, India

Ravindra DharCentre of Materials Science University of Allahabad Prayagraj, India

Prachee DubeyGovernment G.I. College Malwan, Fatehpur Uttar Pradesh, India

Mansi GandhiDepartment of Chemistry School of Advanced Sciences Vellore Institute of Technology Vellore Tamil Nadu, India

Institute of Chemistry The Hebrew University of Jerusalem Jerusalem, Israel

Waseem Hassan Department of Pharmacy COMSATS University Islamabad Lahore campus Lahore, Pakistan

Faraza JavaidQuaid-e-Azam College of Pharmacy Sahiwal, Pakistan

Gülen Ecem KalkanDepartment of Nutrition and Dietetics Faculty of Health Science Istanbul Okan University Istanbul, Turkey

Ahu Korkut Department of Obstetrics and Gynecology Faculty of Medicine Eskisehir Osmangazi University Turkey

Umah Rani KuppusamyDepartment of Biomedical Science Faculty of Medicine University of Malaya Kuala Lumpur, Malaysia

Subir Kumar MandalCSIR-Central Salt & Marine Chemicals Research Institute Bhavnagar Gujarat, India

Suparna MandalLaboratory of Gerontology Department of Zoology Bangalore University Bangalore Karnataka, India

Sonam MishraCentre of Materials Science University of Allahabad Prayagraj, India

Jigeesha MishraJacob Institute of Biotechnology & Bio-Engineering Sam Higginbottom University of Agriculture Technology & Sciences Prayagraj, India

David J. NewmanNIH Special Volunteer Wayne, Pennsylvania USA

Shashank Kumar OjhaMedicine Department School of Pharmacy Hebrew University of Jerusalem Israel

Burcu Ateş ÖzcanDepartment of Nutrition and Dietetics Faculty of Health Science Marmara University Istanbul Turkey

Murali Krishna PaidiAcademy of Scientific and Innovative Research (AcSIR) Ghaziabad India

Bishnu Kumar PandeyDepartment of Physics SPM College, University of Allahabad Prayagraj, India

Kanti Bhooshan PandeyCSIR-Central Salt & Marine Chemicals Research Institute Bhavnagar, Gujarat, India

Academy of Scientific and Innovative Research (AcSIR) Ghaziabad India

S. Raja SekharPathology Section, MPMMCC Banaras Hindu University Campus Varanasi U.P., India

Andleeb ShahzadiDepartment of Medical Pharmacology Faculty of Medicine Istanbul University-Cerrahpaşa Istanbul, Turkey

Sandeep SinghHadassah Biological Psychiatry Laboratory Hadassah - Hebrew University Medical Center Jerusalem, Israel

Haktan SonmezDepartment of Medical Pharmacology Faculty of Medicine Istanbul University-Cerrahpaşa Istanbul, Turkey

Shailendra Kumar SrivastavaJacob Institute of Biotechnology & Bio-Engineering Sam Higginbottom University of Agriculture Technology & Sciences Prayagraj, India

Maitree SuttajitThai Vegetarian Association Changpuak Chiang Mai, Thailand

Brahm Kumar TiwariDepartment of Paramedical Sciences SGT University Gurugram Haryana, India

Kanchan Siddaprasad Udata CSIR-Central Salt & Marine Chemicals Research Institute Bhavnagar Gujarat, India

Geeta WatalDepartment of Chemistry University of Allahabad Prayagraj India

Karolin YanarIstanbul University-Cerrahpaşa Cerrahpaşa Medical Faculty Department of Medical Biochemistry Istanbul, Turkey

Zeynep Mine Coşkun YazıcıDemiroğlu Bilim University Department of Molecular Biology and Genetic Istanbul, Turkey

Burcu YeşilkayaDepartment of Nutrition and Dietetics Faculty of Health Science Okan University Istanbul, Turkey

Banu Orta-YilmazDepartment of Biology Faculty of Science Istanbul University Istanbul, Turkey

Preface

Diabetes mellitus (DM), which is commonly known as “sugar disease”, has now become “bitter” for health and this metabolic disease is increasing worldwide at an alarming rate. The combination of chronic pathological disorders in pancreatic β-cells leading to persistent hyperglycemia is connected to serious organ damage followed by failure including kidneys, eyes, feet, nerves, brain, gastrointestinal tract, and cardiovascular system in DM. DM may be of different types; a deficiency of insulin production by the genetic failure of the pancreas at birth (type 1 diabetes mellitus: T1DM), or insufficiency of insulin production in the face of insulin resistance (type 2 diabetes mellitus: T2DM), or insulin resistance through the influence of different hormones during pregnancy (gestational diabetes mellitus: GDM). Progress and development of DM can be prevented/controlled by pharmacological treatments such as insulin therapy and medication by synthetic drugs, but these therapies are either costly or significantly associated with the risk of other health complications and all-cause mortality.

The need to salvage the havoc of chronic complications of DM by bioactive compounds from natural products (NPs) is presently gathering a lot of attention due to their being affordable, clinically effective, and having relatively infrequent side effects than current synthetic drugs. Over the last few decades a large number of natural products have been sought and discovered for their functional values to develop anti-hyperglycemic drugs. However, due to enormous scaffold diversity, structural complexity, and other special features in comparison to conventional synthetic molecules, NPs confer both advantages and challenges for the drug discovery process. NPs enriched with bioactive compounds cover a wider area for optimization of the anti-diabetic drug spectrum by stimulating the proliferation of β-pancreatic cells to produce insulin, modulating enzymes involving glucose uptake and glucose transport and metabolism, modifying gene expression, and hormone activities relating to glucose homeostasis, oxidative stress, and other modifications of mechanisms.

Written by a global team of experts, this book aims to provide readers with an overview of recent research in new drug discovery against diabetic complications based on bioactives from NPs. This book has 20 chapters and is divided in four parts to provide a clearer picture for readers. Part 1 introduces the fundamental concepts of DM and the recent NP-based drug discovery progress, the various druggable targets, and challenges. Part 2 provides a review of bioactive compounds and healthy diets and natural non-insulin drugs against T1DM. Part 3 reviews some effective bioactive compounds from plants against T2DM; and Part 4 presents the updated drug discovery on GDM prevention and management by NPs.

Chapter 1 extends an expert opinion on DM and novel directions towards NP-based drug discovery. The marine ecosystem is one of the major natural treasures for various products; it can play a crucial role in biomedical research and drug development against DM. However, scattered and few studies have bypassed this field. Chapter 2 explores more on this topic. Chapter 3 has been incorporated in the book to explore the carbohydrate-based antidiabetic natural agents. Functional foods rich in bioactive compounds are recently gaining much attention in health promotion. Keeping this rationale in mind, a dedicated Chapter 4 is included in the book that discusses the effectiveness of functional foods in the intervention of diabetic complications and the realistic results in clinical trials.

The implementation of nanotechnology in improving the bioavailability and reducing the threshold dose of bioactive compounds and thus overcoming the associated biopharmaceutical obstacles, and refining the antidiabetic effects of plant bioactives, is discussed in Chapter 5. In understanding the genetics of DM, associated risk genes may introduce new avenues for NP-based drug discovery in preventing complications. Chapters 6 and 20 discuss the genetics of T1DM and GDM and, along with Chapter 16, highlight their interaction with NPs and dietary patterns. Recently, plant polyphenols have gained global interest in DM intervention due to their strong antioxidative, redox restoring and β-cells’ proliferation inducing effects. The book contains dedicated Chapters 7, 11, 14, 17, and 19 on the various antidiabetic mechanisms of action of different polyphenols. The immunomodulatory role of NPs’ bioactives’ relevance in T1DM therapy is incorporated in Chapter 8.

Obesity is now a global public health concern that affects populations of all ages and is linked with the onset of many chronic health impairments; however, the connection between obesity and T1DM is not fully understood. Chapter 9 deals with the discussion on obesity risk factor in patients with T1DM and the possible role of nutritional therapy in its management. Insulin therapy is the most frequently used medication against T1DM; however, its side effects and risks limit its safety. Chapter 10 explores the use of natural non-insulin drugs as a novel approach to enhance therapeutic outcomes against T1DM. Impaired wound healing in T2DM often leads to chronic lesions in these patients, which results in vascular dysfunction, neuropathic abnormalities, immune irregularities, and various deviations in biochemical attributes. Chapter 12 focuses on the potential of clove oil in wound healing and dressing in T2DM. Chapters 13 and 15 highlight nutritive features and bioactivities of thymoquinone and cannabis in the management of T2DM. Chapter 18 discusses the exploration of medicinal and aromatic plants in preventing the pathological events of GDM.

We extend our thanks to all our contributors who provided us with splendid chapters of the field and John Wiley & Sons, Inc., for making every effort to publish this book, when a large group of populations worldwide is concerned with the diabetes associated health issues. Lastly, we hope that readers including professional scientists and experts in various areas of basic, pharmaceutical, and medical research will acknowledge this comprehensive and valuable composition.

Kanti Bhooshan Pandey Bhavnagar, Gujarat, India

Maitree Suttajit Chiang Mai, Thailand

Pinar Atukeren Istanbul, Turkey

Part I Fundamental Concepts of Diabetes Mellitus and Drug Discovery Process

1 Diabetes Mellitus and Natural Product-based Drug DiscoveryNovel Directions

David J. Newman

NIH Special Volunteer, Wayne, PA 19087, USA

1.1 Introduction

In terms of saving lives and/or helping people suffering from this disease, I will demonstrate the history of treatments for the diseases known as “diabetes” in which I include both diabetes 1 (autoimmune destruction of insulin-producing β-cells in the pancreas) and diabetes 2 (inadequate insulin production and/or insulin resistance, though exact mechanisms are not understood). The data presented will exemplify the role(s) of natural products in deriving both the earlier (mainly insulin) and current drugs that ameliorate these diseases. I have included both “versions” of the disease as nowadays there are reports demonstrating adult onset of what would be considered type 1 (T1DM) and a very significant number of type 2 (T2DM), frequently included under the catchall term, “metabolic syndrome” [1] and, later on, some of the current factors that may well lead to such a diagnosis are listed. The chapter will first focus on insulin and its current sources, and will then give details of other agents, some very slightly modified natural products from manifold sources, and then the synthesis of what can be best described as natural product spatial mimics that are in use nowadays, particularly in the treatment of T2DM.

1.2 A Brief History of Insulin

The story surrounding the discovery and utilization of insulin in Canada at the University of Toronto linking the utility of insulin to treat diabetes, was the first clinically reported linkage of this human hormone to the treatment of diabetes. However, reports of this disease went back many centuries, even millennia, with initial reports around 552 BC in the Ebers papyrus (which can be considered the first written description of diseases and potential treatments) by Egyptian scholars. Similar reports from both Chinese and Indian “academics” in a relatively similar time frame also noted the disease, with all reports noting the common link that patients had a constant flow of “sweet urine”. In the time frame of roughly 100 years BCE, Demetrius of Apameia was credited with the introduction of the term “diabetes” (from the Greek word for siphon) since he noted the constant flow of urine from patients Then, in the second century CE, the Greek physician Aretaeus of Cappadocia first described the first accurate clinical description of diabetes [2]. Galen, at approximately the same time as Aretaeus, associated diabetes with a disease of the kidneys, and this persisted for the next 1500 years.

Then, following a number of varied experiments using dogs (with or without their pancreas) and other data from diabetic human patients who had damaged islets of Langerhans in their pancreas, led to the suggestion in 1916 by Sharpey-Schafer of a linkage between a secretion from the pancreas and “control” of carbohydrate metabolism by an as yet unidentified hormone that regulated glucose that he named insulin [2]. The complex interactions, both scientific and personal, that led to the purification of insulin and its initial clinical success are well described by Rosenfeld in 2002 [3]. This report also mentions the first production of crystalline insulin in 1926 by Abel at Johns Hopkins and then, in 1951, Sanger sequenced insulin, the first protein hormone to have its formal structure reported [4, 5]. Until the production of human insulin via biotechnological methods, which will be discussed later in this chapter, all supplies of insulin were effectively from utilization of bovine or porcine sources and, at times, chemical modification to aid in stability and/or ease of utilization.

1.3 Biosynthesis of Insulin

The biosynthetic process produces an inactive 110 residue, preproinsulin, which on translation into the endoplasmic reticulum has the signal peptide removed leaving proinsulin, which folds to give three disulfide linkages between the precursors of the A and B chains. This proinsulin then transits through the Golgi apparatus into the secretory granules. Further removal of selected portions by a number of hydrolytic enzymes produces the active insulin composed of A (21 amino acids) and B (30 amino acids) chains connected via two disulfide bonds. It is stored as an “inactive” hexamer and is now available for release of the monomer following the correct metabolic stimulus. It should also be pointed out that this is a very ancient molecule and is found across many eukaryotic genera including fungi, teleost fish and, in a modified form, in the venom of cone snails.

1.3.1 Humulin®, the Second Human Hormone Produced by Biotechnology

In 1977, somatostatin was the first peptide hormone to be produced by the then new and novel recombinant DNA process [6, 7]. This was also effectively the foundation product of the company Genentech, which had been founded the previous year. Since the human genes corresponding to in vivo production of insulin had not been identified/cloned at that stage of rDNA operations, what could be considered “synthetic genes” were made chemically, corresponding to the formal structure of insulin components. The success of this was demonstrated in a 1979 paper by Goeddel et al. [8], which used the “synthetic human genes” published late the previous year by Crea et al. [9]. Proof of the validity of this work was shown by the approval by the US FDA of Humulin. Just to put the timing in perspective, I have used the following quote from Riggs’ article [7]. “For example by 2020 the genes for insulin can be made in a few hours by an automated instrument and then cloned and expressed by a single person in about a week.”

1.3.2 Further Derivatives of Insulin Using rDNA Techniques

Once the utility of this process was proven, over time since the early 1980s, insulins with improved pharmacology have been approved. In a recent (2019) open access journal, Guney [10] described the number of agents that are currently available and classified them by their pharmacological parameters.

As of the date of that review the following were available (though not perhaps in all countries). I have omitted the premixed and biphasic analogs in Table 1.1.

Table 1.1 Insulin preparations mainly for T1DM treatment.

Type

Generic name

Brand name

Rapid-acting

Glulisine

Apidra

Lispro

Humalog

Aspart

NovoRapid

Short-acting

Insulin isophane

Humulin R

Neutral insulin

Actrarapid

Regular and isophane human insulins

SciLin N

Intermediate

Human insulin isophane

Humulin N

INN insulin human

Protophane

Long-acting

Detemir

Levemir

Glargine

Lantus

Insulin degludec

Tresiba

Thus, there are multiple variations designed to help T1DM patients control their glucose levels before and after meals.

1.4 Current Possible Insulin-based Treatments for T2DM

In a recent paper by Sebastian et al. [11] there is significant discussion of various insulin-based treatments for T2DM with one of the more promising being the Technosphere (TI) inhaled insulin (Afreeza®), which was approved by the FDA in 2014 for both T1DM and T2DM patients, with further details in the 2021 paper by Levin et al. in 2021 [12]. This is in contrast to the current treatments of a glucagon-like peptide (GLP)-1 receptor agonist after metformin, and variations on other mixed oral/injectable treatments.

1.4.1 Metabolic Syndrome (As of June 2022)

In an article in the American Chemical Society’s journal Central Science [13], if a patient has any three of the following five criteria as described in Table 1.2 for metabolic syndrome then they have a high risk of T2DM and cardiovascular diseases.

Table 1.2 Symptoms leading to metabolic syndrome diagnosis.

Criterion

Elevated waist circumference (female ≥88 cm; male ≥102 cm)

Elevated triglycerides (≥150 mg.dL

–1

)

Low HDL (female <50 mg.dL

–1

; male <40 mg.dL

–1

)

Elevated blood pressure (systolic ≥130 mm Hg, or diastolic ≥85 mm Hg or both)

Elevated fasting blood glucose (≥100 mg.dL

–1

)

However, there is at least one major caveat in the values listed in Table 1.2 that needs to be taken into account. A significant number of the values listed were taken from the Framingham heart study where less than 5% of the participants were of other than European ancestry. When current data from more diverse populations are included, particularly in Black populations, the figures for HDL need to be adjusted. In addition, there are data that East and South Asians are more resistant to insulin than other major populations including Hispanic. Thus, absolute reliance on the figures given in Table 1.2 can lead to incorrect over- or under-counting of populations that need treatment.

1.5 Non-insulin-linked Treatments for T1DM and T2DM

Although insulin is the gold standard for T1DM and recent data demonstrated that various insulin modifications may well be the newer treatment for T2DM, over the last 20 or so years, as some, though not all, of the “causes” of carbohydrate metabolic changes that led to T2DM variations in patients are being identified, the pharmaceutical industries in a number of countries began to explore a variety of non-insulin agents as ameliorants of this multi-organ problem, with a significant number being either based on natural products or modifications thereof.

1.5.1 Guanidines: Agents that Began as Herbal Remedies

There is one very well-known series of agents that were too early for the analyses referred to in the next subheading that covered the 1997 onwards reviews of drug sources made by the author and his colleagues. These agents were directly derived from the anecdotal usage of the perennial herb Galega officinalis Linn. as an herbal remedy in the Middle Ages in Europe with versions of Culpeper’s Complete Herbal suggesting that it had antidiabetic properties (effectively the “sweet urine” commented on earlier in this chapter). Culpeper’s Complete Herbal as of 1850 is available as part of the “Project Gutenberg” ebook series [14]. In addition to this ebook, there are other much more recent articles that give information on the use of both the natural product galegine, which was used over centuries but not as the pure chemical, though there are reports in the French literature as late as the mid-1930s of usage of partially purified extracts as treatments [15].

The fundamental chemistry report on the usage of guanidino compounds, in what we now know as T2DM, was a paper in the Journal of Biological Chemistry in 1918 where Watanabe demonstrated that guanidino compounds, including simple derivatives related to galegine (Figure 1.1–1) could reduce blood sugar levels [16]. The initial synthesis of metformin (Figure 1.1–2) was published in 1922 by Werner and Bell [17]. However, even though its glucose lowering potential was published, it was not used as an antidiabetic agent at that time. In the early 1940s, metformin was “rediscovered” in a search for antimalarial agents and then, in 1957, the French physician Jean Steme, first reported its potential as a treatment for adult onset diabetes [18]. Over the next few years, Sterne continued to publish on the utility and mechanism(s) of this agent in a number of publications, with the last one in 1964 before he moved to publishing in books [19].

Figure 1.1 Different antidiabetic structures.

From these reports and discoveries of the potential of this class of compounds, in 1958, metformin was introduced in the UK and other European countries, but it was not until 36 years later, in 1994, that metformin was approved by the US FDA. It was introduced in 1995, with two reports at that time that were key publications that confirmed the favorable risk/benefit ratio in the management of T2DM [20, 21]. In 2017, Bailey published a review giving the history of metformin and in that article, table 1.1 is a timeline with excellent commentary demonstrating the path from 1772 to 2011, with relevant citations given at each major point in the story [22].

From the perspective of using this compound as an antitumor agent, currently (July, 2022), from a search of the NIH clinical trials database (www.clinicaltrials.gov) using metformin as the drug candidate, there are 72 Phase 3 studies using metformin as a potential antitumor drug that are recruiting or are underway, with over 400 at the same trial level that have been completed.

1.5.2 Drugs Other than Guanides that Have Been Approved from 1997 to 09/2019 against T2DM

In a series of reviews written by the author and colleagues from 1997 to the latest in 2020 [23–28], we analyzed the chemistry behind the drugs that were approved by the US FDA or comparable agencies in other areas of the world, and only counted a drug one time. The first review specialized in antitumor and anti-infective agents, but from the 2003 review we extended the reviews to include most diseases where drugs had been approved since 1981.

These reviews were cumulative, with the latest in 2020 [28] being an open access article in the Journal of Natural Products. In the 2003 review [24], we introduced a subset of definitions that further divided the sources when chemical syntheses were used for production as approved drug entities, molecules that required some “chemical forensics” to formally decide if they were based on a natural product, and/or were recognized by the biological system as a mimic. The basic terms are shown in Table 1.3. If more details are desired by the reader, the 2003 review [24] will need to be consulted as detailed reasons with examples were given in that article.

Table 1.3 Newman and Cragg Codes.

Code

Brief definition/review year

B

Biological macromolecule/1997

N

Unaltered natural product/1997

NB

Botanical drug (defined mixture)/2012

ND

Natural product derivative/1997

S

Synthetic drug/1997

S*

Synthetic drug (NP pharmacophore)/1997

V

Vaccine/2003

/NM

Mimic of natural product/2003

As of the latest published review in 2020, there were 39 non-insulin antidiabetic agents approved by at least one governmental agency. Obviously, if one looks at the pharmaceutical industry data, the numbers will be greater, but as mentioned earlier, only the first approval of a drug is counted irrespective of the number of countries that might approve it later on. As of the end of September 2019, their breakdown was as shown in Table 1.4.

Table 1.4 Antidiabetic agent sources as of September 2019.

N

ND

S

S/NM

S*

S*/NM

1

8

4

16

1

9

The single natural product in Table 1.4 is voglibose (Figure 1.1–3), an α-glucosidase inhibitor first isolated in Japan in 1981 from Streptomyces hygroscopicus var limons and approved in 1994 in Japan for treatment for T2DM. Two other natural product derivatives (structures not shown) acarbose and miglitol were also approved in 1990 and 1998, respectively, targeting the same enzyme system.

1.5.2.1 Modified Peptides that are Incretin Mimics (GLP-1 Agonists)

In 2005, the peptide known as extenatide or Byetta®, a 39-residue peptide (Figure 1.1–4) was approved for T2DM treatment. This agent is what is known as a glucagon-like peptide 1 (GLP-1) agonist and it was based on one of the peptides in the saliva of the lizard known colloquially as “Gila monster” Heloderma suspectum. It is also known as an incretin mimic since GLP-1 is the naturally occurring incretin hormone. Since 2005, a number of other GLP-1 mimics, all based upon modifications of the extenatide base skeleton have been approved, including liraglutide (Figure 1.1–5) in 2009, lixisenatide (Figure 1.1–6) in 2013, semaglutide (Figure 1.1–7) in 2017, and a pegylated version, PEG-loxenatide (Figure 1.1–8) in 2019. With semaglutide, a non-natural amino acid Alb (Figure 1.1–7a. X=Alb) was inserted to avoid degradation, and in PEG-loxentenide (Figure 1.1–8) two unusual amino acids were used, the “D” isomer of alanine and norleucine. All of these are used for treatment of T2DM working as GLP-1 agonists and fall under the ND category.

1.5.2.2 Agents against Dipeptidyl Peptidase IV

Another contemporary target in T2DM is DPP-IV (dipeptidyl peptidase IV), and the agents that target this enzyme fall under the S/NM category. Eleven compounds directed against this target were approved between 2006 and 2016, with their structures shown in Figure 1.2 starting with sitagliptin (Figure 1.2–9) in 2006. After this initial agent, over the next ten years other agents were approved as follows: vildagliptin (Figure 1.2–10) in 2007, saxagliptin (Figure 1.2–11) in 2009, alogliptin (Figure 1.2–12) in 2010, linagliptin (Figure 1.2–13) in 2011, teneligliptin (Figure 1.2–14) and anagliptin (Figure 1.2–15) in 2012. Then, in 2015, three more “gliptins” were launched: evogliptin (Figure 1.2–16), omarigliptin (Figure 1.2–17), and trelagliptin (Figure 1.2–18), and in 2016, the latest to date was gosogliptin (Figure 1.2–19) following approval in Russia.

Figure 1.2 Different antidiabetic structures.

1.5.2.3 Agents against the Sodium-dependent Glucose Transporter (SGLT-1/2)

These are nine SGLT-1/2 inhibitors whose structures were based upon the nonselective natural product phlorizin (Figure 1.3–20), which led to dapagliflozin (Figure 1.3–21) in 2012, canagliflozin (Figure 1.3–22) in 2013, and then in 2014, four compounds using this base structure were approved, starting with empagliflozin (Figure 1.3–23), continuing with ipragliflozin proline (Figure 1.3–24) and tofogliflozin (Figure 1.3–25), with the last one in 2014 being luseogliflozin (Figure 1.3–26) where a thio-sugar was used. There was then a gap until 2017 when ertugliflozin (Figure 1.3–27) was approved. It should be noted that this compound structure is close to that of the 2012 dapagliflozin (Figure 1.3–21).

Figure 1.3 Different antidiabetic structures.

In the first nine months of 2019, two more compounds of this class were approved. Sotagliflozin (Figure 1.3–28), which also closely resembles dapagliflozin (Figure 1.3–21), but with a methyl sulfur substitute in the sugar moiety in place of the normal hydroxyl group. In 2019, remogliflozin etabonate (Figure 1.3–29) was approved. The “gliflozins” that are targeted against this protein complex fall under the S*/NM code. In addition, a recent paper by Shaffner et al. [29] covers the pharmacology of these inhibitors in detail and should be consulted in addition to the translational medicine aspect of these agents that was covered by Beitelshees et al. [30].

1.6 Post September 2019 Drug Approvals

Since the publication of the 2020 review [28] as of the middle of June 2022, the following three agents have been approved/launched for the first time (Table 1.5). Please note that their actual dates of approval might differ from their launch date in a specific country and that only the first approval and/or launch is noted.

Table 1.5 Agents approved 2021–2022.

Name/year

Mechanism

Newman and Cragg codes

Structure #

Imeglimin/2021

GSIS enhancement

S*/NM

Figure 1.4

–30

Zegalogue/2021

Glucagon receptor agonist

ND

Figure 1.4

–31

Tirzepatide/2022

GIP/GLP-1 agonist

ND

Figure 1.4

–32

Figure 1.4 Different antidiabetic structures.

These three drugs include one small molecule with a novel triazine structure (Imeglimin, Figure 1.4–30) that has activities similar to metformin and can be considered as a cyclic metformin derivative [31]. From a natural product aspect, the other two are peptidic in nature and are direct agonists of specific receptors with one being approved in 2021 and the other in 2022. The details of producing tirzepatide (Figure 1.4–32) on a kilogram scale was published by the Lilly scientists involved in 2021, and demonstrate the methodologies necessary to proceed from a lab-scale of less than a gram to kilogram quantities under cGMP conditions [32].

Wang, in 2022, published an excellent paper on the design parameters that were used to develop tirzepatide and this discussion is an excellent primer on how to design complex peptidic drugs [33]. In that paper, Wang identifies a web site (www.comparediabetesdrugs.com) that compares drugs used in the treatment of both T1DM and T2DM that is an excellent resource for scientists interested in this class of drugs.

1.8 Conclusion

Although insulin was first obtained for human use by extraction and then chemical modification from bovine or porcine sources, once the biotechnological capabilities of recombinant DNA were demonstrated in other areas (though on much smaller/simpler compounds) such as the production of first Humulin® and then modifications of insulin via these techniques, producing insulin no longer was the bottleneck in treatment of T1DM. In addition, as has been mentioned, there are nowadays treatment regimens for T2DM that include insulin treatments [11, 12], in addition to combination with the regular T2DM oral agents.

However, what is extremely interesting from a natural product chemistry perspective, is the progression from mediaeval herbal remedies (Goat’s rue aka Galega officinalis Linn.) via chemistry to give metformin (Figure 1.1–2) and other derivatives that were developed from another early natural product, phlorizin (Figure 1.3–20), that have been, and in most cases, still are in use as oral treatments for T2DM. What is also of interest is that due to the major advances in peptide synthesis, the two agents referred to in Table 1.5 that were approved for use in 2021 and 2022 under the “ND” code may well be prototypes for molecules in the future directed against specific organelles.

The clinical work around “metabolic syndrome” is ongoing as clinicians learn more about the problems that fall under that term, and it is possible that some of the newer agents may help resolve these problems in due course.

A Note on Structures

All structures were drawn using the program ChemDraw (v.19.1) and then inserted into the text. In the case of the polypeptides, which were greater than 30 amino acids, in certain cases the final structure also contained non-peptidic sidechains such as fatty acids and/or polyethylene glycol (PEG) substituents. Due to their size, the single letter codes corresponding to the international usage for L-amino acids were used within ChemDraw. Details of this nomenclature are shown in the following: https://www.fao.org/3/Y2775E/y2775e0e.htm. If there were modifications of amino acids used then they are shown under the relevant base figure.

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2 Marine Natural Products in the Management of Diabetes Mellitus

Murali Krishna Paidi1,2, Kanchan Siddaprasad Udata1,2 and Subir Kumar Mandal1,2,*

1 Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201002, India 2 Applied Phycology and Biotechnology Division, CSIR-Central Salt and Marine Chemicals Research Institute, Bhavnagar -364002, India * Corresponding author

2.1 Introduction

Diabetes mellitus (DM) is described as a group of metabolic disorders characterized by elevated levels of blood glucose [1]. Either diabetes occurs when the pancreas does not produce sufficient insulin (a peptide hormone that regulates the blood glucose levels), or when the body (cells) ineffectively uses the available insulin that is sufficiently produced from the pancreas. The prevalence of diabetes has been increasing in developing countries more than in developed countries. The International Diabetes Federation (IDF) has projected the global prevalence is 9.3% in 2019, which will increase by 25% in 2030, and 51% in 2045 if the current diabetes risk management and treatment programs remain unchanged [2]. In many developing countries, people are adapting to high-calorie, low-quality fast foods and other processed food items that are directly linked with the metabolic syndrome, obesity and type 2 diabetes mellitus (T2DM).

2.2 Global Trend and Prevalence of Diabetes

Diabetes is a most common chronic disorder, and the global burden of diabetes has increased significantly since 1990. It has imposed a global burden on public health and socioeconomic development [3]. Recently, the world population was projected to be ~7875 million in 2021, out of this number, about 537 million (6.81%) people living with diabetes will be increased significantly to 693 million by 2045 [1]. In 2019, the IDF estimated that 436 million people live with diabetes and the regional percentage of diabetes is higher (38.4%) in the Western Pacific region followed by the lowest (4.5%) in the African region (Figure 2.1). In the case of low and middle-income countries about 3 in 4 adults are living with diabetes [2]. The prevalence of both type 1 diabetes mellitus (T1DM) and T2DM has been increasing among children and adolescents, and it is estimated that those below age 20 with type 1 diabetes exceed one million [3].

Figure 2.1 Pie chart representing the regional percentage of diabetes in the world in 2021. Adapted from [2] (International Diabetes Federation).

2.3 Risk Factors and Complications of Diabetes

Chronic hyperglycemia during diabetes is associated with long-term microvascular complications affecting the eyes, kidneys, and nerves, and increases the risk of cardiovascular diseases (CVD). The majority of diabetes is categorized into two types: T1DM and T2DM (Table 2.1); although some of the hyperglycemia conditions are difficult to classify. For example, gestational diabetes mellitus (GDM) refers to glucose intolerance, and it was first recognized during the pregnancy stage. Currently, in many peoples (non-pregnant women or mass), glucose intolerance is increasing due to changes in modern diets and sedentary lifestyles. These changes are directly linked to obesity and fat accumulation in the body that causes T2DM and CVD.

Table 2.1 Diabetes types, major risk factors, and health related problems.

Type

Risk factors

Stage

Frequency

Complications

Type 1 Diabetes Mellitus (T1DM)/Juvenile DM

Rare type

Childhood and early adulthood

10% of people with diabetes

Increased thirst

Family history (if parent or sibling has T1DM)

Frequent urination

Autoimmune disease

Extreme hunger

Destruction of β-cells

Fatigue, irritations Blurred vision

Absolute insulin deficiency

Glycated hemoglobin (HbA1c)

Depression

Blood vessel damage and other acute symptoms

Type 2 Diabetes (T2DM)

Most common type

~29 to 65 ages

95% of people with diabetes

T1DM symptoms and hyperosmolar, hyperglycemic state (HHS) and other chronic symptoms

Partial dysfunction of β-cells, Insulin resistance

Overweight and obese

Family history (if parent or sibling has T2DM)

Age

Polycystic ovary syndrome

Abnormal cholesterol and triglyceride levels

Immune-mediated DM

Rare T1DM slowly evolving in adults

Adults to older ages

—

May develop T1DM by diabetes autoantibodies

A single glutamic acid decarboxylase antibody (GDA) autoantibody and uncontrolled β-cells function

Prediabetes

Blood glucose levels are higher than normal

~29 to 65 ages

—

Frequent urination

Extreme hunger

Infections of gums and other mouth related infections

Ketosis-prone T2 DM/ Ketosis-prone diabetes (KPD)

Severe dysfunction of β-cells

At any age

—

Hypoglycemia

Cerebral and pulmonary edema and kidney damage

Monogenic DM:

i) Monogenic defect of β-cells function

Specific/single gene mutation causes diabetes by making the pancreas less functional

Neonatal diabetes occurs in the first 6 months

4% of people with diabetes

Both Type 1 and 2 related complications

ii) Monogenic defect in insulin action

or

Maturity onset diabetes of the young (MODY) in early adulthood

Cystic fibrosis related DM (CFRD)

Genetic mutation

Specific to people suffering from cystic fibrosis disease.

2% in children, 19% in adolescents and 50% of individuals aged 20– 75 yr in the CF population

Abnormal glucose metabolism

Dysfunction of both β-cells and islet cells mass and numbers

Microvascular complications

Hyperglycemia and neuro, gastro and retinopathy symptoms

Drug or chemical induced DM

Impair insulin secretion or action

Organ transplant

—

Hyperglycemia

Destroy β-cells function

HIV/AIDS treatment

Glucocorticoid steroids use

Gestational DM

Hyperglycemia is due to the production of excess hormones by the placenta that makes body cells more resistant to insulin

Pregnancy stage

—

In baby: excess growth (macrosomia)

Low blood glucose

T2DM in later life

Women older than 25 years

In mother: preeclampsia and T2DM in the next pregnancy stage

Diabetes Insipidus/ Vasopressin Sensitive Diabetes Insipidus

Central diabetes insipidus

Suddenly at any age

—

Excessive urine production and thirst

Lack of the hormone vasopressin

Chronic dehydration, low blood temperature

Brain injury, tuberculosis and other diseases

Weight loss, hypertension, and kidney damage

Generally, diabetes related complications are divided into chronic and acute complications.

Chronic health complications: untreated diabetes in people with high blood glucose levels induces retinopathy [4, 5], nephropathy (kidney damage), neuropathy (nerve damage), damage to blood vessels, receding gum line in the mouth, amputation of feet, and heart attacks and strokes [6, 7]. All of these symptoms develop gradually and can lead to serious organ damage in diabetic persons if they have untreated or uncontrolled conditions.

Acute health complications: These can develop suddenly and lead to chronic or long-term conditions. Hypoglycemia is due to lower blood glucose levels in the body and hyperglycemia to high blood glucose levels [8]. Hyperosmolar Hyperglycemic State (HHS) is characterized by severe dehydration, very high blood sugars, and diabetic ketoacidosis (DKA) conditions [9]. Unchecked or untreated hypoglycemia or hyperglycemia is a dangerous acute complication that leads to diabetic coma. In 2017, diabetes was recognized as the ninth leading cause of mortality. Annually, more than one million deaths can be attributed to diabetes alone [10]. The World Health Organization (WHO) projected in November 2019 estimates of about 1.5 million deaths directly caused by diabetes worldwide [11]. In the last 10 years from 2011 to 2021, deaths attributable to diabetes have risen in almost all countries (Figure 2.2) [2].

Figure 2.2 Regional projection of the number of deaths attributable to diabetes in the last 10 years. Adapted from [2] (International Diabetes Federation).

The global health care expenditure on diabetes is more than double in 2021 as compared to 2011 and it is increasing continuously. According to the IDF project in 2021, the total health care expenses for diabetes for 2030 and 2045 will be triple in Africa, the Middle East and North Africa, South and Central America, South East Asia, and Western Pacific regional countries (Figure 2.3).

Figure 2.3 Regional-wise projection of the total expenditure for diabetes related health management. Adapted from [2] (International Diabetes Federation).

2.3 Diabetes Management

Numerous synthetic antidiabetic drugs are available in the market for the management of diabetes and related complications. However, these antidiabetic drugs are expensive and show adverse effects in patients. For example, the use of acarbose, metformin, glimepiride, and sodium-glucose co-transporters (SGLT2) inhibitors can induce direct excretion of glucose from the body. Whereas, in the case of prediabetes, overusage of these drugs can cause hypoglycemia. Moreover, the concomitant use of amlodipine and telmisartan along with metformin and glimepiride causes hypoglycemia in diabetic patients [12]. Metformin is the first prescribed drug for T2DM; however, its medication has a serious warning for lactic acidosis. Long-term medication of metformin is also associated with the deficiency of vitamin B12.

Novel antidiabetic drugs like dipeptidyl peptidase 4 (DPP-4) inhibitors are also known as gliptins. Gliptins are a new class of oral antidiabetic agents including sitagliptin, saxagliptin, alogliptin, and vildagliptin, but their consumption also showed some adverse effects such as upper respiratory tract infection, nasopharyngitis, headache, and urinary tract infection in T2DM patients [13]. In addition, gliptins are associated with a risk of hypoglycemia when used in the conjugation of sulfonylureas [14]. In addition, these synthetic antidiabetic drugs are expensive. Due to these reasons, traditional herbal medications [15] and marine based bioactive compounds came into the picture for the management of diabetes related complications [16].

2.4 Marine Natural Bioproducts for the Management of Diabetes

Marine ecosystems are major natural treasures for various products. They play a crucial role in biomedical research and drug development. Marine bioproducts have several inhibitory effects on aldose reductase, α-amylase, α-glucosidase, glycogen synthase kinase 3β (GSK-3β), β-glucosidase, PTP-1B, DPP-4, lipase enzymes, and enhancing the AMPK enzyme phosphorylation. All these enzymes are biocatalysts and are the key components regulating carbohydrate metabolism that is involved in the pathogenesis of diabetes related complications. In particular, the marine organisms cyanobacteria, bacteria, and actinomycetes have bioactive compounds that can inhibit α-amylase and α-glucosidase, and are the key enzymes in sugar metabolism as they play an important role in the degradation of polysaccharides and processing of glycolipids and glycoproteins that leads to an increase of blood sugar levels. Hence, this enzyme activity regulation is good for the treatment of diabetes and obesity [17]. Pyrostatin A and B compounds derived from Streptomyces sp. show the specific inhibitory activity of N-Acetyl-β-d-glucosaminidase (GlcNAc-ase) and β-d-Galactosidase enzymes [18]. Aquastatin A is a fungal derivative extracted from the marine fungus Cosmospora Sp. SF-5060 isolated from inter-tidal sediments. Aquastatin-A has the potential to control sugar levels in T2DM patients by the inhibition of protein tyrosine phosphatase-1B (PTP-1B). PTP-1B is a negative regulator of the insulin signaling pathway and it is considered a primary therapeutic target for the management of T2DM [19].

In addition to cyanobacteria, bacteria, and fungi, marine algae including macro and microalgae have a great potential contribution to the production of various antioxidants, anti-inflammatory, anticancer, antidiabetic, and other bioactive compounds. Microalgae (phytoplankton) are unicellular photosynthetic microorganisms that can thrive in almost all water bodies. They are a rich source of primary and secondary metabolites that have potential bioactivity. Advanced work in the field of aquatic biotechnology has isolated a series of microalgae with promising antidiabetic properties [17]. Recently, marine microalgae cultivation has gained attention and is attracting many natural green chemists and pharmacists due to this being a potential source of new antidiabetic compounds [20]. The diatom Thalassiosira species are a very large complex genus and distributed in almost all parts of temperate, tropical, and subtropical regions. They have high productivity of fucoxanthin [21] and are a primary source of omega-3 PUFAs [22]. The microalgae Isochrysis galbana and Nannochloropsis oculata have a high percentage of water soluble and insoluble polysaccharides and also contain polyunsaturated fatty acids (PUFAs) including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) [23]. Diabetic rats treated with microalgae, either I. galbana or N. oculata for 8 weeks, showed significantly declined glucose levels from 600 mg/dl to 100 mg/dl as compared to untreated diabetic rats [24]. Microalgae derived compounds or crude extracts show strong inhibitory effects of α-amylase, α-glucosidase, β-glucosidase, PTP-1B, DPP-4, and lipase enzymes [25]. For example, the ethyl acetate fraction from green algae Chlorella and diatom Nitzscia laevis showed a negative effect on the formation of total advanced glycation end products (AGEs) [26]. Similarly, the methanolic extracts of Porphyridium sp., Chlorella sp.,