Understanding Insulin and Insulin Resistance

By Anil Gupta

Understanding Insulin and Insulin Resistance is written in a simple and clear language illustrated with diagrams that show the complex interplay of various factors in the initiation of insulin resistance. The design is systematic and meticulous, portraying topics in a flow from simple to complex. This resource is intended for a broad audience spanning across biochemistry, medicine, dentistry, academia, physicians, and research scholars. It extends the approach to biochemistry, physiology, metabolism of insulin along with the coverage of pathophysiology of insulin resistance, its effects on the body tissues, and its analysis on insulin resistance syndrome.

• Language: English
• Publisher: Elsevier Science
• Release date: Nov 17, 2021
• ISBN: 9780128203798

Anil Gupta

Dr. Anil Gupta is Professor & Head, Department of Physiology and Biochemistry, Eklavya Dental College & Hospital, Kotputli under Rajasthan University of Health Sciences, Jaipur, India. He graduated in Bio-Sciences from Punjab University, received his Masters in Biochemistry, and completed his PhD in Biochemistry from SJJT University, Rajasthan. He is persistently pursuing post-doctoral research, independently, related to “Nutritional Status of Children between 2 years to below 5 years of Age.” He has got more than 30 research papers accepted and published in high impact, peer reviewed and indexed journals. He is accorded with merit certificates, merit scholarships and medals. He has more than 10 years of teaching experience and over 20 years of clinical experience. He is a mentor to PhD scholars working in fields, such as predisposition of blood groups to diabetes mellitus and dyslipidemia. He serves as reviewer and member, editorial boards in national and international journals.

Book preview

Understanding Insulin and Insulin Resistance

Anil Gupta

Former Dean Research and Professor in Department of Physiology and Biochemistry, Desh Bhagat University, Mandi Gobindgarh, Punjab, India

Table of Contents

Cover image

Title page

Copyright

Dedication

Foreword by Anissa Atif Mirza

Foreword by Vimal K. Sikri

Foreword by Arpit Garg

Foreword by O.P. Jangid

Foreword by S.P.S. Sodhi

Foreword by Rakesh Arora

Foreword by Priyanka Garg

Foreword by Sanjay Bansal

Foreword by Rajwant Kaur Randhava

Preface

Acknowledgments

Chapter 1. Discovery of insulin

Abstract

1.1 Introduction

1.2 Chronology of diabetes mellitus

1.3 Period before the discovery of insulin

1.4 Period toward the discovery of insulin

1.5 Period of insulin discovery

1.6 Period of insulin development

1.7 Postinsulin period

References

Chapter 2. Structure and properties of insulin

Abstract

2.1 Structure of insulin

2.2 Insulin monomer

2.3 Insulin dimer

2.4 Insulin hexamer formation

2.5 Chemical properties of insulin

2.6 Physical properties of the insulin

2.7 Types of insulin formulation

2.8 Insulin zinc suspension

2.9 Human isophane insulin

2.10 Protamine zinc insulin

2.11 Concentrated insulins

2.12 Insulin analogs

2.13 Insulin lispro

2.14 Insulin glargine

2.15 Insulin aspart

2.16 Insulin detemir

2.17 Insulin glulisine

2.18 Degludec insulin

2.19 Inhaled insulin

2.20 Transdermal delivery of insulin

2.21 Oral insulin

2.22 Nasal insulin

2.23 Continuous subcutaneous insulin infusion

References

Chapter 3. Biosynthesis of insulin

Abstract

3.1 Introduction

3.2 Human insulin gene

3.3 Transcription of insulin gene

3.4 Role of transcription factors in insulin gene transcription

3.5 Nutrients regulation of insulin gene expression

3.6 Hormonal regulation of insulin gene expression

3.7 Dysregulation of insulin gene expression

3.8 Posttranscriptional modifications of PPImRNA

3.9 Translation of insulin

3.10 Oxidative folding of proinsulin

3.11 COP-II-dependent export of proinsulin from endoplasmic reticulum to Golgi

3.12 Biogenesis of insulin secretory granules

3.13 Maturation of secretory granules

References

Chapter 4. Biosynthesis, intracellular-trafficking, and exocytosis of insulin granules

Abstract

4.1 Introduction

4.2 Biogenesis of insulin secretory granules

4.3 Sorting proinsulin into immature secretory granules

4.4 Maturation of secretory granules

4.5 Structure of the insulin granule

4.6 Intracellular-trafficking of insulin granules

4.7 Exocytosis of insulin granules

References

Chapter 5. Regulation of insulin secretion

Abstract

5.1 Introduction

5.2 Microvasculature in the pancreatic islets

5.3 Models of capillary blood flow in pancreatic islets

5.4 Insulin secretion pathways

5.5 Modulators of insulin secretion

5.6 Noradrenaline-induced inhibition of adenylyl cyclase

5.7 Noradrenaline-induced activation of K+ channels

References

Chapter 6. Direct and indirect actions of insulin: role of insulin receptor, glucose transporters (GLUTs), and sodium-glucose linked transporters (SGLTs)

Abstract

6.1 Introduction

6.2 Mitogen-activated protein kinase pathway

6.3 Insulin signaling in skeletal muscle: effector molecules and actions

6.4 Insulin signaling in liver: effector molecules and actions

6.5 Insulin signaling in white adipose tissues: effector molecules and actions

6.6 Conclusion

References

Chapter 7. Metabolic and physiological effects of insulin

Abstract

7.1 Metabolic effects of insulin

7.2 Effect on carbohydrate metabolism

7.3 Effect on protein metabolism

7.4 Effect on lipid metabolism

7.5 Physiological effects of insulin

7.6 Physiological effect of insulin on skeletal muscle

7.7 Physiological effect of insulin on liver

7.8 Physiological effect of insulin on adipose tissues

7.9 Physiological effect of insulin on vasculature and endothelium

7.10 Physiological effect of insulin on brain tissues

7.11 Physiological effect of insulin on kidneys

7.12 Physiological effect of insulin on bones

7.13 Physiological effect of insulin on heart

7.14 Conclusion

References

Chapter 8. Etiopathogenesis of insulin resistance

Abstract

8.1 Overview of insulin resistance

8.2 Definition of insulin, insulin resistance, compensatory hyperinsulinemia, Insulin resistance syndrome (IRS), and metabolic syndrome

8.3 Etiopathogenesis of insulin resistance

7.14 Conclusion

References

Chapter 9. Insulin resistance syndrome

Abstract

9.1 Introduction

9.2 Types of insulin resistance syndrome

9.3 Components of insulin resistance syndrome

9.4 Conclusion

References

Index

Copyright

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Dedication

Dedicated to

SHREE SHIRDI SAI BABA

Foreword by Anissa Atif Mirza

Anissa Atif Mirza, Biochemistry Department, AIIMS, Rishikesh, India

Your book contents seem to be completely related to your book title.

I am pleased to see its contents on publication.

It gives me immense pleasure to congratulate you for your sincere hardships toward the society to spread your knowledge through your writing material.

I wish you good luck for your future endeavors as well as for a brilliant academic career ahead.

Foreword by Vimal K. Sikri

Vimal K. Sikri¹, ², ¹Former Director, Punjab Institute of Medical Sciences, Jalandhar, India, ²Former Dean, Punjab Govt. Dental College and Hospital, Amritsar, India

We are in the midst of rapidly advancing scientific developments in all areas of medical profession. The vast experience of Prof. (Dr.) Anil Gupta, coupled with his aptitude for writing, conceived a nice way of presenting his vision in the present book.

The book Understanding Insulin and Insulin resistance comprehensively deals with alleviating all types of doubts with regard to the use and misuse of insulin. This book clearly shows the inherent vision of the author. The author’s emphasis on originality and the language of the subject matter is perfectly evident in the book.

The current concepts of physiology of insulin and also the possibilities of insulin resistance are excellently described in the book. The chapter on the Effects of Insulin resistance on Organs deserves special mention, as it describes the vision of the author. I hope that the students, teachers, and practitioners will be benefitted from the subject matter in the book.

It is advisable to consider Dr. Anil Gupta’s book for application in our daily teaching and clinical practice. With my profound faith and respect for Dr. Gupta, who is a popular teacher with vast experience, I wish him excel in academics, guiding future budding scholars in this specified field. I hope the book would become a treasure of knowledge among students and teachers as well.

Foreword by Arpit Garg

Arpit Garg, Consultant Endocrinologist, Amar Hospital, Patiala, India

It is with great pleasure that I write a foreword to this book on Understanding Insulin and Insulin Resistance. Diabetes is the most studied disease in the history of medicine, tracing its history back to ancient Indian textbooks. This book is an elaborate text shedding light on insulin, a molecule discovered in 1921 that has revolutionized diabetes treatment, prognosis, and improved the life of people with diabetes and diseases affected by insulin resistance. It starts with describing the history leading to the discovery of insulin and results reported in the American Society of Physiology. Since then scientists have intensified their efforts to obtain pure insulin preparations, and with continued evolution of insulin through the years, various formulations and delivery systems are now available that have been illustrated in the following chapters. The goal now is toward insulin therapy where the patient shares with the physician the ability to glycemic control in such a way that the treatment and the management become truly personalized. I wish to congratulate Dr. Anil Gupta who has written an excellent book to advance our understanding on insulin action and physiology so that we can translate this exciting biology into interventions to alter the course of disease. The key conceptual advance of this work is that it’s a Womb to Tomb module on insulin where we are yet to find the tomb of insulin resistance, and I am most hopeful that with ongoing research, we will have future editions from Dr. Anil Gupta and his team that will equip doctors and other health care professionals for a better understanding of insulin and its disease states.

The important thing in science is not so much to obtain new facts as to discover new ways of thinking about them

–Sir William Bragg

Foreword by O.P. Jangid

O.P. Jangid, Former Professor, FELM, IASE (Deemed to be) University, Gandhi Vidya Mandir, Sardarshahr, India

This book furnishes valuable, coherent, and exhaustive knowledge of factors and pathogenesis of insulin resistance in insulin-sensitive tissues.

The section on Biosynthesis of insulin and its relation with obesity constitutes a remarkable portion of the book. Along with scientific advancements, human population is plagued with obesity, insulin resistance, atherogenic coronary artery disease, and stroke. These clinical disorders are the interplay in the diagnosis of insulin resistance syndrome.

The outline of this book is prepared to provide details systematically to the readers including endocrinologists, academicians, research scholars, and students. This book also defines the meticulous discovery of insulin, latest insulin formulation, and update on the novel delivery devices with pros and cons.

I find highly updated and unique information in the book related to the role of advanced glycation end products and the role of gene polymorphisms on the insulin resistance.

I wish a grand success for the forthcoming book for the benefit of readers.

Foreword by S.P.S. Sodhi

S.P.S. Sodhi, Principal and Professor, Dashmesh Institute of Research and Dental Sciences, Faridkot, Punjab, India

World’s population in developed as well developing countries is plagued with obesity, insulin resistance, atherogenic coronary artery disease, and strokes. These clinical disorders are intimately the interplay in the diagnosis of insulin resistance syndrome, a clinical disorder that is synonymously used with the term metabolic syndrome. Dr. Anil Gupta who is an academician as well as a scholar has already many publications as paper and the author of a book to his credit. This book elaborates the recent concepts and knowledge on insulin delivery covering various approaches namely tansdermal, inhalation, oral, nasal, subcutaneous, and bionic pancreas. It also provides the role of several hormones, transcription factors (neuro D1, Pdx-1, and MafA) on the expression of human insulin gene. This bookprudently provides systematic minute details to the readers including endocrinologists, academicians, research scholars, and students. In addition, it meticulously defines the discovery of insulin, latest insulin formulations, and update on the novel insulin delivery devices with pros and cons. The chapters emphasize the synthesis of insulin, actions of insulin, intricate signaling pathways mediated by insulin, and manifestations of insulin resistance syndrome. I find the highly updated and unique information in the book related to the role of advanced glycation end products and the role of gene polymorphisms on insulin resistance are very relevant.

This book may be named as All about Insulin as the subtitle of this book.

I wish a grand success of the forthcoming book for the benefit of several sections of society.

Foreword by Rakesh Arora

Rakesh Arora, DM Endocrinology, Amritsar, India

World’s population in developed as well developing countries is plagued with obesity, insulin resistance, atherogenic coronary artery disease, and strokes. These clinical disorders are intimately the interplay in the diagnosis of insulin resistance syndrome, a clinical disorder that is synonymously used with the term, metabolic syndrome. The outline of the book is prudently prepared to provide systematic minute details to the readers including endocrinologists, academicians, research scholars, and students. It defines the meticulous discovery of insulin, latest insulin formulations, and update on novel insulin delivery devices with pros and cons. In addition, it emphasizes on the synthesis of insulin, actions of insulin, intricate signaling pathways mediated by insulin, and manifestations of insulin resistance syndrome. I find the highly updated and unique information in the book related to role of advanced glycation end-products and role of gene polymorphisms on the insulin resistance are highly relevant.

I wish a grand success of forthcoming book for the benefit of several sections of society.

Foreword by Priyanka Garg

Priyanka Garg, Department of Biochemistry, Government Medical College and Hospital, Patiala, India

Better understanding about the role of insulin becomes pivotal in the diagnosis, risk stratification, and treatment of such patients. Insulin is a peptide hormone produced by beta cells of the pancreatic islets, which regulates the metabolism of carbohydrates, fats, and proteins by promoting the absorption of glucose from the blood into liver, fat, and skeletal muscle cells.

It is well known that Type 1 diabetes mellitus (DM) is caused by the destruction of pancreatic cells owing to autoimmune destruction thereby resulting in a decreased or an absence of insulin activity.

However, Type 2 DM, which is linked to metabolic syndrome is caused by insulin resistance. A panoply of studies have contributed in making this concept of insulin resistance more explicable.

Endeavors of better understanding of insulin mechanism and its regulation have paved the way for the introduction of newer drugs and expanding the spectrum of treatment of metabolic diseases related to insulin and its regulatory pathways.

Foreword by Sanjay Bansal

Sanjay Bansal, Principal and Professor, Eklavya Dental College and Hospital, Kotputli, India

An estimated 500 million people have diabetes worldwide (approximately 9% of the adult population), with Type 2 diabetes making up about 90% of the cases. Diabetes at least doubles a person's risk of early death. In 2019 diabetes resulted in approximately 4.2 million deaths. It is the seventh leading cause of death globally. Diabetes is due to either the pancreas not producing enough insulin or the cells of the body not responding properly to the insulin produced. To control diabetes, one should have in-depth knowledge about insulin. The work done by Prof. (Dr.) Anil Gupta provides an excellent and detailed insight about the properties, synthesis, delivery systems, effects, and resistance of insulin. It will help the researchers and students of biochemistry and pharmacology to understand all the concepts regarding insulin in detail. It can also lead to better research in drug delivery systems and also to control diabetes and hence lead to improvement in human life. I wish all the best for the success of this book.

Foreword by Rajwant Kaur Randhava

Rajwant Kaur Randhava, Principal, Community Health Nursing, Desh Bhagat University, Punjab, India

Health is Wealth is a common saying, and it is a state of normal functioning. The immense value of health to human life has been universally acknowledged. Every one has the right to a standard of living adequate for health and well-being of himself and his family, including food, clothing, housing and medical care, and necessary social services and the right to security in the event of unemployement, sickness, disability, old age, or other lack of livelihood in circumstances beyond control.

It gives me immense pleasure to write the forward for the book, Understanding Insulin and Insulin Resistance written by Prof. (Dr.) Anil Gupta, who is continuously working in the medical field. He is an enthusiastic person with braod visions and is trustworthy. He has published numerous research papers and books, which are worth reading. This book provides a detailed knowledge about the discovery of insulin, its synthesis, insulin resistance, and insulin resistance syndrome. This book is framed according to the needs of medical students and fulil their academic expectations in particular subject and a revealing work of his untired steps toward his goal achievement. This book is highly recommended for researchers and medical students. What I like about Dr. Anil’s book is that it mainly focuses on concerns related to insulin, its administration, and it bursts myths realted to insulin administration. Giving, receiving, touching others lives, expanding the circle of concerns to include others, being authentic, being open to reviews, new ideas, and suggestions are his unbeatable qualities that I admire most. While he has worked in different fields, he shares his abundant knowledge with his colleagues and other professionals. I wish him success in the every means of life and hope this book proves to be of immense value to all medical professionals.

Preface

Anil Gupta

The discovery of insulin heralded a new era in the world of medicine and paved the way for the efficient, safe, and long-term glycemic control and management of diabetes mellitus. Since discovery, insulin therapy has contributed substantially in the prevention of associated comorbidities.

Chapter 1, Discovery of Insulin, describes the discovery of insulin coherently starting from the chronology of diabetes mellitus to the proinsulin era followed by the insulin era and finally explains the latest innovations in the field of insulin therapy for the systematic understanding of readers. This chapter mentions the contribution of revered scientists Paul Langerhans, von Mering, Minkowski, Banting, and Best including the work by Paulescu, Lydia Maria Adams DeWitt, Conrad Bruner, Joslin, Rollo, Pierre Adolphe Piorry, and others who laid the foundation for the discovery of insulin.

Insulin is a peptide hormone. It is a wonderful drug molecule. Chapter 2, Structure and Properties of Insulin, describes the structure, properties, and formulations of insulin. Insulin structure in terms of polypeptide, monomer, dimer, and hexamer forms helps readers to follow the concept easily. The rapid-acting, short-acting, intermediate-acting, long-acting, ultralong acting, concentrated, premixed insulin formulations enable patients to achieve glycemic control. It describes the minute details of the formulations with a specific mention about the recombinant DNA-based insulin and insulin analogs along with an intensive description of the latest insulin delivery methods covering the latest approaches in transdermal delivery, oral, inhalational, nasal, continuous subcutaneous infusions, and artificial pancreas for the rapid revision for clinicians, academicians, and updated knowledge for the scholars and students in wide streams.

Chapter 3, Biosynthesis of Insulin, describes the molecular basis of the biosynthesis of insulin mentioning intricate mechanisms and signaling pathways. It mentions the location and structure of human insulin gene coupled with a single gene versus two gene systems of insulin gene. Comprehensive knowledge about insulin gene transcription covering the effect of regulatory elements as enhancers and suppressors has been explained.

Hormones, nutrients, Pdx-1, NeuroD1, and MafA have their effects on the expression of insulin gene. This chapter provides knowledge about several factors contributing to the biosynthesis of insulin including elucidation about the effect of glucotoxicity, lipotoxicity, oxidative stress, and unfolded protein response (UPR) on the transcription of insulin.

Furthermore, this chapter deals with the role of capping at 5' end of mRNA, Splicing of mRNA, processing at 3' end, and nuclear export of pre-proinsulin mRNA in the posttranslational stage in insulin biosynthesis. Thorough depiction of cotranslational translocation of nascent insulin molecules and biogenesis of insulin secretory granules are excellent characteristics of the chapter in the book.

Chapter 4, Biosynthesis, Intracellular-Trafficking, and Exocytosis of Insulin Granules, describes the minute particulars in biosynthesis, cytosolic trafficking, and exocytosis of insulin secretory granules covering the concept of biphasic insulin secretion, constitutive secretory pathway, regulated secretory pathways mechanism of sorting for entry, maturation of insulin secretory granule, the structure of insulin granule, coupled with the role of actin, kinesis, myosin on cytosolic trafficking of insulin secretory granule, and exhaustive knowledge on the physiology of exocytosis of insulin granule.

The capillary blood flow determines the biphasic insulin secretion via triggering and amplifying pathways. Chapter 5, Regulation of Insulin Secretion, focuses on the secretion of insulin giving vast explanation about all the physiological and biochemical phenomena covering the role of glucose transporter-2, glucokinase, pyruvate, glycerol-3-phosphate, ATP-sensitive Potassium channels, calcium ions, amino acids, fatty acids, hormones, sympathetic innervation and parasympathetic nerve fibers and many other effectors on insulin secretion. Additionally, several signaling pathways involved in insulin secretion are explained in the chapter.

Chapter 6, Direct and Indirect Actions of Insulin: Role of Insulin Receptor, GLUTs, and SGLTs, describes the mechanism of insulin action focusing on the mechanisms of direct as well as indirect actions of insulin. Insulin receptor isoforms and their ultrastructure provide details about the direct and indirect actions of insulin. Mitogen-activated protein kinase and protein kinase B mediated signaling pathways in the book and describe proximal insulin signaling mechanisms. Mechanisms of direct insulin actions on skeletal muscle, adipose tissues, and liver cells are the unique features of the book. All the facilitative glucose transporters (GLUTs) and sodium-glucose-linked transporters (SGLTs) have been narrated prudently in the chapter.

Chapter 7, Metabolic and Physiological Effects of Insulin, describes the actions of insulin in terms of its metabolic and physiological effects on the tissues. Almost, every organ system has been covered for its interaction with insulin hormone covering specific topics as RANKL/RANK/OPG axis in osteoclastogenesis and bone resorption, phosphoinositide-3-kinase, synthesis of nitric oxide, vasculature and endothelium, Randle Cycle, insulin-mediated activation on eIF2B, aminoacyl-tRNA synthetase, and FoxOI protein in the chapter.

The world population is distressed with insulin resistance coupled with widespread comorbidities among adults, adolescents, school-age children, and preschool children.

World’s most urbanized countries, Venezuela (46.5%) and Texas-United States (39.1%) exhibit the highest prevalence rate of insulin resistance in their populations.

Insulin resistance and insulin resistance syndrome are emerging as Global Health Hazards. Distinctive and incomparable features of the book entail the contents of Chapter 8, Etiopathogenesis of Insulin Resistance, that furnishes the most extensive as well as most intensive coverage on the etiopathogenesis of insulin resistance.

The concept of insulin resistance is comprehensively explained on the basis of the latest studies in the fields of molecular biology, physiology, pathology, genetic, and randomized clinical controlled trials. This chapter describes the role of genetic polymorphisms in the pathogenesis of insulin resistance covering FAB-1 gene, FAB-2 gene, alleles APOEε2, APOEε3 and APOEε4, UCP-1 gene, UCP2gene, and many other genes. The roles of hemochromatosis, Cushing syndrome, non-alcoholic fatty liver, lipotoxicity, and hepatic apoptosis in the pathogenesis of insulin resistance have been described. Potential of tumor necrosis factor-alpha, inducible Nitric Oxide synthase, interleukin-6, leptin hormone, resistin hormone, monocyte Chemo-attractant Protein-1, and others in the etiology of inflammation in beta cells, hepatic cells, adipose tissues and their implications on the insulin resistance represent the specific features of the book.

Advanced glycation end products (AGEs) and their implications in the pathogenesis of insulin resistance encompass the exceptional feature of the book.

Prevalence of overweight and obesity (>2 SDs from weight-for-height median) in children between 0 and 5 years during 1990 to 2020 witnessed a rise in global prevalence from 4.2% to 9.1%, in developed countries including Europe, Northern America, Australia, New Zealand, and Japan, the increase in obesity prevalence was from 7.9% to 14.1%, while the developing countries exhibited a rise in obesity prevalence from 3.7% to 8.6% indicate worldwide doubling trend in obesity.

Chapter 9, Insulin Resistance Syndrome, describes insulin resistance syndrome covering every detail about its etiology, types, and components.

The rising prevalence of obesity will initiate obesity-associated complications namely hypertension, dyslipidemia, type 2 diabetes mellitus, and atherogenic cardiovascular diseases.

Distinctive and specific knowledge on insulin and insulin resistance covering almost every aspect of the subject in the first edition of the book would serve as an effective, efficient, and additional armamentarium on the desk of pediatric and adult endocrinologists, useful monograph for the academicians, and prudent guide for the research scholars and students alike.

I hope this book would be an operative tool in disseminating knowledge to all readers. I have made my sincere and honest efforts to prepare and present this book. With humble submission, I welcome criticism, comments, or suggestions for the improvement of the forthcoming edition of the book.

Acknowledgments

Shree Shirdi Sai Baba bestowed upon me the knowledge and perseverance in writing the book. I acknowledge my father, Shree Ved Parkash Gupta, for constantly inspiring me for achieving high goals and for instilling passion toward study since my school days.

I am highly thankful to my wife, Dr. Deepali Gupta, for her persistent motivation to accomplish my task. She has been a constant support throughout my journey.

I acknowledge the support provided by my daughter, Deeksha Gupta (third year MBBS student), in writing the book.

Furthermore, I owe my sincere gratitude to Dr. Timothy Bennett, Editorial Project Manager, Life Science, Elsevier (World’s leading publisher of science and health information) and production team for providing valuable guidance and attention helpful for the successful completion of this book.

Chapter 1

Discovery of insulin

Abstract

The discovery of insulin exemplifies the customary knowledge about diabetes mellitus in the holistic literature and medical text by renowned people across different time periods. The discovery of insulin also epitomizes their honest attempts and sincere efforts undertaken at various time intervals to mitigate the manifestations of diabetes mellitus. It additionally represents the human instinctive behavior in terms of controversies, jealousy, disputes, and disappointments among the rivals in the field of medicine throughout the discovery of insulin. Nevertheless, the discovery of insulin has flagged the new era of scientific understanding of the etiology and pathogenesis of disease. It has paved the way for the emergence of new devices for monitoring diabetes mellitus that in turn aids in the diagnosis and prognosis of disease. The discovery of insulin has finally yielded a novel drug molecule that has transformed the therapeutics of diabetes mellitus.

Keywords

Diabetes chronology; insulin discovery; endocrine pancreas; low-calorie diet; endocrine; madhumeha; Paul Langerhans; Joseph von Mering; Oscar Minkowski; Banting; Best; Frederick Sanger; Edmonton protocol

1.1 Introduction

The discovery of insulin exemplifies the customary knowledge about diabetes mellitus in the holistic literature and medical text possessed by renowned people across different time periods. The discovery of insulin also epitomizes their honest attempts and sincere efforts undertaken at various time intervals to mitigate the manifestations of diabetes mellitus. It additionally represents the human instinctive behavior in terms of controversies, jealousy, disputes, and disappointments among the rivals in the field of medicine throughout the discovery of insulin. Nevertheless, the discovery of insulin has flagged the new era of scientific understanding of the etiology and pathogenesis of disease. It has paved the way for the emergence of new devices for monitoring diabetes mellitus that in turn aids in the diagnosis and prognosis of disease. The discovery of insulin has finally yielded a novel drug molecule that has transformed the therapeutics of diabetes mellitus.

1.2 Chronology of diabetes mellitus

Diabetes mellitus is one of the oldest diseases in the history of mankind since ancient times. The ancient medical texts available today describe the customary knowledge about the disease by holistic persons, priests, and medical persons in various periods of time in the history of mankind.

1.2.1 Transition from customary knowledge to modern understanding about diabetes mellitus

1.2.1.1 Ebers Papyrus

The customary knowledge about diabetes mellitus can be traced in the history of medicine to collection of Egyptian medical texts, which were written around 1552 BC. These are called as Ebers Papyrus (an Egyptian medical papyrus containing herbal knowledge) (Ignazio et al., 2018; Oubre et al., 1997; Quianzon and Cheikh, 2012).

1.2.1.2 Georg Ebers in Thebes

The Egyptologist, Georg Ebers in Thebes in 1872 (Ripoll, 2011), discovered the mentions of disease in terms of too great emptying of the urine in the Ebers Papyrus dating back to 1500 BC.

Ebers Papyrus mentioned about the treatment of diabetes. It included a decoction made of bones, wheat, grain, grit, green lead and earth (Ignazio et al., 2018).

1.2.1.3 Atharva Veda

Atharva Veda (one of the four Vedas; scriptures of Hinduism) was written around 1200–1000 BCE, and it mentioned the description of diabetes in the name, Madhumeha (Das, 2013).

1.2.1.4 Sushruta and Caraka

Ancient physician Sushruta and the renowned ancient surgeon, Caraka (CE 400–500) described in details about the "madhumeha" (honey urine). They described the disease in terms of an enigmatic disease with excessive thirst, urine output, and wasting of the body (Das, 2013; Das and Shah, 2011).

1.2.1.5 Rigvedas

The Rigveda (one of the four Vedas; scriptures of Hinduism) was written around 1200–1000 BCE mentioned about a prayer offered by Rishi Vasistha to God Indira and God Varuna as, I am trembling as an inflated leather bladder; if through sickness, pardon me. Further, Rishi Vasistha mentioned that excessive thirst plights me thy worshiper in the midst of water, give me happiness and wealth.

According to (Das, 2013), the manifestations narrated by Rishi Vasistha are indicative of Kimmelstiel-Wilson syndrome (kidney disorder with prolonged diabetes) which found mention in Rigveda as early as 1200–1000 BCE.

1.2.1.6 Charaka Samhitā

The Charaka Samhitā (compendium of Charaka; Ancient medical text of India) describes the etiology, symptomology, and therapeutics of various diseases including diabetes (Glucklich, 2008). Charaka Samhita additionally mentions in details about the value of balanced diet, and role of hygiene in prevention of diseases and importance of medical education, and role of a physician, nurse, and patient in the recovery to health (Svoboda, 1992). It was written around 100 BCE and CE 200 (Jan Meulenbeld, 1999).

Intake of diet rich in fats and oils (unctuous diet), sour food, and drinking excessive amount of sweet juices, little physical activity, excessive sleep, and constipation were identified as the etiological factors in the diabetes mellitus. The text further identified the occurrence of boils (termed Pidakas) in patients with uncontrolled diabetes. the text described characteristics of boils that resemble diabetic boils as recognized in modern medical science.

The text describes physical and chemical characteristic of urine of a patient of Madhumeha as, passing astringent, sweet and pale colored urine and disease was looked as incurable (Das, 2013).

1.2.1.7 Vāgbhata

Vāgbhata (medical genius of ancient medical text of India) and the most proficient influential classical writers of ayurveda agreed with Charaka related to the etiology and symptoms of Madhumeha, while he supplemented one manifestation of madhumeha that the sweetness was also prevalent in whole body in addition to urine.

Dhātupāka Janya Vikriti was the additional and new term was coined for madhumeha as dhātupāka janya vikriti and this term describes complete impairment of the metabolism of body (where Dhātupāka refers to metabolism and vikriti means impairment).

In modern medical science, diabetes mellitus is recognized as metabolic and endocrinal disorder affecting the metabolism of proteins, carbohydrates and lipids. The modern knowledge about diabetes mellitus is the rediscovery of the ancient Indian knowledge about the madhumeha that is found in the ancient Indian medical text.

The word, DIABETES is derived from Greek word "διαβńτης (transliterated diabḕ ḕtēs) that signifies passing through and meaning siphon" (Gemmill, 1972).

Moreover, ambiguity prevailed regarding the first authority who coined the term diabetes.

According to author (Mac Cracken, 1997), The Greek Apollonius of Memphis was possibly the first who coined term diabetes around 250 BC.

1.2.1.8 Araetus of Cappodocia

Another author (Ahmed, 2002) mentioned that the term diabetes was first coined by Araetus of Cappodocia in 2nd century CE. The Aretaeus of Cappadocia was Greek physician (CE 81–138) and was associated with diabetes through his descriptions about diabetes in his medical texts.

He furnished vast description of the effects of disease in one of his text.

"Diabetes is a magnificent affection, not very common among men, present as melting down of the flesh and limbs into urine (Witters et al., 2008). The patients never stop making water, but the stream is continuous, as if from the opening of channels (Witters et al., 2008). The form of the disease then is chronic, and it requires a long period to establish; but the patient is short-lived if the form of the disease be finally established, for the melting is very fast, the death speedy. patients pass urine with pain, and the emaciation is terrible; nor does any great portion of the drink get into the system, and various parts of the flesh pass out along with the urine." (Witters et al., 2008).

1.2.1.9 Demetrius of Apamea

Still, another author (Gemmill, 1972) mentioned that the term diabetes was introduced by Greek physician, Demetrius of Apamea.

The Demetrius of Apamea connected polyuria in diabetes patients to the siphoning of wine between pots, a practice which is called racking. This method has been in practice at the time of fermentation for removal of remnants of dead yeast. Manifestation of excessive flow of urine in patients was possibly linked by Demetrius with the Greek word diabetes that connoted meaning as a passer-through, or siphon (Witters et al., 2008).

1.2.1.10 Thomas Willis

The word MELLITUS is derived from Latin word meaning honey due to the presence of sweetness in the urine. It was Thomas Willis (reputed English physician, anatomist, and physiologist of 17th century) who added the word mellitus to the word diabetes in 1675 (Mac Cracken, 1997).

Thomas Willis called the diabetes mellitus as pissing evil. He tasted the urine of a diabetic patient and remarked as quasi melle aut saccharo imbutam, mire dulcescere(Witters et al., 2008) (whether prepared from honey or sugar, taste amazingly sweet) (Witters et al., 2008).

1.2.1.11 Claudius Galenus

During the period from CE 125 to 199, Claudius Galenus, a Roman physician mentioned the words dipsatos, and diarrhea urinosa for describing diabetes. Claudius Galenus described about only two cases of diabetes in his period and it was of rare prevalence in the 2nd century AD.

1.2.1.12 Avicenna

Later on, in the period from CE 980 to1037, the Persian Polymath, Avicenna mentioned in the The Canon of Medicine, about the symptoms of the diabetes as increased appetite, erectile dysfunction and gangrene in the patients (Vecchio et al., 2018).

1.2.1.13 Matthew Dobson

The sweet character of urine in diabetes patients was first experimentally worked upon by Matthew Dobson, an English physician and physiologist in the late 18th century. He first reported the increased sugar level in blood (hyperglycemia) and passing increased sugar in urine (glycosuria) (Dods, 2013; Witters et al., 2008).

Dobson’s work was published as "Experiments and Observations on the Urine in Diabetics" in 1776.

He wrote as: It seems … that a large quantity of saccharine matter [is] passed out by the kidneys, in this case of diabetes, and possibly does so in each imbalance of this disease, in which the urine has a sweet taste … It additionally seems like this saccharine matter is not produced in the secretory organ but was present earlier in the serum of the blood. (MacFarlane, 1990; Vecchio et al., 2018; Witters et al., 2008).

It appears that the Dobson’s observations as mentioned in his medical text were based on his gustatory perception of the blood and urine of the diabetic patient. Moreover, Dobson’s observations paved the way to further research in the field of diabetes mellitus.

1.2.1.14 Claude Bernard

Claude Bernard was a French physiologist (1813–78) who was authoritarian of blind experiments, contributed scientifically through his experiments a new understanding in the diabetes mellitus. He initiated scientific methods in medicine and disapproved many earlier misconceptions about various diseases (Kiple, 2003; Young, 1957).

Claude Bernard reported the presence of excess sugar in blood and urine of diabetes patients. He described that sugar came from the breakdown of glycogen in liver and was secreted into blood and urine of diabetes patients (Kiple, 2003; Young, 1957).

1.2.1.15 Paul Langerhans

A landmark discovery in the history of diabetes mellitus and insulin was the recognition of two types of cells in the pancreas provided by the Paul Langerhans (1847–88). He was physiologist, pathologist and biologist in Germany. He was credited with the discovery of minute details of the microscopic structure of pancreas in which he mentioned the occurrence of nine different types of cells including small polygonal cells which were named after him as the islets of Langerhans. His discovery of cells came during his doctorate study at the Berlin pathological institute in 1869 (Sakula, 1988).

Langerhans in February, 1869 submitted a thesis entitled Contributions to the microscopic anatomy of the pancreas. He mentioned about islands of clear cells which he found scattered through the pancreas and the staining of these cells was different from the surrounding tissue. He identified that these cells were richly innervated; moreover, he was unable to assign specific function to these cells and suggested that cluster of these cells might serve as lymph nodes (Langerhans, 1868a,b).

1.2.1.16 Edouard Laguesse

A French pathologist and histologist born in Dijon, the Edouard Laguesse (1861–1927) made his contribution in further discovery of inulin. Laguesse named small polygonal cells in pancreas discovered by Langerhans as ilots de Langerhans after the name of discoverer and their insulin secretion function was thus established (Jolles, 2002).

Laguesse asserted that the Islets of Langerhans synthesized and released secretions which had important role in digestion (Das, 2013).

Hence, his research work was recognized as a flagship in the discovery of insulin that proved novel hormone in the previous history of medicine.

1.2.1.17 Gerald M Reaven

In 1988 the Gerald M Reaven who was American endocrinologist and regarded as father of insulin resistance was the first who linked diabetes mellitus with central obesity, hypertension, insulin resistance and impaired glucose metabolism in metabolic syndrome and refuted the earlier concept that diabetes mellitus was a kidney disorder (Vecchio et al., 2018).

1.3 Period before the discovery of insulin

Period before the discovery of insulin was marked with honest efforts to manage the manifestations of diabetes mellitus either through nonsubstantive therapeutic approach like use of opium or via dietary modifications.

Although, manifestations of diabetes have been acknowledged by the clinicians for more than 2500 years, but its precise treatment was not known to the physicians. Earlier, diabetes was considered as incurable in the absence of proper understanding about its pathology and specific treatment protocols (Pandit, 1999).

1.3.1 Pierre Adolphe Piorry

The Pierre Adolphe Piorry recommended high caloric diet to diabetic patients. He was a French physician and was born in Poitiers. He was credited with invention of pleximetry (technique for investigation of internal organs with percussion).

Piorry studied medicine in Paris and his work on diabetes provided dietary instruction for patients to control glycosuria. He postulated that diabetic patients continuously pass sugar in urine and it led to loss of body weight (Tattersall, 2009). He recommended intake of high calorie diet comprising large amount of sugar to compensate for loss of sugar in urine (glycosuria) in diabetic patients. However, the dietary recommendation by Piorry resulted into death of a patient and was discredited as a diabetic treatment (Bliss, 2007; Colwell, 1968; Ignazio et al., 2018).

Another concept emerged regarding the etiology of diabetes in a period before the discovery of insulin. It was John Rollo in 1776 who was proponent of the view that diabetes was the result of excessive intake of diet and could be managed through dietary restriction (Ignazio et al., 2018).

Rollo was born in Scotland. He got his medical education at Edinburgh. He was appointed as a surgeon in the Royal Artillery in 1776.

In 1797, Rollo published "Notes of a Diabetic Case" at Deptford (an area of south-east London). it mentioned the treatment of a diabetic patient by using meat diet. The diet led to improvement in the symptoms of patient (Aristidis and Malik, 2007; Chalem, 2009; Joslin, 2005a,b; Priscilla, 1932; Sidney, 1897).

Rollo utilized the Dobson’s work of glycosuria in diabetes patients and planned a diabetic diet for the patients for improving the metabolism of body (Aristidis and Malik, 2007; Chalem, 2009; Joslin, 2005a,b; Priscilla, 1932; Sidney, 1897).

Rollo diabetic diet consisted of milk, bread, butter, lime water, blood pudding, meat, and rancid fat(Aristidis and Malik, 2007; Chalem, 2009; Joslin, 2005a,b; Priscilla, 1932; Sidney, 1897). Rollo diet was low in carbohydrates. He was the first person to recommend low carbohydrate and high protein diet for the management of diabetic patients.

1.3.2 Elliott Proctor Joslin

Elliott Proctor Joslin (1869–1962) work on the diabetes in the United States was memorable and he founded Joslin Diabetes Center. He was in practice to keep a record of the diabetes patients which is unique in the world. Joslin in association with physiologist, Francis Benedict in 1908 conducted several metabolic studies focusing on the fasting state and feeding state of patients in various stages of diabetes mellitus (Donald, 1999).

Joslin advocated intake of low carbohydrates and low-calorie diet for the benefit of diabetic patients.

He was proponent of the idea of strict control of glucose through consuming low carbohydrate diet and adequate exercise that would be helpful in prevention of complications of diabetes including acute acidosis in patients (Donald, 1999; Joslin, 2005a,b).

Joslin published in 1916 a monograph titled, The Treatment of Diabetes Mellitus which included Joslin observations of 1000 patients of diabetes. in 1918, Joslin published "Diabetic Manual—for the Doctor and Patient" that described minute details for patients to manage diabetes mellitus.

1.3.3 Frederick Madison Allen

Still other proponent of the carbohydrate restricted and low-calorie diet for diabetes patients was the Frederick Madison Allen (1879–1964). He was born in Iowa and studied medicine in California. He was a physician. His work on diabetes was remarkable. In 1913 he published a book of 1179 pages related to his experiments on animals on diabetes.

Allen postulated that carbohydrate rich diet in diabetes patients could lead to acidosis and coma. He proposed starvation diet consisted of carbohydrate restricted and low-calorie diet for the benefit of patients.

He identified that intensively restricted diet consisting of liquids-only diet could abolish glycosuria and acidosis in diabetes patients. He further advocated that diabetic patients should start taking diet gradually and must be increased until the reappearance sugar in the urine of patients. This test was proposed by Allen to determine the exact quantity of calorie needed for the diabetic patients (Michael, 1982).

Allen treated diabetic patients on starvation diet containing very low carbohydrates with very low calories as low as 400 calories per day. The dietary regimen of Allen helped to eliminate glycosuria in patients. Moreover, patients could not sustain themselves on very low-calorie diet for longer periods and most of the patients stopped intake of low-calorie diet and retained their earlier dietary schedule. It proved fatal for the patients and they died afterwards. Contrarily, the patients who maintained themselves on low-calorie diet became emaciated after a short interval and died of starvation (Austin, 2003).

The period before the discovery of insulin witnessed common dietary modifications for managing complications of diabetes like glycosuria and acidosis. Authors (Westman et al., 2006) reported from the review of Frederick M. Allen’s case histories that diet with 70% fats and only 8% carbohydrates was advocated to overcome glycosuria in hospitalized patients. It was popular as Allen diet that found its mention in a book entitled Studies concerning glycosuria and diabetes and it was published in 1913 (Bliss, 1982).

1.4 Period toward the discovery of insulin

The history of the anatomy of pancreas and discovery of insulin overlaps partially. The word Pancreas is derived from Greek word that means all-flesh and was identified by Greek anatomist and surgeon, Herophilus, first of all.

It was the German pathologist, biologist and physiologist Paul Langerhans, in 1869 who described the presence of two types of cells in pancreas (Ignazio et al., 2018; Langerhans, 1869; Marianna et al., 2016).

1.4.1 Work of Paul Langerhans toward discovery of insulin

Paul Langerhans was the German physiologist, pathologist, and biologist. He was the first who performed detailed study of the microscopic structure of the pancreas.

In 1869 he contributed to the invention of the cells that secrete insulin in pancreas. The cells were named after him as islets of Langerhans (Marianna et al., 2016).

Paul Langerhans reported nine types of cells in the pancreas, moreover, his description about specific type of cells named as zellhaufen (clusters of cells) inside the pancreas was marked with invention of insulin in the medical arena (Marianna et al., 2016).

Langerhans mentioned the occurrence of small irregularly shaped, and polygonal in outline which were without granules and constituted the heaps of cells. Each cell measured between 0.1 and 0.24 mm in diameter in the pancreas (Jolles, 2002; Langerhans, 1868a,b; Marianna et al., 2016).

Langerhans could not assign function to these cells in the pancreas. In 1893 GE Languesse, the French histologist coined the term ilots de Langerhans for the heap of cells. The function of these cells was discovered afterwards (Jolles, 2002; Langerhans, 1868a,b; Marianna et al., 2016). About 30 years later, it was discovered that insulin hormone was secreted by these cells in pancreas.

1.4.2 Work of Joseph von Mering toward discovery of insulin

Period between 1886 and 1889 witnessed series of experiments conducted by Oscar Minkowski and Joseph von Mering that revolutionized the history of treatment of diabetes mellitus (Marianna et al., 2016).

JOSEPH FREIHERR VON MERING was born in Cologne (1849–1908). He was a German physician. He was credited for his pioneer work related to diabetes and discovery of insulin. He published his paper in association with Oscar Minkowski in the "Archiv für experimentelle Pathologie und Pharmakologie" (26, 371; 1890) that stated the manifestation of diabetes in a dog after the extirpation of the pancreas (von Mering, 1949).

Four years earlier in 1886, Joseph von Mering worked upon a compound named as phlorizin (glucoside of phloretin belonging to family of bicyclic flavonoids and it acts as progenitors of the present day SGLT2 inhibitors). He experimentally produced transient glucuresis (physiological condition involving excretion of large quantity of sugar in the urine after intake of excessive carbohydrates in diet; compare it with Glycosuria which is a pathological condition due to diabetes mellitus or disorder of kidneys). The von Mering described the condition as glucosuric effect of phlorizin and he worked on the compound in Hoppe Seyler’s Institute at the University of Strasbourg (Marianna et al., 2016; von Engelhardt, 1989; von Mering and Minkowski, 1889). von Mering’s interest in compound was possibly due to work of his teacher, Kussmaul, who coined the term acetonæmia in diabetic coma, which was called as acidosis by Naunyn (von Mering, 1949).

The Joseph von Mering also reported the hypoglycemic effect of phlorizin. He asserted that the main site of action of phlorizin was in the kidney and this hypothesis of von Mering was found to be true by the work of Oscar Minkowski. Additionally, von Mering reported the manifestation of acidosis after the administration of phlorizin in 1888 (Jörgens and Porta, 2020).

The first SGLT2 inhibitor, Canagliflozin was approved for the management of diabetes mellitus in the United States in March 2013. Around 130 years earlier, von Mering studied the action of phlorizin and declared its acidosis producing effect which is supplemented by the declaration of FDA that SGLT2 inhibitor causes severe ketoacidosis.

The von Mering, while at University of Strasbourg identified and established the physiological role of pancreas. The von Mering in association with Oskar Minkowski performed pancreatectomy on the dog. The von Mering illustrated the symptoms that developed thereafter as the manifestations of diabetes (López-Muñoz et al., 2005; Marianna et al., 2016).

1.4.3 Work of Oscar Minkowski toward discovery of insulin

Oskar Minkowski (1858–1931) was a German physician and physiologist. He was appointed as Professor at the University of Breslau and was a renowned personality on the research on diabetes (Luft, 1989).

In 1889 Oscar Minkowski visited the Hoppe Seyler’s Institute in search of the chemical books in the library. The Oscar Minkowski and von Mering interacted by chance in the Hoppe Seyler’s Institute where a conversation was held between the two researchers about the role of on Lipanin (the oil with mixture of olive oil and oleic oil) which was administered by von Mering to patients manage digestive disturbances (Marianna et al., 2016; von Engelhardt, 1989; von Mering and Minkowski, 1889).

The von Mering held the opinion that free fatty acids were essential for the digestion of fats. But the Oscar Minkowski disapproved the use of lipanin for digestive problems and commented on the role of pancreas in the digestion of fats. Earlier, the von Mering ligated the pancreatic duct of dog to establish the role of pancreas in the digestion of fats but was unsuccessful. Two researchers discussed about the complete pancreatectomy in dog to see its effect on the fats (Marianna et al., 2016; von Engelhardt, 1989; von Mering and Minkowski, 1889).

Later on, pancreatectomy in the dog was performed in the Naunyn’s laboratory and the surgical procedure was successful (Marianna et al., 2016).

The dog was alive and was carefully monitored by Oscar Minkowski as the von Mering left the place for some urgent work at home. The Oscar Minkowski was unaware about the consequent manifestations of complete pancreatectomy in dog (Marianna et al., 2016).

To the surprise of Oscar Minkowski, diabetes developed in the dog after the removal of pancreas. The condition was manifested as polyuria, glycosuria and severe hunger. These symptoms appeared few days after the extirpation of pancreas in dog and continued for few weeks till the death of dog (Marianna et al., 2016; von Engelhardt, 1989; von Mering and Minkowski, 1889). The Oscar Minkowski tested urine for concentration of glucose and it was reported to be 12%.

The Oscar Minkowski was unable to correlate the pancreatectomy in dog and development of diabetes (Marianna et al., 2016). He believed that the dog developed diabetes due to the prolonged administration of phlorizin to the dog by von Mering before surgery. Later on, the Oscar Minkowski repeated the procedure of extirpation of pancreas in three dogs to ascertain the appearance of diabetes after pancreatectomy (Marianna et al., 2016). The Oscar Minkowski confirmed the absence of glucose in the urine in three dogs prior to extirpation of pancreas.

All the three dogs after the procedure developed glycosuria (Marianna et al., 2016; von Engelhardt, 1989; von Mering and Minkowski, 1889). According to author (Luft, 1989), one of three pancreatectomized dogs, excreted 5%–6% of sugar in urine after a fasting of 48 hours. The ketone