Insulin Therapy: Current Concepts [1 ed.] 9789352501045, 9789351520023

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INSULIN THERAPY Current Concepts

INSULIN THERAPY Current Concepts Editors

Ambrish Mithal  MD DM Chairman and Head, Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Ganesh Jevalikar  MD Consultant, Pediatric Endocrinology Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Pankaj Shah 

MD DM

Division of Endocrinology, Metabolism, and Diabetes Mayo Clinic Rochester, MN 55905, USA Foreword

Robert Rizza

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Dedication This book is dedicated to our patients who continue to have faith in us despite the imperfections of our treatment

Contents Contributors Foreword Preface

ix xi xiii

1. The History of Insulin Therapy Shama Mahendru, Ambrish Mithal

1

2. Physiology of Insulin Secretion and Action Monashis Sahu

8

3. Insulin Types and Pharmacokinetics Ganesh Jevalikar, Suchitra Behl

16

4. Insulin Analogs Jasjeet S Wasir

26

5. Advances in Insulin Delivery Devices Ramchandra Naik, Arundhati Dasgupta

39

6. Insulin Therapy in Type 1 Diabetes Ganesh Jevalikar

52

7. Initiation and Intensification of Insulin Therapy in Type 2 Diabetes Sunil K Mishra, Ambrish Mithal

68

8. Insulin Therapy for Diabetic Ketoacidosis and Hyperosmolar Hyperglycemic State Gagan Priya

82

9. Insulin Therapy in Hospitalized Patients Beena Bansal, Ambrish Mithal

103

10. Insulin Therapy in Special Situations Pankaj Shah, Julie Probach, Tricia Veglahn

112

11. Adverse Effects of Insulin Treatment Vaishali S Naik, Ambrish Mithal, Ganesh Jevalikar

129

Insulin Therapy: Current Concepts

APPENDICES Appendix 1: Storage of Insulin Shubhda Bhanot

143

Appendix 2: Insulin Injection Sites Shubhda Bhanot, Ganesh Jevalikar

145

Appendix 3: Injection Technique, Needle Reuse, and Needle Disposal Shubhda Bhanot Appendix 4: Guidelines on Safe Use of Insulin in Hospital Beena Bansal Appendix 5: Peri-operative and Peri-procedure Orders for Type 2 Diabetes Patients Undergoing Surgery Under GA (e.g., Coronary Artery Bypass Grafting) Beena Bansal Appendix 6: Peri-operative and Peri-procedure Orders for Type 2 Diabetes for Procedures Under Regional Anesthesia When NPO for Less than Half Day Beena Bansal, Ganesh Jevalikar

viii

143-162

147 155

157

159

Appendix 7: Glucose Monitoring Chart for Patients on Subcutaneous Insulin Beena Bansal

160

Index

163

Contributors Editors Ambrish Mithal  MD DM Chairman and Head, Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Pankaj Shah MD DM Division of Endocrinology, Metabolism, and Diabetes Mayo Clinic Rochester, MN 55905, USA

Ganesh Jevalikar  MD Consultant, Pediatric Endocrinology Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Contributing Authors Beena Bansal  MD DM Senior Consultant Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India Suchitra Behl  MD Consultant Fortis C-DOC Centre of Excellence for Diabetes, Metabolic Diseases and Endocrinology Chirag Enclave and Vasant Kunj New Delhi, India Shubhda Bhanot  MSc Senior Diabetes Educator Medanta - The Medicity Gurgaon 122 001, Haryana, India

Arundhati Dasgupta  MD DM Consultant Endocrinologist Neotia Getwell Healthcare Centre Siliguri 734 010 West Bengal, India Shama Mahendru  MBBS Attending Consultant Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001 Haryana, India Sunil K Mishra  MD DM Senior Consultant Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Insulin Therapy: Current Concepts

Ramchandra Naik  MD DM DNB Director Metabolism Clinical, Science Unit Global Development – Specialty Care Novartis Pharmaceuticals Corporation East Hanover, New Jersey, USA Vaishali S Naik MD DM Consultant Endocrinologist and Diabetologist Holy Family Hospital and Medical Research Centre Bandra (West) 400 050 Mumbai, Maharashtra, India Gagan Priya  MD DM Consultant Endocrinologist Fortis Hospital Mohali 160 062, Punjab, India

x

Julie Probach  RN MSN CNP Division of Endocrinology Mayo Clinic Rochester, MN 55905, USA Monashis Sahu  MD DM Consultant Endocrinologist VIMHANS, MAX, and ADIVA Hospital New Delhi, India Tricia Veglahn  RN MSN CFNP Division of Endocrinology Mayo Clinic Rochester, MN 55905, USA Jasjeet S Wasir  MD Consultant Division of Endocrinology and Diabetes Medanta - The Medicity Gurgaon 122 001, Haryana, India

Foreword Robert A Rizza MD Professor of Medicine Mayo Clinic Rochester, MN 55905, USA

We have come a long way from the exciting discovery of insulin in 1921. Diabetes mellitus in children has evolved as a result from a lethal acute to subacute disease to a chronic condition. Newer discoveries of insulin therapy are making management of diabetes less inconvenient for the patients. Education of the people with diabetes, their nurses, and physicians is making insulin use more effective. Together these measures seem to be reducing the incidence of diabetic complications. There are still several unresolved problems with insulin use: improved rapidity of rapid-acting insulin, stability of basal insulin concentrations, provision of more than one basal rate through a 24-hour period, administration of insulin without puncturing the skin, and consistency of insulin action from dose to dose. Improvements in the technologies for continuous subcutaneous insulin (CSII) delivery have further simplified management of type 1 diabetes. Use of continuous glucose monitoring (CGM) can predict hypoglycemia before it becomes life-threatening. Introduction of CGM augmented CSII is now able to suspend insulin delivery with hypoglycemia or anticipated hypoglycemia. Further research of the closed loop system will possibly need the appropriate use of both insulin and anti-insulin hormone like glucagon. It will probably also need the input from lifestyle factors: food, activity, mood, etc. History of discovery of insulin and the modification of the native insulin molecule is a reflection of how meticulous perseverant science leads to improves health of individual patients leading to healthier and longer life of the multitude of people with diabetes. Understanding of the physiology of insulin and glucagon secretion and action has led to a more rational effective clinical utilization of these hormones in the intensive insulin regimen used widely and the possible development of a dual-hormone pump in the future. Without doubt the newer insulin analogs have made the so-called intensive insulin therapy a little less inconvenient especially for the people with type 1 diabetes mellitus: reduced time the person has to wait between the meal dose and the food, and reduced fear of hypoglycemia when not eating. This convenience has been further enhanced by the availability of the newer insulin

Insulin Therapy: Current Concepts

delivery systems: pens and pumps. Subcutaneous continuous insulin infusion can provide just the right amount of basal insulin (e.g., more than one basal insulin rate), reducing the theoretical risk of hypoglycemia when insulin needs are the lowest (middle of the night) and when not eating. Acute glycemic complications like ketoacidosis and hypoglycemia can often be effectively self-managed by the patient. Further understanding of pathophysiology and good clinical studies have improved treatment enhancing survival while reducing utilization of useless therapeutic interventions in severe hospitalized cases. Most hospitalizations of people with diabetes mellitus are for other co-morbid conditions. Systemic standardized approach for a good glycemic control with meticulous attention to prevention and prompt treatment of hypoglycemia is likely to improve outcomes in our patients with hyperglycemia during the hospitalizations. Management of hyperglycemia in complex clinical situations require modification of goal, targets, and means to achieve the glycemic targets while attempting to minimize the additional burden of management. Insulin therapy carries substantial risks. Allergies are rare. Hypoglycemia often limits the ability of our patients to reach the targets of glycemic control. Physiologic use of insulin, anticipation and prompt recognition of hypoglycemia, and appropriate therapy of hypoglycemic episodes is an ongoing goal of insulin therapy. These issues have been extensively reviewed in a reader friendly format in this book. I am pleased to write this foreword for this book on insulin. In the true spirit of collaboration, the book reflects the opinion of competent authorities from India and abroad, and, public and private sector. This book has been compiled and edited with expertise from Dr Mithal, Dr Shah, and Dr Jevalikar. Authors, both from India and the United States, include people with extensive clinical experience in insulin use and are leaders in clinical research.

xii

Preface Diabetes mellitus is one of the commonest chronic disorders worldwide. The number of diabetics in the world was estimated to be 366 million in 2011 and is expected to rise to 552 million by 2030. In India alone, more than 60 million are estimated to be affected by this condition. Optimum management of diabetes, however, remains an elusive goal. Although major advances have taken place in the therapies available for both type 1 and type 2 diabetes, treatment continues to fall far short of ideal. Insulin was the first agent used for treating diabetes more than 90 years ago and is the only, life saving, treatment for type 1diabetes. It is also an important treatment modality for type 2 diabetes. Since its discovery in 1921, incremental improvements in insulin therapy have taken place resulting in insulins with superior kinetics, greater ease of administration and convenient dosing schedules. Increasing use of genetic engineering has opened up numerous possibilities of developing new and ingenious “designer” insulin analogs. Recent years have witnessed rapid progress in this area, with a range of short-, long-, and ultra-long acting insulins now available, and several more innovative molecules under development. There is a need for physicians to have a thorough understanding of practical aspects of newer insulins to ensure best use and practice. It is important to simplify apparently complex regimens and choose the best suited insulin for a particular patient. This book is an attempt to provide practical guidance for using insulin, at the same time explaining the theory and logic behind choices and decisions. It provides information in an easy and comprehensible manner to practicing physicians and medical students. Chapters have been authored by renowned experts in the field from academia, corporate hospitals, and industry from India and the United States of America. They have drawn on their stores of knowledge and wisdom to contribute wholeheartedly to this project. The book has 11 chapters which cover history, physiology, pharmacokinetics, insulin analogs, newer delivery devices, insulin pump therapy, emergencies and practical use in type 1 and type 2 diabetes, as well as in special situations.

Insulin Therapy: Current Concepts

We would like to thank our colleagues at the Division of Endocrinology and Diabetes, Medanta the Medicity for ideas, suggestions, and constructive criticism throughout the writing of this volume. We would also like to express our gratitude to Jaypee Brothers Medical Publishers for tolerating our tardiness and numerous idiosyncrasies! Ambrish Mithal Ganesh Jevalikar Pankaj Shah

xiv

1 The History of Insulin Therapy Shama Mahendru, Ambrish Mithal

Abstract Although diabetes has been known to mankind since a long time, it was only in 1921 at the University of Toronto, Frederick Banting, an orthopaedician; John Macleod, a physiologist; Charles Best, a student at the university; and James Collip, a biochemist succeeded in extracting the active principle in purified form and performed the first affirmative trials in humans. Since then, the journey of insulin has seen several milestones including various sources, types, and delivery devices. The “Flame of Hope” adjacent to Banting House National Historic Site in Ontario, Canada, kindled in 1989 reminds that insulin is only control of diabetes and cure is yet to be achieved. The flame will be extinguished only when the cure for diabetes is found.

INTRODUCTION The discovery of insulin as a treatment of diabetes is one of the greatest achievements of 20th century. However, diabetes was known to mankind much before this. The history of recognition of diabetes, its types, etiology, and development of insulin is a fascinating journey which is interesting and important to read.

HISTORY OF COGNIZANCE OF DIABETES Primitive narrative of symptoms of diabetes has been detailed by Egyptian physician Hesy-Ra of the 3rd Dynasty in Egyptian document; Ebers Papyrus in 1550s BC. Diabetes has also been described in ancient Indian literature. More than 2,000 years ago, two Indian physicians Charaka and Sushruta identified diabetes as characterized by “honeyed urine”, hence the name “madhumeha”. Sushruta also described that the condition primarily affects obese and sedentary people. He highlighted the role of physical activity in control of diabetes. The chronicle of diabetes symptoms as described by Galen and Arateus (Greek physicians) is worth mentioning. They gave a lucid portrayal of

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diabetes as “relentless flow of urine, insatiable thirst leading to wasting of flesh and limbs into the urine followed by a very speedy death.” Arateus coined the term “Diabetes” which in Greek means “siphon”. John Rollo, a surgeon was the first to add adjective “Mellitus” which means honey. In 1674, Thomas Willis, a professor of natural philosophy at Oxford, brought into notice the fact that urine of patients with diabetes was sweet but he could not isolate the sweet chemical in the urine. About a century later, in 1776, Mathew Dobson of England isolated and identified the sweet substance in urine as “brown sugar”.

ESTABLISHMENT OF THE CAUSE OF DIABETES

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Although it was known that diabetics excrete sugar in the urine, its cause still could not be ascertained. Because of the unlimited flow of urine, kidneys were thought to be the seat of the disease. Due to its role in glycogen and glucose metabolism, some physicians thought liver to be the culprit. Finding of liver enlargement in diabetics also supported this theory. However, now it is well known that this finding is because of fatty infiltration of liver due to uncontrolled blood glucose (BG). It was also observed that plant-based food products increased glucosuria, whereas animal-based foods caused lesser glucosuria. It was concluded that starch containing foods underwent saccharification in stomach and hence stomach was pointed as the nasty organ. Cawley in 1788 reported a case with shriveled pancreas with stones. Till the middle of the 19th century, many other physicians observed postmortem findings of diseased, atrophic, or calculus pancreas. But contradictory to that, pancreas of many patients were absolutely normal at autopsy. This negated the view that pancreas could be the causative organ. Negative role of pancreas in causation of diabetes was further strengthened by separate experiments in dogs by Claude Bernard and Moritz Schiff between 1840s and 1860s. Their experiments involved ligation of pancreatic ducts and injecting them with oil or paraffin to block all duct secretions which led to near total atrophy of pancreas. But the dogs did not show any symptoms or signs suggestive of diabetes. It was to be discovered later that pancreas not secrete only the digestive enzymes but was also a gland of internal secretion. It was Bouchardat, whose published work in 1875 suggested pancreas to be the organ responsible for diabetes. Two years later, Lancrereaux in 1877 published similar results and described at least two different types of diabetes: 1. Diabetes maigre: Diabetes of the thin (the severe type in younger patients and response to dietary treatment was poor).

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The History of Insulin Therapy

2. Diabetes gras: Diabetes of the fat (the more rampant type in whom dietary restriction and increased physical exertion showed good results). As diabetes gras was much more prevalent than the diabetes maigre, it became clearer that why postmortem findings of pancreatic lesions were most of the times negative. In 1889, Joseph von Mering and Oscar Minkowski performed experiments on dogs which proved that pancreas is a gland of internal secretion. They did total pancreatectomy in dogs subsequent to which dogs developed polyuria within few hours and the urine tested positive for glucose. Mering and Minkowski implanted a small portion of pancreatic gland in the subcutaneous tissue of the depancreatized dogs which corrected the glucosuria and the symptoms of diabetes. This was a historical ascertainment which ultimately led to establishment of pancreas as the causative organ for diabetes. A German medical student, Paul Langerhans in 1869 described heaps of cells different from pancreatic acinar cells but did not hypothesize their function. Laguesse in 1893 named these heaps of cells as “Islets of Langerhans” and suggested them to be the gland of internal secretion of pancreas. The description of hyalinization of islets in patients with diabetes by American pathologist Eugene Opie in 1900s linked islets to diabetes. Even after it was clear that the glucose lowering molecule was secreted from the islets, its exact nature was still elusive. John de Meyer was the first to coin the term “Insulin” (Latin: insula, island) in 1909 for the glucose lowering pancreatic islet secretion which was still not isolated.

ISOLATION OF INSULIN Though the role of insulin deficiency in the etiology of diabetes was established by late 19th century, for almost a quarter of the early 20th century, the pancreatic islet extract could not be sequestered in purified form to be useful in human patients. For almost 35 years, many researchers prepared pancreatic extracts that were often successful in lowering BG in test animals. However, inability to remove impurities and presence of toxic reactions like fever, infections, and hypoglycemia prevented its use in diabetics.

THE ACTUAL BREAKTHROUGH In 1921, at the University of Toronto, Frederick Banting, an orthopedician; John Macleod, a physiologist; Charles Best, a student at the university; and James Collip, a biochemist succeeded in extracting the active principle in purified form and performed the first affirmative trials in humans.

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An article written by Moses Barron in 1920s describing a case of pancreatic stone that blocked the main pancreatic duct stimulated Banting’s research interests. The case described degeneration of acinar glandular cells secondary to the stone but not the islet cells. Banting attributed earlier failures in isolation of the active principle to digestive enzyme “Trypsin” secreted by pancreas. He hypothesized that ligation of pancreatic ducts before extraction of pancreatic extract destroys trypsin secreting part though islets remained intact. Banting was provided by Macleod a laboratory space, a student assistant, Charles Best, and an allotment of dogs to test his hypothesis. Applying Banting’s hypothesis into practice, Banting and Best with the help of Macleod succeeded in isolating an extract of pancreas that reduced the signs and symptoms of hyperglycemia in depancreatomized dogs. They next developed a procedure for extraction from the entire pancreas without prior duct ligation. This extract prepared from beef pancreas was successful for treating humans. Purification of the extract was mainly a work of Collip. In cooperation with Eli Lilly and company, the yield and standardization were improved. In 1922, Leonard Thompson, a 14 years old suffering from type 1 diabetes, was the first patient who received the crude pancreatic extract developed by Banting et al. Following the first injection, the hyperglycemia reduced slightly but the symptoms did not go. But over next 3 weeks with repeated injections, he became euglycemic and came out of metabolic acidosis. A few months later, Banting and his team started facing difficulty in extracting active principle from pancreas. George Walden, a chemical engineer employed by Eli Lilly then observed the importance of isoelectric point of insulin which helped in extraction of beef and pork insulin for commercial use. In 1923, the Nobel Prize for the discovery of insulin was awarded to Banting and Macleod. Banting was outraged as the Nobel committee had ignored the significant contribution made by Best. He publically announced to share his prize money with Best and Macleod announced to share his award with Collip.

FURTHER EVOLUTION OF INSULIN

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By the year 1923 insulin was available for human use. For many years physicians were confused about insulin in the sense that it rapidly brought type 1 diabetes patients out of metabolic acidosis and improved their life expectancy but these patients subsequently struggled with multiple serious

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The History of Insulin Therapy

chronic complications of diabetes which marred the quality of life for these patients. For almost 50 years after the isolation of insulin, only porcine or bovine insulin was available. The development of purified porcine insulin reduced the incidence of insulin allergy and development of lipoatrophy. Initially, crystalline insulin was available in concentrations of 10, 20, or 40 U per mL and, therefore, had to be taken with more than one shot in patients requiring large doses of insulin at a time. In 1972, U-100 insulin was made available which reduced number of injections to be taken and improved the patient compliance. In 1936, Christian Hagedorn introduced the first “delayed-action” preparation of insulin. Subsequently, protamine zinc insulin (with controlled amounts of protamine), isophane insulin in 1946, and lente insulin (acetate buffering of zinc insulin) in 1952 were introduced. They had to be given twice a day and their introduction into the treatment regimen provided much better control than soluble insulin alone. In 1958, Frederick Sanger was awarded the Nobel Prize in chemistry for his work on structure of proteins, especially that of insulin. He determined that the insulin molecule was composed of two different chains of amino acids held together by two bridges of sulfur atoms. Other important milestones in the journey of insulin as available today have been highlighted in table 1.

Table 1

Important milestones in the history of insulin

Year

Event

1921

Isolation of insulin by Banting and Best

1923

Bovine soluble insulin available for clinical use

1936

First delayed action insulin introduced by Hagedorn

1955

Amino acid sequence of insulin characterized by Frederick Sanger

1965

Synthesis of complete insulin molecule from amino acids by Wang YingLai et al.

1969

Three dimensional structure of insulin delineated by Kelly and Lillehei

1977

Yalow and Berson receive Nobel prize for first radioimmunoassay of insulin

1979

First human insulin produced using recombinant DNA technique (Goeddel)

1980

Illustration of DNA sequence of human insulin gene

1982

Human insulin put to therapeutic use

1996

First insulin analog, lispro introduced

DNA, deoxyribonucleic acid.

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HUMAN INSULIN After several years of work during 1960s, human insulin was chemically synthesized. However, large scale production was not undertaken till 1978, when scientists from San Francisco succeeded in producing insulin from a genetically manipulated plasmid of Escherichia coli. Commercial production on human insulin was started using recombinant deoxyribonucleic acid (DNA) technology in 1982. Over next 2 decades, human insulin largely replaced older animal derived insulin.

INSULIN Analogs Using recombinant DNA technology and by some modification of native insulin molecule, insulin analogs (designer insulins) were introduced in the year 1996. These genetically designed insulins have much improved pharmacokinetics, closely mimic the physiological secretion of insulin, and have a predictable time-action profile. They offer a greater flexibility in treatment than soluble or delayed action preparations. Insulin lispro (rapid-acting) was the first insulin analog to be introduced followed by aspart and glulisine. Glargine was the first peakless basal insulin analog introduced in year 2001, shortly followed by the introduction of detemir.

INSULIN PUMPS Continuous subcutaneous insulin infusion (CSII), commonly known as insulin pump was introduced as a plausible substitute to multiple insulin injections in patients with type 1 diabetes. The meticulous experiments for CSII began in the 1970s. The prototype of the first pump was a backpack style introduced by an American clinician Arnold Kadish. The auto syringe model, also known as the Big Blue Brick was the first commercial pump. It was only in 1990s that more user-friendly pumps were made available.

FLAME OF HOPE Though the journey of insulin is very interesting and a lot has been achieved in the last almost 90 years, researchers are still striving to make the treatment of diabetes as smooth as possible. Queen Elizabeth in 1989 kindled the “Flame of Hope” adjacent to Banting House National Historic Site in Ontario, Canada, which in addition to giving hope also reminds that insulin is only control of diabetes and cure is yet to be achieved. The flame will be extinguished only when the cure for diabetes is found. 6

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Suggested Reading 1. Canadian Diabetes Association. The History of Diabetes. [online] Available from: www.diabetes.ca/diabetes-and-you/what/history/ [Accessed 23 march, 2012]. 2. Sanders LJ. From Thebes to Toronto and 21st century: an incredible journey. Diabetes Spectrum. 2002;15:56-60. 3. Barnett DM, Krall LP. The History of Diabetes. In: Kahn CR, Weir G, King G, Jacobson A, Smith R, Moses A, editors. Joslin’s Diabetes Mellitus, 14th ed. Philadelphia: Lippincott, Williams and Wilkins; 2005. p. 1-17. 4. Dwivedi G, Dwivedi S. Sushruta-the Clinician-Teacher par Excellence. Indian J Chest Dis Allied Sci. 2007;49:243-4. 5. Jolles S. Paul Langerhans-a historical perspective. J Clin Pathol. 2002;55:243. 6. Rosenfeld L. Insulin: discovery and controversy. Clin Chem. 2002;48:2270-88. 7. Karamitos DT. The story of insulin discovery. Diabetes Res Clin Pract. 2011; 93:S2‑8.

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2

Physiology of Insulin Secretion and Action

Monashis Sahu

Abstract In healthy individuals, plasma glucose remains in a narrow range between 70–120 mg/dL. Such tight control is brought about by a fine balance between glucose absorption from intestine, glucose production by liver and glucose utilization by tissues, such as muscle, fat, and liver where glucose uptake and storage is facilitated by insulin hormone. Apart from promoting glucose utilization, insulin inhibits basal, and glucagon stimulated hepatic glucose production, and also has an anabolic role by promoting glycogen, protein synthesis and lipogenesis.

INTRODUCTION In healthy individuals plasma glucose remains in a narrow range between 70 and 120 mg/dL. Such tight control is brought about by a fine balance between glucose absorption from intestine, glucose production by liver, and glucose utilization by tissues, such as muscle, fat, and liver where glucose uptake and storage is facilitated by insulin hormone. Apart from promoting glucose utilization, insulin inhibits basal and glucagon stimulated hepatic glucose production, and also has an anabolic role by promoting glycogen, protein synthesis, and lipogenesis. The source of insulin is pancreas which is composed of two major types of tissues: (1) the exocrine component, acini and (2) the endocrine component, islets of Langerhans. A healthy human pancreas contains 1–2 million of islets. Each individual islet comprises of three major types of cells distinguished by their morphological and staining characteristics: (1) insulin and amylin expressing beta (β) cells (~60% of adult human islet cells); (2) glucagon expressing alpha (α) cells (~20–30% of human islets); and (3) somatostatin expressing delta cells (~10% of islets). Human beings need continuous energy but eat intermittently ingesting food in abundance of the immediate caloric needs. Normal physiology of fuel

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homeostasis thus facilitates storage of energy during fed state that can be used during postabsorptive state or periods of starvation. Secretion of insulin from β cells is in the fed state of energy abundance that helps in storage of excess of calories in the form of hepatic and muscle glycogen, and adipose tissue triglyceride. Normal insulin secretion and action is essential for maintenance of normal glucose tolerance. Pancreatic islets play a central role in orchestrating whole body fuel homeostasis and not just regulation of plasma glucose. It is thus no surprise that a vast range of receptors are expressed in β cells that are modulated by various other hormones, gastrointestinal (GI) peptides, and neuro­ transmitters. In this chapter, the normal physiology of insulin secretion and its action is reviewed.

INSULIN BIOSYNTHESIS, STORAGE, AND RELEASE Insulin is a peptide hormone composed of 51 amino acids that is produced and stored by the highly specialized β cells with ability to release insulin rapidly in response to metabolic demand. Insulin is first synthesized as preproinsulin in the ribosomes of the endoplasmic reticulum. The gene coding for preproinsulin is located on chromosome 11 close to that for insulin like growth factor 2 (IGF-2). Preproinsulin is then cleaved by proteolytic enzymes to proinsulin, which is then transported to the Golgi apparatus where it is packaged into secretory granules that are located close to the cell membrane. Proinsulin contains the A chain (21 amino acid) and B chain (30 amino acids) of insulin that is joined by the connecting C peptide (30–35 amino acids). Conversion of proinsulin to insulin by removal of C peptide happens in the maturing granules through action of prohormone convertases and then carboxypeptidases. High concentrations of zinc within the secretory granule help in crystallization and stabilization of insulin. The final products of insulin and C peptide are stored together in the secretory granules till they are released by process of exocytosis, a process in which the granule membrane and plasma membrane of cell first fuse together, and then release the granule contents into the interstitial space. Insulin and C peptide are released in equimolar amounts (Fig. 1). This knowledge that C peptide is secreted in equimolar concentrations to insulin along with the fact that C peptide is not extracted by liver (unlike insulin) has led to its use as a marker of β cell function, both in research and clinical practice. 9

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Fig. 1: Insulin synthesis and processing. The initial precursor of insulin is preproinsulin that consists of four distinct domains: (1) the signal peptide, (2) A chain of insulin, (3) B chain of insulin, and (4) C peptide that links the A and B chain. The signal peptide is cleaved off in rough endoplasmic reticulum to produce proinsulin. Conversion of proinsulin to insulin occurs at Golgi apparatus at the pairs of basic residues that links A and B chain to C peptide. The final release of insulin products from β cell is an equimolar quantity of insulin (A chain linked by disulfide bond to B chain) and C peptide.

MECHANISMS OF INSULIN SECRETION

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The major physiologic factor that affects insulin release is the circulating concentration of blood glucose (BG). Other nutrient and non-nutrient factors that increase or decrease insulin secretion are listed in table 1. While the nutrient factors initiate β cell insulin secretory response, some of the other non-nutrient factors like hormones and neurotransmitters act to amplify or inhibit the nutrient-induced response. The basic cellular mechanism for insulin secretion is provided in figure 2. Glucose is transported from extracellular space into β cells by glucose transporters (GLUT-2). After entry to β cells, glucose is first phosphorylated to glucose-6-phosphate by glucokinase which acts like a glucose sensor by determining the rate of glycolysis. As BG increases and more glucose enters β cells, the rate of glycolysis increases leading to an increased rate of insulin secretion. Glucose-6-phosphate is ultimately oxidized to form adenosine triphosphate (ATP) which blocks the ATP sensitive potassium channels. The β cell ATP-sensitive potassium channel (KATP) channel is formed by four potassium channel subunits (Kir6.2) that form the pore through which potassium ions flow, surrounded by four sulfonylurea receptor subunits (SUR1). ATP generated by β cells binds to Kir6.2 subunits inducing channel closure leading to depolarization of cell (sulfonylureas bind to SUR1 subunits also leading to channel closure),

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Physiology of Insulin Secretion and Action

Table 1

Factors that increase or decrease insulin secretion

Increase insulin secretion

Decrease insulin secretion

Nutrient factors •• Increase blood glucose

•• Decrease blood glucose

•• Increase fatty acids •• Increase amino acids Islet hormones •• Glucagon

•• Somatostatin-14 •• Ghrelin

Gastrointestinal hormones •• Glucagon like peptide-1

•• Somatostatin-28

•• Glucose dependent insulinotropic peptide, cholecystokinin

•• Ghrelin

Adipokines •• Adiponectin

•• Leptin •• Resistin

Neurotransmitters •• Acetylcholine

•• Norepinephrine •• Dopamine

Fig. 2: Cellular mechanisms leading to insulin secretion from β cell of pancreas.

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that in turn leads to opening of voltage-gated L-type calcium channels. The resultant influx of calcium into the β cells stimulates exocytosis of insulin secretory granules. Apart from nutrient derived glucose, some of the amino acids, notably leucine, lysine, and arginine also induce insulin secretion. While per se amino acids induce a small increase in insulin secretion in absence of elevation of glucose, however, they potentiate the glucose stimulated insulin release, and can increase by as much as twofold. Insulin secretion is also modulated by various non-nutrient factors, such as other islet hormones, GI hormones, neural control by sympathetic or parasympathetic innervation of islets, and others. With advancement of research, there is a continuing appreciation of these factors being physiologically relevant. Among islet hormones, glucagon enhances insulin secretion while somatostatin has an inhibitory effect on insulin secretion. There are some suggestions that ghrelin is also expressed in islet cells and has an inhibitory effect on secretion of insulin. Gastrointestinal derived hormones, also termed “incretins”, are released from endocrine cells of GI tract after oral intake. They are released into circulation, from where they reach pancreatic islets and act via their specific receptors present on β cells to modulate glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, originally called gastric inhibitory polypeptide) are among the most potent identified incretins that amplify glucose mediated insulin secretion. Autonomic nerves also regulate islet hormone secretion. There is a decrease in insulin secretion by sympathetic nerve stimulation with the opposite effect on parasympathetic stimulation. In response to glucose, insulin is released in a biphasic pattern that consists of a rapid early insulin peak , probably signifying the immediate dumping of preformed insulin store available in β cells, followed by a second more slowly rising and more prolonged phase resulting from additional release of preformed insulin and activation of synthesis and release of new insulin. While short-term exposure high glucose leads to cascade of events culminating in insulin synthesis and secretion, long-term effect of exposure of high levels of glucose to pancreatic β cells, sometimes called “glucotoxicity”, leads to reduction of expression of genes critical for normal β cell function and consequently suppresses insulin secretion. At a normal fasting level of BG, the rate of insulin secretion is minimal. The dose response curve of glucose-induced insulin secretion is sigmoidal in nature, i.e., concentration of glucose below approximately 90 mg/dL

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Physiology of Insulin Secretion and Action

does not affect the basal insulin release, and the rate of secretion increases progressively beyond 90 mg/dL. It is interesting to note that the threshold glucose level for the stimulation of insulin release (~90 mg/dL) is higher than the threshold glucose level for insulin biosynthesis, thus ensuring an adequate reserve of insulin within β cells. It is estimated that in a 24-hour period, 50% of the insulin secreted by pancreas is secreted under basal conditions, and the remainder is secreted in response to meals. On meal ingestion, insulin levels rise approximately fivefold of baseline reaching this peak within 1 hour.

INSULIN ACTION At a cellular level: Insulin first binds to and activates its receptor present on the cell membrane to activate multiple signal transduction. Insulin receptor is a large transmembrane glycoprotein consisting of two α and two β subunits. Insulin binds to the extracellular α subunits causing a conformational change of the receptor enabling ATP to bind to the intracellular domain of β subunits. This autophosphorylation of the β subunit in turn augments the intrinsic activity of the β subunit as tyrosine kinase. The activation of tyrosine kinase then leads to phosphorylation of multiple other intracellular signaling molecules, such as insulin receptor substrates (IRS). Different types of IRS are expressed in different tissues. Among various types of IRS, IRS1 and IRS2 are considered critically important with IRS1 as principal IRS in skeletal muscle and IRS2 prominent in liver and β cells. IRS provides a major point of divergence of further signal transduction leading to mitogenic or various metabolic pathways. As an example, phosphatidylinositol-3-kinase (PI3 kinase) is among several proteins that bind to IRS1 or IRS2, and its activation signals further downstream pathways to finally stimulate translocation of glucose transporters (GLUT-4) to cell surface (Fig. 3). For turning off the insulin signal: The following mechanisms have been proposed: insulin may dissociate from the receptor and be degraded, or the phosphorylation of insulin receptor and IRS is reversed by action of protein tyrosine phosphatases, or serine phosphorylation of the insulin receptor, or mechanisms like internalization and degradation of the receptor. At a tissue level: Skeletal muscle, liver, and adipose tissue are the three major organs that are responsible for fuel uptake and storage under the influence and action of insulin. The major bulk of insulin-stimulated glucose uptake occurs in skeletal muscle. The major transporter of glucose across cell membrane responsive to insulin action is GLUT-4, which normally resides within the cell and is recruited to the plasma membrane upon insulin action.

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Insulin Therapy: Current Concepts

Fig. 3: Insulin signaling pathways. Insulin binds to the α subunit of the receptor that leads to autophosphorylation of β subunit, that induces the tyrosine kinase activity. This leads to phosphorylation of various enzymes and substrates. The distribution of different types of substrates in different tissues leads to difference in action of insulin at tissue level.

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Muscle contraction also leads to translocation of GLUT-4, independent of insulin mediated translocation. If muscles are not exercising, and yet glucose is transported into muscle cells as occurs after meals, most of the glucose is stored as muscle glycogen, which can be later used as source of energy. Insulin promotes glycogen synthesis in muscles, liver, and adipose tissue by activating glycogen synthase. Mechanisms by which insulin increases amount of glycogen in liver are: •• Enhanced uptake of glucose by liver cells by increasing the activity of enzyme glucokinase •• Inactivation of liver phosphorylase, an enzyme that breaks down liver glycogen to glucose •• Enhanced activity of glycogen synthase. Insulin also inhibits gluconeogenesis and reduces hepatic glucose output by suppressing two key enzymes: (1) phosphoenolpyruvate carboxy­ kinase that catalyzes one of the rate limiting steps of gluconeogenesis and (2) glucose-6-phosphatase that catalyzes the final step of gluconeogenesis producing free glucose. At the site of adipose tissue, as is the case with carbohydrate metabolism, insulin promotes synthesis of lipids and inhibits its degradation. In adipocytes, glucose is primarily stored as lipids. Insulin augments the availability of glycerol and fatty acids for triglyceride synthesis. Lipolysis in adipose tissue is extremely sensitive to inhibition by insulin.

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Physiology of Insulin Secretion and Action

SUMMARY The physiological tight control of BG in normal individuals is brought about by significant interaction between the pancreatic islet cells, gastrointestinal derived “incretin” hormones, and the autonomic nervous system that leads to appropriate release of islet hormones. While glucose concentration is the principle factor that induces insulin release from pancreatic β cells, other factors, such as incretins can potentiate and amplify the glucosemediated insulin secretion. At a cellular level, pathways leading to insulin secretion from β cells have been well elucidated from entry of glucose to its rate limiting phosphorylation by glucokinase leading to ATP generation that closes potassium channel thereby leading to cellular depolarization and calcium influx culminating in stimulation of insulin release. Secretion of insulin from β cells occurs in a biphasic pattern with the initial rapid phase and then a prolonged second phase. Insulin acts at a cellular level on its tyrosine kinase insulin receptor initiating a downstream series of enzymatic phosphorylation. The different responses to insulin at tissue level depend on the kind of molecules phosphorylated in the downstream pathway. At the tissue level, insulin promotes utilization of glucose and storage of glycogen and fat.

Suggested Reading 1. Jensen MV, Joseph JW, Ronnebaum SM, et al. Metabolic cycling in control of glucose-stimulated insulin secretion. Am J Physiol Endocrinol Metab. 2008;295:E1287-97. 2. Tripathy D, Chavez AO. Defects in insulin secretion and action in the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep. 2010;10:184-91. 3. Kido Y, Nakae J, Accili D. Clinical review 125: the insulin receptor and its cellular targets. J Clin Endocrinol Metab. 2001;86:972-9. 4. Persaud SJ, Howell SL. The biosynthesis and secretion of insulin. In: Pickup JC, Williams G, editors. Textbook of Diabetes. 3rd ed. Oxford: Blackwell Scientific Publications; 2003. p. 13.1-13.17. 5. Buse JB, Polonsky KS, Burant CF. Type 2 diabetes mellitus. In: Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of Endocrinology. 11th ed. Philadelphia PA: Saunders Elsevier; 2008. p. 1329-90.

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3

Insulin Types and Pharmacokinetics

Ganesh Jevalikar, Suchitra Behl

Abstract Insulin is 51 amino acid peptide hormone composed of two polypeptide chains (Chain A and B). Endogenous insulin is directly secreted in the portal circulation leading to an immediate glucose lowering effect whereas subcutaneous insulin hexamers are broken down to monomers before absorption leading to delayed onset of action. Secreted insulin undergoes extensive metabolism in liver before reaching the systemic circulation. The remaining is metabolized by kidney and adipose tissue. There is significant renal tubular reabsorption of insulin before degradation. Insulin from animal sources has now been replaced with human insulin and insulin analogs. Synthesis of newer insulin analogs has made the insulins more physiological. Knowledge of insulin pharmacokinetics is essential for choosing appropriate insulin type and regimen. In addition to type of insulin, other factors like age, dose, mixing, and physical activity influence insulin absorption and action. Several new formulations of insulin are under development. However, efforts at producing effective alternative route of administration for insulin have met with limited success till now.

INTRODUCTION Since its discovery in 1921, insulin treatment has undergone substantial changes from time to time. Animal insulin, which was the standard of treatment for diabetes for many decades, has now been replaced by human insulin and “designer insulins”—insulin analogs. Certain formulations like lente and ultralente are not available anymore whereas some new formulations are increasingly being used. Development of analogs of human insulin with structural modifications to parent insulin molecule has brought insulin therapy closer to normal physiology. A detailed description of pharmacology of insulin is beyond the scope of this book. However, understanding various types and formulations of insulin and certain important aspects of pharmacokinetics is essential for clinicians. Aspects related to insulin secretion and action are discussed in chapter 2.

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Insulin Types and Pharmacokinetics

STRUCTURE OF INSULIN MOLECULE Insulin is 51 amino acid peptide hormone composed of two polypeptide chains (chain A and B) joined by disulfide bridges. Chain A has 21 amino acid residues and chain B has 30 amino acid residues. Chain A contains an intrachain disulfide bridge between amino acid 6 and 11. Insulin is formed after the C peptide chain which connects chains A and B is cleaved off from the precursor molecule proinsulin (Fig. 1).

METABOLISM OF INSULIN Insulin secretion involves small amounts of hormone released from pancreas in fasting state which works as basal insulin and a larger prandial dose with a sharp peak released in response to secretagogues, mainly glucose. Endogenous insulin is directly secreted in the portal circulation leading to an immediate glucose lowering effect. In the fasting state, when blood glucose (BG) tends to drop, effective suppression of endogenous insulin and release of counter regulatory hormones (glucagon, catecholamines, cortisol, and growth hormone) maintains BG. Secreted insulin undergoes extensive metabolism in liver before reaching the systemic circulation. The remaining is metabolized by kidney and adipose tissue. There is significant renal tubular reabsorption of insulin before degradation.

Differences between Exogenous and Endogenous Insulin Insulin tends to form hexamers in presence of zinc and phenolic excipients. On injection into subcutaneous (SC) space, these are broken down to monomers which are then absorbed in SC capillaries. Thus the onset of action of SC insulin is delayed. As SC insulin is absorbed into systemic circulation and not into portal circulation; its level does not match the rise and fall of BG with meals as good as the endogenous insulin. Since many factors affect absorption of insulin from SC tissues, there is variability in the levels achieved between subjects and within a subject

Fig. 1: Structure of insulin (black lines denote disulfide bonds).

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Insulin Therapy: Current Concepts

Despite these differences, considerable success can be achieved in diabetes treatment with proper use of exogenous insulin. Newly available rapid-acting insulin analogs are non-hexameric and are rapidly absorbed from the injection site, making the insulin absorption more physiological. On intravenous (IV) administration, the insulin is rapidly degraded (half-life up to 5 minutes). Hence continuous infusion is necessary to have sustained effect. Only short or rapid-acting insulin can be used intravenously. Intermediate, long-acting or premixed insulin should “not” be used intravenously. Like endogenous inslulin, synthetic is metabolized in liver (60–80%), kidney (10–20%), muscle, and adipose tissue (10–20%) and is excreted in urine. Renal and hepatic dysfunction (renal more than hepatic) can delay the metabolism and excretion prolonging insulin effect.

Sources of Insulin Insulin from Animal Sources In 1921, insulin was isolated from dog pancreas. This was followed by further research and advancement in isolation and purification of insulin. The earliest forms of insulin to be used clinically were of beef, pork, and beef-pork origin. Bovine insulin differs from human insulin at the following three positions: (1) alanine for threonine at position A8 (8th position on A chain); (2) valine for isoleucine at A10; and (3) alanine for threonine at the carboxyl terminal of the B chain whereas porcine insulin derived from pork pancreas differs from human insulin in the substitution of alanine for threonine at the carboxyterminal of the B chain. The aforementioned insulins were standard of therapy for many decades. Although clinical efficacy is not very different from human insulin, antibody production due to antigenic differences is greater especially with bovine insulin. These antibodies, in high titer, can alter insulin action. Impurities in production (non-insulin proteins) can also lead to allergic reactions. Incidence of injection site lipoatrophy is more with animal insulins. The process of purification improves the quality of insulin and leads to reduction in allergy and local side effects.

Human Insulin

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Earliest human insulin was produced by substituting alanine for threonine in position B30 of porcine insulin. It is now synthesized by introducing human insulin or proinsulin gene into cells of special strains of Escherichia coli or

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Insulin Types and Pharmacokinetics

yeast Saccharomyces cerevisiae through recombinant deoxyribonucleic acid (DNA) technology. Human insulin has been shown to have faster absorption and shorter duration of action than animal insulin in clinical and pharmacologic studies. These differences are more pronounced and can be of clinical relevance with intermediate- and long-acting insulin in the form of waning insulin effect in the early morning hours (dawn phenomenon).

Insulin Analogs These are synthesized by structural modifications in insulin molecule which change the pharmacokinetic properties without changing antigenic properties. For a detailed discussion on insulin analogs and their clinical use, the reader is referred to chapter 4.

AVAILABLE FORMULATIONS OF INSULIN Currently used insulin formulations are given in table 1. These can be classified depending on the duration of action as rapid-acting analogs (lispro, Table 1

Pharmacokinetics of different types of insulin: approximate times of onset, peaking, and duration of action of various insulins

Insulin type

Onset

Peak

Duration

Appearance

5–15 mins

1 hr

3–5 hrs

Clear

30 mins

2–3 hrs

6–8 hrs

Clear

2–4 hrs

5–8 hrs

10–16 hrs

Cloudy

Glargine, detemir

2–4 hrs

Peakless*

24 hrs†

Clear

Degludec

2–4 hrs

Peakless

Up to 40 hrs Clear

30 mins

Dual

1–16 hrs

Cloudy

5–15 mins

Dual

10–16 hour

Cloudy

Rapid-acting Lispro, aspart, glulisine Short-acting Regular (plain or crystalline) Intermediate NPH (isophane) Long-acting

Premixed conventional insulin NPH + regular (70:30, 50:50) Premixed analogs Protaminated lispro + lispro (75:25, 50:50), Protaminated aspart + aspart (70:30, 50:50)

*Some peak action can be seen especially with detemir. † Duration of action in some patients can be less than 24 hours. NPH, neutral protamine Hagedorn.

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Fig. 2: Graph showing approximate pharmacokinetic properties of human insulin and insulin analogs. Source: Hirsch B. Insulin Analogues. N Engl J Med. 2005;352:174-83.

aspart, glulisine), short-acting (regular or plain), intermediate [neutral protamine Hagedorn (NPH)], long-acting analogs (glargine, detemir), and recently introdued ultralong-acting analog degludec. Short- or rapid-acting insulins are used for mealtime boluses, whereas intermediate or long-acting insulins are used for basal insulin requirement. Important pharmacokinetic features of available insulins are shown in table 1 and figure 2 and are discussed in details in the text below. Zinc-containing intermediate acting insulin (lente) and long-acting insulin (ultralente) are no longer available commercially and are not discussed hereafter. In India, insulin vials are available in two concentrations 40 IU/mL and 100 IU/mL. It is necessary to match the vials with appropriate syringes (i.e., 100 IU syringe for 100 IU/mL vial). The penfills are available only in 100 IU/mL strength.

Regular (Plain or Crystalline) Insulin

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Regular insulin remains as a clear solution at neutral pH. The addition of zinc [0.4%] allows the molecules of insulin to aggregate into stable hexamers. Phenol or meta-cresol is added to prevent the growth of microorganisms. On SC injection, regular insulin has an onset of action in 15–60 minutes hence it should be injected at least 30 minutes prior to meals. Its action peaks in 2–4 hours and lasts for upto 5–8 hours. The extended duration of action causes “tailing effect” and risk of later hypoglycemia necessitating between meal snacks. Regular insulin is suitable for IV infusion in diabetic ketoacidosis, hyperosmolar hyperglycemic state, and patients undergoing surgical procedures under general anesthesia.

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Insulin Types and Pharmacokinetics

On SC administration, bioavailability of regular insulin is 55–77% with doses between 0.1 and 0.2 unit/kg and elimination half-life is about 1 hour. Regular insulin can be mixed with NPH in syringe but not with glargine or detemir. It cannot be mixed with lente or ultralente insulin as excess zinc can bind with regular insulin causing erratic action of the latter. Regular insulin should not be used if the appearance is cloudy or viscous.

Rapid-acting Insulin Analogs: Lispro, Aspart, and Glulisine Rapid-acting insulin analogs are synthesized by modifying amino acid sequence of insulin to prevent self-association into hexamers. This leads to favorable pharmacokinetics without changing antigenic properties. Lispro, aspart, and glulisine are the three rapid-acting analogs currently in use. Details regarding individual analogs are discussed in chapter 4. The three analogs have more or less similar pharmacokinetic properties. The absorption is faster and the action starts within 5–15 min, making administration just before meals possible. The peak concentration is achieved earlier and is twice that of regular insulin leading to better postprandial control. There is no tailing effect like regular insulin; hence the risk of delayed hypoglycemia and the need for mid-meal snack is less. Both Lispro and Aspart have been shown to be associated with lower incidence of nocturnal and severe hypoglycemia compared to regular insulin. These properties make them suitable for basal bolus therapy and insulin pump therapy. Bioavailability, receptor binding, metabolic effects, and potency is similar to regular insulin. There is immunologic cross reactivity between regular insulin and analogs. However, antibodies formed against these do not have any clinical consequences. All three rapid-acting analogs are suitable for IV use. However, the action profile and glucose lowering effect is similar to regular insulin by this route. Hence, there is no distinct advantage over regular insulin. Mixing of rapid-acting analogs with NPH in same syringe or in premixed formulations does not change pharmacokinetics. However, mixing with glargine or detemir has been shown to markedly flatten the peak and shift action curve to right, hence this should not be done. Rapid-acting insulin analogs can lead to early postprandial hypo­ glycemia in patients with diabetic gastroparesis due to their rapid onset of action. In these patients, insulin injection may be delayed to after consumption of meal. 21

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Insulin Therapy: Current Concepts

Neutral Protamine Hagedorn Insulin or Isophane Insulin Neutral protamine Hagedorn is a suspension of regular insulin combined with protamine in a phosphate buffer. Protamine ionizes the insulin molecule and delays absorption leading to prolonged action. Phenol or m-Cresol are added as preservative. It is cloudy in appearance. The insulin molecules tend to form precipitate and settle to the bottom of vial. Hence, the vial should be tipped or rolled between hands to resuspend insulin. Action of NPH starts within 1–4 hours of injection, there is a distinct peak effect noted between 4 hours and 10 hours after injection and the action tails over 14–24 hours. The “tail,” however, is relatively ineffective, so duration of effective glucose lowering is much less than 24 hours. Due to this, NPH has to be administered twice daily in most of the cases. The distinct peak seen is unphysiologic for a basal insulin and increases risk for hypoglycemia and need for a mid-meal snack. Intrasubject and intersubject variability is higher with NPH than glargine or detemir. NPH is widely used for type 1 as well as type 2 diabetes, as it can be conveniently mixed with short- or rapid-acting insulins either as a premixed preparation or separately in a syringe. The cost of NPH is 5–7 times less as compared to newer long-acting analogs which offers a distinct advantage in resource limited settings.

Long-acting Insulin Analogs: Glargine, Detemir, and Degludec

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Glargine and detemir are currently available long-acting analogs, whereas degludec has been recently appoved for use in patients older than 18 years. In these, modifications in insulin structure lead to prolonged peakless insulin effect as a result of precipitation at physiologic pH of subcutaneous tissues (glargine), binding to proteins (detemir) or formation of multihexamer assemblies (degludec). The usual onset of action is in 2–4 hours and action lasts for up to 24 hours. Duration of action is dose-dependent with larger doses lasting longer. Insulin degludec has been shown to have action up to 40 hours in studies. Although the action is usually peakless, some peak may be observed, but is not as prominent as with NPH. The pharmacokinetic properties enable once daily dosing in most cases. This dose can be given at any time of the day, usually bedtime or in the morning, but at the same time each day. In some cases, especially with detemir, splitting of dose may be required. Intersubject and intrasubject variability of these insulins is less compared to NPH leading to a more predictable action. The peakless action contributes to decreased risk of nocturnal and severe

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Insulin Types and Pharmacokinetics

hypoglycemia. Detemir has been shown to be associated with less weight gain compared to glargine and NPH. It is not advised to mix long-acting analogs with other insulins as this has not been widely studied. Acidic pH and high zinc content precludes mixing of glargine with other insulins. Available studies mixing glargine or detemir with lispro or aspart show flattening of peak of rapid-acting analogs and shift in its action curve to right.

Premixed Insulin Preparations These are combinations of short- or rapid-acting insulin with intermediate, acting insulin in fixed proportions. Conventional premixed insulin contains regular insulin with NPH, whereas premixed analogs are combinations of lispro or aspart with their protaminated forms. Available preparations and pharmacokinetic properties are listed in table 1. Advantages include convenient twice daily dosing and no need for mixing. The latter is especially useful for elderly and those with visual problems. These preparations are commonly used in treatment of type 2 diabetes. The fixed percentages of short- or rapid-acting and basal insulin make them less suitable for type 1 diabetics. Premixed analogs provide better postprandial glucose control compared to conventional premixed insulin and can be administered just before meals. Conventional premixed insulin should be injected at least 30–60 minutes prior meals. Disadvantages of premixed insulin include lack of flexibility and need for relatively rigid meal and snack timings. Individual adjustment of doses of short- and intermediate-acting insulin is not possible; hence increase in dose of one component leads to increased dose of other, which may cause undesirable fluctuations in BG. Some important considerations when prescribing insulin preparations are listed in table 2. Practical aspects of insulin storage and administration are discussed in appendices 1–3 of this book. Table 2

Considerations while prescribing insulin formulations

•• Appearance of insulin whether clear or cloudy needs to be told to patients •• Look alike or sound alike insulins should be carefully explained and written in full (for example Novomix 30/70 and Novomix 50/50, Humalog Plain and Humalog Mix) •• Strength of preparation 40 unit/mL or 100 unit/mL •• Syringes and insulin preparation should be matched e.g., 40 IU syringe for 40 IU/mL vial •• The word “UNITS” should be written as full and not as abbreviation “U” •• Right dose and time of administration in relation to food

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Insulin Therapy: Current Concepts

Table 3

Factors affecting insulin absorption

Factor

Comments

Age

Children have faster absorption

Subcutaneous fat

Large SC fat thickness slows absorption

Dose

Larger dose leads to slower absorption

Route of administration IV >IM >SC, accidental IM injections can cause hypoglycemia Exercise

Faster absorption in an exercising muscle

Injection site

Faster absorption from abdomen compared to thighs

Lipodystrophy

Erratic absorption

Local circulation

Massage, hot shower, or sauna may increase absorption

SC, subcutaneous; IV, intravenous; IM, intramuscular.

FACTORS AFFECTING INSULIN ABSORPTION Absorption of SC insulin is affected by various factors. It is important to understand these factors as they can lead to variable effect of insulin with the same dose. These factors are discussed in table 3.

NEWER INSULIN FORMULATIONS

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Degludec is a newer long-acting analog, which has been recently approved for use in type 1 as well as type 2 diabetes in European Union and India for patients older than 18 years of age. Deletion of threonine at B30 and addition of a fatty acid chain to lysine at B28 results in formation of multihexamer assemblies leading to ultra-long action. Studies in both type 1 and type 2 diabetes have shown longer duration of action (more than 40 hours) and less variability compared to glargine. One of the distinct advantage over presently available insulin analogs is its miscibility with short-acting analogs which has been used in its premixed formulation IDegAsp with insulin aspart. Clinical studies have shown noninferiority to glargine with reduced risk of nocturnal hypoglycemia. It has been discussed in more details in chapter 4.In addition to this, newer formulations of glargine permitting mixing with other insulin, LY2963016 and BIOD-Adjustable Basal and some new longacting analogs are currently undergoing clinical trials. Protaminated lispro, which is currently used as premixed formulation is being investigated as a long-acting analog. Linjeta (formerly called VIAject) is a different formulation of regular insulin. It contains ethylenediamine-tetraacetic acid and citric acid which prevent hexamer formation giving a rapid onset of action, potentially faster than rapidacting analogs. Combination of human recombinant human hyaluronidase with rapid-acting analogs to increase their absorption is undergoing studies.

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Insulin Types and Pharmacokinetics

Limited success has been achieved in alternative routes of insulin delivery. Exubera was an inhaled formulation of insulin introduced in 2006, but was taken off the market. Possible reasons for its failure were poor patient acceptance, higher cost, and no distinct advantage over regular insulin. Presently, other improved formulation of inhaled insulin, Technosphere insulin, is under consideration for approval. It is a delivery system with regular insulin incorporated into microspheres and formulated into a dry powder for inhalation.

SUMMARY Conventional insulins from animal sources have now been replaced with human insulin and analogs of insulin. Synthesis of newer insulin analogs have made the insulins more physiological. Knowledge of insulin pharmacokinetics is essential for choosing appropriate insulin type and regimen. In addition to type of insulin, other factors like age, dose, mixing, and physical activity influence insulin absorption and action. Efforts at producing effective alternative route of administration for insulin have met with limited success till now.

Suggested Reading 1. Binder C, Loritzen T, Faber O, et al. Insulin pharmacokinetics. Diabetes Care. 1984;7:188-99. 2. Gualandi-Signorini AM, Giorgi G. Insulin formulations—a review. Eur Rev Med Pharmacol Sci. 2001;5:73-83. 3. Insulin, oral hypoglycemic agents, and the pharmacology of endocrine pancreas. In: Brunton LL, Parker KL, Blumenthal DK, Buxton IL, editors. Goodman and Gillman’s Manual of Pharmacology and Therapeutics. New York: McGraw Hill Medical; 2008. pp. 1039-60. 4. Rosenstock J, Schwartz SL, Clark CM, et al. Basal insulin therapy in type 2 diabetes: 28 week comparison of insulin glargine and NPH insulin. Diabetes Care. 2001;24:631-6. 5. Vague P, Selam JL, Skeie S, et al. Insulin detemir is associated with more predictable glycemic control and reduced risk of hypoglycemia than NPH insulin in patients with type 1 diabetes on a basal bolus regimen with premeal insulin aspart. Diabetes Care. 2003;26:590-6. 6. Borgoño CA, Zinman B. Insulins: past, present and future. Endocrinol Metab Clin North Am. 2012;41:1-24. 7. Reynolds LR. Comparing insulins detemir and glargine in type 2 diabetes: more similarities than differences. Postgrad Med. 122 (1):201-3. 8. Hirsch IB. Insulin Analogues. N Engl J Med. 2005;352:174-83. 9. Strack T. The pharmacokinetics of alternative insulin delivery systems. Curr Opin Investig Drugs. 2010;11:394-401. 10. Lucchesi MB, Komatsu WR, Gabbay MA, et al. A 12-wk follow-up study to evaluate the effects of mixing insulin lispro and insulin glargine in young individuals with type 1 diabetes. Pediatr Diabetes. 2012;13(7):519-24.

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4 Insulin Analogs Jasjeet S Wasir

Abstract Insulin analogs are synthesized by changes in the structure of insulin molecule and are not similar to any naturally occurring insulin. Rapid-acting insulin analogs (lispro, aspart, and glulisine) have rapid onset of action (5–15 min), higher and earlier peak concentration levels leading to more physiologic insulin action compared to regular insulin. Long-acting analogs glargine and detemir have relatively peakless action profile compared to neutral protamine Hagedorn and lesser day to day variability which makes them more suitable as basal insulins. Premixed formulations of insulin offer advantages of convenience of administration particularly in elderly and visually impaired subjects but are not ideally suitable for type 1 diabetes. Degludec is the recently launched novel basal insulin with ultra-long duration of action and even lesser variability which is expected to further reduce occurrence of hypoglycemia.

INTRODUCTION Insulin was first used for treatment of diabetes in 1922 in Canada. However, our ability to mimic physiological insulin secretion remains a challenge. Landmark studies like diabetes control and complications trial (DCCT) have clearly demonstrated superiority of physiologic insulin replacements over conventional twice daily treatment. Attempts to make insulin therapy more physiological include change in the sources (animal to human), delivery devices (insulin pump), and structure (newer insulin analogs). Physiological insulin secretion (Fig. 1) consists of basal component which limits hepatic glucose production and prandial component which is secreted in response to meals. Ideal basal insulin, therefore, should not have a peak level and ideal prandial insulin should have similar concentration, peak action, and duration of action as endogenous insulin. In this regard, limitations of conventional insulin include: •• A lag phase from administration to onset of action

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Insulin Analogs

Fig. 1: Physiological secretion of endogenous insulin.

•• Unphysiologic action profiles causing fluctuations in blood glucose (BG) •• Variability in the action between subjects and within subject. To overcome some of these problems, research has led to production of newer insulin analogs. These are synthesized by changes in the structure of insulin molecule and are not similar to any naturally occurring insulin. In this chapter, structure, pharmacokinetics, pharmacodynamics, clinical uses, and possible concerns of currently available insulin analogs are discussed.

STRUCTURE While designing insulin analogs, recombinant bioengineering methods are used to make structural changes into the parent insulin molecule (amino acid substitutions, inversions, or additions of amino acids or side chains) which modify the amino acid sequence. This changes pharmacokinetic properties of the resultant molecule leading to change in selfssss-aggregation and rate of absorption from subcutaneous (SC) space. The changes, however, do not affect receptor binding, postreceptor signaling, and antigenic properties of insulin. Based on the rate of diffusion from SC tissue, insulin analogs can be classified as rapid-acting and long-acting. The analogs in current clinical use with their structure and pharmacokinetic properties are listed in table 1. Premixed formulations of rapid-acting analogs with protaminated analogs in various proportions line 30/70, 25/75, and 50/50 are also used commonly in type 2 diabetes. The names of analogs give some hint at the structural changes; e.g., “lis-pro” indicates change in lysine and proline, “aspart” indicates addition of aspartic acid, “glu-lisine” indicates changes involving glutamic acid and lysine, and “gl-argine” indicates changes involving glycine and arginine.

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Table 1

Insulin analogs in current use

Insulin preparation*

Structural change

Onset of action

Peak action

Duration of action

Lispro

Transposition of lysine at B29 with proline at B28

5–15 mins

30–90 mins

3–5 hrs

Aspart

Replacement of proline at B28 5–15 mins with aspartic acid

30–90 mins

3–5 hrs

Glulisine

Replacement of lysine at B29 by glutamic acid and asparagine at B3 by lysine

5–15 mins

30–90 mins

3–5 hrs

Glargine

Replacement of asparagine at A21 with glycine and addition of two arginine residues at B30

1–3 hrs

Peakless¶

24 hrs†

Detemir

Deletion of threonine at B30 and acylation and addition of myristic acid to lysine at B29

1–3 hrs

Peakless¶

24 hrs†

Rapid-acting

Long-acting

*Names in parentheses indicate common brand names available in India. ¶ A small peak (much less than neutral protamine Hagedorn) can be seen with both glargine and detemir. † Duration may not be 24 hours in all patients.

RAPID-ACTING INSULIN AnalogS The amino acid modifications in the currently available rapid-acting analogs are done in B chain of insulin molecule and include transposition of lysine on B chain at position 29 (B29) with proline at position 28 (Lispro), replacement of proline at position B28 by the negatively charged aspartic acid (Aspart), or replacement of lysine at B29 with glutamine and asparagine at B3 with lysine (Glulisine).

Pharmacokinetic Properties

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Human regular insulin tends to form hexamers in solutions. Various factors like structure of molecule, presence of zinc, insulin concentration, and pH of solution affect hexamer formation. Before absorption, hexamers dissociate into dimers and monomers which diffuse across capillaries rapidly and are biologically active (Fig. 2). Modifications in rapid-acting analogs decrease the propensity to self-aggregate through charge repulsion, hence the analogs exist predominantly in a monomeric form (Fig. 2) leading to faster absorption, early and higher peak, short duration of action, and lesser variability in

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Insulin Analogs

Fig. 2: Subcutaneous absorption of regular (grey) and rapid-acting (dark blue) insulin.

Fig. 3: Comparison of endogenous insulin, analogs, and standard insulin.

concentration achieved thus mimicking endogenous insulin more closely than regular insulin (Fig. 3). Factors which modifying absorption of human insulin after a SC injection like age, thickness of SC fat, injection site, local circulation, exercise also influence absorption of analogs in a similar way. Like regular insulin, insulin analogs are metabolized in liver and kidney and excreted in urine. Hence, renal dysfunction delays excretion and prolongs insulin effect. Pharmacodynamic studies using glucose infusion rates (GIR) in euglycemic clamp studies have demonstrated time to reach peak concen­ tration (tmax) almost half that of regular insulin, peak concentration double that of regular insulin, and shorter residence time. This translates into better control of postprandial glucose and shorter time of action, hence lesser risk of delayed hypoglycemia. After SC injection, the action of rapid-acting analogs

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starts at 5–15 min, peaks at 60–90 min, and is over by 4 hours (Table 1). All three analogs (1) lispro, (2) aspart, and (3) glulisine have more or less similar pharmacokinetics and action.

Clinical Use of Rapid-acting Insulin in Diabetes Mellitus Type 1 Diabetes Mellitus (Also See Chapter 6) Type 1 diabetics have no insulin reserve beyond the honeymoon phase. Hence, insulin replacement should be matched to physiological insulin secretion as far as possible. Best way of doing this is continuous subcutaneous insulin infusion (CSII) or multiple subcutaneous insulin injections (MSI). Superiority of these regimens has been proven by the DCCT study. These regimen consist of prandial boluses given before each of the major meals or snacks, basal insulin that regulates lipolysis and hepatic glucose output, and correction-dose insulin (usually small dose as compared to prandial or basal) to address in between-meal hyperglycemia, independent of the prandial insulin. Endogenous insulin response to meals occurs in a robust first-phase secretion and then a more prolonged second-phase release. Subcutaneous injection of rapid-acting insulin analogs mimics the first phase of insulin secretion; however, it will never precisely replicate the second-phase release. Based on the kinetics and duration of action of the currently available insulin preparations, regular and neutral protamine Hagedorn (NPH) insulin span both the prandial and basal components of insulin replacement, whereas insulin analogs (rapid- and long-acting) target each of these components separately. In keeping with pharmacokinetic properties, potential indications of rapid-acting analogs in type 1 diabetes are summarized in table 2.

Table 2

Potential indications of rapid-acting analogs in type 1 diabetes

•• Insulin pump therapy •• Prandial or correction doses in MSI regimen •• Infants, toddlers and young children (unpredictable eating habits) •• Sick day management and correction boluses •• Known or suspected delayed or nocturnal hypoglycemia •• Unwillingness or inconvenience of waiting for injecting 20–30 mins before meals •• Avoidance of extra mid-meal or bedtime snacking •• Postprandial hyperglycemia despite of regular insulin dose and timing adjustment

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MSI, multiple subcutaneous insulin injections.

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Insulin Analogs

Although regular insulin can be used in pumps and for correction doses, rapid-acting analogs are more suitable for this. When used in insulin pumps (CSII), the rapid-acting insulin preparations when given continuously mimic the basal insulin profile. Use in young children with unpredictable eating habits makes it possible to administer insulin after meals, hence reducing risk of hypoglycemia or hyperglycemia. Several studies in type 1 diabetes have shown that rapid-acting analogs are associated with improved flexibility, reduction of severe hypoglycemic episodes, and decreased postprandial hyperglycemic events resulting in improved quality of life. Most of the studies and meta-analysis comparing rapid-acting analogs with regular insulin have shown no or minimal benefit in terms of glycemic control as measured by glycosylated hemoglobin (HbA1c) (-0.1 to -0.2% in favor of analogs). Benefits are more with pump therapy than with MSI. Similarly, incidence of mild hypoglycemia has not been proven to be significantly less with their use. In addition to this, with long meal gaps, the premeal readings may become high due to short duration of action. Basal insulin doses may not adequately control blood glucose in this time period particularly if snacks are unaccompanied by a bolus dose. Similar problem may occur with fatty meals and diabetic gastroparesis where regular insulin’s tailing effect might be of benefit. Cost of these insulins is nearly 3–4 times higher than conventional insulins and is a major impediment to its widespread use particularly in developing countries. Rapid-acting Analogs in Type 2 Diabetes Rapid-acting insulin analogs have a limited role in the conventional treatment of type 2 diabetes. Indications for their use are essentially similar to indications of human regular insulin (with advantages as noted above) and include the following: •• Patients with acute illness or complications (e.g., severe acute coronary syndromes, pyelonephritis, lower respiratory tract infections, hyper­ glycemic hyperosmolar state, etc.) of diabetes •• Patients with advanced end-organ damage, e.g., chronic kidney or liver disease, and congestive heart failure •• Secondary failure of oral agents in those who are also receiving basal insulin •• At diagnosis in patients with severe osmotic symptoms and uncontrolled hyperglycemia [the new diabetes management guidelines (American Diabetes Association, International Diabetes Federation, and American Association of Clinical Endocrinologists) endorse early use of insulin for fast and effective glycemic control for prevention of complications].

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When used in type 2 diabetes, rapid-acting analogs potentially can give better postprandial control, improved flexibility, and some reduction of severe hypoglycemic events. However, clear superiority of insulin analogs in glycemic control and diabetes complication rate is not proven.

LONG-ACTING INSULIN AnalogS Structure and Pharmacokinetics Based on the basal physiological insulin, the optimal characteristics of “ideal” basal insulin should include the following: •• The pharmacodynamic profile should be flat (peakless) and should be associated with a low risk of hypoglycemia (e.g., commonly seen with NPH insulin the phenomenon of nocturnal hypoglycemia due to peak activity occurring several hours after injection) •• The duration of action should be around 24 hours to control fasting plasma glucose with just one daily injection •• Variability within individual patients should be low, meaning that identical doses of insulin administered to the same patient on different occasions should lead to identical and predictable effects, thus lowering the risk of hypoglycemia or hyperglycemia.

Insulin Glargine Based on the above mentioned principles, long-acting insulin analogs were developed towards the end of the 20th century (glargine was the first to be introduced in 2001). Insulin glargine differs from human insulin at position A21 of the A chain (substitution of asparagine with glycine) and position B31 and B32 of the B chain (addition of two arginines). These changes shift the isoelectric point (pH at which insulin exists in a soluble state) from pH 5.4 to pH 6.7. Insulin glargine is injected as a clear acidic solution (pH 4), which forms microprecipitates that must dissolve before absorption can take place. Precipitation and slow redissolution are inherently associated with substantial variability. Nonetheless, the time-action profile of insulin glargine is flatter and of longer duration compared with NPH insulin (Fig. 4).

Insulin Detemir

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The other long-acting insulin analog available is insulin detemir. Manufacture of detemir involves removal of threonine at position B30 and acylation of lysine at B29 with a 14-carbon fatty acid (myristic acid). The prolonged duration of action for insulin detemir is attributable to a combination of increased self-association (hexamer stabilization and

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Insulin Analogs

Fig. 4: Pharmacokinetic profile of glargine versus neutral protamine Hagedorn (NPH) insulin.

hexamer-hexamer interaction) and albumin [detemir is highly albuminbound (98.8%), binding because of the acylation]. The analog is supplied as a clear neutral solution and remains in solution in the subcutaneous depot, in the circulation and in the target tissues until interaction with the insulin receptor. Absorption of insulin detemir is, therefore, dependent on neither appropriate resuspension before injection and dissolution of crystals, as is the case with NPH insulin, nor on formation and redissolution of microprecipitates, as is the case for insulin glargine. As compared to NPH insulin, detemir is longer-acting and has a flatter action profile. However, the duration of action is shorter than glargine needing twice daily dosing in many patients. Advantages compared to glargine include lesser within subject variability and lesser weight gain.

Clinical Uses of Long-acting Analogs Type 1 Diabetes Mellitus Long-acting insulin analogs are used as basal insulin in MSI regimen in type 1 diabetics along with prandial boluses of regular insulin or rapidacting analogs. Basal insulin requirement is generally 40–50% of total daily dose and is given as a single daily dose. Twice daily dosing may be required especially with detemir. The dose can be administered at any time of the day (morning, evening, or bedtime) but it is important that it is given at same time each day. Advantages of long-acting analogs include convenient dosing, no need of mandatory snacking (as with peak level of NPH), improved flexibility, and reduced risk of severe and nocturnal hypoglycemia. The reduced rates of hypoglycemia seen with long-acting analogs make the dose increments easier so as to achieve greater degree of glycemic control at a lesser risk (hypoglycemia).

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Several clinical studies comparing long-acting analogs with NPH have shown small but significant improvements in HbA1c. For example, in an observational study of 1,942 patients who were switched from NPH insulin to insulin glargine, mean HbA1c declined by 0.8% over 6 weeks of treatment from 8.0% at baseline. In a second study of longer duration, 1,447 patients who were switched from various insulin regimens to basal-bolus therapy with insulin glargine and insulin glulisine experienced a significant mean reduction in HbA1c of 1% over 6 months from a baseline of 8.0%. However, this improvement is not consistent across all the studies. A recent metaanalysis did not find significant differences between long-acting analogs and NPH in children and adolescents with type 1 diabetes. Disadvantages of long-acting analogs include higher cost (6–7 times more costly than NPH). Mixing of these insulins with short-and rapid-acting insulin is not possible with present formulations as it leads to significant blunting of effects of the latter. Being an acidic solution, glargine is sometimes associated with a stinging or burning sensation at the injection site. Type 2 Diabetes Mellitus

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Landmark studies like the United Kingdom Prospective Diabetes Study have clearly shown that early and intensive glycemic control is associated with better outcomes. This clearly defines the role of early and aggressive glucose lowering therapy including insulin in type 2 diabetes. Interestingly, in reality only a small percentage of type 2 diabetics are on basal insulin. This may reflect the general trend of using insulin as a last resort in controlling hyperglycemia and reluctance on part of both the patient and the physician until two or even three oral agents have failed to achieve glycemic control. However, progressive nature of b-cell loss in type 2 diabetes is well known and early use of insulin may help in preservation of β cells, reduce apoptosis, decrease glucotoxicity, reduce cytokines, atherosclerosis, and have beneficial effect on the lipids and blood pressure. Long-acting analogs are used as basal insulin, in combination with oral antidiabetic drugs and as basal-bolus therapy with prandial insulins in advanced insulinopenic type 2 diabetes, during periods of surgery or stress and ketoacidosis. Advantages of long-acting insulin analogs in comparison to NPH in type 2 diabetes: •• More physiological profile of long-acting insulin analogs as compared to human insulin (NPH) •• Less hypoglycemia as compared to human insulin •• Greater flexibility in timing of injections.

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Insulin Analogs

Based on these advantages, long-acting analogs have found its place right at the top of the treatment algorithm for diabetes. All the major associations including American Diabetic Association, American Association of Clinical Endocrinologists, International Diabetes Federation and European Association for the Study of Diabetes have endorsed this superiority in their treatment guidelines. In summary, the guidelines clearly state that in addition to metformin and therapeutic lifestyle changes long-acting insulin may be added in preference to other oral agents if HbA1c is in between 8 and 10%, patient has severe osmotic symptoms (e.g., weight loss), if fasting glucose is >250 mg/dL or the random BG levels are consistently >300 mg/dL. Finally, prandial insulin may be added along with basal insulin in patients with HbA1c >10%.

PREMIXED AnalogS These are fixed mixtures of rapid-acting analogs with their protaminated component in various proportions. Three formulations commonly available include: (1) 50% lispro/aspart +50% protaminated lispro/aspart (Humalog® Mix 50/50, Novomix 50) (2) 25% lispro +75% protaminated lispro (Humalog® 25/75), and (3) 30% aspart +70% protaminated aspart (Novomix 30/70). Due to distinct pharmacokinetics of rapid-acting analogs, in comparison to conventional premixes of human insulin, premixed analogs have more desirable pharmacokinetic and pharmacodynamic profile, leading to better postprandial glycemic control. Flexible injection timing in relation to meals is likely to improve adherence to therapy. HbA1c levels and rates of hypoglycemia are comparable to conventional premixes. Both premixed analogs and conventional premixes are suitable for type 2 diabetics who are elderly, have poor vision, and poor hand eye coordination or are noncompliant to physiologic insulin regimen. They are not ideal for type 1 diabetes as separate adjustment of two components is not possible and a comparatively rigid lifestyle is necessary.

INSULIN AnalogS AND CANCER Type 2 diabetes appears to be associated with increased risk of cancers like breast, colorectal, and pancreatic cancer. Insulin has been shown to have growth promoting effect on cancer cells in laboratory studies. Concerns of association between insulin analogs and cancer stem from epidemiologic studies reporting increased risk of some cancers in patients treated with insulin glargine. Methodological limitations and confounding factors like diabetes, obesity, and sedentary lifestyle make interpretation of these

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findings difficult. Plausible mechanisms for cancer risk with analogs are due to increased affinity to insulin-like growth factor-1 (IGF-1) and altered binding kinetics leading to growth promoting effect. In general, evidence linking or excluding relation between analogs and cancer is limited. Most of the professional societies recommend that cancer risk should not be a deterrent to choosing appropriate antidiabetic treatment including insulin.

RECENT ADVANCES Degludec Currently, used long-acting analogs have advantages over NPH in terms of relatively peakless profile and lesser variability. But it is well understood now that the action may not be entirely peakless, particularly at high doses. In addition, the duration of action may fall short of 24 hours needing twice daily dosing, particularly with use of detemir in type 1 diabetes. Hypoglycemia continues to be the most significant barrier to good glycemic control in both type 1 and type 2 diabetes. Degludec an ultra-long acting insulin has recently been developed which may in the near future effectively take care of some of the existing limitations of the approved long acting insulins. At the time of writing this chapter, degludec has been approved for use in European Union for use more than 18 years of age in both type 1 and type 2 diabetes as well as in India. Structure and Pharmacokinetics Insulin degludec differs from human insulin in deletion and threonine at B30 position and addition of hexadecandioyl (fatty diacid) moiety attached to lysine at B29 via a glutamic acid spacer. After injection in subcutaneous space, after dispersion of phenol, it forms large soluble multihexamers from which insulin monomers dissociate at a slow and steady rate. This leads to a longer half-life (approximately 25 hours) and a glucose lowering effect of more than 40 hours at steady state. In comparison to insulin glargine, degludec has longer duration of action and importantly, lesser pharmacodynamic variability. Regimens like thrice a week regimen or variable timing regimen have been studied but not recommended at present in clinical practice. Degludec in Type 1 Diabetes

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In an open label, treat to target, noninferiority trial, reduction in HbA1c with degludec was, not inferior to glargine. Rates of nocturnal hypoglycaemia were 25% lower in degludec group compared to glargine but overall hypoglycaemic

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Insulin Analogs

events were not different. A recent study has reported once daily flexible dosing to be as effective as glargine but at present in clinical practice, once daily regimen is advised preferably same time everyday. Degludec in Type 2 Diabetes Evidence from two randomized controlled trial has shown degludec to be noninferior to glargine in terms of HbA1c reduction. Rates of nocturnal and severe hypoglycemia were shown to be significantly lesser with degludec. In comparison to sitagliptin, degludec had better glycemic control but increased occurrence of hypoglycemia. Insulin degludec is given once daily at any time of the day, preferably at the same time every day. On occasions when this is not possible, there can be some flexibility in the timing of insulin administration. The summary of product characteristics states that a minimum of 8 hours between injections should always be ensured. Insulin Degludec/Insulin Aspart (IDegAsp) One of the unique advantage of degludec over other basal analogs is its miscibility with short-acting analogs. IDegAsp is a mixture of degludec and aspart in 70/30 percentage and has been shown to be equally efficacious to glargine in type 2 diabetes. In keeping with available evidence, degludec use can be considered in adults (age>18 years) with type 1 or type 2 diabetes, particularly in presence of repeated nocturnal hypoglycaemias despite titration of insulin. Some other analogs under development are discussed in chapter 3.

CONCLUSION Development of long- and short-acting analogs of insulin is an important milestone in the history of insulin. This is a step closer to making insulin therapy more physiological. Insulin analogs have more physiological pharmacokinetic and pharmacodynamic profile. They provide increased flexibility in terms of injection timing and less rigid requirement of snacking. Risk of severe and nocturnal hypoglycemia is lesser compared to conventional insulins. Till date, benefit in terms of glycemic control as measured by HbA1c is at best modest. The possible link between insulin analogs and cancer has limited evidence and needs more epidemiologic and observational studies. This should not be a deterrent in choosing best therapy for a patient. Ongoing developments and newer analogs are being developed and the quest for making insulin therapy physiological continues.

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Suggested Reading 1. Hirsch IB. Insulin analogues. N Engl J Med. 2005;352:174-83. 2. Evans M, Schumm-Draeger PM, Vora J, et al. A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvement and limitations. Diabetes Obes Metab. 2011;13:677-84. 3. Singh SR, Ahmad F, Lal A, et al. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis. CMAJ. 2009;180:385-97. 4. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-53. 5. Weyer C, Heise T, Heinemann L. Insulin aspart in a 30/70 premixed formulation. Pharmacodynamic properties of a rapid-acting insulin analog in stable mixture. Diabetes Care. 1997;20(10):1612-4. 6. Anderson JH, Brunelle RL, Koivisto VA, et al. Reduction of postprandial hyperglycemia and frequency of hypoglycemia in IDDM patients on insulinanalog treatment. Multicenter Insulin Lispro Study Group. Diabetes. 1997;46(2): 265-70. 7. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35:S11-63. 8. IDF Clinical Guidelines Task Force. Global guideline for type 2 diabetes. Brussels: International Diabetes Federation; 2005. 9. Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2006;29(8):1963-72. 10. Berger M, Jörgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care. 1999;22:C71-5.

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Advances in Insulin Delivery Devices

5

Ramchandra Naik, Arundhati Dasgupta

Abstract For many years, the vial and syringe have been standard means of delivering insulin. In the recent past, newer insulin delivery devices have been introduced and offer key advantages in terms of easier administration and adjustment, higher patient satisfaction, and adherence. Reusable or disposable pens are easy to use, less threatening, and less painful. Recent pens provide dosing in half unit increments and also have confirmatory clicks. Insulin pumps use rapid-acting analogs at basal rates and bolus doses. Ability to adjust different basal rates at different times of the day and different physiologic situations like stress and exercise make basal insulin replacement most physiologic. Different types of boluses like square wave or dual offer distinct advantage. In addition to higher cost, pump therapy demands more involvement of patient and family in terms of adherence to testing, carbohydrate counting, and follow-up. Hence, candidates for pump therapy should be carefully selected. Sensor augmented pump therapy and low glucose suspend features are newer features of insulin pump. Closed loop insulin delivery linking continuous glucose monitors to continuous insulin infusion via various algorithms is likely to be available in near future for patients with type 1 diabetes.

INTRODUCTION Insulin was first used 90 years ago and ever since then, it has been the mainstay of therapy for all type 1 diabetes mellitus (T1DM) patients and many type 2 diabetes mellitus (T2DM) patients. Recent studies have shown that early intensive insulin therapy at the onset of T2DM arrests b-cell function decline. There are several barriers to initiation of insulin therapy. Patients are often reluctant to take multiple daily injections and make changes to their lifestyle. Many are also apprehensive that insulin therapy once initiated would probably be for life. In a recently published cross sectional study to explore the barriers to initiating insulin, patient resistance was cited by 64% and problems with patient self-management by 43%. An important barrier to

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Insulin Therapy: Current Concepts

insulin use is the limitation of the conventional insulin delivery process. For many years, the vial and syringe have been the standard means of delivering insulin—this method of insulin administration remains time consuming, cumbersome, inconvenient, painful, and also associated with high risk of dosage errors especially in the visually compromised or elderly. These factors can act as barriers to insulin therapy and thereby negatively influence treatment adherence and achievement of euglycemia. The situation, however, has improved with development of newer ways of administering insulin. These delivery devices offer key advantages in terms of easier administration and adjustment, higher patient satisfaction, and adherence. The following sections provide an overview of the newer insulin delivery devices. Insulin syringes continue to be an important delivery device worldwide and practical considerations regarding their use are discussed in appendices 1–3 of this book.

INSULIN PEN DEVICES Development of insulin pens as the first alternative to vials and syringes started in the mid-1980s. These devices combine the insulin container and syringe in a single unit. Insulin pens can be broadly classified as reusable (refillable) and disposable (prefilled).

Reusable Pens Reusable pens use single-use cartridges that are replaced by patient when empty. Advantages of reusable pens over prefilled pens include lesser cost and convenience of not having to change the pen in the event of change in insulin type (for example from premixed to regular). Thus longer duration of use is possible. Some refillable pens have added features, such as a memory function or ability to dial in half unit increments that are not available with prefilled pens. Disadvantages of reusable pen include potential loss of sterility and possible damage to pen over time.

Disposable Pens

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Disposable pens are prefilled pens designed for discarding after single time use. Prefilled pens have a built-in, single-use insulin cartridge that does not require loading by the patient. These lightweight pens are particularly useful for patients with difficulty in handling the cartridges in reusable pens or for those with busy schedules. Compared to reusable pens, prefilled pens are slightly more expensive.

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Advances in Insulin Delivery Devices

Insulin pens have a number of “advantages” over the conventional vialsyringe method: •• Portable and more convenient to use •• Greater degree of flexibility in both static and mobile use •• More accurate dosages with lesser time spent in loading •• Insulin pens being factory calibrated have diminished risk of dosing error •• Easier to use for those with impairment of vision or fine motor skills; e.g., patients with neuropathy and retinopathy •• Less painful injections: pens have fine (30–32 G) short needles that are associated with minimal or virtually no pain from injection •• Increased safety: introduction of protective shields with needles have reduced needle-stick injuries •• Some pens have an electronic memory function that enable patients to maintain a record of the insulin dose. These are not available in India currently. All these reasons have resulted in greater social acceptability for pens and patient preference for pens as the mode of insulin injection has grown significantly in recent years. “Disadvantages” of pens include: •• Greater expense: the unit cost of insulin is higher with pen devices. However, several studies have found that overall diabetes-related treatment costs are lower with pen devices than with the vial-syringe method •• Inability to mix different types of insulin •• Potential for introduction of air and/or biological matter into the pen: in a study, non-inert matter including epithelial cells and squama was found in 28% of needles and 58% of cartridges •• Mechanically, more complex than syringes and vials with greater chances for malfunction •• Not interchangeable between manufacturers of insulin, thus a preferred type of pen may not correspond with the prescribed drug.

Device Preparation The technique for dose preparation and insulin administration are generally similar irrespective of the type of pen chosen. Once a disposable needle is attached on to the pen, it is primed by pushing a small dose of insulin (generally 2 units) in air. This makes sure that the needle is not blocked. Subsequently, the desired dose is dialed and confirmed in the device’s display window. After inserting the needle subcutaneously, the plunger injection button is pressed completely to deliver the dose. The needle should remain

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in the subcutaneous (SC) tissue for up to 5 seconds to ensure complete dose delivery. This can be done by asking the patient to slowly count till five. The needle is then removed. The plunger is removed only after removing the needle. It is not unusual for 1–2 tiny drops of insulin to leak from pen after removal but leakage of more than this should prompt review of the injection technique. Pens containing insulin suspension [neutral protamine Hagedorn (NPH) insulin or an insulin premix] must be carefully rolled or tipped for the recommended number of times according to the package insert to ensure adequate mixing of the insulin suspension before attaching the needle. Whichever type of pen is used, a new pen needle needs to be attached for every use. An insulin pen must never be used by more than one individual, even if the pen needle is changed, because of the risk of transmission of blood-borne diseases. In Case of Accidental Dialing of Larger Dose Some of the modern pens have dial back facility by simply reversing the dialup action. In older pens, partial disassembly of the pen has to be done by pulling the mechanical section and the cartridge holder apart and pressing the dial-up button back to zero.

Storage The pen may be kept at room temperature while in use in order to avoid producing air bubbles, which can form when the insulin expands or contracts during a temperature change. The insulin should not be exposed to direct sunlight. Unused insulin pen cartridges and prefilled pens should be kept in the refrigerator. Once in use, most insulin analog vials, cartridges, and prefilled pens must be discarded after 28 days (insulin detemir: 42 days; biphasic insulin aspart 70/30 prefilled: 14 days; and biphasic insulin lispro 70/30 prefilled: 10 days).

Considerations while Selecting an Insulin Pen Device

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The major consideration in the choice of insulin pen is the prescribed insulin regimen. Certain pens offer benefits as compared to others: •• Pens which have a larger maximum dose (up to 80 units) may be preferable in patients who take large doses of insulin •• Children may benefit from a “simple to use” insulin pen since non­ adherence and compliance issues are more prominent in this patient group •• Infants and toddlers may require very small doses, hence pens with half unit adjustments are useful in this group •• In case of visual handicap, pens providing confirmatory click may be used

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Advances in Insulin Delivery Devices

•• Push button mechanism has been introduced in many pens to reduce the injection force required, making the injection more comfortable especially for those with impaired manual dexterity or arthritis •• Color coded pens have been developed to help in differentiating various insulin types. To summarize, the use of insulin pens offers many options to allow insulin delivery to be tailored to the individual patient. Newer designs of pens are increasingly user-friendly and convenient to use requiring little or no instruction. They have the potential to increase patient satisfaction and adherence to therapy.

JET INJECTERS Jet injectors deliver a high-pressure stream of insulin into the subcutaneous tissue. However, they are not widely used and they are not to be viewed as a routine option for use in patients with diabetes.

INHALED INSULIN Researchers have explored other options of insulin administration including inhaled insulin. In this mode of administration, insulin particles in a powder form are delivered through an inhaler. Though the idea of inhaling insulin had been around for decades, it was not until the 1990s when it became a reality. Exubera: It was the first inhaled insulin to be approved by FDA in September 2006, for use in both T1DM and T2DM patients. The onset of action was comparable to rapid-acting insulin analogs and duration of action to regular human insulin. Its efficacy was shown to be equivalent to conventional human insulin regimens and it was well tolerated. However, it was taken off market in 2007 due to low adoption rates; it was not commercially viable and higher incidence of cough, and a small, nonprogressive decline in forced expiratory volume was noted. In 2008, the FDA also expressed concern that Exubera could be linked to pulmonary toxicities and lung cancer. AERx insulin: Development of another inhaled insulin formulation, the AERx insulin Diabetes Management System (AERx® iDMS), has also been discontinued. Although no safety issues were involved in the decision, it was concluded that the inhaled insulin was unlikely to offer significant clinical or convenience benefits over modern insulin analogs with pen devices. Technosphere® Insulin Inhalation Powder: Though there are no inhaled insulin preparations currently on the market, the quest for one still continues.

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Another version of inhaled insulin formulation currently in development is Technosphere® Insulin (TI) Inhalation Powder containing recombinant human insulin adsorbed onto Technosphere® Inhalation Powder. TI Inhalation Powder is delivered to the deep lung using a proprietary delivery system. Afrezza®, whistle-sized inhaler is designed to administer ultra rapid-acting, meal-time doses of powdered insulin in metered, single-use cartridges to treat patients with T1DM and T2DM. However, due to the concerns associated with the redesign of the device, the FDA declined to approve Afrezza® in early 2011 pending additional data including evidence from new trials in T1DM and T2DM with the next-generation device.

INSULIN PUMPS The first human trials of continuous subcutaneous insulin infusion (CSII) pump therapy were done in the late 1970s and since then numerous studies have demonstrated the potential of this insulin delivery system as an efficient alternative to multiple subcutaneous insulin regimen, in the long-term management of glycemic control in patients of T1DM and T2DM. The insulin pump device includes the following (Fig. 1): •• The pump (including controls, processing module, and batteries) •• A disposable insulin reservoir •• A disposable infusion set, including a very thin stainless steel or flexible Teflon cannula (inserted just under the skin at a 30–90° angle and a depth of 6–8 mm) and a tubing system to connect the insulin reservoir to the cannula. The tubing may be short (average 23 inch) or long (average 43 inch) tubing depending on patient preference.

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Fig. 1: Insulin pump.

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Only rapid-acting insulins are used in the pumps. Insulin analogs, such as insulin lispro, aspart, and glulisine are increasingly being used in CSII due to their rapid absorption, greater pharmacodynamic predictability, and improved glycemic control compared with regular human insulin. Doses can be adjusted by the patient to give bolus delivery with food and provide a basal rate of insulin infusion. Basal rates may be different for different times of the day. Similarly, different types of boluses (normal, square, and dual) can be taken for different types of meals thus allowing for greater flexibility.

Advantages of Continuous Subcutaneous Insulin Infusion •• Insulin delivery more precise than that by syringe or injection pen •• Basal insulin can be adjusted in increments as small as 0.025 unit and bolus insulin can be dosed to within 0.1 unit increments or even 0.05 unit, depending on the model of pump •• Associated with fewer swings •• Insulin pumps have the unique ability to continuously infuse insulin, closely mimicking that of physiological secretion from a normal pancreas. The use of these pumps by decreasing the trend for huge swings, decreases glycemic variability which by activation of oxidative stress has been shown to have deleterious effects in the development of diabetic complications. •• Allows for controlled adjustable basal levels of insulin to cover −− Disparate levels of exercise −− Dawn phenomenon and −− Fasting hypoglycemia •• Allows for adjustable bolus doses of insulin to cover ingested carbohydrates •• Eliminates the need for and discomfort associated with individual injections •• Improvement in HbA1c levels (although benefits in HbA1c reductions are only modest) •• Scientific evidence from published studies have proven added benefit of insulin pumps in improving quality of life, normalizing sugars in recalcitrant diabetes and relieving the intractable pain of diabetic neuropathy.

Disadvantages of Continuous Subcutaneous Insulin Infusion •• More expensive compared to syringes and pens. This is a major limitation especially in India where pump therapy is not covered under any insurance •• Discomfort: though the insulin pumps have come a long way from the time they were the size of a backpack to the present size of a pager, some

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users find wearing the pump throughout the day uncomfortable. Also participation in activities like rough sports which may damage the pump needs special considerations •• Malfunction: pump battery discharge, empty insulin reservoir, loose tubing, insulin leaks, and kinked cannula are some of the causes of malfunction of the pump that may decrease or stop delivery of insulin and result in diabetic ketoacidosis (DKA). The fear of missing this often results in pump users typically monitoring their blood sugars more frequently to evaluate the effectiveness of insulin delivery •• Skin problems: users may experience scar tissue buildup around the inserted cannula. Allergic reactions or skin irritation may occur from the adhesive on the back of an infusion set •• Weight gain: taking advantage of the ability to adjust insulin according to carbohydrate intake many patients have a tendency to overeat and thereby gain weight. Practical problems amongst pump users include inadequate testing, forgetting to bolus, poor understanding of families in adjustment of doses and increased frequency of snacking and weight gain.

Appropriate Candidates for Pump Therapy Conscientious patient selection is the key to realizing the potential advantages of pump therapy. Characteristics of suitable insulin pump candidates include patients of three types: 1. Class I A. Patients with type 1 diabetes who do not reach glycemic goals despite adherence to maximum multiple dose insulin (MDI), especially if they have: •• Very labile DM (erratic and wide glycemic excursions, including recurrent DKA) •• Frequent severe hypoglycemia and/or hypoglycemia unawareness •• Significant “dawn phenomenon” •• Extreme insulin sensitivity. B. Special populations like pregnant women, children, adolescents with eating problems, and competitive athletes. 2. Class II Patients with type 1 diabetes who are on a maximized basal-bolus MDI insulin regimen, regardless of their level of glycemic control and who, after investigation and careful consideration, feel that CSII would be helpful or more suitable for lifestyle reasons. 46

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3. Class III A. Selected patients with insulin requiring T2DM that satisfy any or all of the following: •• C-peptide positive but with suboptimal control on a maximal dose of basal or bolus injections •• Substantial “dawn phenomenon” •• Erratic lifestyle (e.g., frequent long distance travel, shift-work, and unpredictable schedules leading to difficulty in maintaining timing of meals) •• Severe insulin resistance candidate for U500 insulin by CSII. B. Selected patients with other DM types (e.g., post-pancreatectomy).

Inappropriate Candidates for Pump Therapy •• Unable or unwilling to perform frequent blood glucose (BG) monitoring (≥4–6 tests/day) and carbohydrate counting •• Lack of motivation and/or history of nonadherence to insulin injection protocols •• Psychological or psychiatric condition(s) •• Reservations about pump usage interfering with lifestyle (e.g., contact sports or sexual activity) •• Unrealistic expectations from pump therapy.

Initial Insulin Dose Calculation The approximate total daily dose (TDD) of insulin of an adult T1DM patient can be calculated by multiplying the patient’s weight in kg by 0.7. Adolescents require more (~1–1.2 U/kg/day) whereas older patients require lesser (0.5 U/kg/day). If a patient is switching from MDI to insulin pump therapy, the initial TDD derived from MDI doses should be reduced by 10–20% due to pharmacokinetic differences between the modalities of delivery. About 40–50% of the average daily insulin requirements are given as basal insulin with the dose divided by 24 to determine a beginning hourly basal rate. The hourly basal rate is then adjusted higher or lower based on the pattern of glycemic variation. The remaining 50–60% of insulin is delivered primarily as premeal boluses.The bolus dose can be delivered all at once, in a “normal” bolus or it can be given over a period of time in a prolonged bolus; the bolus can also incorporate some insulin up-front with an initial normal bolus followed by extended delivery of the remaining bolus (combination bolus). Patients using rapid-acting insulin should deliver the bolus about 15 minutes before the meal to avoid a postprandial glycemic spike. 47

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Premeal bolus doses are determined according to: •• Preprandial blood glucose level: insulin sensitivity factor (ISF) can be calculated by dividing 1,800 by the TDD of insulin to determine the BG reduction per unit of insulin •• Carbohydrates content of meal: the insulin carbohydrate ratio (ICR) is determined by 500 (or 450) divided by TDD of insulin. Bolus dose then depends on number of carbohydrates in the meal •• Anticipated activity level after eating: effective dose adjustment strategies include reducing the bolus for the meal prior to exercise, consuming carbohydrate just before exercise, and/or lowering the basal rate starting 1–2 hours prior to exercise •• Prior personal experience with insulin requirements for similar meals •• All modern pumps have bolus wizard t o calculate bolus dose. Fine tuning of insulin rates can be done following careful assessment of several readings of fasting blood sugar (including a 3 AM reading) or using a continuous glucose monitoring. The basal rate is considered accurate if the glucose level remains steady overnight. If the glucose level rises more than 30 mg/dL between readings, the basal rate should be increased at least 1 hour before the rise is observed. If the level decreases by more than 30 mg/dL, the rate should be reduced a minimum of 1 hour before the decline starts. Once the overnight rate is established, the rate between waking and lunch can be evaluated by asking the patient to skip breakfast accompanying bolus dose and test BG level every 2 hours during the morning hours. Once the morning rate is established, the patient can skip other meals and again monitor BG every 2 hours to determine basal rates during the day. The process of fine-tuning boluses relies on the individual patient’s correct insulin to carbohydrate (I:C) ratio(s) and ISF. Temporary basal rates: during periods of deviation from normal daily activity, basal insulin can be adjusted as needed. Dose can be decreased during periods of inactivity like prolonged driving or extended fast like Ramadan and doses increased during periods of increased demand like illness, stress, or menses when additional basal insulin is needed.

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Role of diabetic educators: during the first few weeks after insulin pump therapy initiation, the patient and main care provider for pump therapy should have daily contact. Blood glucose records should be communicated to the educator at least weekly for the first 6 weeks of insulin pump therapy. Subsequently, the patient and diabetes educator may communicate about pump-specific issues once a month and eventually, according to the patient’s preference. During such meetings, the patient can be assessed to determine whether his or her therapy is meeting treatment goals.

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Infusion Site Management The infusion set and cannula needs to be changed every 72 hourly, but may require replacement sooner in warm temperatures as sweat can affect the adhesive and also encourage bacterial growth.

Use In the United States, the level of insulin pump penetration has been estimated at 20–30% in patients with T1DM and less than 1% in insulin-treated patients with T2DM. In contrast, a paper in 2010 reported insulin pumps use restricted to 1,000 patients on a continuous basis in India, with the majority of pump users being type 2 diabetes patients.

ADVANCES IN INSULIN PUMPS Sensor Augmented Insulin Pumps These combine insulin pump with a real time continuous glucose monitoring system. Sensor augmented pump therapy has been shown to be associated with improved glycosylated hemoglobin and reduced rates of hypoglycemic in type 1 diabetes.

Implantable Pumps These pumps are being developed which deliver insulin directly to the portal venous system via the peritoneal cavity, bypassing the liver similar to physiological insulin. However, the need for changing the pump every year or sometimes more frequently is the major disadvantage.

Closed-loop Insulin Delivery (Fig. 2) Also referred to as the artificial pancreas, this is an emerging therapeutic approach for people with diabetes mellitus. It consists of an insulin pump linked to a continuous glucose monitor where the data is transferred between the two components without human intervention. Various algorithms have been developed of which two are most relevant: (1) model predictive control algorithms are proactive and they forecast glucose levels in anticipation of the glucose lowering effect of administered insulin and of announced disturbances such as meals and physical activity; (2) proportional, integral, and derivative algorithms, by contrast, can be considered reactive, as they respond to observed glucose levels and are less equipped to handle announced meals and patient-directed insulin boluses. Approaches to prevent hypoglycemia like low glucose suspend in which the closed-loop automatically suspends insulin delivery for up to 2 hours when hypoglycemia

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Fig. 2: Closed-loop insulin pump: continuous glucose sensing is linked to insulin delivery by a control algorithm.

is detected and thereby offers a considerable safety window have also been incorporated in the closed loop devices.

CONCLUSION There are many choices available for insulin delivery, each having its own advantages and disadvantages. While the traditional syringe and vial combination continues to be important for a large number of people with diabetes in countries like India, availability of modern pens, needles, and pumps are valuable additions to the armamentarium. The key to the optimum utilization of the delivery devices is to ensure that the mode of insulin delivery is tailored to best suit the needs of each individual patient’s requirement.

Suggested Reading

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1. Asakura T, Seino H, Kageyama M, et al. Evaluation of injection force of three insulin delivery pens. Expert Opin Pharmacother. 2009;10:1389-93. 2. Brunton S. Insulin delivery systems: reducing barriers to insulin therapy and advancing diabetes mellitus treatment. Am J Med. 2008;121:S35-41. 3. Garg SK. Impact of insulin delivery devices in diabetes care. Diabetes Technol Ther. 2010;12:S1-3.

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Advances in Insulin Delivery Devices 4. Hänel H, Weise A, Sun W, et al. Differences in the dose accuracy of insulin pens. J Diabetes Sci Technol. 2008;2:478-81. 5. Hirsch IB. Practical pearls in insulin pump therapy. Diabetes Technol Ther. 2010;12:S23-7. 6. Hovorka R, Allen JM, Elleri D, et al. Manual closed-loop insulin delivery in children and adolescents with type 1 diabetes: a phase 2 randomised crossover trial. Lancet. 2010;375:743-51. 7. Bode B, Beck RW, Xing D, et al. Sustained benefit of continuous glucose monitoring on A1c, glucose profiles and hypoglycemia in adults with type 1 diabetes. Diabetes Care. 2009;32:2047-9. 8. Valentine V, Kruger DF. Considerations in insulin delivery device selection. Diabetes Technol Ther. 2010;12:S98-S100. 9. Grunberger G, Bailey TS, Cohen AJ, et al; AACE insulin Pump Management Task Force. Consensus Panel on insulin pump management. Endocr Pract. 2010;16(5):746-62. 10. Kesavadev J, Das AK, Unnikrishnan R, et al. Use of insulin pumps in India: suggested guidelines based on experience and cultural differences. Diabetes Technol Ther. 2010;12(10):823-31.

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6

Insulin Therapy in Type 1 Diabetes

Ganesh Jevalikar

Abstract Insulin is the only available treatment for type 1 diabetes till date. A patient centered multidisciplinary approach is necessary for type 1 diabetes treatment. In addition to insulin, monitoring of glycemic control, healthy nutrition, exercise, and self-management education are pillars of diabetes management. The treatment is aimed at optimizing glycemic control appropriate for age without having frequent hypoglycemia. The regimen of insulin needs to be individualized. The use of multiple subcutaneous injection or pump therapy offers more physiologic regimen and reduced risk of complications. Insulin doses need to be adjusted for glycemic patterns, premeal blood glucose, diet, physical activity, and various other situations. With appropriate use of insulin therapy, it is possible for a type 1 diabetic to have normal lifespan, good quality of life, and prevention of complications.

CASE SCENARIO A 6 year old boy was brought with complaints of polyuria, polydipsia, and weight loss for past 2 weeks. There was no family history of diabetes. Urine examination done for above complaints showed urine glucose 4+ following which blood glucose (BG) was checked and was 477 mg/dL. Urine ketones were negative. He weighed 20 kg and his height was 115 cm. He was diagnosed to have type 1 diabetes mellitus (T1DM) based on clinical presentation and high BG. It is obvious that he is a candidate for immediate insulin initiation. How should insulin therapy be initiated and monitored in him?

BACKGROUND Type 1 diabetes is one of the most common chronic metabolic disorders of childhood. It is characterized by hyperglycemia and a range of metabolic abnormalities resulting from deficiency of insulin secondary to destruction of β cells of pancreas.

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Insulin Therapy in Type 1 Diabetes

Worldwide, type 1 diabetes is the most common form of diabetes in children and adolescents. In a Multicenter Survey of Early Onset Diabetes in India (MEDI), 89% of individuals with diabetes onset below 20 year of age had T1DM. At Medanta Medicity, which is a tertiary care center in the National Capital Region (NCR) of India, 84% diabetics with onset below 18 years were classified as type 1 diabetes. Amongst diabetics with onset 250

>600

Arterial pH

7.2–7.3

7.1–7.2

7.3

Serum Bicarbonate (mmol/L)

10

>12

>12

15,000/mm3 should warrant diligent search for infection

Urine and blood cultures

If suspicion of infection is present

Chest radiography

If suspicion of pneumonia or pulmonary disorder

Electrocardiography

Should be done in all patients to assess effect of potassium status and rule out ischemia or myocardial infarction

CBC, complete blood count; DKA, diabetic ketoacidosis.

MANAGEMENT Both DKA and HHS are endocrine emergencies that require immediate hospitalization, rapid clinical assessment and frequent monitoring. The aims of management are to correct dehydration, hyperglycemia, acidosis and electrolyte deficits associated with these conditions. Any comorbid or precipitating event should be identified and treated appropriately. Figure 2 summarizes a flow chart for the management of DKA and HHS. A flow sheet should be maintained with careful documentation of the following parameters: •• Heart rate and BP—every hour until stable •• Careful intake output record •• Hourly plasma glucose—send laboratory sample if plasma glucose more than 500 mg/dL •• Neurological status—hourly for any signs of cerebral edema •• Blood gas analysis and serum electrolytes every 2–4 hours. Venous blood gas may be used.

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Fig. 2: Flowchart for assessment and management of adults with diabetic ketoacidosis and hyperosmolar hyperglycemic state.

Fluid Therapy

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Initial fluid bolus is given to expand extracellular (intravascular and extravascular) volume and restore renal perfusion. 0.9% saline should be used as rapid intravenous (IV) bolus at 10–20 mL/kg (approximately 1–1.5 liters in adults). Initial bolus is not routinely indicated in children and is given if there are weak pulses, hypotension or oliguria. The initial fluid bolus

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.

Insulin Therapy for Diabetic Ketoacidosis and Hyperosmolar...

may have to be repeated if the patient is severely dehydrated or urine output is massive, but it should not exceed 40 mL/kg. There is no data to support the use of colloid solutions except if the patient is in hypovolemic shock despite of crystalloids. Subsequent fluid therapy is aimed at correction of intracellular volume deficit and the choice of fluid depends on the state of hydration, urine output and serum sodium. 0.9% saline is recommended for the initial 4–6 hours. Thereafter, if the serum sodium is less than 135 mEq/L, continue 0.9% saline but if serum sodium is normal or elevated, switch to 0.45% saline. Fluid should be administered at a rate of 4–14 mL/kg/hour. Early in the course of treatment, plasma glucose will decrease even before insulin is started and this may serve as an index for the adequacy of fluid replacement. If plasma glucose fails to decline by 75–100 mg/dL/hour, this usually indicates inadequate fluid replacement or inadequate insulin therapy. In patients with severe dehydration, renal impairment or cardiac disease, fluid therapy should be guided by central venous pressure and arterial pressure monitoring. Once the plasma glucose is in the range of 200–250 mg/dL, switch to 5% dextrose in 0.45% saline to ensure continuation of insulin therapy. This is important to avoid further ketone body production and to keep the patient in an anabolic state. The estimated fluid deficit should be corrected over 48 hours, half over the first 18–24 hours and the remaining over the next 24 hours. A rapid change in serum osmolarity (>3 mmol/L) should be avoided especially in children who are at greater risk of cerebral edema. Table 6 depicts the calculations for maintenance fluid therapy in children. This is added to fluid deficit and any fluids already given are subtracted from this volume. This gives the total volume of fluid to be infused which is corrected over 48 hours. Fluids that the patient has already received before coming to the hospital need to be subtracted from the calculations. Table 6

Calculation of maintenance fluid requirement in children with diabetic ketoacidosis*

Body weight

24 hour fluid maintenance requirement

20 kg

1,500 mL + 20 mL/kg over 20 kg

*The table provides maintenance fluid calculations, deficit fluids are calculated based on level of dehydration.

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Insulin Therapy

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Most guidelines recommend the use of regular insulin by continuous intravenous infusion in the management of DKA and HHS. IV bolus protocols are not preferred, as a sustained gradual and steady fall in plasma glucose is more physiological and avoids the potential complications of hypoglycemia and hypokalemia. Recent data suggests that subcutaneous (SC) rapid-acting analogs given every 1–2 hourly can be as effective IV infusion of insulin. Although most recommendations suggest a bolus dose of insulin (0.1–0.15 U/Kg) in adults, there are no data to support any advantage of such a protocol. In children bolus dose of insulin is not necessary and can be harmful as it can cause rapid lowering of osmolality. The critical point to remember is that adequate fluids should be given first. If insulin is administered before fluids, the water will move intracellularly and may cause potential worsening of hypotension. Insulin infusion should be started at 0.1 U/kg/hour and this causes a gradual reduction in plasma glucose of 75–100 mg/dL/hour. Rate of insulin infusion should be lower (0.05 U/kg/hour) if the child demonstrates marked insulin sensitivity, provided the acidosis continues to resolve. If plasma glucose fails to decline by 75 mg/dL, hydration status should be reassessed and fluid rates and insulin rates should be revised. Once plasma glucose reduces to 200–250 mg/dL, the insulin infusion is reduced and 5% dextrose is added to the maintenance fluid. It is important to remember that it takes longer to correct ketosis than hyperglycemia. Unless a patient is in hypoglycemia, the insulin infusion rate should not be decreased to less than 0.05 U/kg/hour and 10% dextrose can be used to maintain optimal plasma glucose levels. Subsequent insulin infusion is titrated to maintain plasma glucose in the range of 150–250 mg/dL till acidosis (in DKA) or hyperosmolarity (in HHS) is corrected. Rapid-acting analogs of insulin (aspart, lispro, or glulisine) can be used in infusions but have no clear advantage over regular insulin infusion. If metabolic acidosis persists beyond 8–10 hours of initiating treatment, insulin effect may be inadequate. This may occur if the insulin infusion is too dilute causing insulin to adhere to the tubing, or if insulin is being given subcutaneously causing inadequate absorption. Persistent acidosis may also be caused by lactic acidosis due to an episode of hypotension, hypoxia or renal hypoperfusion. The use of large amounts of 0.9% saline or potassium chloride has also been associated with the persistent acidosis due to the development of hyperchloremic metabolic acidosis. Once ketoacidosis or hyperosmolarity has been corrected and patient is able to take orally, multiple dose SC insulin regimens should be instituted.

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Insulin Therapy for Diabetic Ketoacidosis and Hyperosmolar...

Criteria for resolution of ketoacidosis include serum bicarbonate level more than15 mmol/L and venous pH more than 7.3. Resolution of HHS is associated with normal osmolarity and regain of normal mental status. The first SC dose of regular insulin should be given 30 minutes before discontinuing insulin infusion to allow sufficient time for insulin to be absorbed from the SC injection site. For most patients, an initial basal-bolus insulin regimen would be appropriate during recovery from acute hyperglycemic state.

Role of Bicarbonate Therapy in Diabetic Ketoacidosis The cause of acidosis in DKA is primarily ketogenesis due to insulin deficiency and counterregulatory hormone excess. Insulin and fluid replacement reverses the acidosis and bicarbonate therapy is usually not needed. In fact most existing evidence points against using bicarbonate therapy in the management of DKA. Treatment with bicarbonate may be associated with a higher risk of cerebral edema. Bicarbonate crosses the blood-brain barrier slowly but the carbon dioxide formed from bicarbonate rapidly permeates into central nervous system (CNS), thus causing paradoxical CNS acidosis and decreased CNS oxygenation. By a similar mechanism, it may also lead to paradoxical intracellular acidosis and decreased tissue perfusion. Bicarbonate therapy may also cause a more rapid initial correction of acidosis and worsening of hypokalemia and hypocalcemia. Bicarbonate therapy is reserved for patients with severe acidosis (pH 145 mEq/L) or normal (135–145 mEq/L), then 0.45% sodium chloride may be administered at a rate of 4–14 mL/kg/hour depending on the state of dehydration. If the corrected serum sodium level is low (