Insulin Therapy: Made Easy Sanjay Kalra, Binayak Sinha
Page numbers followed by f refer to figure, fc refer to flowchart, and t refer to table.
Acetylcholine 7
Acute myocardial infarction 44
Alloxan 7
Alpha-adrenergic stimulators 7
Alpha-glucosidase inhibitor 47
American Association of Clinical Endocrinologists 49, 74
American College of Endocrinology 49, 74
American College of Obstetricians and Gynecologists 74
American Diabetes Association 1, 44, 45, 61, 74, 79, 88, 88t
Amino acid 2, 7, 15
Antidiabetic drugs 47f
Antioxidant 46
Anxiety 89
Arginine 7
Basal insulin 16, 28, 31, 74
pharmacology of 28t
regimen 49
secretion 3
therapy 72, 75
titration of 50t
use of 31t
Basal-bolus insulin therapy 73
Basal-bolus regimen 51, 54
action profile of 52f
dosing of 62
Basal-plus insulin 53
Basal-plus regimen 53
Beta-adrenergic blockers 7
Beta-adrenergic stimulators 7
Beta-cell rest 46
Beta-keto acids 7
Biphasic human insulin 56
Biphasic insulin
aspart 33, 34, 56
lispro 33, 35
Body weight 81
Bolus insulin 74
dose 64
Carbohydrate 88
metabolism 46
Cardioprotection 46
Cholecystokinin 7
Confusion 89
Continuous glucose monitoring 62, 64, 66f
Continuous subcutaneous insulin infusion 63, 93
devices 17
Conventional premix human insulin 32
Convulsions 89
C-reactive protein 46
Cyclic adenosine monophosphate 46
Degludec 31
Deoxyglucose 7
Detemir 31
Devices 98, 102
Diabetes in Pregnancy Study Group India 74
Diabetes 1, 70
adult-onset 43
mellitus 70, 91
gestational 73, 74
Diabetic ketoacidosis 44
Diazoxide 7
Dipeptidyl peptidase 4 47
Dizziness 89
Drowsiness 89
Durable pen device 99f
Endoplasmic reticulum-induced stress, and apoptosis 43
Endothelial nitric oxide synthase 46
Enuresis 89
Epinephrine 7
Escherichia coli 15
Estimated glomerular filtration rate 76
European Association for Study of Diabetes 44, 45
European Medicines Agency 24, 31
Fast-acting insulin aspart 19, 22, 24
Fasting plasma glucose 25, 45, 50, 74
Fatigue, chronic 89
Fatty acid 26
Flash glucose monitoring 66
Food and Drug Administration 24, 31, 36
Galanin 7
Gastric inhibitory polypeptide 7
Gastrin 7
Glomerular filtration rate 76
Glucagon 7
Glucagon-like peptide-1 7, 47, 53, 91
receptor agonist 16, 56
Gluconeogenesis 9
Glucose 7
levels, tracing of 66f
transporter type 4, translocation of 8
Glucotoxicity 43
Glycemia 61
Glycemic management during hindu fasts 79
Glycine, substitution of 26
Glycogen synthase 8
Glycogenesis, process of 8
Glycogenolysis 9
Golgi bodies 3
Headache 89
Hemoglobin, glycosylated 18, 45, 71, 73, 81
Hexamers 17
High postprandial glucose 43
High-mix insulin regimen 55
Human and analog premix insulin, time action profile of 32f
Hyperglycemia 9, 43
management of 81fc
Hyperglycemic hyperosmolar nonketotic coma 44
Hypertriglyceridemia 9
Hypoglycemia 51, 71, 73, 75, 77, 8789, 89t
causes of 88
classification of 88t
prevention of 90t
signs of 88
symptomatic 88
Ideglira 16
Indian Insulin Guideline 54
Indian National Consensus Group 45
Guidelines 51
site 95
techniques 96
Insulin 3, 25
action of 8
allergy 93
analog 16, 17, 21, 72, 7577
long-acting 29, 29f
aspart 16, 17, 19, 21, 24, 35, 56, 62, 72, 73, 79
co-formulation 33
and analog premix insulin, time action profile of 34f
deficiency 9
degludec 16, 28, 30, 35, 49, 56, 72, 73, 79
delivery devices 73
detemir 16, 26, 28, 29, 49, 56, 72, 79
development of 1
discovery of 2, 2f
dose adjustments during fasting conditions 79t
edema 87, 91
management of 92
effects of 46t
glargine 16, 26, 2830, 49, 56, 72, 79, 91
glulisine 16, 17, 19, 20, 23, 24, 62, 72
history of 2
human 21
inhibitors 7
storage of 102
technique 95
usage of 102
lispro 16, 17, 19, 20, 23, 24, 62, 72
management, principles of 61
metabolism of 3, 9, 10, 10fc
milestones in development of 3, 4, 4t, 6, 6t
needles 98
pens 99
physiology of 3, 10
preparations 56t
profile of 15
pump 101
advantages of 101t
therapy 64, 65, 65t, 101t
receptors 8
regimens 55, 62
regulation and action 9fc
secretion of 3, 7t
short-acting 17, 18f, 19, 21
side effects of 87
stimulators 7
storage 93
structure of 3, 7f
synthesis 3, 6f
therapy 43, 47, 61, 70, 71, 7477, 80, 102
barriers to 47
benefits of 44, 46t
five M's of 90t
indications for 44, 45
initiation of 49
intensification of 52
management of 87
practical aspects of 87
types of 16, 16t, 19, 24, 26, 26t, 100
Intercellular adhesion molecule 1 46
International Diabetes Federation 1, 75
International Society for Pediatric and Adolescent Diabetes 61
Intestinal hormones 7
Isophane 25, 62
insulin 25, 75, 79
Kidney disease, chronic 24, 31, 36, 75, 76
Langerhans pancreatic islets 3
Leucine 7
Lipid metabolism 46
Lipoatrophy 87
Lipohypertrophy 87, 92, 92f, 93f
Lipotoxicity 43
Liver disease, chronic 24, 31, 36, 70, 76, 77
Mannoheptulose 7
Mannose 7
Maximum serum insulin concentration 18
Medical nutrition therapy 74
Metabolic memory 46
Microtubule inhibitors 7
Mitogen-activated protein-kinase 8
Monocyte chemoattractant protein-1 46
Mood changes 89
Morning headache 89
Multiple daily injection 61, 64, 65
regimen 62
action profile of 63
Myristic acid 26
National Institute for Health and Care Excellence 50, 75
Nausea 89
Neuroprotection 46
Neutral protamine Hagedorn 16, 25, 26, 28, 31, 49, 56, 91
Night sweats 89
Nitric oxide 46
Noninsulin-dependent diabetes 43
Norepinephrine 7
Oral antidiabetic
agents, properties of 70
drugs 1, 45, 61
Palpitation 89
Pen devices 97, 99, 100
advantages of 101t
disadvantages of 101t
Peripheral vascular diseases 45
Phenytoin 7
Phosphofructokinase 8
Phosphoinositide 3 kinase 46
Plasminogen activator inhibitor-1 46
Postprandial blood glucose 72, 74
Postprandial glucose 16, 45, 52, 62
Postprandial glycemic excursion 15
Potassium 7
Prandial insulin 16
pharmacology of 19t
titration of 52t
Premix insulin 16, 32, 33, 36, 72, 75
analogs 34
pharmacology of 33t
regimen 50, 54
titration of 51t
use of 36t
Propranolol 7
Protamine 26
zinc insulin 25
Protein metabolism 46
Protraction, mode of 18f
Pump therapy, dosing guidance on 64t
Random blood glucose 44
Rapid-acting insulin 17, 18f, 19
analogs 19
against regular human insulin, advantages of 18t
structure of 21
therapy 72, 75
Regular human insulin 19, 21, 24
Research Society for Study of Diabetes in India 45
Rough endoplasmic reticulum 3
Saccharomyces cerevisiae 19
Self-measured plasma glucose 52
Severe hypoglycemia 64, 90
Skin infections 87, 93
Sodium-glucose cotransporter-2 47, 91
Somatostatin 7
South Asian Federation of Endocrine Societies 78, 79
Split-mixed insulin regimen 55
Sulfonylurea 7, 47
Sweating 89
Theophylline 7
Thiazide diuretics 7
Thiazolidinedione 47
Type 1 diabetes mellitus 1, 15, 61, 62, 73, 91
Type 2 diabetes mellitus 1, 15, 4345, 52, 53, 53fc, 57, 61, 72, 91
Ultra-fast acting insulin 19
analog 19
Unstable angina 44
Vision changes 89
Weakness 89
Weight gain 87, 91
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History and Milestones in Development of Insulins, Normal Physiology and MetabolismCHAPTER 1

Siddharth Shah,
SK Sharma
According to the American Diabetes Association, “Diabetes is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.”1 Patients with diabetes may suffer from frequent urination, excessive thirst, unexplained weight loss, extreme hunger, very dry skin, fatigue and sudden vision changes; though some patients may also be asymptomatic.2 Uncontrolled diabetes can cause serious health complications such as blindness, heart and kidney diseases, stroke, and lower-extremity amputations.3
Year on year, the burden of diabetes is increasing. The incidence of diabetes had risen from 108 million in 1980 to 425 million in 2017 and now is 463 million in 2019.4,5 The global diabetes age-adjusted comparative prevalence in adults 20–79 years is 8.3%. As per recent International Diabetes Federation (IDF) Diabetes Atlas 2019, the number of patients with diabetes, aged between 20 and 79 years, is estimated to increase from 77 million in 2019 to 134.2 million by 2045.
With regards to the management of diabetes, insulin therapy has been the cornerstone for treatment of patients with type 1 diabetes mellitus (T1DM) and is also an important component for treatment of type 2 diabetes mellitus (T2DM). Traditionally, insulin was used when multiple oral antidiabetic drugs (OADs) failed to control blood glucose. However, current international and national guidelines suggest timely initiation of insulin to effectively control glycemic levels and delay diabetes-related complications.68 Out of all the options available for the management for T2DM, insulin has the maximum efficacy for glycemic control. Additionally, insulin has anti-inflammatory, antioxidant, antiapoptotic, antilipolytic, cardioprotective, and neuroprotective properties.9,10
This chapter discusses important milestones in the development of insulin therapy, its physiology, metabolism, and mechanism of action.2
The discovery of insulin was one of the greatest milestones in the history of medicine. Sharpey-Schafer's in the year 1910 coined the term insulin.10 In 1921, Frederick G Banting and his assistant Charles H Best, working with John Macleod, succeeded in lowering the high blood glucose level of pancreatectomized dogs by injecting them with chilled saline pancreatic extracts from healthy dogs (Fig. 1).11 In December 1921, biochemist James Collip further demonstrated that this extract could also restore hepatic glycogen mobilization and had the capacity to clear ketone bodies from circulation.11
On 11th January 1922, a young house physician, Dr Edward Jeffrey, injected 15 cc (7.5 cc into each buttock) of the pancreatic extract into a patient with T1DM, Leonard Thomson, a 14-year-old boy in Toronto General Hospital.12 Injecting a purified form of insulin helped in restoring and symptomatically improving Leonard's health.13
These purified pancreatic extracts were subsequently used to treat other patients in the hospital, and this heralded the onset of insulin era for treating diabetes. In 1923, Frederick G Banting and John Macleod were awarded with the Nobel Prize in the field of physiology and medicine for the discovery of insulin.15 In 1955, Frederick Sanger fully sequenced the bovine insulin and discovered its exact amino acid (AA) composition. Sanger was then awarded Nobel Prize for Chemistry in 1958 for full sequencing of bovine insulin. In 1977, the American physician and scientist, Solomon Berson along with Rosalyn Sussman Yalow received Nobel Prize in the field of physiology/medicine for their project which helped in understanding that human insulin are better suited than animal insulin for people with diabetes.16 Further, in 1964, Dorothy Mary Crowfoot-Hodgkin was awarded the Nobel Prize in Chemistry for discovery of the physical structure of insulin.17
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FIG. 1: Discovery of Insulin–Frederick G Banting and Charles H Best.Adapted from: Reference no. 14.
Milestones in the Development of Insulin
Key milestones in the development of insulin have been summarized as in Tables 1 and Table 2.
Synthesis and Secretion of Insulin
The term “insulin” was derived from the Latin word “insula” or “island” to describe its origin from the pancreatic islets of Langerhans.76 Insulin is produced and secreted by β cells located in the pancreatic islets of Langerhans. In 1969, Paul Langerhans discovered the β cells that produce insulin.77 Insulin-secreting β cells constitute 65–80% of the cells of the islets and 2% of the pancreatic weight (β cell mass is ~1–2 g).78,79
Insulin synthesis involves sequential cleavage of its two precursor molecules, preproinsulin and proinsulin. The preproinsulin molecule (a single chain of 110 amino acids) is synthesized in the ribosomes of rough endoplasmic reticulum (RER) in the β cells of pancreas. It undergoes rapid enzymatic cleavage where the signal peptide from preproinsulin is cleaved to generate a 3D proinsulin (86 AAs) configuration, which contains 2 chains of AAs (α and β chains) linked by connecting or C-peptide (12 AAs).80 After maturation, proinsulin is transported from RER to Golgi bodies, with the help of secretory vesicles, where it is packaged/stored into small secretory granules (β granules), which then migrate toward the cell surface and accumulates in the cytoplasm. As the granules mature, β cell carboxypeptidase E removes C terminal peptide chain and yields mature insulin comprising of two peptide chains (α and β) linked through disulfide bonds. Hence, mature secretory granules form a large storage pool for insulin (Fig. 2).81
In vivo insulin secretion shows a characteristic biphasic pattern in presence of enough blood glucose levels.82 The “first phase” shows a sharp increase in insulin levels, due to secretion of preformed insulin, within 5–10 min of carbohydrate ingestion. However, this insulin depletes significantly in a very short span of time. The “second-phase” is directly related to the level of blood glucose and newly synthesized insulin is secreted in a slow and sustained manner between meals and night-time. Overall, insulin secretion relates to the total dose of glucose and its rate of administration.83,84 Basal insulin secretion occurs in regular pulses (independent of blood glucose concentrations) and accounts for about 50% of total daily production.6 Various factors such as decreased blood glucose, fasting state, somatostatin, sympathetic stimulation such as epinephrine, leptin inhibit insulin release from secretory granules (Table 3).83,85,86
Structure of Insulin
Insulin, a 51-AA peptide hormone of approximately 6,000 Daltons, consists of 2 polypeptide chains (α and β). In human species, the α chain consists of 21 AAs and the β chain of 30 AAs (Fig. 3). These two chains are held together by 2 disulfide bonds (between cysteine residues at positions A7 and B7, and A20 and B19).4
TABLE 1   Milestones in the development of insulin.
Milestone in insulin development
Paul Langerhans discovered a distinct collection of cells within the pancreas18
von Mering and Minkowski demonstrated that total pancreatectomy led to severe diabetes in the dog19
Edouard Laguesse introduced the term “islets of Langerhans”18
LB Zuelzer made extracts of animal pancreases and obtained some hypoglycemic activity in diabetic patients20
Nikolai Kravkov developed an extract of the pancreas and showed that it lowers blood glucose in diabetic dogs21
Moses Barron published a paper, “The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis”22
Frederick Banting and Charles Best performed experiments on dogs in Toronto with help from John Macleod and James B Collip Discovery of insulin23
14-year-old Leonard Thompson having type 1 diabetes mellitus given the first medical administration of insulin24
Frederick Banting and John Macleod awarded the Nobel Prize in Physiology/Medicine for discovery of insulin. Purified animal insulins manufactured and sold25
Hans Christian Hagedorn discovered that the action of insulin can be prolonged with the addition of protamine17
Protamine zinc insulin (PZI) developed26
Isophane insulin (neutral protamine Hagedorn [NPH]) developed27,28
Standardized insulin syringes produced17
Nordisk marketed NPH insulin29
Lente insulin such as semilente, lente, and ultralente developed30
Regular U-500 insulin first introduced in US31
Frederick Sanger characterized the amino acid (AA) sequence of insulin32
Full sequence of insulin published33
Frederick Sanger awarded the Nobel Prize in Chemistry for sequencing insulin17
Isolation of S-sulfonated form of α and β chains of sheep insulin34
Biphasic insulin developed35
First full synthesis of human insulin and study of the differences between the amino acid sequences between previously isolated sheep and human insulin done34
Dorothy Hodgkin determined the three-dimensional crystal structure of insulin using X-ray crystallography36
Standardized U-100 insulin introduced37
Sieber and co-workers successfully completed the total chemical synthesis of human insulin for better safety than that of animal origin385
Wearable insulin pumps invented39
Rosalyn Sussman Yalow received the Nobel Prize in Medicine for developing a radioimmunoassay to measure insulin in the body40,41
Genentech developed biosynthesis of recombinant human insulin in E. coli bacteria using recombinant DNA technology42
Portable insulin pumps developed43
First commercially viable semi-synthesis of human insulin
Concepts on Basal-bolus and intensive insulin therapy introduced44
First recombinant insulin available commercially11
Lilly produced biosynthetic recombinant human insulin45,46
Insulin Bovine Neutral and Insulin Bovine Protamine Zinc approved47
Insulin Bovine Lente approved48
Novo Nordisk produced synthetic, recombinant human insulin49
Approval of biphasic human insulin in US
Insulin analogs with fast action commercialized
Insulin Lispro (ILis) approved50
Insulin Porcine Neutral, Insulin Porcine Isophane, and Insulin Porcine
30/70 approved51,52
Insulin Glargine(IGlar) approved53
Biphasic insulin Aspart (BIAsp) 30 and insulin aspart approved54,55
IGlar became commercially available56
Biphasic insulin aspart 30 launched in the international market57
European Union approval for Biphasic human insulin58
Insulin Glulisine (IGlu) approved in US59
Insulin Detemir (IDet) approved in EU60
Inhaled human insulin commercially made available in US61
Inhaled human insulin withdrawn from US market61
Insulin Degludec (IDeg) and Insulin Degludec/insulin Aspart (IDegAsp) approved in EU
Insulin degludec/liraglutide (IDegLira) approved in EU62
Inhaled insulin returns to the US market61
US regulatory approval for Insulin Degludec (IDeg) and Insulin Degludec/insulin Aspart (IDegAsp)63
Insulin glargine/lixisenatide (IGlarLixi) approved in US64 Insulin degludec/liraglutide (IDegLira) approved in US
Insulin glargine/lixisenatide (IGlarLixi) approved in EU
Insulin pump with interoperable technology approved that aids in customization of the treatment through individual diabetes management devices65
TABLE 2   Milestones in insulin development in India.
Milestone in Insulin Development
Import of insulin to Indian market66,67
Neutral insulin and Insulin zinc suspension (Human insulin) injection approved68
40 IU vial of human insulin launched69
Biphasic human insulin launched
Insulin pump introduced in India for usage at homes70
Insulin Lispro 40 IU/10ml (rDNA origin) vial injection launched71
Biphasic Insulin Lispro (rDNA) injection launched71
Insulin Glargine launched in India67,68
Modern insulin such as biphasic insulin aspart (30:70) and insulin aspart introduced66
Human insulin (Biosimilar) approved72
Insulin glulisine approved73
Insulin detemir launched in India74
Human insulin (rDNA) powder inhaler launched68
Insulin Glargine (Biosimilar) approved72
Ultra-long-acting insulin degludec introduced66
A new basal and bolus insulin co-formulation (70% insulin degludec and 30% insulin aspart) introduced
Insulin glargine U-300 prefilled pens launched75
Fast-acting insulin aspart launched
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FIG. 2: Insulin synthesis.Adapted from: Reference no. 80.
TABLE 3   Factors affecting insulin secretion.
Insulin stimulators
Insulin inhibitors
Amino Acids (leucine, arginine)
Intestinal hormones (GIP, GLP-1, gastrin, secretin, CCK)
α-Adrenergic stimulators (norepinephrine, epinephrine)
β-Keto acids
β-Adrenergic blockers (propranolol)
Cyclic AMP and various cAMP-generating substances
Thiazide diuretics
β-adrenergic stimulators
K+ depletion
Microtubule inhibitors
(CCK: cholecystokinin; GIP: gastric inhibitory polypeptide; GLP-1: glucagon-like peptide 1; K: potassium) Adapted from: References no. 87, 88.
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FIG. 3: Structure of insulin.Adapted from: Reference no. 93.
An additional disulfide bridge is formed within the α chain (between A6 and A11).89 This additional disulfide bridge is important for determining the tertiary structure and receptor binding of the molecule. The AA sequence is highly conserved among vertebrates, and insulin from one mammal is biologically active in another. Insulin derived from pig is clinically effective in humans and has been widely used in the past for treating diabetes.90
Insulin molecules tend to form dimers, hexamers, and complex crystalline structures at low pH and in presence of zinc ions.91,92 Monomers and dimers readily diffuse into the circulation from subcutaneous depot, whereas hexamers diffuse poorly. Hence, absorption of insulin preparations, containing a high proportion of hexamers, is delayed and somewhat slow.498
Action of Insulin
Insulin receptors are located in cells such as hepatocytes, adipocytes, skeletal muscle cells as well as in cells not considered to be typical target organ cells.94 An insulin receptor consists of two α subunits and two β subunits linked together by disulfide bonds.95 The α subunits are completely extracellular and carry sites which bind to insulin while the transmembrane β subunits have tyrosine protein kinase activity.96
When insulin binds to the extracellular α subunit of a receptor, it causes auto-phosphorylation of the β subunit and activates the catalytic activity.97 The β subunit, a tyrosine specific protein kinase, transfers phosphate groups from adenosine triphosphate to tyrosine residues on intracellular target proteins termed as insulin receptor substrate proteins.90 A cascade of phosphorylation and dephosphorylation reactions is set into motion which amplifies the signal and results in stimulation or inhibition of enzymes involved in the rapid metabolic actions of insulin.98
Action of insulin on metabolic enzymes are also mediated by second messengers such as phosphatidylinositol trisphosphate. They play a crucial role in translocation of glucose transporter type 4 (GLUT4) from cytosol to the plasma membrane, especially in skeletal muscle and adipose tissue.99 Expressions of genes directing synthesis of GLUT4 are also promoted by insulin over time. Insulin also regulates genes for a large number of enzymes and carriers through mitogen-activated protein-kinase (MAP-Kinase) as well as through phosphorylation cascade (Fig. 4).100
Insulin stimulates the liver to store glucose in the form of glycogen (by the process of glycogenesis) and fatty acids (which is further exported from the liver as lipoproteins for use in other tissues such as adipocytes).101 It activates enzyme hexokinase, which helps in trapping glucose molecule within a cell. Insulin stimulates several enzymes, including phosphofructokinase and glycogen synthase, which are involved in glycogenesis.102 However, when insulin levels decline, several counter-regulatory hormones are released, glycogen synthesis in the liver diminishes, and breakdown is stimulated.
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FIG. 4: Interaction between insulin and insulin receptor.Adapted from: Reference no. 100.
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FLOWCHART 1: Insulin regulation and action.Adapted from: Reference no. 95.
The most important amongst them are glucagon and adrenaline, which promote glycogenolysis and gluconeogenesis, thereby raising the glucose level in blood and restoring normoglycemia (Flowchart 1).103 Insulin deficiency results in hyperglycemia, hypertriglyceridemia, and altered protein metabolism.
Once the liver gets saturated with glycogen, any additional glucose uptake promotes the synthesis of fatty acids, which are exported as lipoproteins. The lipoproteins provide free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride. Glucose gets converted into glycerol and in combination with fatty acids, it leads to the generation of triglycerides.87
Insulin is the most potent anabolic hormone in the body. Within the muscles, insulin promotes glucose uptake and inhibits proteolysis. It also inhibits release of amino acids, pyruvate, and lactate into the blood which otherwise would have been substrates for gluconeogenesis in liver. Insulin inhibits lipolysis in the adipose tissues. Release of free fatty acids and glycerol which may form substrates for gluconeogenesis in liver is prevented. It also increases the uptake of glucose for storage as fat and glycogen.104
Metabolism of Insulin
The half-life of insulin in the circulation is short and is approximately 4–6 min.81,105 40–50% of endogenous insulin produced by the pancreas is metabolized and excreted by the liver in its first pass whereas 30–80% of exogenous insulin is metabolized and cleared by the kidney.106 Hence, kidney is the main organ responsible for metabolizing exogenous insulin administered to patients with diabetes.81 Some degradation occurs within the insulin secretory granule or after binding to the insulin receptor complex, where it is endocytosed, and insulin is enzymatically degraded after fusion with intracellular lysosomes (Flowchart 2).6710
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FLOWCHART 2: Metabolism of insulin.Adapted from: Reference no 107.
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