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.6–8 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.
HISTORY OF INSULIN
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
Milestones in the Development of Insulin
PHYSIOLOGY AND METABOLISM OF INSULIN
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).
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.49
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.
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).67
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