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The Pancreas and Classifications of Insulin
Chapter 2
The Pancreas and Classifications of Insulin In adults, the pancreas is oriented transversely and extends from the C-loop of the duodenum to the hilum of the spleen. Though its name is derived from a Greek word, pancreas, which means all flesh, the pancreas is actually a complicated organ with many lobules. It has separate exocrine and endocrine components. The exocrine pancreas makes up most (80% 85%) of the organ. It consists of acinar cells that secrete the enzymes required for digestion. Acinar cells are pyramid-shaped epithelial cells. They contain membrane-bound granules that are rich in proenzymes, also called zymogens. These include trypsinogen, chymotrypsinogen, procarboxypeptidase, kallikreinogen, proelastase, and prophospholipase A and B. When these proenzymes and enzymes are secreted, many ducts and ductules carry them to the duodenum, where they are activated by proteolytic cleavage in the gastrointestinal tract. The endocrine pancreas is made up of approximately one million cell clusters known as the islets of Langerhans. These cells are scattered throughout the pancreas, and secrete insulin, glucagon, and somatostatin. The islet cells make up only 1% 2% of the pancreas.
THE PANCREAS The pancreas is located below and behind the stomach, but in front of the spine. It is a spongy gland of 12 15 cm (6 10 in.) in length, and is mostly retroperitoneal. The pancreas is grayish-pink in color, and weighs about 60 g. The head of the pancreas is on the right side of the abdomen. It is connected to the first section of the small intestine, the duodenum, via the small pancreatic duct. The narrow tail of the pancreas extends to the left side of the body (see Fig. 2.1A). The pancreas is surrounded by the small intestine, stomach, liver, and spleen. Because of the deep location of the pancreas, when tumors develop, they are rarely able to be palpated by pressing on the abdomen.
The Pancreatic Islets The tissues of the pancreas contain approximately one to two million clusters of cells that are called pancreatic islets or islets of Langerhans (see Fig. 2.1B). The pancreatic islets actually make up ,2% of the total pancreatic tissues. However, they are extremely important because they secrete hormones needed primarily in the regulation of glycemia, which is the blood glucose concentration. Each islet is about 75 3 175 µm in size, and contains as little as a few cells to approximately 3000 cells. These cells are of three primary types: the alpha cells, which make up 20% of the total amounts of cells; the beta cells, 70%; and the delta cells, 5%. All of the islet cells directly respond to nutrient levels in the blood that are related to eating and fasting. Approximately 5% of the pancreatic cells consist of pancreatic polypeptide (PP) cells. There are four types of hormone-secreting cells: G G G G
Alpha cells—which secrete glucagon Beta cells—which secrete insulin and amylin Delta cells—which secrete gastrin and somatostatin F (or PP) cells—which secrete PP; this stimulates gastric secretions, and antagonizes cholecystokinin.
These hormones regulate the metabolism of carbohydrates, fats, and proteins. The pancreatic islets are innervated by nerves from the sympathetic and parasympathetic divisions of the autonomic nervous system. The vagus nerves innervate the pancreas, liver, gallbladder, stomach, small intestine, and the proximal half of the large intestine. Epidemiology of Diabetes. DOI: https://doi.org/10.1016/B978-0-12-816864-6.00002-X © 2019 Elsevier Inc. All rights reserved.
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Epidemiology of Diabetes
FIGURE 2.1 The pancreas. (A) Pancreas dissected to show main and accessory ducts. The main duct may join the common bile duct, as shown here, to enter the duodenum by a single opening at the major duodenal papilla, or the two ducts may have separate openings. The accessory pancreatic duct is usually present and has a separate opening into the duodenum. (B) Exocrine glandular cells (around small pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to blood capillaries). Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon, and beta cells secrete insulin. Adapted from K.T. Patton, G.A. Thibodeau. The Human Body in Health & Disease, 7 ed., St Louis, 2018, Elsevier.
The alpha, beta, and delta cells are most numerous in the anterior lobe of the pancreas. Perfusion of this lobe comes from branches of the superior mesenteric artery. This is a large and unpaired artery arising from the abdominal aorta at the L1 level, just below the celiac trunk. It runs deep to the pancreas, entering the mesentery, where its many anastomosing branches serve almost all of the small intestine. Branches of the celiac trunk perfuse the posterior lobe of the pancreas. The common hepatic artery branches to the pancreas, stomach, and duodenum. The splenic artery branches to the pancreas and stomach, with its branches terminating in the spleen. Although the pancreatic islets make up only about 1% of the mass of the pancreas, they receive 10% of pancreatic blood flow. This is essential so that islet hormones can be oxygenated and delivered to target cells. The splenic vein collects blood from parts of the pancreas, stomach, and spleen. It joins the superior mesenteric vein, forming the hepatic portal vein.
Functions of the Pancreas The functions of the pancreas are primarily as an exocrine digestive gland. It is essential in converting food into fuel for the body’s cells. When healthy, the pancreas produces specific chemicals in exact quantities, when they are needed, to digest foods. Its exocrine glands produce digestive enzymes that include trypsin and chymotrypsin to digest proteins. It also produces amylase to digest carbohydrates and lipase to break down fatty acids and cholesterol. As food enters the stomach, the pancreatic juices are released into a duct system ending in the main pancreatic duct. The pancreatic duct joins the common bile duct to form the ampulla of Vater at the duodenum. The common bile duct actually originates in the liver and gallbladder. It produces bile, another important digestive juice. Therefore, bile and pancreatic juices are released into the duodenum to help digest proteins, carbohydrates, and fats. A healthy pancreas produces about 2.2 pints (1 L) of enzymes each day. The endocrine functions of the pancreas occur via the pancreatic islets, primarily via the hormones, insulin and glucagon. The maintenance of blood glucose levels is crucial for normal body functions.
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Alpha Cells The alpha (α) cells secrete glucagon in between meals, when concentrations of blood glucose are below 100 mg/dL. Glucagon is important in the liver for glycogenolysis and gluconeogenesis. Glycogenolysis is the degradation of glycogen into glucose. Gluconeogenesis is the synthesis of glucose from proteins and fats. Both processes result in glucose being released into the circulation, which raises blood glucose levels. Glucagon, in the adipose tissue, stimulates release of free fatty acids and the catabolism of fats. Glucagon is secreted as a response to increasing levels of amino acid in the blood, following high-protein meals. Amino acid absorption is promoted by glucagon, which also provides cells with raw materials required for gluconeogenesis. Glucagon binds to receptors on hepatocytes, kidney cells, and other cells to elevate glucose levels. This activates the enzyme glycogen phosphorylase inside hepatocytes, and glycogen is hydrolyzed to glucose. The alpha cells are located in the peripheral areas of the islets as well as inside them. Under an electron microscope, alpha cells are identified by their characteristic granules. They have large, dense cores and small white halo, or circular ring.
Beta Cells The beta (β) cells secrete the hormones insulin and amylin. Insulin is concerned with abundance of nutrients. It is secreted during and just after meals, as blood nutrient levels are increasing. Beta cells are able to quickly respond to spikes in blood glucose concentrations by secreting stored insulin while producing more insulin at the same time. Insulin regulates the rate of glucose uptake into many different cells. At a target cell, it binds with an enzyme-linked plasma membrane receptor. This receptor contains tyrosine kinase on the surface of the cytosol. Insulin receptor binding sends a signal cascade, which activates glucose transporters (GLUT) for the entry of glucose into the cell. The main glucose transporter is called GLUT4. It is stored in the cellular vesicles. Once activated by the insulin receptor, it translocates to the cell surface. Here, it facilitates diffusion of glucose into the cell. When GLUT4 translocates to the cell surface, glucose diffusion into the cell increases to 10 21 times the amount. This is especially true in cardiac and skeletal muscle, liver, and adipose cells (see Fig. 2.2). The main component in maintaining normal cell function is sensitivity of insulin receptors. Insulin resistance is linked to diabetes, hypertension, and many cardiovascular diseases. The adipocytes release a variety of hormones that are altered in obese patients, which have important effects on insulin sensitivity. The cell surface membranes of beta cells have embedded voltage-gated calcium channels and ATP-sensitive potassium ion channels. The calcium channels are usually closed and the potassium channels are open. Potassium ions diffuse out of beta cells, down the concentration gradient. The inside of the cells becomes more negative compared to the outside, since the potassium ions carry a positive charge. While resting, this creates a potential difference across the cell surface membranes of 270 mV. When glucose concentrations outside beta cells are high, glucose molecules move into them via facilitated diffusion, down the concentration gradient, through the GLUT2 transporter. Beta cells use glucokinase to catalyze the first step of glycolysis. Therefore, metabolism only occurs around and above physiological blood glucose levels. Metabolism of glucose produces ATP. This increases the ATP-to-ADP ratio. When this ratio increases, ATP-sensitive potassium ion channels close. The ions cannot diffuse out of beta cells anymore at this point. The potential difference across the membrane becomes more positive as potassium ions are accumulating inside the cells. The voltage-gated calcium channels open and allow calcium ions to diffuse outward down the concentration gradient. As calcium enters the cells, vesicles containing insulin move to the cell surface membrane and fuse with it. Insulin is released via exocytosis. A hormone from bone osteoblasts, known as osteocalcin, helps to stimulate multiplication of beta cells, secretion of insulin, and body tissue sensitivity to insulin. The liver, adipose tissue, and skeletal muscles are directly targeted by insulin. When nutrients are sufficient, insulin stimulates body cells to absorb, store, and metabolize amino acids, fatty acids, and glucose. As a result, insulin lowers levels of blood glucose and various nutrients. It also encourages synthesis of fat, glycogen, and protein (see Table 2.1). This action promotes storage of excessive nutrients to be used at a later time. It also enhances the growth and differentiation of cells. Insulin antagonizes glucagon, to suppress the use of previously stored fuels. Glucose is absorbed and used by the brain, kidneys, liver, and red blood cells without any need for insulin. However, insulin still promotes the synthesis of glycogen in the liver. When there is an insulin insufficiency or inaction, diabetes mellitus will result. Amylin The other beta cell hormone, amylin, helps reduce “spikes” in blood glucose. Amylin is also called islet amyloid polypeptide. It slows down stomach emptying; regulates secretion of acids, bile, and gastric enzymes; restricts secretion of
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Epidemiology of Diabetes
FIGURE 2.2 Insulin action on cells. Binding of insulin to its receptor causes autophosphorylation of the receptor, which then itself acts as a tyrosine kinase that phosphorylates insulin receptor substrate 1. Numerous target enzymes, such as protein kinase B and MAP kinase, are activated, and these enzymes have a multitude of effects on cell function. The glucose transporter, GLUT4, is recruited to the plasma membrane, where it facilitates glucose entry into the cell. The transport of amino acids, potassium, magnesium, and phosphate into the cell is also facilitated. The synthesis of various enzymes is induced or suppressed, and cell growth is regulated by signal molecules that modulate gene expression. MAP, mitogen-activated protein. Redrawn from M.N. Levy, B.M. Koeppen, B.A. Stanton. Principles of Physiology, 4 ed. St Louis, 2006, Mosby. (McCance 705) K. McCance, S. Huether. Pathophysiology: The Biologic Basis for Disease in Adults and Children, 7th ed. Mosby, 122013. VitalBook file.
TABLE 2.1 Effects of Insulin Actions
Adipose Cells
Liver Cells
Muscle Cells
Glucose uptake
Increased
Increased
Increased
Glucose use
Increased glycerol phosphate
None
None
Glycogenesis
None
Increased
Increased
Glycogenolysis
None
Decreased
Decreased
Glycolysis
Increased
Increased
Increased
Gluconeogenesis
None
Increased
None
Other actions
Increased fat esterification
Increased fatty acid synthesis
Increased amino acid uptake
Decreased lipolysis
Decreased ketogenesis
Increased protein synthesis
Increased fat storage
Decreased urea cycle activity
Decreased proteolysis
glucagon; and stimulates the sense of fullness or satiety, so that additional eating will not occur. Therefore, amylin acts with antihyperglycemic effects. Aggregation of amylin has cytotoxic effects, aiding in loss of beta cells, either in type 2 diabetes, or when islet cells are transplanted. Amylinomimetics are new drugs used to treat type 1 and type 2 diabetes. The effects of glucagon are summarized in Table 2.2.
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TABLE 2.2 Effects of Glucagon Glucose Glucose transport
None
Glycogen synthesis
Increases breakdown of glycogen
Gluconeogenesis
Increases gluconeogenesis
Proteins Amino acid transport
Amino acid uptake by the liver cells is increased, as well as their conversion to glucose via gluconeogenesis
Protein synthesis
None
Protein breakdown
None
Fats Synthesis of fatty acid and triglyceride
None
Storage of fat in adipose tissue
Adipose cell lipase is activated; increasing amounts of fatty acids available to be used as energy by the body
Delta Cells The delta (δ) cells secrete somatostatin, which is also known as growth hormone-inhibiting hormone. They are located in the pancreatic islets, stomach, and intestines. Secretion of somatostatin occurs at the same time that the beta cells are releasing insulin. Somatostatin, along with amylin, limits stomach acid secretion. The secretion of somatostatin is influenced mostly not only by the peptide hormone urocortin3 (Ucn3) but also by ghrelin. When viewed under an electron microscope, delta cells have smaller, slightly more compacted granules than beta cells. Delta cells in the stomach contain cholecystokinin B receptors (CCKBR), which respond to gastrin. These delta cells also have muscarinic acetylcholine (M3) receptors, which respond to ACh. The CCKBR receptors increase somatostatin output while the M3 receptors decrease it. Vasoactive intestinal peptide acts positively upon delta cells, causing more somatostatin to be released. Inside the stomach, somatostatin has direct actions upon the acid-producing parietal cells. It does this via a G-protein-coupled receptor that inhibits adenylate cyclase. This antagonizes the stimulatory effect of histamine, reducing acid secretion. Somatostatin also directly decreases stomach acid by preventing the release of hormones such as gastrin and secretin. This slows down the digestive process. There are a few other minor types of pancreatic cells, which make up only about 5% of the total cells. They are known as pancreatic polypeptide (PP) cells and gastrin (G) cells, but have insignificant functions. The PP cells produce pancreatic polypeptides in the pancreatic islets. The G cells secrete gastrin, and are also present in the stomach and duodenum.
Hyperglycemic and Hypoglycemic Hormones A hyperglycemic hormone is one that raises blood glucose concentrations. Aside from glucagon, the counter-regulatory hormones include catecholamines, growth hormone, and glucocorticoid hormones. Insulin is classified as a hypoglycemic hormone since it lowers the blood glucose levels. This will be discussed later in this chapter.
SECRETION OF GLUCAGON The alpha cells of the pancreatic islets of Langerhans release the protein hormone known as glucagon. They do this as a response to low blood glucose levels and increase plasma amino acids. Glucagon is mostly a 29-amino-acid peptide hormone related to the postabsorptive stage of digestion. This stage happens when fasting in between meals. Glucagon is primarily a catabolic hormone, meaning that it breaks down various substances. Generally, glucagon opposes the effects of insulin. It antagonizes insulin by inhibiting the movement of glucose into the cells. Glucagon stimulates liver gluconeogenesis and helps to break down the stored glycogen so that it can be used for energy in the place of glucose.
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Epidemiology of Diabetes
Glucagon encourages fat breakdown as well as the release of free fatty acids to the bloodstream. There, they are used for energy instead of glucose being used. As a result, blood glucose levels increase. The sympathetic nerves stimulate release of glucagon from the pancreas. In the liver and other peripheral tissues, the insulin to glucagon ratio determines extremely fine controls of gluconeogenesis and glycogenolysis. Glucagon has complex actions within the liver. It involves regulation of transcription factors and signal transduction networks that converge for control of amino acid, carbohydrate, and lipid metabolism. Cell-specific expression of prohormone convertase enzymes control tissue-specific liberation of proglucagon. Circulating glucagon is important in regulating the proliferation and survival of alpha cells. Glucagon is also synthesized in the central nervous system (CNS), where it is believed to control peripheral glucoregulation. Release of glucagon is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin.
SYNTHESIS AND SECRETION OF INSULIN The synthesis of insulin occurs in large quantities only in the beta cells of the pancreas. Insulin mRNA is translated as a single chain precursor known as preproinsulin. When its signal peptide is removed during insertion into the endoplasmic reticulum, proinsulin is generated. Proinsulin is made up of three components: 1. One amino-terminal B chain 2. One carboxy-terminal A chain 3. A connecting peptide between these chains, known as the C peptide. In the endoplasmic reticulum, proinsulin is exposed to certain endopeptidases that remove the C peptide. This action generates the mature form of insulin. In the Golgi complex, insulin and free C peptide are packaged into secretory granules that accumulate in the cytoplasm. With sufficient beta cell stimulation, insulin is secreted from the cell via exocytosis. It diffuses into the islet capillary blood. Though C peptide is also secreted into the blood, it has no known biological activity. The structure of proinsulin is shown in Fig. 2.3. Regarding the control of insulin secretion, this mostly occurs in response to elevated blood glucose. Insulin secretion is also promoted by neural stimuli, such as seeing or tasting food, as well as increased blood concentrations of fuel molecules such as fatty acids and amino acids. Glucose is transported into the beta cells via facilitated diffusion through a glucose transporter. In the extracellular fluid, elevated concentrations of glucose result in elevated concentrations of glucose inside the beta cells themselves. In the beta cells, elevated glucose concentrations ultimately result in membrane depolarization, and an influx of extracellular calcium. Intracellular calcium increases, and is believed to be one of the main triggers for exocytosis of FIGURE 2.3 Structure of proinsulin. With removal of the connecting peptide (C peptide), proinsulin is converted to insulin.
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FIGURE 2.4 Insulin secretion with glucose infusion over time.
the secretory granules that contain insulin. Exactly how depolarization is caused by elevated glucose in the beta cells probably occurs from glucose (and other fuel molecules) being metabolized within the cells. The increased amounts of beta cell glucose also appear to activate calcium-independent pathways involved in insulin secretion. The effect on insulin secretion when sufficient glucose is infused to maintain blood levels 2 3 times that of the fasting level, for 1 hour, is shown in Fig. 2.4. Just after the infusion begins, there is a dramatic increase in plasma insulin levels. This increase is due to secretion of preformed insulin, which is quickly used up. The secondary rise in insulin shows the large amount of newly synthesized insulin being immediately released. Therefore, elevated glucose also stimulates transcription of the insulin gene and translation of its mRNA.
CLASSIFICATIONS OF INSULIN Today all of the different types of insulin are made using human recombinant DNA technology. This involves the use of human insulin molecules, which give pharmacokinetic advantages in insulin absorption, distribution, metabolism, and excretion. There are a variety of different insulins for the treatment of type 1 and type 2 diabetes. These include long-acting, intermediate-acting, rapid-acting, and ultra-rapid-acting forms. The majority of insulins are available as U-100, which means they contain 100 units of insulin per milliliter. Newer formulations include U-200, U-300, and U-500. Since they are more concentrated, a lower dose needs to be injected, which sometimes improves absorption. While insulin is primarily injected, there is also an inhalation form available. Oral formulations have not been used with success because they degrade very quickly.
Long-Acting Insulins Most forms of long-acting insulin are administered once per day. The long-acting insulins include insulin glargine U-100 (Lantus and Basaglar), insulin glargine U-300 (Toujeo), insulin detemir (Levemir), and insulin degludec (either U-100 or -200; Tresiba). Both insulin glargine U-100 and insulin detemir have shorter durations of action, and are administered more than once per day. These forms sometimes act in ,24 hours, meaning that twice daily dosing offers better glucose control. Basaglar is the first long-acting insulin described as a follow-on biologic, though other forms are being developed. It is similar to Lantus because it uses the same amino acid sequence and has the same pharmacokinetic profile. However, it has slightly different inactive ingredients or excipients. Insulins are considered to be biologic drugs made of living cells. Therefore, they cannot have interchangeable generics. Since the patent for Lantus expired, various manufacturers are making less expensive versions of this drug. Toujeo is three times more concentrated than Lantus, with a longer half-life and duration of action. The long-acting insulins have one-to-one versions when patients are switched between them. This means that 10 units of insulin detemir is equivalent, for example, to 10 units of insulin glargine. However, Toujeo often requires doses that are up to 20% higher, or more, than Lantus. Both the U-100 and U-200 forms of Tresiba have the same duration of action. The more concentrated version is advantageous because its pen can contain up to 160 units in a single dose. This offers an insulin-resistant patient the ability to use a high dose in just one injection. The longer duration of action found in insulin degludec offers patients more flexibility with missed doses. They can alternate taking this insulin earlier or later every day, without losing their insulin coverage. In clinical trials, insulin degludec has been proven to have lower rates of hypoglycemia than insulin glargine. Also, its longer duration of action
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Epidemiology of Diabetes
TABLE 2.3 Long-Acting Insulins Properties
Degludec U-100 (Tresiba)
Degludec U-200 (Tresiba)
Detemir U-100 (Levemir)
Glargine U-100 (Lantus)
Glargine U-300 (Toujeo)
Onset
30 90 min
30 90 min
1.1 2 h
1.1 h
6h
Duration of action
42 h
42 h
7.6 24 h
10.8 24 h
24 36 h
Formulation
Pen
Pen
Pen or vial
Pen or vial
Pen
Concentration
100 units per mL
200 units per mL
100 units per mL
100 units per mL
300 units per mL
Expiration
56 days
56 days
42 days
28 days
42 days
Max units injected per dose
80 units
160 units
80 units
80 units
80 units
Pen dial
1 unit
2 units
1 unit
1 unit
1 unit
Units per pen
300 units in 3 mL
600 units in 3 mL
300 units in 3 mL
300 units in 3 mL
450 units in 1.5 mL
FIGURE 2.5 Insulin pen, syringe, and vial. Available at: https://commons.wikimedia.org/w/index.php?search 5 insulin 1 pen&title 5 Special: Search&go 5 Go&searchToken 5 4ejmpcz1nnu1tp1tjv9llqpa2#/media/File:Blausen_0580_Insulin_Syringe%26Pen.png.
means that dosing changes should not be made any sooner than every fourth day. Other insulins require dosing changes to occur every three days. Except for degludec U-200, insulin pens are limited to only 80 units per dose. However, Levemir and Lantus are also available in vials, for which a syringe is used for administration. There are a variety of sizes of insulin syringes, with 100 units being the maximum size. Long-acting insulins are compared in Table 2.3.
Rapid-Acting Insulins For insulin coverage at mealtimes, rapid- and short-acting insulins are used. For type 1 diabetes, several forms are often matched, covering a specific amount of carbohydrates. This offers patients flexibility with their meals. However, some patients must be on strictly regulated doses, and eat consistent meals every day. Rapid-acting insulins are usually injected 5 10 minutes before a meal, or at the start of a meal. This provides coverage with the meal, avoiding a spiking of blood glucose. The rapid-acting insulins include: insulin aspart (Novolog), insulin lispro U-100 (Humalog and Admelog), and insulin glulisine (Apidra). They are all available in disposable pens as well as in vials (see Fig. 2.5). The
The Pancreas and Classifications of Insulin Chapter | 2
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disposable pens may be dosed up to 60 units per injection. Additionally, reusable pens, which use pen cartridges, are available. Many types of reusable pens offer half-unit dosing, which is very helpful for patients who only need extremely low doses of insulin. Admelog is the first rapid-acting follow-on biologic insulin ever available. Recently, insulin lispro became available in a disposable pen, able to dose in half-units. All of the rapid-acting insulins are frequently used in insulin pumps. Insulin lispro is also marketed in a U-200 formulation (Humalog U-200). This form basically has the same pharmacokinetics as Humalog U-100, except its injection volume is less. Humalog U-200 is only available as a pen, but its stronger concentration means that the pens contain 600 units, instead of the 300 units that the other rapid-acting insulin pens contain. Switching between these insulins involves a one-to-one conversion; for example, 10 units of insulin glulisine is equivalent to 10 units of insulin aspart.
Ultra-Rapid-Acting Insulins The newest type of insulin is insulin aspart (Fiasp), which is classified as an ultra-rapid-acting insulin. It allows an onset of only 2.5 minutes, as compared to the 15-minute onset of rapid-acting insulins (including the different formulation of insulin aspart, marketed as Novolog). Patients can have more flexibility, injecting insulin immediately after a meal if they do not know exactly how much they will eat. Fiasp is available both as pens and vials. It is possible that the ultra-rapid-acting insulins may become the preferred form for use in insulin pumps since they are excellent at bringing down high blood glucose levels quickly.
Inhaled (Short-Acting) Insulins The first form of inhaled insulin was marketed as Exubera in 2005, but it was withdrawn because its large administration device was not easy to carry or use. In 2014, Afrezza reached the market, which provided an option to administer insulin without injection. Inhaled insulin, for type 1 diabetes, must be administered with a basal insulin, and not be the only type of insulin used. Afrezza offers a small, disposable inhaler, and cartridges of 4, 8, or 12 in blister packs (see Fig. 2.6). Since patients must round doses to the nearest four units, dosing is less exact as other insulins. Proper inhalation technique must be learned so that the amount absorbed is correct. Patients must be properly trained so that they will maintain a consistent method of inhalation. Both onset and offset of inhaled insulin is faster than with injectable rapid-acting insulins. Afrezza cannot be used by people with asthma, chronic obstructive pulmonary disease, or other chronic lung diseases. Smokers should also avoid this drug. Potential lung diseases must be identified before the drug is started. This involves detailed medical histories, physical examinations, and spirometry to measure lung capacity. Spirometry is performed again after 6 months, and then every year. The blister packs are stored in a refrigerator until use, and once opened, the cartridges must be used within 3 days. Any sealed cartridges at room temperature must be used within 10 days. Inhalers should be replaced every 15 days. The same inhaler can be used for all of the cartridge sizes. The rapidacting, ultra-rapid-acting, and short-acting insulins are compared in Table 2.4.
FIGURE 2.6 This needs to be a photo showing Afrezza’s inhaler and the various cartridges it uses. Available at: http://www.multivu.com/players/ English/7412351-sanofi-mannkind-afrezza/gallery/image/b05aaeb0-53cf-4d4c-8358-498d426c5290.jpg - need to arrange for permission.
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Epidemiology of Diabetes
TABLE 2.4 Rapid-Acting, Ultra-Rapid-Acting, and Short-Acting Insulins Property
Insulin Aspart (Fiasp)
Insulin Aspart (Novolog)
Insulin Glulisine (Apidra)
Insulin Lispro (Humalog) U100, U-200
Human Insulin Regular (Novolin R, Humulin R)
Inhaled Insulin (Afrezza)
Onset
2.5 min
10 20 min
25 min
15 30 min
30 min
15 30 min
Duration of action
3 5h
3 5h
4 5.3 h
3 6.5 h
8h
160 min
Expiration
28 days
28 days
28 days
28 days
Humulin R: 31 days; Novolin R: 42 days
Open strips: 3 days; unopened foil package: 10 days; inhaler: 15 days
Max units injected per dose
60 units
60 units
80 units
60 units
60 units
4, 8, or 12 units cartridges
Units per pen
300 units in 3 mL
300 units in 3 mL
300 units in 3 mL
U-100: 300 units in 3 mL; U-200: 600 units in 3 mL
300 units in 3 mL
Not applicable
Dosage form
Vial or pen
Vial or pen
Vial or pen
U-100: vial or pen; U-200: pen only
Vial
Inhaled
Meal timing
Subcutaneous (SC): at start of meal, 20 min after meal
SC: 5 to 10 min before meals
SC: within 15 min before or 20 min after starting meal
SC: up to 15 min before or immediately after a meal
SC: 30 min before meal
Inhaled at start of meal
Older (Intermediate-Acting) Types of Insulin The older types of insulin include regular insulin (Humulin R and Novolin R), and neutral protamine Hagedorn (or NPH) insulin, which is also known as isophane insulin. These types are mostly been replaced by the newer long-acting and rapid-acting insulins, which offer effects that are closer to the functions of a normal human pancreas. The regular insulins are used as a bolus insulin but have largely been replaced by the rapid-acting insulins due to their faster coverage and offset, which helps reduce chances of hypoglycemia. Regular insulins also take longer to become effective, and should be given 30 minutes before meals. Between regular and rapid-acting insulins, a one-to-one ratio is used. The NPH form of insulin has a shorter duration of action, and is usually dosed twice per day for type 1 diabetes. It is used as a basal insulin, but has a peak that may predispose patients to hypoglycemia. Twice-daily NPH requires a 20% reduction in dose when switching to a long-acting insulin. Situations in which older insulins are required include: during pregnancy and in individuals taking steroids such as prednisone. In such situations, the “peak” of NPH may be beneficial. Since NPH insulin has been available for a long time, there is more accumulated pregnancy safety data. The longer duration of regular insulin may also be better for patients with slowed stomach emptying or gastroparesis. Also, NPH is able to be mixed in a syringe with regular insulin or rapid-acting insulins. This is not commonly done today, but allows for two injections per day instead of multiple injections. This method usually does not offer close control of blood glucose, but it may help patients who cannot, or are not willing to administer more than two injections every day. Additionally, NPH and regular insulins are available in over-the-counter, inexpensive vials. The older, intermediate-acting insulins are compared in Table 2.5.
Premixed Insulins Premixed insulins are also available in various formulations. Novolog mix 70/30, for example, contains 70% insulin aspart protamine and 30% insulin aspart. Twice-daily dosing is offered, instead of the usual four-per-day injections
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TABLE 2.5 Older, Intermediate-Acting Insulins Property
Humulin N, Novolin N
Humulin R, U-500
Onset
1 2h
30 min
Duration of action
16 24 h
12 24 h
Concentration
100 units per mL
500 units per mL
Expiration
Humulin N vial: 31 days; Novolin N vial: 42 days; Humulin N Kwikpen: 14 days
Vials: 40 days; pens: 28 days
Dosage form
Vial or Kwikpen
Vial or pen
Pen dial
1 unit
5 units
Meal timing
Taken without regard to meals
30 min before meals
Typical dosing
1 2 times per day alone, or mixed with rapid- or short-acting insulin
3 4 times per day before meals or snacks
used in basal or bolus regimens with one long-acting injection and three mealtime injections. Most often, these are not given at lunch since the peak from the protamine helps cover the lunchtime meal. Such insulin formulations are not as flexible. When a dose is adjusted because it was premixed, both the intermediate-acting and mealtime insulin must be adjusted simultaneously. Tight glycemic control is usually hard to achieve without significant hypoglycemia occurring. Other examples of premixed insulins include Humalog mix 75/25, Humulin 70/30, Humalog mix 50/50, and Humulin 50/50. They all have an intermediate-acting protamine component that allows the insulin to last longer. This is mixed with either regular insulin (Humulin or Novolin), or rapid-acting insulin (Novolog or Humalog). Overall, premixed insulins are good for patients needing an easier regimen, or who have problems adhering to their injections. With these formulations, patients must eat on a regular schedule, and avoid skipping meals or snacks, in order to reduce hypoglycemia.
U-500 Insulin The form known as Humulin U-500 is usually used only for patients with serious insulin resistance, and who are taking more than 200 units of insulin every day. When the body can no longer respond to insulin and glucose storage at safe levels, higher blood glucose results, and insulin resistance occurs. Therefore, U-500 insulin is commonly used for type 2 diabetics. It is also possible for type 1 diabetics to develop insulin resistance—primarily if they are obese. This type of insulin is usually dosed 2 4 times daily, before meals. It functions closely to the intermediate-acting insulins, and should be given 30 minutes before meals or snacks. Since U-500 insulin is five times more potent than other forms, there is a long history of dosing errors. Over time, patients often used U-100 syringes, resulting in much confusion, since just five units in a U-100 syringe is actually 25 units of U-500 insulin. Today, there are dedicated U-500 syringes and insulin pens. They have greatly reduced dosing errors of this type of insulin.
THE BRAIN, GLUCOSE, AND INSULIN Brain cells are somewhat unique because they do not need insulin for glucose entry. Most other cells do require insulin for this purpose. Brain cells also do not use free fatty acids or amino acids for energy. Instead, they only use glucose or glycogen to meet energy demands and power cellular functions. Therefore, gluconeogenesis in the liver is very important. Between meals, if glucose were not produced by the liver, the brain would not have a usable source of energy. The brain is the most energy-demanding organ in the body, using 50% of all sugar energy. Learning, memory, and thinking are closely linked to glucose levels, and how efficiently the brain is able to use glucose. When glucose in the brain is insufficient, neurotransmitters are not produced and communication between the neurons breaks down. Hypoglycemia can also lead to a loss of energy for brain function. This is linked to poor attention and cognitive function. However, too much glucose is also harmful to brain function, and is linked to memory and cognitive deficiencies. High glucose levels can actually cause the brain to atrophy or shrink, and lead to small-vessel disease that restricts blood flow. This leads to cognitive difficulties, and possibly, vascular dementia.
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Epidemiology of Diabetes
Insulin is not required for glucose transport into most brain cells. However, insulin acts as a neuroregulatory peptide. Insulin is believed to be essential for regulating when we eat, and for monitoring available stores of energy. Insulin has functional effects in many different areas of the brain. For example, it affects areas of the hippocampus that are used in the recognition of rewards, and in areas less specific for cognitive and memory functions. Insulin easily crosses the blood brain barrier and is concentrated in all CNS tissues. Impaired systemic insulin delivery to the cerebrospinal fluid could contribute to changes in feeding behaviors, dysregulated hepatic and adipose tissue metabolism, and increased risks for cognitive decline.
SECRETION OF SOMATOSTATIN Somatostatin, from the delta cells of the islets of Langerhans, is also released by the hypothalamus. Somatostatin from the pancreas only has a slight effect upon growth hormone release from the pituitary. It helps to control metabolism by inhibiting secretion of insulin and glucagon. However, somatostatin from the hypothalamus more strongly inhibits growth hormone release from the anterior pituitary. Somatostatin is released in the blood, synaptic clefts, and intercellular spaces. When released from neurons, it acts as a hypophysiotropic hormone as well as a neurotransmitter or neuromodulator. It may also act as a paracrine in the intercellular spaces. In the pancreatic islets, somatostatin influences the activities of nearby alpha and beta cells. The delta cells of the gastrointestinal tract release somatostatin into the bloodstream, intercellular spaces, and the gastric and intestinal lumen. In the lumen, somatostatin may affect other endocrine and nonendocrine cells, actually of the mucous membranes.
COUNTER-REGULATORY HORMONES There are other hormones that affect the blood glucose levels. These include catecholamines, growth hormone, and the glucocorticoids. Along with glucagon, these counter-regulatory hormones oppose the storage actions of insulin. This helps regulate blood glucose levels during fasting, exercise, and whenever glucose intake is limited or stores of glucose are depleted.
Catecholamines Epinephrine is a catecholamine. It aids in maintaining blood glucose levels when stress is present. Epinephrine strongly stimulates glycogenolysis in the liver. This causes significant amounts of glucose to be released into the circulation. Additionally, epinephrine inhibits insulin release from the beta cells. This decreases movement of glucose into muscle cells. Simultaneously, it increases the breakdown of glycogen stores in muscles. Though glucose from these stores cannot be released into the circulation, mobilization of this glycogen for use by the muscles will conserve blood glucose to be used by the brain, nervous system, and other tissues. Epinephrine also causes direct lipolysis of adipose cells. This increases mobilization of fatty acids to be used for energy. When hypoglycemia develops, the effect of elevating blood glucose by epinephrine acts as an important part of homeostasis.
Growth Hormone Growth hormone has many metabolic effects. Throughout the body, it increases protein synthesis. It also antagonizes insulin and mobilizes fatty acids from the adipose tissues. Growth hormone increases blood glucose levels by decreasing cellular uptake and glucose use. When blood glucose has increased, additional insulin secretion is stimulated by the beta cells. Normally growth hormone secretion is inhibited by insulin as well as the increased levels of blood glucose. When fasting, as there is reduced blood glucose levels and secretion of insulin, the levels of growth hormone increase. Its levels are also increased by exercise, and stressors such as anesthesia, fever, or trauma. In conditions such as acromegaly, in which there is chronic hypersecretion of growth hormone, there is a likelihood of glucose intolerance and diabetes mellitus developing. In diabetics, if even slight elevations of growth hormone occur during stress or childhood growth periods, a wide range of metabolic abnormalities may occur. This can occur even with adequate treatment with insulin.
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Glucocorticoid Hormones Glucocorticoid hormones are synthesized in the adrenal cortex, similar to other corticosteroid hormones. The glucocorticoid hormones are essential for survival, when fasting or during starvation. They encourage gluconeogenesis in the liver. As much as 6 10 times more hepatic glucose can be produced. These hormones also slightly decrease the use of glucose by the body tissues. Several steroid hormones have glucocorticoid activity. The most essential of these is cortisol, which makes up about 95% of all glucocorticoid activities. Physical or emotional stressors cause immediate increases in secretion of adrenocorticotropic hormone by the anterior pituitary gland. Within a few minutes, this is followed by highly increased cortisol secretion from the adrenal gland. Cortisol secretion is greatly stimulated by hypoglycemia. If a person is predisposed, chronic elevation of glucocorticoid hormones may cause hyperglycemia, and development of diabetes mellitus. In diabetics, slight increases in cortisol and seriously harm homeostasis.
FURTHER READING [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
[13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27]
AACE. ACE glucose monitoring consensus statement. Endocr Pract 2016;22(2):239. AADE. The art & science of diabetes self-management education desk reference. 4th ed AADE; 2017. Beta Bionics. Available at: https://www.betabionics.org/. Centers for Disease Control and Prevention. National diabetes statistics report. Atlanta, GA: US Department of Health and Human Services; 2017. Available from: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Children and adolescents. Diabetes Care 2017;40(Suppl. 1):S105 S113. doi: 10.2337/dc17-S015. Classification and diagnosis of diabetes. Diabetes Care 2017;40(Suppl. 1):S11 S24. doi: 10.2337/dc17-S005. Dexcom G4 Professional CGM. Available at: https://provider.dexcom.com/products/professional-cgm. Dexcom G5. Available at: https://www.dexcom.com/g5-mobile-cgm. https://www.endocrineweb.com/endocrinology/overview-pancreas. Fiasp Product Information. Available at: https://www.fiasppro.com/. Freestyle Libre Professional CGM. Available at: https://www.myfreestyle.com/provider/freestyle-libre-pro-product. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2017 executive summary. Endocr Pract 2017;23 (2):207 38. Available from: https://doi.org/10.4158/EP161682.CS. Glucagon directions for use. Available at: http://pi.lilly.com/us/rglucagon-ppi.pdf. Glycemic targets. Diabetes Care 2017;40(Suppl. 1):S48 S56. doi: 10.2337/dc17-S009. Humulin U-500 Package Insert. Available at: http://pi.lilly.com/us/humulin-r-u500-pi.pdf. Klonoff DC, Ahn D, Drincic A. Continuous glucose monitoring: A review of the technology and clinical use. Diabetes Res Clin Pract 2017;133:178 92. Available from: https://doi.org/10.1016/j.diabres.2017.08.005. Lifestyle management. Diabetes Care 2017;40(Suppl. 1):S33 S43. doi: 10.2337/dc17-S007. McCrea DL. A primer on insulin pump therapy for health care providers. Nurs Clin North Am 2017;52(4):553 64. Available from: https://doi. org/10.1016/j.cnur.2017.07.005. Microvascular complications and foot care. Diabetes Care 2017;40(Suppl. 1):S88 S98. doi: 10.2337/dc17-S013. Millstein R, Becerra NM, Shubrook JH. Insulin pumps: beyond basal-bolus. Cleve Clin J Med 2015;82(12):835 42. Available from: https:// doi.org/10.3949/ccjm.82a.14127. Nyenwe EA, Kitabchi AE. The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism 2016;65(4):507 21. Available from: https://doi.org/10.1016/j.metabol.2015.12.007. Omnipod Insulin Pump. Available at: https://www.myomnipod.com/. Petrie JR, Peters AL, Bergenstal RM, Holl RW, Fleming GA, Heinemann L. Improving the clinical value and utility of CGM systems: issues and recommendations. Diabetologia 2017;60(12):2319 28. Available from: https://doi.org/10.1007/s00125-017-4463-4. Pharmacologic approaches to glycemic treatment. Diabetes Care 2017;40(Suppl. 1), S64 S74. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescriber’s Letter. March 2015. SymlinPen Product Information. Available at: https://www.symlin.com/. www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html.
The Pancreas and Classifications of Insulin In adults, the pancreas is oriented transversely and extends from the C-loop of the duodenum to the hilum of the spleen. Though its name is derived from a Greek word, pancreas, which means all flesh, the pancreas is actually a complicated organ with many lobules. It has separate exocrine and endocrine components. The exocrine pancreas makes up most (80% 85%) of the organ. It consists of acinar cells that secrete the enzymes required for digestion. Acinar cells are pyramid-shaped epithelial cells. They contain membrane-bound granules that are rich in proenzymes, also called zymogens. These include trypsinogen, chymotrypsinogen, procarboxypeptidase, kallikreinogen, proelastase, and prophospholipase A and B. When these proenzymes and enzymes are secreted, many ducts and ductules carry them to the duodenum, where they are activated by proteolytic cleavage in the gastrointestinal tract. The endocrine pancreas is made up of approximately one million cell clusters known as the islets of Langerhans. These cells are scattered throughout the pancreas, and secrete insulin, glucagon, and somatostatin. The islet cells make up only 1% 2% of the pancreas.
THE PANCREAS The pancreas is located below and behind the stomach, but in front of the spine. It is a spongy gland of 12 15 cm (6 10 in.) in length, and is mostly retroperitoneal. The pancreas is grayish-pink in color, and weighs about 60 g. The head of the pancreas is on the right side of the abdomen. It is connected to the first section of the small intestine, the duodenum, via the small pancreatic duct. The narrow tail of the pancreas extends to the left side of the body (see Fig. 2.1A). The pancreas is surrounded by the small intestine, stomach, liver, and spleen. Because of the deep location of the pancreas, when tumors develop, they are rarely able to be palpated by pressing on the abdomen.
The Pancreatic Islets The tissues of the pancreas contain approximately one to two million clusters of cells that are called pancreatic islets or islets of Langerhans (see Fig. 2.1B). The pancreatic islets actually make up ,2% of the total pancreatic tissues. However, they are extremely important because they secrete hormones needed primarily in the regulation of glycemia, which is the blood glucose concentration. Each islet is about 75 3 175 µm in size, and contains as little as a few cells to approximately 3000 cells. These cells are of three primary types: the alpha cells, which make up 20% of the total amounts of cells; the beta cells, 70%; and the delta cells, 5%. All of the islet cells directly respond to nutrient levels in the blood that are related to eating and fasting. Approximately 5% of the pancreatic cells consist of pancreatic polypeptide (PP) cells. There are four types of hormone-secreting cells: G G G G
Alpha cells—which secrete glucagon Beta cells—which secrete insulin and amylin Delta cells—which secrete gastrin and somatostatin F (or PP) cells—which secrete PP; this stimulates gastric secretions, and antagonizes cholecystokinin.
These hormones regulate the metabolism of carbohydrates, fats, and proteins. The pancreatic islets are innervated by nerves from the sympathetic and parasympathetic divisions of the autonomic nervous system. The vagus nerves innervate the pancreas, liver, gallbladder, stomach, small intestine, and the proximal half of the large intestine. Epidemiology of Diabetes. DOI: https://doi.org/10.1016/B978-0-12-816864-6.00002-X © 2019 Elsevier Inc. All rights reserved.
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Epidemiology of Diabetes
FIGURE 2.1 The pancreas. (A) Pancreas dissected to show main and accessory ducts. The main duct may join the common bile duct, as shown here, to enter the duodenum by a single opening at the major duodenal papilla, or the two ducts may have separate openings. The accessory pancreatic duct is usually present and has a separate opening into the duodenum. (B) Exocrine glandular cells (around small pancreatic ducts) and endocrine glandular cells of the pancreatic islets (adjacent to blood capillaries). Exocrine pancreatic cells secrete pancreatic juice, alpha endocrine cells secrete glucagon, and beta cells secrete insulin. Adapted from K.T. Patton, G.A. Thibodeau. The Human Body in Health & Disease, 7 ed., St Louis, 2018, Elsevier.
The alpha, beta, and delta cells are most numerous in the anterior lobe of the pancreas. Perfusion of this lobe comes from branches of the superior mesenteric artery. This is a large and unpaired artery arising from the abdominal aorta at the L1 level, just below the celiac trunk. It runs deep to the pancreas, entering the mesentery, where its many anastomosing branches serve almost all of the small intestine. Branches of the celiac trunk perfuse the posterior lobe of the pancreas. The common hepatic artery branches to the pancreas, stomach, and duodenum. The splenic artery branches to the pancreas and stomach, with its branches terminating in the spleen. Although the pancreatic islets make up only about 1% of the mass of the pancreas, they receive 10% of pancreatic blood flow. This is essential so that islet hormones can be oxygenated and delivered to target cells. The splenic vein collects blood from parts of the pancreas, stomach, and spleen. It joins the superior mesenteric vein, forming the hepatic portal vein.
Functions of the Pancreas The functions of the pancreas are primarily as an exocrine digestive gland. It is essential in converting food into fuel for the body’s cells. When healthy, the pancreas produces specific chemicals in exact quantities, when they are needed, to digest foods. Its exocrine glands produce digestive enzymes that include trypsin and chymotrypsin to digest proteins. It also produces amylase to digest carbohydrates and lipase to break down fatty acids and cholesterol. As food enters the stomach, the pancreatic juices are released into a duct system ending in the main pancreatic duct. The pancreatic duct joins the common bile duct to form the ampulla of Vater at the duodenum. The common bile duct actually originates in the liver and gallbladder. It produces bile, another important digestive juice. Therefore, bile and pancreatic juices are released into the duodenum to help digest proteins, carbohydrates, and fats. A healthy pancreas produces about 2.2 pints (1 L) of enzymes each day. The endocrine functions of the pancreas occur via the pancreatic islets, primarily via the hormones, insulin and glucagon. The maintenance of blood glucose levels is crucial for normal body functions.
The Pancreas and Classifications of Insulin Chapter | 2
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Alpha Cells The alpha (α) cells secrete glucagon in between meals, when concentrations of blood glucose are below 100 mg/dL. Glucagon is important in the liver for glycogenolysis and gluconeogenesis. Glycogenolysis is the degradation of glycogen into glucose. Gluconeogenesis is the synthesis of glucose from proteins and fats. Both processes result in glucose being released into the circulation, which raises blood glucose levels. Glucagon, in the adipose tissue, stimulates release of free fatty acids and the catabolism of fats. Glucagon is secreted as a response to increasing levels of amino acid in the blood, following high-protein meals. Amino acid absorption is promoted by glucagon, which also provides cells with raw materials required for gluconeogenesis. Glucagon binds to receptors on hepatocytes, kidney cells, and other cells to elevate glucose levels. This activates the enzyme glycogen phosphorylase inside hepatocytes, and glycogen is hydrolyzed to glucose. The alpha cells are located in the peripheral areas of the islets as well as inside them. Under an electron microscope, alpha cells are identified by their characteristic granules. They have large, dense cores and small white halo, or circular ring.
Beta Cells The beta (β) cells secrete the hormones insulin and amylin. Insulin is concerned with abundance of nutrients. It is secreted during and just after meals, as blood nutrient levels are increasing. Beta cells are able to quickly respond to spikes in blood glucose concentrations by secreting stored insulin while producing more insulin at the same time. Insulin regulates the rate of glucose uptake into many different cells. At a target cell, it binds with an enzyme-linked plasma membrane receptor. This receptor contains tyrosine kinase on the surface of the cytosol. Insulin receptor binding sends a signal cascade, which activates glucose transporters (GLUT) for the entry of glucose into the cell. The main glucose transporter is called GLUT4. It is stored in the cellular vesicles. Once activated by the insulin receptor, it translocates to the cell surface. Here, it facilitates diffusion of glucose into the cell. When GLUT4 translocates to the cell surface, glucose diffusion into the cell increases to 10 21 times the amount. This is especially true in cardiac and skeletal muscle, liver, and adipose cells (see Fig. 2.2). The main component in maintaining normal cell function is sensitivity of insulin receptors. Insulin resistance is linked to diabetes, hypertension, and many cardiovascular diseases. The adipocytes release a variety of hormones that are altered in obese patients, which have important effects on insulin sensitivity. The cell surface membranes of beta cells have embedded voltage-gated calcium channels and ATP-sensitive potassium ion channels. The calcium channels are usually closed and the potassium channels are open. Potassium ions diffuse out of beta cells, down the concentration gradient. The inside of the cells becomes more negative compared to the outside, since the potassium ions carry a positive charge. While resting, this creates a potential difference across the cell surface membranes of 270 mV. When glucose concentrations outside beta cells are high, glucose molecules move into them via facilitated diffusion, down the concentration gradient, through the GLUT2 transporter. Beta cells use glucokinase to catalyze the first step of glycolysis. Therefore, metabolism only occurs around and above physiological blood glucose levels. Metabolism of glucose produces ATP. This increases the ATP-to-ADP ratio. When this ratio increases, ATP-sensitive potassium ion channels close. The ions cannot diffuse out of beta cells anymore at this point. The potential difference across the membrane becomes more positive as potassium ions are accumulating inside the cells. The voltage-gated calcium channels open and allow calcium ions to diffuse outward down the concentration gradient. As calcium enters the cells, vesicles containing insulin move to the cell surface membrane and fuse with it. Insulin is released via exocytosis. A hormone from bone osteoblasts, known as osteocalcin, helps to stimulate multiplication of beta cells, secretion of insulin, and body tissue sensitivity to insulin. The liver, adipose tissue, and skeletal muscles are directly targeted by insulin. When nutrients are sufficient, insulin stimulates body cells to absorb, store, and metabolize amino acids, fatty acids, and glucose. As a result, insulin lowers levels of blood glucose and various nutrients. It also encourages synthesis of fat, glycogen, and protein (see Table 2.1). This action promotes storage of excessive nutrients to be used at a later time. It also enhances the growth and differentiation of cells. Insulin antagonizes glucagon, to suppress the use of previously stored fuels. Glucose is absorbed and used by the brain, kidneys, liver, and red blood cells without any need for insulin. However, insulin still promotes the synthesis of glycogen in the liver. When there is an insulin insufficiency or inaction, diabetes mellitus will result. Amylin The other beta cell hormone, amylin, helps reduce “spikes” in blood glucose. Amylin is also called islet amyloid polypeptide. It slows down stomach emptying; regulates secretion of acids, bile, and gastric enzymes; restricts secretion of
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Epidemiology of Diabetes
FIGURE 2.2 Insulin action on cells. Binding of insulin to its receptor causes autophosphorylation of the receptor, which then itself acts as a tyrosine kinase that phosphorylates insulin receptor substrate 1. Numerous target enzymes, such as protein kinase B and MAP kinase, are activated, and these enzymes have a multitude of effects on cell function. The glucose transporter, GLUT4, is recruited to the plasma membrane, where it facilitates glucose entry into the cell. The transport of amino acids, potassium, magnesium, and phosphate into the cell is also facilitated. The synthesis of various enzymes is induced or suppressed, and cell growth is regulated by signal molecules that modulate gene expression. MAP, mitogen-activated protein. Redrawn from M.N. Levy, B.M. Koeppen, B.A. Stanton. Principles of Physiology, 4 ed. St Louis, 2006, Mosby. (McCance 705) K. McCance, S. Huether. Pathophysiology: The Biologic Basis for Disease in Adults and Children, 7th ed. Mosby, 122013. VitalBook file.
TABLE 2.1 Effects of Insulin Actions
Adipose Cells
Liver Cells
Muscle Cells
Glucose uptake
Increased
Increased
Increased
Glucose use
Increased glycerol phosphate
None
None
Glycogenesis
None
Increased
Increased
Glycogenolysis
None
Decreased
Decreased
Glycolysis
Increased
Increased
Increased
Gluconeogenesis
None
Increased
None
Other actions
Increased fat esterification
Increased fatty acid synthesis
Increased amino acid uptake
Decreased lipolysis
Decreased ketogenesis
Increased protein synthesis
Increased fat storage
Decreased urea cycle activity
Decreased proteolysis
glucagon; and stimulates the sense of fullness or satiety, so that additional eating will not occur. Therefore, amylin acts with antihyperglycemic effects. Aggregation of amylin has cytotoxic effects, aiding in loss of beta cells, either in type 2 diabetes, or when islet cells are transplanted. Amylinomimetics are new drugs used to treat type 1 and type 2 diabetes. The effects of glucagon are summarized in Table 2.2.
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TABLE 2.2 Effects of Glucagon Glucose Glucose transport
None
Glycogen synthesis
Increases breakdown of glycogen
Gluconeogenesis
Increases gluconeogenesis
Proteins Amino acid transport
Amino acid uptake by the liver cells is increased, as well as their conversion to glucose via gluconeogenesis
Protein synthesis
None
Protein breakdown
None
Fats Synthesis of fatty acid and triglyceride
None
Storage of fat in adipose tissue
Adipose cell lipase is activated; increasing amounts of fatty acids available to be used as energy by the body
Delta Cells The delta (δ) cells secrete somatostatin, which is also known as growth hormone-inhibiting hormone. They are located in the pancreatic islets, stomach, and intestines. Secretion of somatostatin occurs at the same time that the beta cells are releasing insulin. Somatostatin, along with amylin, limits stomach acid secretion. The secretion of somatostatin is influenced mostly not only by the peptide hormone urocortin3 (Ucn3) but also by ghrelin. When viewed under an electron microscope, delta cells have smaller, slightly more compacted granules than beta cells. Delta cells in the stomach contain cholecystokinin B receptors (CCKBR), which respond to gastrin. These delta cells also have muscarinic acetylcholine (M3) receptors, which respond to ACh. The CCKBR receptors increase somatostatin output while the M3 receptors decrease it. Vasoactive intestinal peptide acts positively upon delta cells, causing more somatostatin to be released. Inside the stomach, somatostatin has direct actions upon the acid-producing parietal cells. It does this via a G-protein-coupled receptor that inhibits adenylate cyclase. This antagonizes the stimulatory effect of histamine, reducing acid secretion. Somatostatin also directly decreases stomach acid by preventing the release of hormones such as gastrin and secretin. This slows down the digestive process. There are a few other minor types of pancreatic cells, which make up only about 5% of the total cells. They are known as pancreatic polypeptide (PP) cells and gastrin (G) cells, but have insignificant functions. The PP cells produce pancreatic polypeptides in the pancreatic islets. The G cells secrete gastrin, and are also present in the stomach and duodenum.
Hyperglycemic and Hypoglycemic Hormones A hyperglycemic hormone is one that raises blood glucose concentrations. Aside from glucagon, the counter-regulatory hormones include catecholamines, growth hormone, and glucocorticoid hormones. Insulin is classified as a hypoglycemic hormone since it lowers the blood glucose levels. This will be discussed later in this chapter.
SECRETION OF GLUCAGON The alpha cells of the pancreatic islets of Langerhans release the protein hormone known as glucagon. They do this as a response to low blood glucose levels and increase plasma amino acids. Glucagon is mostly a 29-amino-acid peptide hormone related to the postabsorptive stage of digestion. This stage happens when fasting in between meals. Glucagon is primarily a catabolic hormone, meaning that it breaks down various substances. Generally, glucagon opposes the effects of insulin. It antagonizes insulin by inhibiting the movement of glucose into the cells. Glucagon stimulates liver gluconeogenesis and helps to break down the stored glycogen so that it can be used for energy in the place of glucose.
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Epidemiology of Diabetes
Glucagon encourages fat breakdown as well as the release of free fatty acids to the bloodstream. There, they are used for energy instead of glucose being used. As a result, blood glucose levels increase. The sympathetic nerves stimulate release of glucagon from the pancreas. In the liver and other peripheral tissues, the insulin to glucagon ratio determines extremely fine controls of gluconeogenesis and glycogenolysis. Glucagon has complex actions within the liver. It involves regulation of transcription factors and signal transduction networks that converge for control of amino acid, carbohydrate, and lipid metabolism. Cell-specific expression of prohormone convertase enzymes control tissue-specific liberation of proglucagon. Circulating glucagon is important in regulating the proliferation and survival of alpha cells. Glucagon is also synthesized in the central nervous system (CNS), where it is believed to control peripheral glucoregulation. Release of glucagon is stimulated by hypoglycemia and inhibited by hyperglycemia, insulin, and somatostatin.
SYNTHESIS AND SECRETION OF INSULIN The synthesis of insulin occurs in large quantities only in the beta cells of the pancreas. Insulin mRNA is translated as a single chain precursor known as preproinsulin. When its signal peptide is removed during insertion into the endoplasmic reticulum, proinsulin is generated. Proinsulin is made up of three components: 1. One amino-terminal B chain 2. One carboxy-terminal A chain 3. A connecting peptide between these chains, known as the C peptide. In the endoplasmic reticulum, proinsulin is exposed to certain endopeptidases that remove the C peptide. This action generates the mature form of insulin. In the Golgi complex, insulin and free C peptide are packaged into secretory granules that accumulate in the cytoplasm. With sufficient beta cell stimulation, insulin is secreted from the cell via exocytosis. It diffuses into the islet capillary blood. Though C peptide is also secreted into the blood, it has no known biological activity. The structure of proinsulin is shown in Fig. 2.3. Regarding the control of insulin secretion, this mostly occurs in response to elevated blood glucose. Insulin secretion is also promoted by neural stimuli, such as seeing or tasting food, as well as increased blood concentrations of fuel molecules such as fatty acids and amino acids. Glucose is transported into the beta cells via facilitated diffusion through a glucose transporter. In the extracellular fluid, elevated concentrations of glucose result in elevated concentrations of glucose inside the beta cells themselves. In the beta cells, elevated glucose concentrations ultimately result in membrane depolarization, and an influx of extracellular calcium. Intracellular calcium increases, and is believed to be one of the main triggers for exocytosis of FIGURE 2.3 Structure of proinsulin. With removal of the connecting peptide (C peptide), proinsulin is converted to insulin.
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FIGURE 2.4 Insulin secretion with glucose infusion over time.
the secretory granules that contain insulin. Exactly how depolarization is caused by elevated glucose in the beta cells probably occurs from glucose (and other fuel molecules) being metabolized within the cells. The increased amounts of beta cell glucose also appear to activate calcium-independent pathways involved in insulin secretion. The effect on insulin secretion when sufficient glucose is infused to maintain blood levels 2 3 times that of the fasting level, for 1 hour, is shown in Fig. 2.4. Just after the infusion begins, there is a dramatic increase in plasma insulin levels. This increase is due to secretion of preformed insulin, which is quickly used up. The secondary rise in insulin shows the large amount of newly synthesized insulin being immediately released. Therefore, elevated glucose also stimulates transcription of the insulin gene and translation of its mRNA.
CLASSIFICATIONS OF INSULIN Today all of the different types of insulin are made using human recombinant DNA technology. This involves the use of human insulin molecules, which give pharmacokinetic advantages in insulin absorption, distribution, metabolism, and excretion. There are a variety of different insulins for the treatment of type 1 and type 2 diabetes. These include long-acting, intermediate-acting, rapid-acting, and ultra-rapid-acting forms. The majority of insulins are available as U-100, which means they contain 100 units of insulin per milliliter. Newer formulations include U-200, U-300, and U-500. Since they are more concentrated, a lower dose needs to be injected, which sometimes improves absorption. While insulin is primarily injected, there is also an inhalation form available. Oral formulations have not been used with success because they degrade very quickly.
Long-Acting Insulins Most forms of long-acting insulin are administered once per day. The long-acting insulins include insulin glargine U-100 (Lantus and Basaglar), insulin glargine U-300 (Toujeo), insulin detemir (Levemir), and insulin degludec (either U-100 or -200; Tresiba). Both insulin glargine U-100 and insulin detemir have shorter durations of action, and are administered more than once per day. These forms sometimes act in ,24 hours, meaning that twice daily dosing offers better glucose control. Basaglar is the first long-acting insulin described as a follow-on biologic, though other forms are being developed. It is similar to Lantus because it uses the same amino acid sequence and has the same pharmacokinetic profile. However, it has slightly different inactive ingredients or excipients. Insulins are considered to be biologic drugs made of living cells. Therefore, they cannot have interchangeable generics. Since the patent for Lantus expired, various manufacturers are making less expensive versions of this drug. Toujeo is three times more concentrated than Lantus, with a longer half-life and duration of action. The long-acting insulins have one-to-one versions when patients are switched between them. This means that 10 units of insulin detemir is equivalent, for example, to 10 units of insulin glargine. However, Toujeo often requires doses that are up to 20% higher, or more, than Lantus. Both the U-100 and U-200 forms of Tresiba have the same duration of action. The more concentrated version is advantageous because its pen can contain up to 160 units in a single dose. This offers an insulin-resistant patient the ability to use a high dose in just one injection. The longer duration of action found in insulin degludec offers patients more flexibility with missed doses. They can alternate taking this insulin earlier or later every day, without losing their insulin coverage. In clinical trials, insulin degludec has been proven to have lower rates of hypoglycemia than insulin glargine. Also, its longer duration of action
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Epidemiology of Diabetes
TABLE 2.3 Long-Acting Insulins Properties
Degludec U-100 (Tresiba)
Degludec U-200 (Tresiba)
Detemir U-100 (Levemir)
Glargine U-100 (Lantus)
Glargine U-300 (Toujeo)
Onset
30 90 min
30 90 min
1.1 2 h
1.1 h
6h
Duration of action
42 h
42 h
7.6 24 h
10.8 24 h
24 36 h
Formulation
Pen
Pen
Pen or vial
Pen or vial
Pen
Concentration
100 units per mL
200 units per mL
100 units per mL
100 units per mL
300 units per mL
Expiration
56 days
56 days
42 days
28 days
42 days
Max units injected per dose
80 units
160 units
80 units
80 units
80 units
Pen dial
1 unit
2 units
1 unit
1 unit
1 unit
Units per pen
300 units in 3 mL
600 units in 3 mL
300 units in 3 mL
300 units in 3 mL
450 units in 1.5 mL
FIGURE 2.5 Insulin pen, syringe, and vial. Available at: https://commons.wikimedia.org/w/index.php?search 5 insulin 1 pen&title 5 Special: Search&go 5 Go&searchToken 5 4ejmpcz1nnu1tp1tjv9llqpa2#/media/File:Blausen_0580_Insulin_Syringe%26Pen.png.
means that dosing changes should not be made any sooner than every fourth day. Other insulins require dosing changes to occur every three days. Except for degludec U-200, insulin pens are limited to only 80 units per dose. However, Levemir and Lantus are also available in vials, for which a syringe is used for administration. There are a variety of sizes of insulin syringes, with 100 units being the maximum size. Long-acting insulins are compared in Table 2.3.
Rapid-Acting Insulins For insulin coverage at mealtimes, rapid- and short-acting insulins are used. For type 1 diabetes, several forms are often matched, covering a specific amount of carbohydrates. This offers patients flexibility with their meals. However, some patients must be on strictly regulated doses, and eat consistent meals every day. Rapid-acting insulins are usually injected 5 10 minutes before a meal, or at the start of a meal. This provides coverage with the meal, avoiding a spiking of blood glucose. The rapid-acting insulins include: insulin aspart (Novolog), insulin lispro U-100 (Humalog and Admelog), and insulin glulisine (Apidra). They are all available in disposable pens as well as in vials (see Fig. 2.5). The
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disposable pens may be dosed up to 60 units per injection. Additionally, reusable pens, which use pen cartridges, are available. Many types of reusable pens offer half-unit dosing, which is very helpful for patients who only need extremely low doses of insulin. Admelog is the first rapid-acting follow-on biologic insulin ever available. Recently, insulin lispro became available in a disposable pen, able to dose in half-units. All of the rapid-acting insulins are frequently used in insulin pumps. Insulin lispro is also marketed in a U-200 formulation (Humalog U-200). This form basically has the same pharmacokinetics as Humalog U-100, except its injection volume is less. Humalog U-200 is only available as a pen, but its stronger concentration means that the pens contain 600 units, instead of the 300 units that the other rapid-acting insulin pens contain. Switching between these insulins involves a one-to-one conversion; for example, 10 units of insulin glulisine is equivalent to 10 units of insulin aspart.
Ultra-Rapid-Acting Insulins The newest type of insulin is insulin aspart (Fiasp), which is classified as an ultra-rapid-acting insulin. It allows an onset of only 2.5 minutes, as compared to the 15-minute onset of rapid-acting insulins (including the different formulation of insulin aspart, marketed as Novolog). Patients can have more flexibility, injecting insulin immediately after a meal if they do not know exactly how much they will eat. Fiasp is available both as pens and vials. It is possible that the ultra-rapid-acting insulins may become the preferred form for use in insulin pumps since they are excellent at bringing down high blood glucose levels quickly.
Inhaled (Short-Acting) Insulins The first form of inhaled insulin was marketed as Exubera in 2005, but it was withdrawn because its large administration device was not easy to carry or use. In 2014, Afrezza reached the market, which provided an option to administer insulin without injection. Inhaled insulin, for type 1 diabetes, must be administered with a basal insulin, and not be the only type of insulin used. Afrezza offers a small, disposable inhaler, and cartridges of 4, 8, or 12 in blister packs (see Fig. 2.6). Since patients must round doses to the nearest four units, dosing is less exact as other insulins. Proper inhalation technique must be learned so that the amount absorbed is correct. Patients must be properly trained so that they will maintain a consistent method of inhalation. Both onset and offset of inhaled insulin is faster than with injectable rapid-acting insulins. Afrezza cannot be used by people with asthma, chronic obstructive pulmonary disease, or other chronic lung diseases. Smokers should also avoid this drug. Potential lung diseases must be identified before the drug is started. This involves detailed medical histories, physical examinations, and spirometry to measure lung capacity. Spirometry is performed again after 6 months, and then every year. The blister packs are stored in a refrigerator until use, and once opened, the cartridges must be used within 3 days. Any sealed cartridges at room temperature must be used within 10 days. Inhalers should be replaced every 15 days. The same inhaler can be used for all of the cartridge sizes. The rapidacting, ultra-rapid-acting, and short-acting insulins are compared in Table 2.4.
FIGURE 2.6 This needs to be a photo showing Afrezza’s inhaler and the various cartridges it uses. Available at: http://www.multivu.com/players/ English/7412351-sanofi-mannkind-afrezza/gallery/image/b05aaeb0-53cf-4d4c-8358-498d426c5290.jpg - need to arrange for permission.
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Epidemiology of Diabetes
TABLE 2.4 Rapid-Acting, Ultra-Rapid-Acting, and Short-Acting Insulins Property
Insulin Aspart (Fiasp)
Insulin Aspart (Novolog)
Insulin Glulisine (Apidra)
Insulin Lispro (Humalog) U100, U-200
Human Insulin Regular (Novolin R, Humulin R)
Inhaled Insulin (Afrezza)
Onset
2.5 min
10 20 min
25 min
15 30 min
30 min
15 30 min
Duration of action
3 5h
3 5h
4 5.3 h
3 6.5 h
8h
160 min
Expiration
28 days
28 days
28 days
28 days
Humulin R: 31 days; Novolin R: 42 days
Open strips: 3 days; unopened foil package: 10 days; inhaler: 15 days
Max units injected per dose
60 units
60 units
80 units
60 units
60 units
4, 8, or 12 units cartridges
Units per pen
300 units in 3 mL
300 units in 3 mL
300 units in 3 mL
U-100: 300 units in 3 mL; U-200: 600 units in 3 mL
300 units in 3 mL
Not applicable
Dosage form
Vial or pen
Vial or pen
Vial or pen
U-100: vial or pen; U-200: pen only
Vial
Inhaled
Meal timing
Subcutaneous (SC): at start of meal, 20 min after meal
SC: 5 to 10 min before meals
SC: within 15 min before or 20 min after starting meal
SC: up to 15 min before or immediately after a meal
SC: 30 min before meal
Inhaled at start of meal
Older (Intermediate-Acting) Types of Insulin The older types of insulin include regular insulin (Humulin R and Novolin R), and neutral protamine Hagedorn (or NPH) insulin, which is also known as isophane insulin. These types are mostly been replaced by the newer long-acting and rapid-acting insulins, which offer effects that are closer to the functions of a normal human pancreas. The regular insulins are used as a bolus insulin but have largely been replaced by the rapid-acting insulins due to their faster coverage and offset, which helps reduce chances of hypoglycemia. Regular insulins also take longer to become effective, and should be given 30 minutes before meals. Between regular and rapid-acting insulins, a one-to-one ratio is used. The NPH form of insulin has a shorter duration of action, and is usually dosed twice per day for type 1 diabetes. It is used as a basal insulin, but has a peak that may predispose patients to hypoglycemia. Twice-daily NPH requires a 20% reduction in dose when switching to a long-acting insulin. Situations in which older insulins are required include: during pregnancy and in individuals taking steroids such as prednisone. In such situations, the “peak” of NPH may be beneficial. Since NPH insulin has been available for a long time, there is more accumulated pregnancy safety data. The longer duration of regular insulin may also be better for patients with slowed stomach emptying or gastroparesis. Also, NPH is able to be mixed in a syringe with regular insulin or rapid-acting insulins. This is not commonly done today, but allows for two injections per day instead of multiple injections. This method usually does not offer close control of blood glucose, but it may help patients who cannot, or are not willing to administer more than two injections every day. Additionally, NPH and regular insulins are available in over-the-counter, inexpensive vials. The older, intermediate-acting insulins are compared in Table 2.5.
Premixed Insulins Premixed insulins are also available in various formulations. Novolog mix 70/30, for example, contains 70% insulin aspart protamine and 30% insulin aspart. Twice-daily dosing is offered, instead of the usual four-per-day injections
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TABLE 2.5 Older, Intermediate-Acting Insulins Property
Humulin N, Novolin N
Humulin R, U-500
Onset
1 2h
30 min
Duration of action
16 24 h
12 24 h
Concentration
100 units per mL
500 units per mL
Expiration
Humulin N vial: 31 days; Novolin N vial: 42 days; Humulin N Kwikpen: 14 days
Vials: 40 days; pens: 28 days
Dosage form
Vial or Kwikpen
Vial or pen
Pen dial
1 unit
5 units
Meal timing
Taken without regard to meals
30 min before meals
Typical dosing
1 2 times per day alone, or mixed with rapid- or short-acting insulin
3 4 times per day before meals or snacks
used in basal or bolus regimens with one long-acting injection and three mealtime injections. Most often, these are not given at lunch since the peak from the protamine helps cover the lunchtime meal. Such insulin formulations are not as flexible. When a dose is adjusted because it was premixed, both the intermediate-acting and mealtime insulin must be adjusted simultaneously. Tight glycemic control is usually hard to achieve without significant hypoglycemia occurring. Other examples of premixed insulins include Humalog mix 75/25, Humulin 70/30, Humalog mix 50/50, and Humulin 50/50. They all have an intermediate-acting protamine component that allows the insulin to last longer. This is mixed with either regular insulin (Humulin or Novolin), or rapid-acting insulin (Novolog or Humalog). Overall, premixed insulins are good for patients needing an easier regimen, or who have problems adhering to their injections. With these formulations, patients must eat on a regular schedule, and avoid skipping meals or snacks, in order to reduce hypoglycemia.
U-500 Insulin The form known as Humulin U-500 is usually used only for patients with serious insulin resistance, and who are taking more than 200 units of insulin every day. When the body can no longer respond to insulin and glucose storage at safe levels, higher blood glucose results, and insulin resistance occurs. Therefore, U-500 insulin is commonly used for type 2 diabetics. It is also possible for type 1 diabetics to develop insulin resistance—primarily if they are obese. This type of insulin is usually dosed 2 4 times daily, before meals. It functions closely to the intermediate-acting insulins, and should be given 30 minutes before meals or snacks. Since U-500 insulin is five times more potent than other forms, there is a long history of dosing errors. Over time, patients often used U-100 syringes, resulting in much confusion, since just five units in a U-100 syringe is actually 25 units of U-500 insulin. Today, there are dedicated U-500 syringes and insulin pens. They have greatly reduced dosing errors of this type of insulin.
THE BRAIN, GLUCOSE, AND INSULIN Brain cells are somewhat unique because they do not need insulin for glucose entry. Most other cells do require insulin for this purpose. Brain cells also do not use free fatty acids or amino acids for energy. Instead, they only use glucose or glycogen to meet energy demands and power cellular functions. Therefore, gluconeogenesis in the liver is very important. Between meals, if glucose were not produced by the liver, the brain would not have a usable source of energy. The brain is the most energy-demanding organ in the body, using 50% of all sugar energy. Learning, memory, and thinking are closely linked to glucose levels, and how efficiently the brain is able to use glucose. When glucose in the brain is insufficient, neurotransmitters are not produced and communication between the neurons breaks down. Hypoglycemia can also lead to a loss of energy for brain function. This is linked to poor attention and cognitive function. However, too much glucose is also harmful to brain function, and is linked to memory and cognitive deficiencies. High glucose levels can actually cause the brain to atrophy or shrink, and lead to small-vessel disease that restricts blood flow. This leads to cognitive difficulties, and possibly, vascular dementia.
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Epidemiology of Diabetes
Insulin is not required for glucose transport into most brain cells. However, insulin acts as a neuroregulatory peptide. Insulin is believed to be essential for regulating when we eat, and for monitoring available stores of energy. Insulin has functional effects in many different areas of the brain. For example, it affects areas of the hippocampus that are used in the recognition of rewards, and in areas less specific for cognitive and memory functions. Insulin easily crosses the blood brain barrier and is concentrated in all CNS tissues. Impaired systemic insulin delivery to the cerebrospinal fluid could contribute to changes in feeding behaviors, dysregulated hepatic and adipose tissue metabolism, and increased risks for cognitive decline.
SECRETION OF SOMATOSTATIN Somatostatin, from the delta cells of the islets of Langerhans, is also released by the hypothalamus. Somatostatin from the pancreas only has a slight effect upon growth hormone release from the pituitary. It helps to control metabolism by inhibiting secretion of insulin and glucagon. However, somatostatin from the hypothalamus more strongly inhibits growth hormone release from the anterior pituitary. Somatostatin is released in the blood, synaptic clefts, and intercellular spaces. When released from neurons, it acts as a hypophysiotropic hormone as well as a neurotransmitter or neuromodulator. It may also act as a paracrine in the intercellular spaces. In the pancreatic islets, somatostatin influences the activities of nearby alpha and beta cells. The delta cells of the gastrointestinal tract release somatostatin into the bloodstream, intercellular spaces, and the gastric and intestinal lumen. In the lumen, somatostatin may affect other endocrine and nonendocrine cells, actually of the mucous membranes.
COUNTER-REGULATORY HORMONES There are other hormones that affect the blood glucose levels. These include catecholamines, growth hormone, and the glucocorticoids. Along with glucagon, these counter-regulatory hormones oppose the storage actions of insulin. This helps regulate blood glucose levels during fasting, exercise, and whenever glucose intake is limited or stores of glucose are depleted.
Catecholamines Epinephrine is a catecholamine. It aids in maintaining blood glucose levels when stress is present. Epinephrine strongly stimulates glycogenolysis in the liver. This causes significant amounts of glucose to be released into the circulation. Additionally, epinephrine inhibits insulin release from the beta cells. This decreases movement of glucose into muscle cells. Simultaneously, it increases the breakdown of glycogen stores in muscles. Though glucose from these stores cannot be released into the circulation, mobilization of this glycogen for use by the muscles will conserve blood glucose to be used by the brain, nervous system, and other tissues. Epinephrine also causes direct lipolysis of adipose cells. This increases mobilization of fatty acids to be used for energy. When hypoglycemia develops, the effect of elevating blood glucose by epinephrine acts as an important part of homeostasis.
Growth Hormone Growth hormone has many metabolic effects. Throughout the body, it increases protein synthesis. It also antagonizes insulin and mobilizes fatty acids from the adipose tissues. Growth hormone increases blood glucose levels by decreasing cellular uptake and glucose use. When blood glucose has increased, additional insulin secretion is stimulated by the beta cells. Normally growth hormone secretion is inhibited by insulin as well as the increased levels of blood glucose. When fasting, as there is reduced blood glucose levels and secretion of insulin, the levels of growth hormone increase. Its levels are also increased by exercise, and stressors such as anesthesia, fever, or trauma. In conditions such as acromegaly, in which there is chronic hypersecretion of growth hormone, there is a likelihood of glucose intolerance and diabetes mellitus developing. In diabetics, if even slight elevations of growth hormone occur during stress or childhood growth periods, a wide range of metabolic abnormalities may occur. This can occur even with adequate treatment with insulin.
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Glucocorticoid Hormones Glucocorticoid hormones are synthesized in the adrenal cortex, similar to other corticosteroid hormones. The glucocorticoid hormones are essential for survival, when fasting or during starvation. They encourage gluconeogenesis in the liver. As much as 6 10 times more hepatic glucose can be produced. These hormones also slightly decrease the use of glucose by the body tissues. Several steroid hormones have glucocorticoid activity. The most essential of these is cortisol, which makes up about 95% of all glucocorticoid activities. Physical or emotional stressors cause immediate increases in secretion of adrenocorticotropic hormone by the anterior pituitary gland. Within a few minutes, this is followed by highly increased cortisol secretion from the adrenal gland. Cortisol secretion is greatly stimulated by hypoglycemia. If a person is predisposed, chronic elevation of glucocorticoid hormones may cause hyperglycemia, and development of diabetes mellitus. In diabetics, slight increases in cortisol and seriously harm homeostasis.
FURTHER READING [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12]
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AACE. ACE glucose monitoring consensus statement. Endocr Pract 2016;22(2):239. AADE. The art & science of diabetes self-management education desk reference. 4th ed AADE; 2017. Beta Bionics. Available at: https://www.betabionics.org/. Centers for Disease Control and Prevention. National diabetes statistics report. Atlanta, GA: US Department of Health and Human Services; 2017. Available from: https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf. Children and adolescents. Diabetes Care 2017;40(Suppl. 1):S105 S113. doi: 10.2337/dc17-S015. Classification and diagnosis of diabetes. Diabetes Care 2017;40(Suppl. 1):S11 S24. doi: 10.2337/dc17-S005. Dexcom G4 Professional CGM. Available at: https://provider.dexcom.com/products/professional-cgm. Dexcom G5. Available at: https://www.dexcom.com/g5-mobile-cgm. https://www.endocrineweb.com/endocrinology/overview-pancreas. Fiasp Product Information. Available at: https://www.fiasppro.com/. Freestyle Libre Professional CGM. Available at: https://www.myfreestyle.com/provider/freestyle-libre-pro-product. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm 2017 executive summary. Endocr Pract 2017;23 (2):207 38. Available from: https://doi.org/10.4158/EP161682.CS. Glucagon directions for use. Available at: http://pi.lilly.com/us/rglucagon-ppi.pdf. Glycemic targets. Diabetes Care 2017;40(Suppl. 1):S48 S56. doi: 10.2337/dc17-S009. Humulin U-500 Package Insert. Available at: http://pi.lilly.com/us/humulin-r-u500-pi.pdf. Klonoff DC, Ahn D, Drincic A. Continuous glucose monitoring: A review of the technology and clinical use. Diabetes Res Clin Pract 2017;133:178 92. Available from: https://doi.org/10.1016/j.diabres.2017.08.005. Lifestyle management. Diabetes Care 2017;40(Suppl. 1):S33 S43. doi: 10.2337/dc17-S007. McCrea DL. A primer on insulin pump therapy for health care providers. Nurs Clin North Am 2017;52(4):553 64. Available from: https://doi. org/10.1016/j.cnur.2017.07.005. Microvascular complications and foot care. Diabetes Care 2017;40(Suppl. 1):S88 S98. doi: 10.2337/dc17-S013. Millstein R, Becerra NM, Shubrook JH. Insulin pumps: beyond basal-bolus. Cleve Clin J Med 2015;82(12):835 42. Available from: https:// doi.org/10.3949/ccjm.82a.14127. Nyenwe EA, Kitabchi AE. The evolution of diabetic ketoacidosis: an update of its etiology, pathogenesis and management. Metabolism 2016;65(4):507 21. Available from: https://doi.org/10.1016/j.metabol.2015.12.007. Omnipod Insulin Pump. Available at: https://www.myomnipod.com/. Petrie JR, Peters AL, Bergenstal RM, Holl RW, Fleming GA, Heinemann L. Improving the clinical value and utility of CGM systems: issues and recommendations. Diabetologia 2017;60(12):2319 28. Available from: https://doi.org/10.1007/s00125-017-4463-4. Pharmacologic approaches to glycemic treatment. Diabetes Care 2017;40(Suppl. 1), S64 S74. PL Detail-Document, Comparison of Insulins and Injectable Diabetes Meds. Pharmacist’s Letter/Prescriber’s Letter. March 2015. SymlinPen Product Information. Available at: https://www.symlin.com/. www.vivo.colostate.edu/hbooks/pathphys/endocrine/pancreas/insulin.html.