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The pancreas
PHYSIOLOGY
The pancreas
Learning objectives
Jennifer E Cade
After reading this article you should be able to describe: C the functional anatomy of the pancreas C how the endocrine pancreas regulates metabolism and glucose homeostasis C the role the exocrine pancreas plays in digestion
James Hanison
Abstract The pancreas plays a vital role in coordinating and regulating digestion and nutrient metabolism, and does so via endocrine and exocrine processes. Insulin and glucagon are produced within the endocrine pancreas to not only achieve glucose homeostasis, but regulate protein and fat metabolism. Enzymes and zymogens are secreted in alkaline pancreatic fluid to aid digestive function. This article looks at how the pancreas achieves such precise synthetic and secretory functions, and reviews the physiology of the secreted hormones and enzymes.
Pancreatic d cells secrete somatostatin and comprise less than 10% of islet cells. Pancreatic F cells, which secrete pancreatic polypeptide, account for less than 5%. Pancreatic ε cells produce ghrelin, and account for less than 1% of islet cells. Despite comprising only 2% of the total mass of the pancreas, the islets receive around 10% of the pancreatic blood supply, allowing their secreted hormones ready access to the circulation. Blood from the islets drains into the hepatic portal vein. Secretions of islet cell hormones are under tight regulatory control via both neurohumoral and paracrine communication. Islet cells receive both sympathetic and parasympathetic innervation, with tight homeostatic control over the smooth muscle cells of islet blood vessels, regulating local blood flow and therefore hormone release. Cholinergic stimulation augments insulin secretion, and adrenergic stimulation has either a stimulatory of inhibitory effect, depending on whether b-adrenergic or a-adrenergic stimulation dominates. Paracrine, or cell-to-cell regulation, occurs due to the arrangement of both the cells within the islet, and the distribution of the islets alongside the exocrine acinus. The cells within a given islet can influence the secretion of other cells within that islet. Furthermore hormones secreted by the islets of Langerhans are directly transported in the blood to the acinar cells, allowing local regulatory control of both endocrine and exocrine synthesis and secretion. Within each islet, cells are arranged with an abundance of b cells nearest to the centre of the islet, with a cells and d cells more abundant at the periphery. This feature enables humoral communication to occur between cells, as blood enters at the centre of the islet and courses outwards towards the periphery, carrying secreted hormonal products with it. This allows the insulin secreted by b cells to exert influence over the secretions of the a cells.
Keywords Cholecystokinin; endocrinology; glucagon; homeostasis; insulin Royal College of Anaesthetists CPD Matrix: 1A01
The pancreas is a complex organ comprised of both exocrine glands (secreting digestive enzymes into the intestinal lumen) and endocrine glands, called the islets of Langerhans, which secrete hormones directly into the blood stream. Although only 10 cm in length and weighing about 100 g, the pancreas is capable of secreting around 1500 ml of pancreatic fluid per day. It receives a rich blood supply from branches of the coeliac and superior mesenteric artery, and venous drainage is via the portal vein. In addition it is densely innervated by both sympathetic fibres (from the splanchnic nerves), parasympathetic fibres (via the vagus nerve), and peptidergic neurones (which stimulate peptide and amine release).
Endocrine pancreas Functional anatomy The normal human pancreas contains 1e2 million islets, each of which is an aggregate of tens to thousands of cells. The islets are ovoid in shape and are scattered throughout the pancreas, although are more numerous in the pancreatic tail. There are now known to be at least five major secretory cell types in each islet of Langerhans e a, b, d, F and ε cells (Table 1). Pancreatic a cells principally secrete glucagon, and comprise approximately 35% of islet cells. Pancreatic b cells are most numerous and make up around 55% of islet cells. They produce insulin and amylin (or islet amyloid polypeptide (IAPP)).
Insulin Insulin is responsible for maintaining serum glucose between 4 and 8 mmol/litre during periods of feeding and fasting. It regulates lipid and protein metabolism, yet also regulates amino acid and electrolyte transport, and growth. Its net effect is ultimately anabolic, by way of storage of carbohydrate, fat and protein. Insulin is encoded by a single gene on the short arm of chromosome 11, and is synthesized and secreted in response to b cells being exposed to glucose. It is first synthesized as a preprohormone protein called preproinsulin in the rough endoplasmic reticulum of the pancreatic b cells. Successive cleaving processes then occur to first produce proinsulin, before being transported to the Golgi apparatus where it is again cleaved by
Jennifer E Cade BMBS BMedSci FRCA is a Senior Anaesthetic Registrar at St Mary’s Hospital, Central Manchester Foundation Trust, Manchester, UK. Conflicts of interest: none declared. James Hanison BSc MBChB FRCA FFICM PGCert is a Consultant in Anaesthetics and Intensive Care Medicine at Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester, UK. Conflicts of interest: none declared.
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
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PHYSIOLOGY
glucose metabolism) to glucose-6-phosphate, which in turn undergoes glycolysis to produce adenosine triphosphate (ATP). The b cell is rich in ATP-dependent potassium channels, which close in response to a rise in ATP, resulting in membrane depolarization. Depolarization activates voltage-gated calcium channels leading to an influx of calcium into the cell. This causes margination of secretory granules, and exocytosis of insulin and C-peptide into the blood stream (Figure 2). This process characterizes the ‘first phase’ of insulin release, where insulin is detected in the circulation within 3e5 minutes of glucose administration. Loss of this first phase is one of the earliest metabolic defects found in the development of type 2 diabetes mellitus (T2DM). The second, longer lasting phase, reaches a plateau at 2e3 hours. Characterized by dose-dependent mobilization of intracellular granules, it persists as long as the plasma glucose level remains elevated. The amino acids arginine and leucine also stimulate insulin release. Uptake in this case is via a cationic amino-acid transporter (CAT), leading to membrane depolarization and calcium influx. Other modulators of secretion stimulate different intracellular signalling pathways. Glucagon, which stimulates insulin release, acts via adenylyl cyclase, raising cyclic AMP (cAMP) levels, stimulating protein kinase A and causing degranulation and insulin release. Conversely, somatostatin, which inhibits insulin release, inhibits adenylyl cyclase. The incretin effect further modulates insulin release from pancreatic b cells. Enteric factors known as incretins are peptides released by gut mucosa in response to the presence of nutrients in the gut lumen, and are potent insulin secretagogues. Gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released by duodenal and jejunal K and L cells respectively, and enhance insulin secretion by activation of adenylyl cyclase and cAMP, as above. This explains why orally administered glucose has been shown to stimulate insulin secretion by 25% more than the equivalent intravenously administered dose.
Products of pancreatic islet cells Cell Proportion Hormone secreted Distribution type of islet cells a
35%
Glucagon
b
55%
d F
<10% <5%
ε
<1%
Insulin, amylin, C-peptide Somatostatin Pancreatic polypeptide Ghrelin
Throughout pancreas, abundance in body and tail Throughout pancreas, numerous in the centre Throughout pancreas Uncinate process Sparse
Table 1
proteases to form insulin and C-peptide. The resulting insulin molecule has two polypeptide chains linked by two disulphide bridges (Figure 1). Insulin, along with equimolar concentration of C-peptide and some remaining proinsulin, is then packaged into secretory granules ready for release into the portal blood. Insulin has a half-life of 4 minutes and is rapidly metabolized by the liver and kidneys. In contrast, C-peptide has a half-life of 30 minutes and is excreted unchanged by the kidneys, making it a useful biomarker of endogenous insulin secretion. Insulin is released from b cells by two mechanisms: stimulated and unstimulated secretion. Unstimulated or basal secretion occurs every 6e8 minutes. Stimulated release occurs in response to several stimuli, the principal stimulus being extracellular glucose. Other stimuli such as galactose, mannose, acetylcholine (Ach) and some amino acids (especially arginine and leucine) can also act as secretagogues. In response to a rise in serum glucose, glucose is taken up and metabolized by b cells. The main glucose transporter on b cells is GLUT-2, although GLUT-1 and GLUT-3 expression have recently been recognized. Once intracellular, the glucose is phosphorylated by the enzyme glucokinase (the rate-limiting step of islet
Synthesis of insulin Preproinsulin
Proinsulin NH3
D chain
Insulin
+
NH3+
Signal sequence
Proteolysis
Proteolysis
C chain
NH3+ NH3+
S
S S
S
S S
S
S S
S
S S
B chain COO–
COO–
COO– COO–
Signal sequence
C peptide
Figure 1
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PHYSIOLOGY
Regulation of glucagon and insulin secretion Cortisol Gastrin Glucose
Amino acids CCK Parasympathetic stimulation
+
Opioids GH, TRH, ACTH Fatty acids Glucose Glucagon GIP, VIP, GLP
+ + Paracrine mediators α-cell
β-cell
–
– Glucagon
Insulin
Ketone bodies Fatty acids Insulin Somatostatin GLP-1
Sympathetic stimulation Somatostatin
CCK, cholecystokinin; GH, growth hormone; TRH, thyroid-releasing hormone; ACTH, adrenocorticotrophic hormone; GIP, gastrointestinal peptide; VIP, vasoactive intestinal peptide; GLP, glucagon-like peptide; GLP-1, glucagon-like peptide-1.
Figure 2
The autonomic nervous system further modulates b cell activity. b-adrenergic stimulation augments islet insulin secretion, whereas a-adrenergic stimulation inhibits it. Thus noradrenaline and other synthetic a-adrenergic agonists suppress insulin release, both basally and in response to hyperglycaemia. In contrast, parasympathetic vagal stimulation releases ACh, which acts via muscarinic receptors to stimulate insulin release. Additionally ACh is also known to be released from pancreatic a cells, and acts as a paracrine signaller to release intracellular calcium via the phospholipase C-mediated pathway. During exercise insulin secretion is inhibited through a-adrenergic stimulation in order to prevent hypoglycaemia, and maintain availability of glucose and fatty acids to exercising muscle cells.
is inhibited. Glucagon also promotes hepatic fatty acid oxidation (via the carnitine acylcarnitine translocase (CAT) system) to generate ketone bodies (b-hydroxybutyric acid and acetoacetic acid), which exit the liver to be used as fuel by other body tissues. During fasting, when glucose levels drop, the action of glucagon in promoting ketogenesis is vitally important to maintain energy supply to the central nervous system, as the brain can use only ketone bodies and not fatty acids as fuel.
Effects of insulin and glucagon on metabolism
Hepatic Glycogen synthesis Glycogenolysis Gluconeogenesis Glycolysis Lipogenesis Fatty acid oxidation Protein catabolism Muscle Glycogen synthesis Glycogenolysis Glucose uptake Protein synthesis Adipose tissue Glucose uptake Lipolysis
Glucagon Glucagon is secreted by pancreatic a cells, and counteracts the effect of insulin to mobilize fuel stores and increase blood glucose concentration (Table 2). It is a 29 amino acid peptide, the precursor of which is proglucagon. Proglucagon is also synthesized in the gut, where it is processed differently to make GLP-1. Secretion from islet a cells is mainly in response to amino acids from protein ingestion, though glucagon’s main actions involve carbohydrate and lipid metabolism. Targeting hepatocytes, glucagon is released directly into the portal system and stimulates glycogenolysis, gluconeogenesis and ketogenesis. At physiological concentrations glucagon activates cAMP pathways in hepatocytes, to activate or deactivate enzyme kinases or phosphatases. This results in a rapid rise in glucose concentration due to glycogen breakdown, in tandem with a decrease in glycogen synthesis from glucose. Hepatic gluconeogenesis (from lactate, pyruvate and amino acids) is stimulated, while glycolysis
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Insulin
Glucagon
þ þ þ
þ þ þ þ
þ þ þ þ
þ
Table 2
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PHYSIOLOGY
have clinical potential in the management of today’s obesity epidemic.
Glucagon is inhibited by increased blood glucose concentrations as well as through paracrine interactions of insulin and somatostatin within the islet. Glucagon itself is a potent stimulator of a calls, hence the two hormones can be considered to have reciprocal actions. Table 2 summarizes the factors affecting glucagon and insulin release.
Exocrine pancreas Functional organization and anatomy The functional unit of the exocrine pancreas is formed by the acinus. This structure is a collection of wedge-shapes secretory cells (usually less than 100) that are organized in a round ‘berry’ shape with a central cavity within. These cells secrete fluid laden with proteins, zymogens (enzyme precursors) and enzymes that then drains from the central cavity to a duct. This is named an intercalated duct and is comprised of flattened cuboidal epithelial cells. The epithelial cells within the ducts play a key role in the production of pancreatic juice by the addition of bicarbonate and additional water to dilute and alkalinize the acinar secretions. Many acini and their associated intercalated ducts are organized macroscopically into larger lobules that are evident with the naked eye on gross inspection of the organ. This functional organization is achieved by the presence of bands of connective tissue separating the lobules. Each of these lobules has many intercalated ducts draining and uniting into a main intralobular duct with a typical cuboidal epithelium. These ducts then unite with ducts from other lobules to form interlobular ducts that are characterized by columnar epithelium. As ducts become larger, the presence of goblet cells increases and these produce mucin that hydrates and lubricates the pancreatic juice and has an immunological role in the gut by binding to pathogens. The interlobular ducts unite to form the main pancreatic duct, which typically unites with the common bile duct before draining into the duodenum. Approximately 1500 ml of fluid is secreted per day by the pancreas. The rate of secretion varies significantly during the day, with peak secretion levels associated with feeding.
Somatostatin Somatostatin is an inhibitory hormone secreted by islet d cells, as well as being secreted by the hypothalamus and by d cells in the gastrointestinal tract. It has two active forms. The pancreatic d cells produce prosomatostatin, which is cleaved to form a 14 amino-acid peptide (SS14). Somatostatin is also produced by intestinal wall D cells, however the molecular structure here is 28 amino-acids in length (SS28). Somatostatin is a potent inhibitor of insulin, glucagon and pancreatic polypeptide, amongst others. It suppresses the release of pancreatic hormones by paracrine regulation, as well as travelling to target organs including the anterior pituitary to inhibit growth hormone, and the gastrointestinal tract to inhibit gastrointestinal hormone activity and decrease gut motility. Its broad inhibitory effects make pharmacological somatostatin analogues (octreotide) useful in treating a range of neuroendocrine neoplasias, including those that produce insulin (insulinomas), growth hormone (acromegaly), and serotonin (carcinoid). Recently a multisomatostatin receptor analogue has been marketed to reduce the pancreatic leak complications following pancreatic surgery. Islet amyloid polypeptide (IAPP, or amylin) Amylin is co-secreted alongside insulin by the pancreatic b cells, and contributes towards glycaemic regulation by decreasing the rate of gastric emptying and slowing down the rate of glucose appearance in the blood after eating, thus smoothing out postprandial spikes in blood glucose. Amylin is related to the development of T2DM, where defects in the processing of the pro-polypeptide cause amyloid to accumulate. This impairs b-cell activity and can even induce apoptosis in the insulin-producing b-cells.
Acinar cell function The function of the acinar cell is largely one of protein synthesis. These proteins are the enzymes and zymogens in the pancreatic juice that ultimately will aid in breaking down complex molecules within the gut lumen to assist in digestion. As such, the cells are characterized by large quantities of rough endoplasmic reticulum and numerous granules that have budded off the Golgi apparatus and collected at the apical pole of the cell ready for secretion. These granules contain the proteins involved in digestion that are protected from the rest of the cell and stored until the cell receives a trigger to degranulate and expel their contents into the lumen of the acinus. The acinar cells also secrete chloride ions via secondary active transport into the lumen of the acinus. Sodium ions and water follow the chloride ions resulting in overall secretion of sodium chloride and water into the acinus, which contributes to the overall pancreatic secretions.
Pancreatic polypeptide Produced by islet F cells, pancreatic polypeptide production is stimulated in fasting and hypoglycaemic states, as well as after a protein meal. Its role is thought to be in self-regulating pancreatic secretory activities, yet its precise activity is not completely understood. Levels increase in conditions of starvation such as anorexia nervosa, and decrease in states of satiety or overfeeding. Ghrelin Ghrelin, known as the ‘hunger hormone’, is produced by pancreatic ε cells and acts as a neuropeptide at the hypothalamus. When the stomach is empty ghrelin is secreted, and as the stomach distends with food, secretion stops. It acts on the hypothalamus to increase hunger and increase gastric secretion and motility in preparation for the gastrointestinal tract to receive food. Given that exogenously administered ghrelin can cross the bloodebrain barrier, it is hoped that this will prove to
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Regulation of acinar cell function The acinar cells secrete at a constant rate in the absence of any stimulation, but can increase their secretion in response to several stimuli, both neuronal and hormonal. They secrete numerous proteins (Table 3). Many of these enzymes are secreted as
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PHYSIOLOGY
Acinar proteins Enzyme or zymogen (activated enzyme)
Activating enzyme
Substrate
Mechanism of action
Trypsinogen (trypsin) Chymotrypsinogen (chymotrypsin) Proelastase (elastase) Procarboxypeptidase A (carboxypeptidase A) Procarboxypeptidase B (carboxypeptidase B) Procolipase (colipase) Pancreatic lipase Cholesteryl ester hydrolase Pancreatic a-amylase Ribonuclease Deoxyribonuclease Prophospholipase A (phospholipase A)
Enteropeptidase Trypsin Trypsin Trypsin Trypsin Trypsin N/A N/A ClN/A N/A Trypsin
Proteins Proteins Elastin Proteins Proteins Triglycerides Triglycerides Cholesteryl esters Starch RNA DNA Phospholipids
Endopeptidase Endopeptidase Endopeptidase Exopeptidase Exopeptidase Binds lipase to lipid Cleaves triglyceride to glycerol and fatty acid Cholesterol Hydrolyses starch to short-chain sugars Cleaves RNA into nucleotides Cleaves DNA into nucleotides Cleaves phospholipids into fatty acids and lysophospholipids
Table 3
bicarbonate ions into the lumen of the duct resulting in net secretion of sodium bicarbonate and water into the duct. After they have been exchanged for bicarbonate, chloride ions then leave the cell to reengage with the antiporter via chloride channels expressed in the apical membrane of the ductal cells. These are of clinical importance as the chloride channels include the cystic fibrosis transmembrane conductance regulator. Defects in this transmembrane protein give rise to the disease cystic fibrosis. The inability to remain permeable to chloride ions prevents the extrusion of bicarbonate and water and this results in excessively thick pancreatic secretions in cystic fibrosis.
precursors that are only activated in the small bowel, this reduces the risk of autodigestion within the pancreas. This risk is further reduced by the presence of a protein that inhibits the main protease within the granules called pancreatic trypsin inhibitor. The pancreas is richly invested in sympathetic and parasympathetic nerves that convey afferent fibres which modulate secretion and efferent fibres that are involved in nociception. The principle neurotransmitter acting on the acinar cell is acetylcholine that is secreted by parasympathetic nerve terminals and binds to the muscarinic M3 receptor. Activation of the M3 receptor on the basolateral membrane of the acinar cell increases secretion of enzyme-containing vesicles, water and electrolytes. This reflex is stimulated by a variety of factors including the sight or smell of food. The hormone cholecystokinin (CCK) stimulates acinar cell activity and secretion through binding of the cell surface receptors present on the basolateral membrane of the acinar cell: CCK1 and CCK2. These receptors may also be activated by binding to gastrin. Cholecystokinin is released by neuroendocrine cells (I cells) within the small bowel in response to the presence of food. Other hormones also exert a direct secretagogue effect upon acinar cells, such as secretin and vasoactive intestinal polypeptide (VIP) which bind to associated receptors on the acinar cell membrane.
Regulation of ductal cell function The ductal cells are also subject to neurological and hormonal control. Similar to acinar cells, the ductal cells are also stimulated to upregulate secretion upon parasympathetic activity. This is also mediated by stimulation of acetylcholine binding to M3 receptors expressed on the cell surface. The predominant hormonal influence is the binding of secretin to secretin receptors expressed on the basolateral membrane of the ductal cells. Binding of secretin triggers a greater volume of sodium bicarbonate-rich fluid to be extruded from the cells. Secretin is secreted by neuroendocrine cells (S cells) within the small bowel in response to the presence of acidic stomach contents entering the duodenum. Secretion is also stimulated by gastrin-releasing peptide and inhibited by substance P. Under secretagogue influence, the ductal cells increase the volume of fluid released and the pH of the fluid also, as they secrete relatively higher levels of sodium bicarbonate when stimulated. A
Duct cell function Duct cells differ from acinar cells insofar as their chief function is to secrete electrolytes and water, principally bicarbonate (HCO3) ions. As such, the cells are highly metabolically active and contain numerous mitochondria. They contain the enzyme carbonic anhydrase and produce carbonic acid intracellularly from water and carbon dioxide. Hydrogen ions are actively transported out of the cell from the basolateral membrane and the resulting in the intracellular accumulation of bicarbonate ions. The bicarbonate ions are then extruded into the duct via HCO3/Cl antiporter. Water and sodium ions follow the
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
FURTHER READING Barrett KE. Ganong’s review of medical physiology. 25th edn. New York: McGraw Hill- Lange, 2015. Boron WF, Boulpaep EL. Medical physiology. 3rd edn. Philadelphia: Elsevier-Saunders, 2016.
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Please cite this article in press as: Cade JE, Hanison J, The pancreas, Anaesthesia and intensive care medicine (2017), http://dx.doi.org/10.1016/ j.mpaic.2017.06.021
The pancreas
Learning objectives
Jennifer E Cade
After reading this article you should be able to describe: C the functional anatomy of the pancreas C how the endocrine pancreas regulates metabolism and glucose homeostasis C the role the exocrine pancreas plays in digestion
James Hanison
Abstract The pancreas plays a vital role in coordinating and regulating digestion and nutrient metabolism, and does so via endocrine and exocrine processes. Insulin and glucagon are produced within the endocrine pancreas to not only achieve glucose homeostasis, but regulate protein and fat metabolism. Enzymes and zymogens are secreted in alkaline pancreatic fluid to aid digestive function. This article looks at how the pancreas achieves such precise synthetic and secretory functions, and reviews the physiology of the secreted hormones and enzymes.
Pancreatic d cells secrete somatostatin and comprise less than 10% of islet cells. Pancreatic F cells, which secrete pancreatic polypeptide, account for less than 5%. Pancreatic ε cells produce ghrelin, and account for less than 1% of islet cells. Despite comprising only 2% of the total mass of the pancreas, the islets receive around 10% of the pancreatic blood supply, allowing their secreted hormones ready access to the circulation. Blood from the islets drains into the hepatic portal vein. Secretions of islet cell hormones are under tight regulatory control via both neurohumoral and paracrine communication. Islet cells receive both sympathetic and parasympathetic innervation, with tight homeostatic control over the smooth muscle cells of islet blood vessels, regulating local blood flow and therefore hormone release. Cholinergic stimulation augments insulin secretion, and adrenergic stimulation has either a stimulatory of inhibitory effect, depending on whether b-adrenergic or a-adrenergic stimulation dominates. Paracrine, or cell-to-cell regulation, occurs due to the arrangement of both the cells within the islet, and the distribution of the islets alongside the exocrine acinus. The cells within a given islet can influence the secretion of other cells within that islet. Furthermore hormones secreted by the islets of Langerhans are directly transported in the blood to the acinar cells, allowing local regulatory control of both endocrine and exocrine synthesis and secretion. Within each islet, cells are arranged with an abundance of b cells nearest to the centre of the islet, with a cells and d cells more abundant at the periphery. This feature enables humoral communication to occur between cells, as blood enters at the centre of the islet and courses outwards towards the periphery, carrying secreted hormonal products with it. This allows the insulin secreted by b cells to exert influence over the secretions of the a cells.
Keywords Cholecystokinin; endocrinology; glucagon; homeostasis; insulin Royal College of Anaesthetists CPD Matrix: 1A01
The pancreas is a complex organ comprised of both exocrine glands (secreting digestive enzymes into the intestinal lumen) and endocrine glands, called the islets of Langerhans, which secrete hormones directly into the blood stream. Although only 10 cm in length and weighing about 100 g, the pancreas is capable of secreting around 1500 ml of pancreatic fluid per day. It receives a rich blood supply from branches of the coeliac and superior mesenteric artery, and venous drainage is via the portal vein. In addition it is densely innervated by both sympathetic fibres (from the splanchnic nerves), parasympathetic fibres (via the vagus nerve), and peptidergic neurones (which stimulate peptide and amine release).
Endocrine pancreas Functional anatomy The normal human pancreas contains 1e2 million islets, each of which is an aggregate of tens to thousands of cells. The islets are ovoid in shape and are scattered throughout the pancreas, although are more numerous in the pancreatic tail. There are now known to be at least five major secretory cell types in each islet of Langerhans e a, b, d, F and ε cells (Table 1). Pancreatic a cells principally secrete glucagon, and comprise approximately 35% of islet cells. Pancreatic b cells are most numerous and make up around 55% of islet cells. They produce insulin and amylin (or islet amyloid polypeptide (IAPP)).
Insulin Insulin is responsible for maintaining serum glucose between 4 and 8 mmol/litre during periods of feeding and fasting. It regulates lipid and protein metabolism, yet also regulates amino acid and electrolyte transport, and growth. Its net effect is ultimately anabolic, by way of storage of carbohydrate, fat and protein. Insulin is encoded by a single gene on the short arm of chromosome 11, and is synthesized and secreted in response to b cells being exposed to glucose. It is first synthesized as a preprohormone protein called preproinsulin in the rough endoplasmic reticulum of the pancreatic b cells. Successive cleaving processes then occur to first produce proinsulin, before being transported to the Golgi apparatus where it is again cleaved by
Jennifer E Cade BMBS BMedSci FRCA is a Senior Anaesthetic Registrar at St Mary’s Hospital, Central Manchester Foundation Trust, Manchester, UK. Conflicts of interest: none declared. James Hanison BSc MBChB FRCA FFICM PGCert is a Consultant in Anaesthetics and Intensive Care Medicine at Manchester Royal Infirmary, Central Manchester Foundation Trust, Manchester, UK. Conflicts of interest: none declared.
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PHYSIOLOGY
glucose metabolism) to glucose-6-phosphate, which in turn undergoes glycolysis to produce adenosine triphosphate (ATP). The b cell is rich in ATP-dependent potassium channels, which close in response to a rise in ATP, resulting in membrane depolarization. Depolarization activates voltage-gated calcium channels leading to an influx of calcium into the cell. This causes margination of secretory granules, and exocytosis of insulin and C-peptide into the blood stream (Figure 2). This process characterizes the ‘first phase’ of insulin release, where insulin is detected in the circulation within 3e5 minutes of glucose administration. Loss of this first phase is one of the earliest metabolic defects found in the development of type 2 diabetes mellitus (T2DM). The second, longer lasting phase, reaches a plateau at 2e3 hours. Characterized by dose-dependent mobilization of intracellular granules, it persists as long as the plasma glucose level remains elevated. The amino acids arginine and leucine also stimulate insulin release. Uptake in this case is via a cationic amino-acid transporter (CAT), leading to membrane depolarization and calcium influx. Other modulators of secretion stimulate different intracellular signalling pathways. Glucagon, which stimulates insulin release, acts via adenylyl cyclase, raising cyclic AMP (cAMP) levels, stimulating protein kinase A and causing degranulation and insulin release. Conversely, somatostatin, which inhibits insulin release, inhibits adenylyl cyclase. The incretin effect further modulates insulin release from pancreatic b cells. Enteric factors known as incretins are peptides released by gut mucosa in response to the presence of nutrients in the gut lumen, and are potent insulin secretagogues. Gastric inhibitory peptide (GIP) and glucagon-like peptide-1 (GLP-1) are released by duodenal and jejunal K and L cells respectively, and enhance insulin secretion by activation of adenylyl cyclase and cAMP, as above. This explains why orally administered glucose has been shown to stimulate insulin secretion by 25% more than the equivalent intravenously administered dose.
Products of pancreatic islet cells Cell Proportion Hormone secreted Distribution type of islet cells a
35%
Glucagon
b
55%
d F
<10% <5%
ε
<1%
Insulin, amylin, C-peptide Somatostatin Pancreatic polypeptide Ghrelin
Throughout pancreas, abundance in body and tail Throughout pancreas, numerous in the centre Throughout pancreas Uncinate process Sparse
Table 1
proteases to form insulin and C-peptide. The resulting insulin molecule has two polypeptide chains linked by two disulphide bridges (Figure 1). Insulin, along with equimolar concentration of C-peptide and some remaining proinsulin, is then packaged into secretory granules ready for release into the portal blood. Insulin has a half-life of 4 minutes and is rapidly metabolized by the liver and kidneys. In contrast, C-peptide has a half-life of 30 minutes and is excreted unchanged by the kidneys, making it a useful biomarker of endogenous insulin secretion. Insulin is released from b cells by two mechanisms: stimulated and unstimulated secretion. Unstimulated or basal secretion occurs every 6e8 minutes. Stimulated release occurs in response to several stimuli, the principal stimulus being extracellular glucose. Other stimuli such as galactose, mannose, acetylcholine (Ach) and some amino acids (especially arginine and leucine) can also act as secretagogues. In response to a rise in serum glucose, glucose is taken up and metabolized by b cells. The main glucose transporter on b cells is GLUT-2, although GLUT-1 and GLUT-3 expression have recently been recognized. Once intracellular, the glucose is phosphorylated by the enzyme glucokinase (the rate-limiting step of islet
Synthesis of insulin Preproinsulin
Proinsulin NH3
D chain
Insulin
+
NH3+
Signal sequence
Proteolysis
Proteolysis
C chain
NH3+ NH3+
S
S S
S
S S
S
S S
S
S S
B chain COO–
COO–
COO– COO–
Signal sequence
C peptide
Figure 1
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PHYSIOLOGY
Regulation of glucagon and insulin secretion Cortisol Gastrin Glucose
Amino acids CCK Parasympathetic stimulation
+
Opioids GH, TRH, ACTH Fatty acids Glucose Glucagon GIP, VIP, GLP
+ + Paracrine mediators α-cell
β-cell
–
– Glucagon
Insulin
Ketone bodies Fatty acids Insulin Somatostatin GLP-1
Sympathetic stimulation Somatostatin
CCK, cholecystokinin; GH, growth hormone; TRH, thyroid-releasing hormone; ACTH, adrenocorticotrophic hormone; GIP, gastrointestinal peptide; VIP, vasoactive intestinal peptide; GLP, glucagon-like peptide; GLP-1, glucagon-like peptide-1.
Figure 2
The autonomic nervous system further modulates b cell activity. b-adrenergic stimulation augments islet insulin secretion, whereas a-adrenergic stimulation inhibits it. Thus noradrenaline and other synthetic a-adrenergic agonists suppress insulin release, both basally and in response to hyperglycaemia. In contrast, parasympathetic vagal stimulation releases ACh, which acts via muscarinic receptors to stimulate insulin release. Additionally ACh is also known to be released from pancreatic a cells, and acts as a paracrine signaller to release intracellular calcium via the phospholipase C-mediated pathway. During exercise insulin secretion is inhibited through a-adrenergic stimulation in order to prevent hypoglycaemia, and maintain availability of glucose and fatty acids to exercising muscle cells.
is inhibited. Glucagon also promotes hepatic fatty acid oxidation (via the carnitine acylcarnitine translocase (CAT) system) to generate ketone bodies (b-hydroxybutyric acid and acetoacetic acid), which exit the liver to be used as fuel by other body tissues. During fasting, when glucose levels drop, the action of glucagon in promoting ketogenesis is vitally important to maintain energy supply to the central nervous system, as the brain can use only ketone bodies and not fatty acids as fuel.
Effects of insulin and glucagon on metabolism
Hepatic Glycogen synthesis Glycogenolysis Gluconeogenesis Glycolysis Lipogenesis Fatty acid oxidation Protein catabolism Muscle Glycogen synthesis Glycogenolysis Glucose uptake Protein synthesis Adipose tissue Glucose uptake Lipolysis
Glucagon Glucagon is secreted by pancreatic a cells, and counteracts the effect of insulin to mobilize fuel stores and increase blood glucose concentration (Table 2). It is a 29 amino acid peptide, the precursor of which is proglucagon. Proglucagon is also synthesized in the gut, where it is processed differently to make GLP-1. Secretion from islet a cells is mainly in response to amino acids from protein ingestion, though glucagon’s main actions involve carbohydrate and lipid metabolism. Targeting hepatocytes, glucagon is released directly into the portal system and stimulates glycogenolysis, gluconeogenesis and ketogenesis. At physiological concentrations glucagon activates cAMP pathways in hepatocytes, to activate or deactivate enzyme kinases or phosphatases. This results in a rapid rise in glucose concentration due to glycogen breakdown, in tandem with a decrease in glycogen synthesis from glucose. Hepatic gluconeogenesis (from lactate, pyruvate and amino acids) is stimulated, while glycolysis
ANAESTHESIA AND INTENSIVE CARE MEDICINE --:-
Insulin
Glucagon
þ þ þ
þ þ þ þ
þ þ þ þ
þ
Table 2
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PHYSIOLOGY
have clinical potential in the management of today’s obesity epidemic.
Glucagon is inhibited by increased blood glucose concentrations as well as through paracrine interactions of insulin and somatostatin within the islet. Glucagon itself is a potent stimulator of a calls, hence the two hormones can be considered to have reciprocal actions. Table 2 summarizes the factors affecting glucagon and insulin release.
Exocrine pancreas Functional organization and anatomy The functional unit of the exocrine pancreas is formed by the acinus. This structure is a collection of wedge-shapes secretory cells (usually less than 100) that are organized in a round ‘berry’ shape with a central cavity within. These cells secrete fluid laden with proteins, zymogens (enzyme precursors) and enzymes that then drains from the central cavity to a duct. This is named an intercalated duct and is comprised of flattened cuboidal epithelial cells. The epithelial cells within the ducts play a key role in the production of pancreatic juice by the addition of bicarbonate and additional water to dilute and alkalinize the acinar secretions. Many acini and their associated intercalated ducts are organized macroscopically into larger lobules that are evident with the naked eye on gross inspection of the organ. This functional organization is achieved by the presence of bands of connective tissue separating the lobules. Each of these lobules has many intercalated ducts draining and uniting into a main intralobular duct with a typical cuboidal epithelium. These ducts then unite with ducts from other lobules to form interlobular ducts that are characterized by columnar epithelium. As ducts become larger, the presence of goblet cells increases and these produce mucin that hydrates and lubricates the pancreatic juice and has an immunological role in the gut by binding to pathogens. The interlobular ducts unite to form the main pancreatic duct, which typically unites with the common bile duct before draining into the duodenum. Approximately 1500 ml of fluid is secreted per day by the pancreas. The rate of secretion varies significantly during the day, with peak secretion levels associated with feeding.
Somatostatin Somatostatin is an inhibitory hormone secreted by islet d cells, as well as being secreted by the hypothalamus and by d cells in the gastrointestinal tract. It has two active forms. The pancreatic d cells produce prosomatostatin, which is cleaved to form a 14 amino-acid peptide (SS14). Somatostatin is also produced by intestinal wall D cells, however the molecular structure here is 28 amino-acids in length (SS28). Somatostatin is a potent inhibitor of insulin, glucagon and pancreatic polypeptide, amongst others. It suppresses the release of pancreatic hormones by paracrine regulation, as well as travelling to target organs including the anterior pituitary to inhibit growth hormone, and the gastrointestinal tract to inhibit gastrointestinal hormone activity and decrease gut motility. Its broad inhibitory effects make pharmacological somatostatin analogues (octreotide) useful in treating a range of neuroendocrine neoplasias, including those that produce insulin (insulinomas), growth hormone (acromegaly), and serotonin (carcinoid). Recently a multisomatostatin receptor analogue has been marketed to reduce the pancreatic leak complications following pancreatic surgery. Islet amyloid polypeptide (IAPP, or amylin) Amylin is co-secreted alongside insulin by the pancreatic b cells, and contributes towards glycaemic regulation by decreasing the rate of gastric emptying and slowing down the rate of glucose appearance in the blood after eating, thus smoothing out postprandial spikes in blood glucose. Amylin is related to the development of T2DM, where defects in the processing of the pro-polypeptide cause amyloid to accumulate. This impairs b-cell activity and can even induce apoptosis in the insulin-producing b-cells.
Acinar cell function The function of the acinar cell is largely one of protein synthesis. These proteins are the enzymes and zymogens in the pancreatic juice that ultimately will aid in breaking down complex molecules within the gut lumen to assist in digestion. As such, the cells are characterized by large quantities of rough endoplasmic reticulum and numerous granules that have budded off the Golgi apparatus and collected at the apical pole of the cell ready for secretion. These granules contain the proteins involved in digestion that are protected from the rest of the cell and stored until the cell receives a trigger to degranulate and expel their contents into the lumen of the acinus. The acinar cells also secrete chloride ions via secondary active transport into the lumen of the acinus. Sodium ions and water follow the chloride ions resulting in overall secretion of sodium chloride and water into the acinus, which contributes to the overall pancreatic secretions.
Pancreatic polypeptide Produced by islet F cells, pancreatic polypeptide production is stimulated in fasting and hypoglycaemic states, as well as after a protein meal. Its role is thought to be in self-regulating pancreatic secretory activities, yet its precise activity is not completely understood. Levels increase in conditions of starvation such as anorexia nervosa, and decrease in states of satiety or overfeeding. Ghrelin Ghrelin, known as the ‘hunger hormone’, is produced by pancreatic ε cells and acts as a neuropeptide at the hypothalamus. When the stomach is empty ghrelin is secreted, and as the stomach distends with food, secretion stops. It acts on the hypothalamus to increase hunger and increase gastric secretion and motility in preparation for the gastrointestinal tract to receive food. Given that exogenously administered ghrelin can cross the bloodebrain barrier, it is hoped that this will prove to
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Regulation of acinar cell function The acinar cells secrete at a constant rate in the absence of any stimulation, but can increase their secretion in response to several stimuli, both neuronal and hormonal. They secrete numerous proteins (Table 3). Many of these enzymes are secreted as
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PHYSIOLOGY
Acinar proteins Enzyme or zymogen (activated enzyme)
Activating enzyme
Substrate
Mechanism of action
Trypsinogen (trypsin) Chymotrypsinogen (chymotrypsin) Proelastase (elastase) Procarboxypeptidase A (carboxypeptidase A) Procarboxypeptidase B (carboxypeptidase B) Procolipase (colipase) Pancreatic lipase Cholesteryl ester hydrolase Pancreatic a-amylase Ribonuclease Deoxyribonuclease Prophospholipase A (phospholipase A)
Enteropeptidase Trypsin Trypsin Trypsin Trypsin Trypsin N/A N/A ClN/A N/A Trypsin
Proteins Proteins Elastin Proteins Proteins Triglycerides Triglycerides Cholesteryl esters Starch RNA DNA Phospholipids
Endopeptidase Endopeptidase Endopeptidase Exopeptidase Exopeptidase Binds lipase to lipid Cleaves triglyceride to glycerol and fatty acid Cholesterol Hydrolyses starch to short-chain sugars Cleaves RNA into nucleotides Cleaves DNA into nucleotides Cleaves phospholipids into fatty acids and lysophospholipids
Table 3
bicarbonate ions into the lumen of the duct resulting in net secretion of sodium bicarbonate and water into the duct. After they have been exchanged for bicarbonate, chloride ions then leave the cell to reengage with the antiporter via chloride channels expressed in the apical membrane of the ductal cells. These are of clinical importance as the chloride channels include the cystic fibrosis transmembrane conductance regulator. Defects in this transmembrane protein give rise to the disease cystic fibrosis. The inability to remain permeable to chloride ions prevents the extrusion of bicarbonate and water and this results in excessively thick pancreatic secretions in cystic fibrosis.
precursors that are only activated in the small bowel, this reduces the risk of autodigestion within the pancreas. This risk is further reduced by the presence of a protein that inhibits the main protease within the granules called pancreatic trypsin inhibitor. The pancreas is richly invested in sympathetic and parasympathetic nerves that convey afferent fibres which modulate secretion and efferent fibres that are involved in nociception. The principle neurotransmitter acting on the acinar cell is acetylcholine that is secreted by parasympathetic nerve terminals and binds to the muscarinic M3 receptor. Activation of the M3 receptor on the basolateral membrane of the acinar cell increases secretion of enzyme-containing vesicles, water and electrolytes. This reflex is stimulated by a variety of factors including the sight or smell of food. The hormone cholecystokinin (CCK) stimulates acinar cell activity and secretion through binding of the cell surface receptors present on the basolateral membrane of the acinar cell: CCK1 and CCK2. These receptors may also be activated by binding to gastrin. Cholecystokinin is released by neuroendocrine cells (I cells) within the small bowel in response to the presence of food. Other hormones also exert a direct secretagogue effect upon acinar cells, such as secretin and vasoactive intestinal polypeptide (VIP) which bind to associated receptors on the acinar cell membrane.
Regulation of ductal cell function The ductal cells are also subject to neurological and hormonal control. Similar to acinar cells, the ductal cells are also stimulated to upregulate secretion upon parasympathetic activity. This is also mediated by stimulation of acetylcholine binding to M3 receptors expressed on the cell surface. The predominant hormonal influence is the binding of secretin to secretin receptors expressed on the basolateral membrane of the ductal cells. Binding of secretin triggers a greater volume of sodium bicarbonate-rich fluid to be extruded from the cells. Secretin is secreted by neuroendocrine cells (S cells) within the small bowel in response to the presence of acidic stomach contents entering the duodenum. Secretion is also stimulated by gastrin-releasing peptide and inhibited by substance P. Under secretagogue influence, the ductal cells increase the volume of fluid released and the pH of the fluid also, as they secrete relatively higher levels of sodium bicarbonate when stimulated. A
Duct cell function Duct cells differ from acinar cells insofar as their chief function is to secrete electrolytes and water, principally bicarbonate (HCO3) ions. As such, the cells are highly metabolically active and contain numerous mitochondria. They contain the enzyme carbonic anhydrase and produce carbonic acid intracellularly from water and carbon dioxide. Hydrogen ions are actively transported out of the cell from the basolateral membrane and the resulting in the intracellular accumulation of bicarbonate ions. The bicarbonate ions are then extruded into the duct via HCO3/Cl antiporter. Water and sodium ions follow the
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FURTHER READING Barrett KE. Ganong’s review of medical physiology. 25th edn. New York: McGraw Hill- Lange, 2015. Boron WF, Boulpaep EL. Medical physiology. 3rd edn. Philadelphia: Elsevier-Saunders, 2016.
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