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The pancreas
Physiology
The pancreas
enzyme glucokinase (this is the rate-limiting step of islet glucose use). The resulting glucose-6-phosphate undergoes glycolysis to produce ATP. The ATP-sensitive K+ channels in the cell membrane close, causing membrane depolarization. This causes a calcium influx into the cell as calcium channels open. This leads to granule exocytosis and insulin (and c-peptide) release. Insulin and c-peptide are released into the circulation in equimolar amounts. This is used to differentiate hypoglycaemia caused by insulinoma from that caused by factitious exogenous insulin administration (genetically engineered human insulin contains very little c-peptide). Insulin circulates as unbound monomers, in contrast to its state before release from the secretory granule, when it forms insulin hexamers around a core of two zinc molecules (pharmaceutical preparations of insulin are based on crystalline zinc insulin). C-peptide has a plasma half-life of 30 minutes and is excreted unchanged by the kidneys. Its physiological action is unclear. In contrast, insulin has a half-life of 4 minutes and is degraded by the kidney and liver as well as by its target cells, where it is internalized with its receptor. Insulin receptors are found in varying concentrations on virtually all mammalian tissues (even largely insulin-unresponsive red blood cells possess about 70 receptors). In response to a glucose load, insulin secretion is biphasic: there is a sharp peak in plasma insulin levels after 1 minute, preformed insulin is released. After 5–10 minutes, there is a second, slower rise in plasma insulin levels which continues for as long as the glucose stimulus continues. Other nutrients such as amino acids also act as insulin secretagogues. Concentrations of ketoacids found in the fasting state can also promote insulin secretion. Factors affecting insulin release are shown in Figure 2. Interestingly, orally administered glucose induces a greater rise in plasma insulin concentrations than that induced by a similar amount of intravenous glucose. This increased responsiveness of insulin secretion is partly due to the production of incretin hormones such as glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). These hormones are secreted from the GI tract and enhance insulin secretion in response to a glucose load, through direct activation of G-protein-coupled receptors expressed on islet beta cells. This has led to interest in the use of GLP-1 analogues to treat type 2 diabetes. The first member of this class has recently been released as a subcutaneous injection; it induces significant weight loss as well as improving glycaemic control. Other drugs that increase GLP-1 concentrations have also recently been licensed; these are oral medications which inhibit dipeptidyl dipeptidase IV (DPP-IV), the enzyme that breaks down GLP-1. They are not associated with weight loss. After binding to its receptor at the cell surface, insulin causes rapid shifts in the fluxes in various metabolic pathways by the activation or deactivation of enzymes at critical steps. It also leads to alterations in gene expression (e.g. inducing glucokinase gene expression), thus reinforcing the metabolic shifts. Insulin promotes the storage of excess nutrients while inhibiting mobilization of endogenous substrates. It is required for the entry of glucose into most cells, particularly muscle (skeletal and cardiac) cells. The brain and red blood cells are exceptions in which glucose diffuses down a steep concentration gradient into these cells. Insulin also stimulates glycogen formation from
Garry D Tan
Abstract Although only the same weight as an apple, the pancreas fulfils endocrine and exocrine functions, and coordinates metabolism throughout the body. For example, insulin, perhaps the best-known pancreatic hormone, not only influences glucose metabolism but also helps to regulate protein and fat metabolism (thus explaining why diabetes is more than just a disease of sugar). The secretion of pancreatic hormones is highly coordinated to exert a concerted effect on the metabolism of a range of organs, from adipose tissue to muscle. This article looks at the physiology of each of the hormones and enzymes released by the pancreas, the factors influencing their secretion, and how their secretion is coordinated.
Keywords cholecystokinin; endocrinology; glucagon; homeostasis; insulin
The pancreas weighs 70–100 g, yet secretes 1000 g of pancreatic fluid daily. Most cells in the pancreas have an exocrine function, manufacturing digestive enzymes. A small proportion of pancreatic cells (about 1 million) are aggregated into small clusters (tens of cells to several thousand cells) and are scattered throughout the exocrine cells. These aggregations, the islets of Langerhans, contain at least four different cell types (Table 1) which are densely innervated with autonomic and peptidergic nerves. Despite accounting for only 2% of the mass of the pancreas, the islets receive 10% of the pancreatic blood flow.
Endocrine pancreas Insulin and c-peptide Insulin is a polypeptide consisting of two peptide chains, A and B, linked by two disulphide bridges (Figure 1). It is synthesized as preproinsulin, a precursor of insulin. Preproinsulin is cleaved in the endoplasmic reticulum to form proinsulin, which is itself cleaved in the Golgi apparatus to form insulin and c-peptide. These are stored in granules in the β-cell cytoplasm to await secretion. Glucose is one of a number of stimuli that can cause βcell degranulation and insulin release. In order for glucose to do this, it must first be metabolized; glucose enters the β-cell via the glucose transporter type 2 (GLUT-2) and is phosphorylated by the
Garry D Tan, MB (Manc), MRCP (UK), DTM&H (Lond), DPhil (Oxon) is an Associate Professor at the University of Nottingham, UK, and a Consultant Physician in Diabetes, Endocrinology and Metabolism at Derby hospitals, UK.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
424
© 2008 Elsevier Ltd. All rights reserved.
Physiology
Pancreatic islet cell secretion Cell type
Proportion of islet cells
Peptides secreted
Anatomical distribution
α
25%
Glucagon (GLP-1, GLP-2)
β γ PP
60–70% 5–15% 2%
Insulin, c-peptide (islet amyloid peptide) Somatostatin 12 and 14 Pancreatic polypeptide (PP) (and small amounts of gastrin)
Within islets throughout the pancreas with a preference for pancreatic tail and body Within islets throughout the pancreas Within islets throughout the pancreas Within islets throughout the pancreas with a preference for posterior portion of the head. Also found in acini
Table 1
glucose in muscle and liver while simultaneously inhibiting glycogen breakdown in the liver. This produces a reduction in the intracellular concentration of glucose in hepatocytes. Glucose diffuses into hepatocytes down this gradient through the GLUT-2 transporter. In contrast, insulin actively enhances glucose uptake into myocytes and adipocytes by inducing GLUT-4 expression (another specialized plasma membrane glucose protein transporter – the only one to be induced by insulin). In adipose tissue, insulin inhibits mobilization of intracellular triglycerides by suppressing hormone-sensitive lipase activity. Because of this, circulating non-esterified fatty acid (or free fatty acid) levels fall. The resulting fall in their delivery to the liver causes a decrease in their β-oxidation and hence a decrease in the production of ketone bodies. Only tiny concentrations of insulin are required to suppress the production of non-esterified fatty acids from adipose tissue (much lower concentrations than those required to induce glucose uptake by skeletal muscle). Thus, there needs to be a total absence of insulin (as in untreated type 1 diabetes) for there to be unregulated release of non-esterified
fatty acids from adipose tissue, which leads to ketone body production by the liver. If the concentration of ketones overwhelms the body’s acid–base buffering system, diabetic ketoacidosis, the hallmark of type 1 diabetes, results. Other effects of insulin include an anabolic effect on protein metabolism and the promotion of potassium, phosphate and magnesium uptake into muscle cells. The renal tubular reabsorption of potassium, phosphate and sodium is increased. The insulins of different animals differ slightly in their amino acid sequence but have identical biological actions. Glucagon Glucagon is a 29 amino acid peptide produced from proglucagon in α-cells. Proglucagon is also synthesized in the gut, where it is processed differently to produce GLP-1. The factors affecting glucagon secretion are shown in Figure 2; the stimulating and suppressing factors interact. For example, the suppression of glucagon production by high glucose concentrations is potentiated in the presence of insulin. Despite this, plasma glucagon levels vary less than plasma insulin levels. Glucagon promotes mobilization rather than storage of fuels, particularly glucose, maintaining normoglycaemia in the presence of an increased glucose demand. Glucagon binds to a hepatic membrane receptor and prompts a cascade of intracellular events involving cAMP as a second messenger, to activate or to deactivate a number of enzyme kinases or phosphatases. The net result is a rapid increase in glucose production from glycogen breakdown, in tandem with a decrease in glycogen synthesis from glucose. Similarly, hepatic gluconeogenesis (e.g. from lactate, pyruvate, amino acids such as alanine) is increased while glycolysis is decreased. Glucagon also diverts incoming non-esterified fatty acids from triglyceride synthesis to β-oxidation, leading to ketogenesis. Hepatic cholesterol synthesis is also suppressed as hepatic hydroxymethylglutaryl coenzyme A (CoA) reductase is inhibited by glucagon. Other actions of glucagon include activation of myocardial adenylate cyclase, increasing the cardiac output. It also causes natriuresis by inhibiting renal tubular resorption. In adipose tissue, glucagon increases hormone-sensitive lipase activity.
Insulin
C-peptide (connecting peptide) 30 amino acids (33–63) 63 65
1
6
S S 7 11
21 20
A chain
S
1
7
Insulin molecule
S
S
S
B chain
33
30
19
Somatostatin Somatostatin is produced as prosomatostatin, which is processed to produce a 14 amino acid peptide variety of somatostatin (SS14). Prosomatostatin is also produced in intestinal cells but is processed
Amino acids 30–33 and 63–65 are cleaved off during insulin formation Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
425
© 2008 Elsevier Ltd. All rights reserved.
Physiology
differently to form a 28 amino acid product (SS28). Within the islets, SS14 is a potent inhibitor of insulin, glucagon and pancreatic polypeptide secretion. SS28 decreases gastric, duodenal and gall-bladder motility and gastrointestinal secretions, thus enabling nutrient input to be coordinated with substrate disposal.
Factors affecting the endocrine response of the pancreas Factors affecting insulin secretion
Vagal stimulation
Glucagon GIP, CCK, VIP, GLP
+
+
Fatty acids Amino acids
GH TRH ACTH
+
+
Islet amyloid peptide Islet amyloid peptide (amylin) is a 37 amino acid peptide. It is regulated in a similar fashion to insulin. It accumulates in β−cells with age and its accumulation is further increased in type 2 diabetes mellitus. Its physiological role is unclear.
+
+
Glucose
Lowering of glucose levels
Opioids
β-cell
Insulin
Pancreatic polypeptide Pancreatic polypeptide is a 36 amino acid peptide secreted in response to feeding or hypoglycaemia. It is regulated by the autonomic nervous system. Its physiological role is unclear.
– Adrenaline Noradrenaline Somatostatin Sympathetic stimulation (α2-adrenoreceptors)
Coordination of insulin and glucagon action The pancreatic endocrine products act in concert to regulate the metabolism of glucose, non-esterified fatty acids, amino acids and other substrates (Table 2). As insulin and glucagon usually have antagonistic effects, the direction of substrate fluxes through the metabolic pathways is partly determined by the insulin–glucagon ratio. The usual molar ratio is 2:1, but it changes to 1:2 when mobilization of endogenous substrates is required, such as during fasting or prolonged exercise. The change in the ratio is caused by a simultaneous decrease in insulin secretion and an increase in glucagon secretion, promoting glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue, as well as increasing the flux of non-esterified fatty acids to the liver for β-oxidation. In the postprandial state, the insulin–glucagon ratio can rise to more than 10:1, primarily because of increased insulin secretion. This ensures increased glucose uptake along with oxidation and storage of glucose as glycogen in muscle and liver. Adipose
Factors affecting glucagon secretion Rise in glucose levels
Gastrin Vagal stimulation CCK, cortisol
Glucose
Ketone bodies
+
+
Amino acids
+ –
α-cell
Glucagon
– –
Fatty acids
–
–
GLP-1
Insulin somatostatin
Factors affecting somatostatin secretion
Glucagon Ketone bodies, NEFAs, + amino acids Glucose
Insulin
+
Effects of insulin and glucagon on metabolism
β-adrenergic Inhibition of and cholinergic glucagon secretion neurotransmitters CCK, GLP-1
+
+
+
δ-cell
Liver Glycogen synthesis Glycogenolysis Gluconeogenesis Glycolysis De novo lipogenesis Non-esterified fatty acid oxidation Protein catabolism Muscle Glycogen synthesis Glycogenolysis Glucose uptake Protein synthesis from amino acids Adipose tissue Glucose uptake Lipolysis
+ Opioids
Somatostatin
– –
Inhibition of insulin secretion
α-adrenergic neurotransmitters
ACTH, adrenocorticotrophic hormone; CCK, cholecystokinin; GH, growth hormone; GLP-1, glucagon-like peptide 1; GIP, gastrointestinal peptide; NEFA, non-esterified fatty acids; TRH, thyroid-releasing hormone; VIP, vasoactive intestinal peptide Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Insulin
Glucagon
+ − − + + − −
− + + − − + +
+ − + + + −
+
Table 2
426
© 2008 Elsevier Ltd. All rights reserved.
Physiology
tissue lipolysis by hormone-sensitive lipase is suppressed; postprandially, non-esterified fatty acids are not required. The endocrine activity of the pancreas is regulated by a variety of factors as well as glucose (Figure 2). For example, while parasympathetic activity stimulates insulin and glucagon secretion, sympathetic activity increases glucagon but decreases insulin secretion. The response of the pancreas depends on the predominating influence. For example, in minor injury, the glucose levels are raised and the insulin levels elevated appropriately. In contrast, in a more serious injury, when there is marked sympathetic activation and the circulating epinephrine levels are elevated, the insulin secretion is not as high as might be expected for that degree of hyperglycaemia.
Protein and carbohydrate breakdown occur in various parts of the gastrointestinal tract. In contrast, fat digestion occurs only in the small intestine as the pancreas is the only source of intestinal lipase (pancreatic lipase). Pancreatic amylase and lipase are secreted in their active forms. DNA and RNA are hydrolysed to their nucleotide monomers by pancreatic nucleases. Pancreatic exocrine secretion is regulated by a number of factors that are part of the response to food of the gastrointestinal tract. Acid from the stomach causes cells in the duodenal and upper jejunal mucosa to release secretin, which causes the secretion of pancreatic fluid and bicarbonate. Secretin causes virtually no pancreatic enzyme secretion. Stimuli such as long-chain fatty acids and peptides in the duodenum cause the release of cholecystokinin from the duodenum and upper jejunal mucosa. Cholecystokinin stimulates the acinar cells of the pancreas to increase digestive enzyme secretion. Both secretin and cholecystokinin pass from the upper gastrointestinal tract to the pancreas by the bloodstream. Vagal stimulation (and acetylcholine secretion by the enteric nervous system) causes the pancreas to secrete digestive enzymes (though few reach the gastrointestinal tract because vagal stimulation causes the pancreatic fluid secretion to ‘wash’ the enzymes along the pancreatic duct). Vagal stimulation can occur during the cephalic phase or as a result of the presence of food in the stomach. It is important to emphasize that these stimuli of pancreatic secretion usually occur in concert and exert a multiplicative effect on one another. The response of the pancreas to the combination of these factors is greater than the response to the sum. ◆
Exocrine pancreas The secretory units of the exocrine part of the pancreas are groups of cells, known as acini, surrounding the ends of small ducts. These ducts feed into a centrally located pancreatic duct which drains into the hepatic duct and from there into the duodenum. The acinar cells secrete a fluid rich in digestive enzymes, which can digest proteins, carbohydrates, nucleic acids and fat. In general, these digestive enzymes are secreted as proenzymes. The epithelial cells lining the ducts secrete water and bicarbonate ions. This alkaline pancreatic juice (pH 8) neutralizes the hydrochloric acid from the stomach and provides the optimal conditions for the digestive enzymes to function. The pancreatic juice contains the highly active pancreatic amylase which digests starch and glycogen in the small intestine to di- and tri-saccharides. Proteins are cleaved to smaller peptides by trypsin and chymotrypsin. Trypsin is the most abundant protease secreted. Carboxypolypeptidase further divides the peptide fragments into their constituent amino acids. Pancreatic proteases are secreted in an inactive form and are activated in the duodenum. Enterokinase, a membrane-bound intestinal enzyme, activates trypsinogen to its active form, trypsin. Trypsin activates procarboxypolypeptidase and chymotrypsinogen. To prevent pancreatic autodigestion, the acinar cells also produce ‘trypsin inhibitor’. This prevents activation of trypsinogen in the secretory cells and in the ducts of the pancreas.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Further reading Berne R, Levy M, eds. Physiology, 4th edn. St Louis, MO: Mosby, 1998: 822–48. Guyton A, Hall J, eds. Textbook of medical physiology, 10th edn. Philadelphia: W B Saunders, 2000. Pickup J, Williams G, eds. Textbook of diabetes, 2nd edn. Oxford: Blackwell Science, 1996.
427
© 2008 Elsevier Ltd. All rights reserved.
The pancreas
enzyme glucokinase (this is the rate-limiting step of islet glucose use). The resulting glucose-6-phosphate undergoes glycolysis to produce ATP. The ATP-sensitive K+ channels in the cell membrane close, causing membrane depolarization. This causes a calcium influx into the cell as calcium channels open. This leads to granule exocytosis and insulin (and c-peptide) release. Insulin and c-peptide are released into the circulation in equimolar amounts. This is used to differentiate hypoglycaemia caused by insulinoma from that caused by factitious exogenous insulin administration (genetically engineered human insulin contains very little c-peptide). Insulin circulates as unbound monomers, in contrast to its state before release from the secretory granule, when it forms insulin hexamers around a core of two zinc molecules (pharmaceutical preparations of insulin are based on crystalline zinc insulin). C-peptide has a plasma half-life of 30 minutes and is excreted unchanged by the kidneys. Its physiological action is unclear. In contrast, insulin has a half-life of 4 minutes and is degraded by the kidney and liver as well as by its target cells, where it is internalized with its receptor. Insulin receptors are found in varying concentrations on virtually all mammalian tissues (even largely insulin-unresponsive red blood cells possess about 70 receptors). In response to a glucose load, insulin secretion is biphasic: there is a sharp peak in plasma insulin levels after 1 minute, preformed insulin is released. After 5–10 minutes, there is a second, slower rise in plasma insulin levels which continues for as long as the glucose stimulus continues. Other nutrients such as amino acids also act as insulin secretagogues. Concentrations of ketoacids found in the fasting state can also promote insulin secretion. Factors affecting insulin release are shown in Figure 2. Interestingly, orally administered glucose induces a greater rise in plasma insulin concentrations than that induced by a similar amount of intravenous glucose. This increased responsiveness of insulin secretion is partly due to the production of incretin hormones such as glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP). These hormones are secreted from the GI tract and enhance insulin secretion in response to a glucose load, through direct activation of G-protein-coupled receptors expressed on islet beta cells. This has led to interest in the use of GLP-1 analogues to treat type 2 diabetes. The first member of this class has recently been released as a subcutaneous injection; it induces significant weight loss as well as improving glycaemic control. Other drugs that increase GLP-1 concentrations have also recently been licensed; these are oral medications which inhibit dipeptidyl dipeptidase IV (DPP-IV), the enzyme that breaks down GLP-1. They are not associated with weight loss. After binding to its receptor at the cell surface, insulin causes rapid shifts in the fluxes in various metabolic pathways by the activation or deactivation of enzymes at critical steps. It also leads to alterations in gene expression (e.g. inducing glucokinase gene expression), thus reinforcing the metabolic shifts. Insulin promotes the storage of excess nutrients while inhibiting mobilization of endogenous substrates. It is required for the entry of glucose into most cells, particularly muscle (skeletal and cardiac) cells. The brain and red blood cells are exceptions in which glucose diffuses down a steep concentration gradient into these cells. Insulin also stimulates glycogen formation from
Garry D Tan
Abstract Although only the same weight as an apple, the pancreas fulfils endocrine and exocrine functions, and coordinates metabolism throughout the body. For example, insulin, perhaps the best-known pancreatic hormone, not only influences glucose metabolism but also helps to regulate protein and fat metabolism (thus explaining why diabetes is more than just a disease of sugar). The secretion of pancreatic hormones is highly coordinated to exert a concerted effect on the metabolism of a range of organs, from adipose tissue to muscle. This article looks at the physiology of each of the hormones and enzymes released by the pancreas, the factors influencing their secretion, and how their secretion is coordinated.
Keywords cholecystokinin; endocrinology; glucagon; homeostasis; insulin
The pancreas weighs 70–100 g, yet secretes 1000 g of pancreatic fluid daily. Most cells in the pancreas have an exocrine function, manufacturing digestive enzymes. A small proportion of pancreatic cells (about 1 million) are aggregated into small clusters (tens of cells to several thousand cells) and are scattered throughout the exocrine cells. These aggregations, the islets of Langerhans, contain at least four different cell types (Table 1) which are densely innervated with autonomic and peptidergic nerves. Despite accounting for only 2% of the mass of the pancreas, the islets receive 10% of the pancreatic blood flow.
Endocrine pancreas Insulin and c-peptide Insulin is a polypeptide consisting of two peptide chains, A and B, linked by two disulphide bridges (Figure 1). It is synthesized as preproinsulin, a precursor of insulin. Preproinsulin is cleaved in the endoplasmic reticulum to form proinsulin, which is itself cleaved in the Golgi apparatus to form insulin and c-peptide. These are stored in granules in the β-cell cytoplasm to await secretion. Glucose is one of a number of stimuli that can cause βcell degranulation and insulin release. In order for glucose to do this, it must first be metabolized; glucose enters the β-cell via the glucose transporter type 2 (GLUT-2) and is phosphorylated by the
Garry D Tan, MB (Manc), MRCP (UK), DTM&H (Lond), DPhil (Oxon) is an Associate Professor at the University of Nottingham, UK, and a Consultant Physician in Diabetes, Endocrinology and Metabolism at Derby hospitals, UK.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
424
© 2008 Elsevier Ltd. All rights reserved.
Physiology
Pancreatic islet cell secretion Cell type
Proportion of islet cells
Peptides secreted
Anatomical distribution
α
25%
Glucagon (GLP-1, GLP-2)
β γ PP
60–70% 5–15% 2%
Insulin, c-peptide (islet amyloid peptide) Somatostatin 12 and 14 Pancreatic polypeptide (PP) (and small amounts of gastrin)
Within islets throughout the pancreas with a preference for pancreatic tail and body Within islets throughout the pancreas Within islets throughout the pancreas Within islets throughout the pancreas with a preference for posterior portion of the head. Also found in acini
Table 1
glucose in muscle and liver while simultaneously inhibiting glycogen breakdown in the liver. This produces a reduction in the intracellular concentration of glucose in hepatocytes. Glucose diffuses into hepatocytes down this gradient through the GLUT-2 transporter. In contrast, insulin actively enhances glucose uptake into myocytes and adipocytes by inducing GLUT-4 expression (another specialized plasma membrane glucose protein transporter – the only one to be induced by insulin). In adipose tissue, insulin inhibits mobilization of intracellular triglycerides by suppressing hormone-sensitive lipase activity. Because of this, circulating non-esterified fatty acid (or free fatty acid) levels fall. The resulting fall in their delivery to the liver causes a decrease in their β-oxidation and hence a decrease in the production of ketone bodies. Only tiny concentrations of insulin are required to suppress the production of non-esterified fatty acids from adipose tissue (much lower concentrations than those required to induce glucose uptake by skeletal muscle). Thus, there needs to be a total absence of insulin (as in untreated type 1 diabetes) for there to be unregulated release of non-esterified
fatty acids from adipose tissue, which leads to ketone body production by the liver. If the concentration of ketones overwhelms the body’s acid–base buffering system, diabetic ketoacidosis, the hallmark of type 1 diabetes, results. Other effects of insulin include an anabolic effect on protein metabolism and the promotion of potassium, phosphate and magnesium uptake into muscle cells. The renal tubular reabsorption of potassium, phosphate and sodium is increased. The insulins of different animals differ slightly in their amino acid sequence but have identical biological actions. Glucagon Glucagon is a 29 amino acid peptide produced from proglucagon in α-cells. Proglucagon is also synthesized in the gut, where it is processed differently to produce GLP-1. The factors affecting glucagon secretion are shown in Figure 2; the stimulating and suppressing factors interact. For example, the suppression of glucagon production by high glucose concentrations is potentiated in the presence of insulin. Despite this, plasma glucagon levels vary less than plasma insulin levels. Glucagon promotes mobilization rather than storage of fuels, particularly glucose, maintaining normoglycaemia in the presence of an increased glucose demand. Glucagon binds to a hepatic membrane receptor and prompts a cascade of intracellular events involving cAMP as a second messenger, to activate or to deactivate a number of enzyme kinases or phosphatases. The net result is a rapid increase in glucose production from glycogen breakdown, in tandem with a decrease in glycogen synthesis from glucose. Similarly, hepatic gluconeogenesis (e.g. from lactate, pyruvate, amino acids such as alanine) is increased while glycolysis is decreased. Glucagon also diverts incoming non-esterified fatty acids from triglyceride synthesis to β-oxidation, leading to ketogenesis. Hepatic cholesterol synthesis is also suppressed as hepatic hydroxymethylglutaryl coenzyme A (CoA) reductase is inhibited by glucagon. Other actions of glucagon include activation of myocardial adenylate cyclase, increasing the cardiac output. It also causes natriuresis by inhibiting renal tubular resorption. In adipose tissue, glucagon increases hormone-sensitive lipase activity.
Insulin
C-peptide (connecting peptide) 30 amino acids (33–63) 63 65
1
6
S S 7 11
21 20
A chain
S
1
7
Insulin molecule
S
S
S
B chain
33
30
19
Somatostatin Somatostatin is produced as prosomatostatin, which is processed to produce a 14 amino acid peptide variety of somatostatin (SS14). Prosomatostatin is also produced in intestinal cells but is processed
Amino acids 30–33 and 63–65 are cleaved off during insulin formation Figure 1
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
425
© 2008 Elsevier Ltd. All rights reserved.
Physiology
differently to form a 28 amino acid product (SS28). Within the islets, SS14 is a potent inhibitor of insulin, glucagon and pancreatic polypeptide secretion. SS28 decreases gastric, duodenal and gall-bladder motility and gastrointestinal secretions, thus enabling nutrient input to be coordinated with substrate disposal.
Factors affecting the endocrine response of the pancreas Factors affecting insulin secretion
Vagal stimulation
Glucagon GIP, CCK, VIP, GLP
+
+
Fatty acids Amino acids
GH TRH ACTH
+
+
Islet amyloid peptide Islet amyloid peptide (amylin) is a 37 amino acid peptide. It is regulated in a similar fashion to insulin. It accumulates in β−cells with age and its accumulation is further increased in type 2 diabetes mellitus. Its physiological role is unclear.
+
+
Glucose
Lowering of glucose levels
Opioids
β-cell
Insulin
Pancreatic polypeptide Pancreatic polypeptide is a 36 amino acid peptide secreted in response to feeding or hypoglycaemia. It is regulated by the autonomic nervous system. Its physiological role is unclear.
– Adrenaline Noradrenaline Somatostatin Sympathetic stimulation (α2-adrenoreceptors)
Coordination of insulin and glucagon action The pancreatic endocrine products act in concert to regulate the metabolism of glucose, non-esterified fatty acids, amino acids and other substrates (Table 2). As insulin and glucagon usually have antagonistic effects, the direction of substrate fluxes through the metabolic pathways is partly determined by the insulin–glucagon ratio. The usual molar ratio is 2:1, but it changes to 1:2 when mobilization of endogenous substrates is required, such as during fasting or prolonged exercise. The change in the ratio is caused by a simultaneous decrease in insulin secretion and an increase in glucagon secretion, promoting glycogenolysis and gluconeogenesis in the liver and lipolysis in adipose tissue, as well as increasing the flux of non-esterified fatty acids to the liver for β-oxidation. In the postprandial state, the insulin–glucagon ratio can rise to more than 10:1, primarily because of increased insulin secretion. This ensures increased glucose uptake along with oxidation and storage of glucose as glycogen in muscle and liver. Adipose
Factors affecting glucagon secretion Rise in glucose levels
Gastrin Vagal stimulation CCK, cortisol
Glucose
Ketone bodies
+
+
Amino acids
+ –
α-cell
Glucagon
– –
Fatty acids
–
–
GLP-1
Insulin somatostatin
Factors affecting somatostatin secretion
Glucagon Ketone bodies, NEFAs, + amino acids Glucose
Insulin
+
Effects of insulin and glucagon on metabolism
β-adrenergic Inhibition of and cholinergic glucagon secretion neurotransmitters CCK, GLP-1
+
+
+
δ-cell
Liver Glycogen synthesis Glycogenolysis Gluconeogenesis Glycolysis De novo lipogenesis Non-esterified fatty acid oxidation Protein catabolism Muscle Glycogen synthesis Glycogenolysis Glucose uptake Protein synthesis from amino acids Adipose tissue Glucose uptake Lipolysis
+ Opioids
Somatostatin
– –
Inhibition of insulin secretion
α-adrenergic neurotransmitters
ACTH, adrenocorticotrophic hormone; CCK, cholecystokinin; GH, growth hormone; GLP-1, glucagon-like peptide 1; GIP, gastrointestinal peptide; NEFA, non-esterified fatty acids; TRH, thyroid-releasing hormone; VIP, vasoactive intestinal peptide Figure 2
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Insulin
Glucagon
+ − − + + − −
− + + − − + +
+ − + + + −
+
Table 2
426
© 2008 Elsevier Ltd. All rights reserved.
Physiology
tissue lipolysis by hormone-sensitive lipase is suppressed; postprandially, non-esterified fatty acids are not required. The endocrine activity of the pancreas is regulated by a variety of factors as well as glucose (Figure 2). For example, while parasympathetic activity stimulates insulin and glucagon secretion, sympathetic activity increases glucagon but decreases insulin secretion. The response of the pancreas depends on the predominating influence. For example, in minor injury, the glucose levels are raised and the insulin levels elevated appropriately. In contrast, in a more serious injury, when there is marked sympathetic activation and the circulating epinephrine levels are elevated, the insulin secretion is not as high as might be expected for that degree of hyperglycaemia.
Protein and carbohydrate breakdown occur in various parts of the gastrointestinal tract. In contrast, fat digestion occurs only in the small intestine as the pancreas is the only source of intestinal lipase (pancreatic lipase). Pancreatic amylase and lipase are secreted in their active forms. DNA and RNA are hydrolysed to their nucleotide monomers by pancreatic nucleases. Pancreatic exocrine secretion is regulated by a number of factors that are part of the response to food of the gastrointestinal tract. Acid from the stomach causes cells in the duodenal and upper jejunal mucosa to release secretin, which causes the secretion of pancreatic fluid and bicarbonate. Secretin causes virtually no pancreatic enzyme secretion. Stimuli such as long-chain fatty acids and peptides in the duodenum cause the release of cholecystokinin from the duodenum and upper jejunal mucosa. Cholecystokinin stimulates the acinar cells of the pancreas to increase digestive enzyme secretion. Both secretin and cholecystokinin pass from the upper gastrointestinal tract to the pancreas by the bloodstream. Vagal stimulation (and acetylcholine secretion by the enteric nervous system) causes the pancreas to secrete digestive enzymes (though few reach the gastrointestinal tract because vagal stimulation causes the pancreatic fluid secretion to ‘wash’ the enzymes along the pancreatic duct). Vagal stimulation can occur during the cephalic phase or as a result of the presence of food in the stomach. It is important to emphasize that these stimuli of pancreatic secretion usually occur in concert and exert a multiplicative effect on one another. The response of the pancreas to the combination of these factors is greater than the response to the sum. ◆
Exocrine pancreas The secretory units of the exocrine part of the pancreas are groups of cells, known as acini, surrounding the ends of small ducts. These ducts feed into a centrally located pancreatic duct which drains into the hepatic duct and from there into the duodenum. The acinar cells secrete a fluid rich in digestive enzymes, which can digest proteins, carbohydrates, nucleic acids and fat. In general, these digestive enzymes are secreted as proenzymes. The epithelial cells lining the ducts secrete water and bicarbonate ions. This alkaline pancreatic juice (pH 8) neutralizes the hydrochloric acid from the stomach and provides the optimal conditions for the digestive enzymes to function. The pancreatic juice contains the highly active pancreatic amylase which digests starch and glycogen in the small intestine to di- and tri-saccharides. Proteins are cleaved to smaller peptides by trypsin and chymotrypsin. Trypsin is the most abundant protease secreted. Carboxypolypeptidase further divides the peptide fragments into their constituent amino acids. Pancreatic proteases are secreted in an inactive form and are activated in the duodenum. Enterokinase, a membrane-bound intestinal enzyme, activates trypsinogen to its active form, trypsin. Trypsin activates procarboxypolypeptidase and chymotrypsinogen. To prevent pancreatic autodigestion, the acinar cells also produce ‘trypsin inhibitor’. This prevents activation of trypsinogen in the secretory cells and in the ducts of the pancreas.
ANAESTHESIA AND INTENSIVE CARE MEDICINE 9:10
Further reading Berne R, Levy M, eds. Physiology, 4th edn. St Louis, MO: Mosby, 1998: 822–48. Guyton A, Hall J, eds. Textbook of medical physiology, 10th edn. Philadelphia: W B Saunders, 2000. Pickup J, Williams G, eds. Textbook of diabetes, 2nd edn. Oxford: Blackwell Science, 1996.
427
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