Pancreas
The pancreas is an abdominal, mixed type of gland that significantly contributes to digestion and intermediary metabolism. The digestive enzymes secreted from exocrine pancreatic acini aid in intestinal digestion, whereas the different hormones from the endocrine pancreas are implicated in regulating various metabolic processes (Fig.
16.7). The deranged enzymatic and hormone secretory patterns of the pancreas will immediately affect animal metabolism, energy homeostasis, and production status.Fig. 16.7 Histology of pancreas. [The group of specialized endocrine cells dispersed amongst the pancreatic acini known as islets of Langerhans, which function to produce pancreatic hormones that are mainly concerned with regulating carbohydrate metabolism. [BV blood vessel]
Table 16.2 Different pancreatic hormones, their chemical nature, effect, and plasma half-life
| S:No | Cell type | Hormones | Chemical structure | Effect | Half-life (in minutes) |
| 1. | α cells | Glucagon | Peptide 29 a.a | Increase blood glucose levels (Hyperglycemia) | 6-7 |
| 2. | β cells | Insulin | Polypeptide A Chain 21 a.a B Chain 30 a.a | Decrease blood glucose levels (Hypoglycemia) | 3-5 |
| 3. | δ cells | Somatostatin | Polypeptide 32 a.a | Inhibit the secretion of insulin and glucagon | 1-3 |
| 4. | F7γ cells | Pancreatic polypeptide | Polypeptide 36 a.a | Inhibits exocrine pancreatic secretions | 6-7 |
16.2.1 EndocrinePancreas
The endocrine function is imparted by islets of Langerhans, composed of specialized cells dispersed amidst the exocrine regions of the pancreas.
They make up 2-3% of the pancreas, consists of four different endocrine cell types, i.e., α, β, γ, and δ. These distinct endocrine cells are responsible for the production of glucagon, insulin, somatostatin, and pancreatic polypeptide hormones, thereby regulating metabolic homeostasis (Table 16.2).16.2.1.1 Glucagon
The islet α-cells secrete glucagon derived from the precursor proglucagon. The proglucagon is also expressed in other tissues such as the brain stem, hypothalamus, and enteroendocrine L cells. The prohormone convertases (PC1/2/3) further help in the process of conversion of proglucagon. The PC2 in α-cells converts proglucagon into glucagon, a polypeptide hormone with 29 amino acids. Whereas, the PC1 in the intestine and brain converts proglucagon to glucagon-like peptide 1 (GLP-1) and glucagon-like peptide 2 (GLP-2).
16.2.1.1.1 Mechanism of Secretion
Glucagon is primarily released in response to the decreased level of glucose in the blood. The presence of glucose transporter 1 (GLUT1) on the cell membrane of α-cells helps in the influx of glucose during normal conditions. Then, the glucose entered inside will be oxidized to produce ATP, which will be used to open ATP-sensitive potassium channels (KATP channels) and hence prevents depolarization by promoting the efflux of K+ ions. During hypoglycemia, the consequent reduction in ATP production due to reduced glucose influx leads to the closure of KATP channels. Subsequently, the build-up of K+ ions inside the cytoplasm triggers the opening of voltage-dependent Ca2 +channels allowing the influx of Ca2+ions. The rise in the intracellular Ca2+ levels stimulates the exocytosis of glucagon stored in the form of vesicles (Fig. 16.8).
16.2.1.1.2 MechanismofAction
The glucagon exerts its biological actions by binding to the glucagon receptors (GCGR) on the target cells, with the liver having more GCGR than any other tissue.
Being a G-protein coupled receptor; activated GCGR primarily activates the adenylyl cyclase (AC) system resulting in the production of cAMP and followed by the activation of protein kinase A (PKA). Thus, activated PKA migrates to the nucleus, activates transcription factors such as cAMP response element-binding protein (CREB) to promote the transcription of genes that mediate specific biological effects.16.2.1.1.3 Role of Glucagon on Intermediary Metabolism
Glucagon increases hepatic glucose production by stimulating glycogenolysis, gluconeogenesis, along with concomitant inhibition of glycolysis and glycogenesis (Fig. 16.9). It also stimulates the catabolism of lipids and amino acids. In addition, it stimulates a positive effect on heart rate and contractility and inhibits gastric acid secretion and appetite. Altogether, glucagon is a catabolic hormone that profoundly affects intermediary metabolism by stimulating hyperglycemia, ketosis, and ureagenesis.
16.2.1.1.4 Effect on Carbohydrate Metabolism
It stimulates the transcription of glucose 6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) genes that help in enhancing gluconeogenesis. In addition, activated PKA phosphorylates the pyruvate kinase (PK) to suppress glycolysis. Whereas, PKA-dependent activation of glycogen phosphorylase stimulates the release of glucose from the glycogen. The resulting increased glucose output from the liver acts to correct the hypoglycemic state. The increased glucose levels further stimulate the release of insulin from the pancreas, which will help in the mobilization of glucose in peripheral tissues. Henceforth, the hyperglycemic effect of glucagon is essential to ensure the proper functioning of absolute glucose-dependent tissues such as the brain and skeletal muscles.
Fig. 16.8 Mechanism of glucagon secretion by α-cell. [The reduced ATP generation during hypoglycemia inhibits the outward movement of K+, resulting in the depolarization of α-cells and exocytosis of glucagon.
[GLUT1 glucose transporter 1; ATP adenosine triphosphate; G glucagon; K+ potassium; Ca2+ calcium; # decrease; " increase]
Fig. 16.9 Effects of glucagon on intermediary metabolism. [Glucagon increases circulatory levels of glucose by stimulating glycogenolysis, gluconeogenesis both in the liver and skeletal muscle. In addition, it
prevents the utilization of glucose by increasing the lipolysis in adipose tissue and amino acid catabolism in skeletal muscles]
16.2.1.1.5 Effect on Protein Metabolism
It stimulates the uptake, deamination of amino acids to generate ATP in the liver and further facilitates the conversion of ammonia to urea by inducing the enzymes involved in ureagenesis. When the hepatic glycogen stores are depleted, glucagon recruits gluconeogenic amino acids to produce glucose (gluconeogenesis). However, the protein catabolism does not take place in skeletal muscles as they lack glucagon receptors.
16.2.1.1.6 Effect on Lipid Metabolism
Glucagon stimulates the transcription of carnitine palmitoyltransferase I (CPT 1) in hepatocytes, thereby activating the β-oxidation of fatty acids to produce acetate. The acetate reacts with Co-enzyme A to form acetyl-CoA and is metabolized via the citric acid cycle (TCA). Moreover, glucagon-induced PKA-dependent phosphorylation of hormone-sensitive lipase (HSL) in adipocytes leads to the catabolism of triglycerides to free fatty acids and glycerol.
16.2.1.1.7 Regulation of Secretion
Decreased blood glucose levels (hypoglycemia) remain the primary stimulus for the secretion of glucagon, while hyperglycemia has the opposite effect. In addition, ingestion of a protein-rich diet or increased levels of glutamine or alanine, cortisol, and β-adrenergic activity stimulates the release of glucagon.
Other pancreatic hormones such as insulin and somatostatin act in a paracrine manner to inhibit the secretion of glucagon.16.2.1.2 Insulin
Produced by the β-cells in islets of Langerhans, insulin is a heterodimeric polypeptide hormone consisting of A and B chains held together by two disulfide bridges. The A chain consists of 21 amino acids with an intra-chain disulfide bridge, whereas the B chain has 30 amino acid residues. The precursor molecule proinsulin will be acted upon by a trypsin-like enzyme to produce the mature insulin and C-peptide. The mature hormone along with C-peptide is stored as secretory vesicles in the cytoplasm and released when the need arises.
16.2.1.2.1 MechanismofSecretion
Insulin is primarily secreted due to high circulatory glucose levels. The glucose passes through the cell membrane of β-cells through GLUT2, phosphorylated by glucokinase and subsequently metabolized to generate ATP. The energy thus produced decreases the efflux of K+ by inhibiting the Katp channels. The accumulation of K+ ions stimulates the ion gated Ca2+ channels, thereby depolarizing the cell and facilitating the exocytosis of insulin. The concomitant fall of ATP levels during hypoglycemia leads to the hyperpolarization of cells, thereby inhibiting the secretion of insulin (Fig. 16.10).
Fig. 16.10 Mechanism of insulin secretion by β-cells [Increased glucose entry during hyperglycemia prevents the conductance of K+ ions, resulting in the opening of voltagedependent Ca2+ channels and subsequent exteriorization of insulin from the storage vesicles. [GLUT2 glucose transporter 2; ATP adenosine triphosphate; I insulin; C C-peptide; K+ potassium; Ca2+ calcium; # decrease; " increase]
16.2.1.2.2 MechanismofAction
The transmembrane insulin receptor (IR) is a disulfide-linked dimer that belongs to the receptor tyrosine kinase (RTK) family and plays a pivotal role in eliciting the downstream signaling pathways.
The intracellular domain of IR has a tyrosine kinase activity, which will be activated when insulin binds to the extracellular region. The activated tyrosine kinase phosphorylates the tyrosine residues outside the kinase domain and these in turn act as sites for various docking proteins such as insulin receptor substrate 1-6 (IRS 1-6) and Shc (Src homology 2 domain containing). They further mediate the activation of the PI3K/AKT and Raf/Ras/MEK/MAPK pathways that are responsible for various biological effects.16.2.1.2.3 Biological Effects
Insulin is the only hypoglycemic hormone acting against all other hyperglycemic hormones (GH, THs, cortisol, and catecholamines). Hence, it is widely considered as an important regulator of metabolism in animals. Principally, insulin regulates carbohydrate metabolism by affecting glycogenesis, glycogenolysis, gluconeogenesis, and glycolysis. In addition, it also regulates protein and lipid metabolism. With liver, skeletal muscles, adipose tissue, and endothelium as major target tissues, insulin has an overall anabolic effect on intermediary metabolism (Fig. 16.11). Moreover, the control on a wide range of metabolic pathways confers the permissive effect of insulin on the actions of GH.
16.2.1.2.3.1 Effect on Glucose Metabolism
Insulin-dependent regulation of glucose metabolism is mainly due to the activation of the PI3K/AKT pathway in target tissues. Activation of the PI3K/AKT pathway in skeletal muscles and adipose tissue enhances cellular uptake of glucose by stimulating the integration of GLUT4 on their cell membrane. GLUT4 mediated facilitated diffusion of glucose into these cells with its consequent entry into various metabolic pathways remains as the archetype effect of insulin. Thus, the increased glucose uptake increases glycolysis in both skeletal muscle and adipose tissue, while increased glycogen synthesis happens only in skeletal muscle. In the liver, insulin inhibits glycogen phosphorylase and side by side activates glycogen synthase resulting in decreased glycogenolysis with a simultaneous increase in glycogenesis, respectively. In addition, the insulin-dependent downregulation of PEPCK, G6Pase, and fructose-1, 6-bisphosphatase (FBP) genes inhibits gluconeogenesis in hepatocytes. Overall, insulin produces hypoglycemia by increasing glucose uptake in the liver and other peripheral tissues. Together with increased glycogenesis and decreased glycogenolysis, gluconeogenesis results in imparting the anabolic effect of insulin on glucose metabolism.
16.2.1.2.3.2 Effect on Amino Acid Metabolism
Insulin increases the skeletal muscle uptake of amino acids such as isoleucine, leucine, tyrosine, phenylalanine, and valine. Thus, the increased amino acid uptake facilitates the formation of new proteins along with a reduction in amino acid catabolism. Moreover, increased uptake of amino acids and inhibition of gluconeogenesis facilitate protein synthesis in the liver.
Fig. 16.11 Anabolic effects of Insulin on intermediary metabolism. [Insulin establishes normoglycemia by stimulating the glucose uptake, glycogenesis, and lipogenesis in liver, skeletal muscles, and adipose tissues. [GLUT4 glucose transporter 4; PEPCK phosphoenolpyruvate carboxykinase; G6Pase glucose 6-phosphatase; FBP fructose-1,
6-bisphosphatase; GP glycogen phosphorylase; GP glycogen synthase: HSL hormone-sensitive lipase; CPT1 carnitine O-palmitoyltransferase- 1; FAS fatty acid synthase; PDHpyruvate dehydrogenase; ACC acetyl- CoA carboxylase (ACC); # decrease; " increase]
16.2.1.2.3.3 Effect on Lipid Metabolism
The insulin-mediated inhibition of hormone-sensitive lipase (HSL), carnitine O-palmitoyltransferase-1 (CPT1) reduces lipolysis and β-oxidation in adipocytes. Furthermore, increased glucose uptake along with upregulation of fatty acid synthase (FAS), pyruvate dehydrogenase (PDH), and acetyl-CoA carboxylase (ACC) genes helps in lipogenesis. Therefore, the formation of lipid stores along with a reduction in their breakdown results in the anabolism of lipids.
16.2.1.2.4 Regulation of Secretion
The rise in blood glucose levels (hyperglycemia) is the major metabolic stimulus for the secretion of insulin. However, an increase in circulatory levels of fatty acids, amino acids, GH, cortisol, gastrin, secretin, and cholecystokinin (CCK) positively regulates the secretion of insulin. However, hypoglycemia, somatostatin, and leptin inhibit the secretion of insulin.
16.2.1.3 Somatostatin
Produced from δ-cells in the pancreas, enteroendocrine D-cells, and in the brain (GHIH from the hypothalamus). Somatostatin secreted from the pancreas and intestine has 28 amino acids (SS-28) while the hypothalamic type has 14 amino acids (SS-14). SS-14, SS-28 were first isolated in the ovine brain and porcine gut, respectively.
16.2.1.3.1 MechanismofAction
It binds to the somatostatin receptors (SSTRs) belonging to the GPCRs family. Activation of SSTR inhibits adenylyl cyclase (AC), leading to reduced intracellular cAMP and Ca2+ levels that further inhibit hormone secretion from target tissues.
respectively. Hence, they were used in treating diabetes mellitus in humans in the twentieth century.
• Although glucagon and insulin have antagonistic effects on various metabolic pathways, they both increase the cellular uptake of amino acids.
16.2.1.3.2 Biological Effects
Generally, it is a negative regulator of neuroendocrine, pancreatic, and GIT hormones. It inhibits the secretion of growth hormone (GH), thyroid-stimulating hormone (TSH), and prolactin (PRL) in the brain. It inhibits the secretion of insulin and glucagon in the pancreas in a paracrine manner by stimulating the efflux of K+ with subsequent inhibition of Ca2+ influx. In addition, it inhibits the secretion of bile acids, gastric acid, pancreatic enzymes mainly by inhibiting the secretion of GIT hormones such as CCK, VIP, and gastrin.
16.2.1.3.3 Regulation of Secretion
GH, GHRH, and glucose regulate the secretion of the hypothalamic SS-14. The gastric SS-28 is primarily stimulated by the autonomic nervous system (ANS), CCK, and gastrin. In addition, Substance P produced in the intestine has a negative effect on the secretion of SS-28.
16.2.1.4 Pancreatic Polypeptide (PP)
Secreted from F-cells, PP is a peptide hormone with 36 amino acids and belongs to the neuropeptide Y (NPY) family of proteins. It binds to the Y4 receptor, a GPCR belonging to the NPY receptor family. When activated, it inhibits the AC system resulting in a reduction of cAMP levels. PP inhibits gastric motility, gall bladder contraction, and exocrine pancreatic secretion. In addition, it stimulates the secretion of gastric juice and suppresses anxiety. Its secretion is increased by a protein-rich diet, exercise, and fasting.
Know More...
• Insulin is the first peptide hormone/protein to be sequenced by Fredrick Sanger in 1955.
• β-cell is the major cell type present in the islets of Langerhans.
• Diabetes mellitus (DM): A pathological condition due to a reduction in insulin production (Type-I DM) or in the number of insulin receptors (Type-II DM), characterized by hyperglycemia, ketosis, and skeletal muscle depletion.
• Bovine insulin and porcine insulin differ from human insulin only by 3 and 1 amino acids,
16.3