Name four hormones synthesized and secreted by the endocrine pancreas.
What are the three types of pancreatic cells in the Islets of Langerhans that synthesize pancreatic hormones? What do each of them produce?
Alpha cells (A cells) secrete glucagon.
Beta cells (B cells) produce insulin and are the most abundant of the islet cells.
Delta cells (D cells) secrete somatostatin, which is also produced by a number of other endocrine cells in the body.
Describe the synthesis of insulin in the pancreas.
Insulin starts off as a pre-pro-hormone, ie., a long peptide. The pro-hormone synthesis occurs in the pancreatic β-cell’s endoplasmic reticulum. During processing/packaging phase in the Golgi appartus, a convertase enzyme cleaves off a C-peptide to yield active insulin hormone. This mature, active insulin is a 51-amino-acid polypeptide hormone with α & β chains linked by disulphide bridges. Since it’s a peptide hormone, it is stored in vesicles/ granules beneath the β-cell’s plasma membrane. It travels around the circulation, when released upon stimulation by high levels of plasma glucose, unbound to binding proteins.
Describe the process of glucose-stimulated secretion of insulin.
1. Glucose is transported into the beta cell by facilitated diffusion through a glucose transporter (GLUT); elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the beta cell.
2. Elevated concentrations of glucose within the beta cell ultimately leads to membrane depolarization and an influx of extracellular calcium. The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules.
3. Increased levels of glucose within beta cells also appears to activate calcium-independent pathways that participate in insulin secretion.
Describe the secretion of insulin into the bloodstream over time (ie., its phases).
Release/secretion of insulin from pancreatic β-cell granules is biphasic:
In the first phase, the vesicles are immediately exocytosed close to the plasma membrane.
Graphically, this is illustrated by a steep rise in insulin concentration that rapidly drops off in less than 10 minutes as the half-life of insulin in the bloodstream is six minutes due to rapid metabolism by the liver.
In the second phase, insulin levels rise again (about 25-30 mins after initial release), representing the release of the contents of additional granules that have been exocytosed and new insulin synthesis.
What type of receptor does insulin bind to & how does it work on the target cell?
The insulin receptor is a tyrosine kinase. In other words, it functions as an enzyme that transfers phosphate groups from ATP to tyrosine residues on intracellular target proteins.
Binding of insulin to the alpha subunits causes the beta subunits to phosphorylate themselves (autophosphorylation), thus activating the catalytic activity of the receptor.
The activated receptor then phosphorylates a number of intracellular proteins, which in turn alters their activity, thereby generating a biological response.
What is the relationship of insulin to glucose that is transported into cells by the GLUT-4 transporter?
Insulin facilitates entry of glucose into muscle, adipose and several other tissues.
The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of transporters.
In many tissues - muscle being a prime example - the major transporter used for uptake of glucose (called GLUT4) is made available in the plasma membrane through the action of insulin.
When insulin concentrations are low, GLUT4 glucose transporters are present in cytoplasmic vesicles, where they are useless for transporting glucose. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose.
When blood levels of insulin decrease and insulin receptors are no longer occupied, the glucose transporters are recycled back into the cytoplasm.
NB Brain and the liver don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent.
Aside from stimulating the transport of glucose into muscle, fat and other tissues, what else does insulin do with regard to the liver?
Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen.
First, insulin activates the enzyme hexokinase, which phosphorylates glucose, trapping it within the cell.
Coincidently, insulin acts to inhibit the activity of glucose-6-phosphatase.
Insulin also activates several of the enzymes that are directly involved in glycogen synthesis, including phosphofructokinase and glycogen synthase.
The net effect is clear: when the supply of glucose is abundant, insulin "tells" the liver to bank as much of it as possible for use later.
What are the effects of insulin on fat metabolismt?
Insulin has a fat-sparing effect. Not only does it drive most cells to preferentially oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.
1. Insulin promotes synthesis of fatty acids in the liver. When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
2. Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids.
3. Insulin facilitates entry of glucose into adipocytes, and within those cells, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride within the adipocyte. By these mechanisms, insulin is involved in further accumulation of triglyceride in fat cells.
Describe the synthesis of glucagon in the pancreas.
Glucagon is synthesized as proglucagon and proteolytically processed to yield glucagon within alpha cells of the pancreatic islets.
Proglucagon is also expressed within the intestinal tract, where it is processed not into glucagon, but to a family of glucagon-like peptides (enteroglucagon).
What are the two major pathways glucagon uses to increase glucose concentrations in blood?
1. Stimulates breakdown of glycogen stored in the liver aka glycogenolysis.
2. Activates hepatic gluconeogenesis - non-hexose substrates such as amino acids are converted to glucose. As such, it provides another source of glucose for blood. This is especially important in animals like cats and sheep that don't absorb much if any glucose from the intestine - in these species, activation of gluconeogenic enzymes is the chief mechanism by which glucagon does its job.
What are the controls behind glucagon secretion by pancreatic-alpha cells?
Glucagon is secreted in response to:
1. Hypoglycemia or low blood concentrations of glucose.
2. Elevated blood levels of amino acids, as would be seen after consumption of a protein-rich meal: In this situation, glucagon would foster conversion of excess amino acids to glucose by enhancing gluconeogenesis. Since high blood levels of amino acids also stimulate insulin release, this would be a situation in which both insulin and glucagon are active.
Glucagon secretion is inhibited by:
1. High levels of blood glucose. It is not clear whether this reflects a direct effect of glucose on the alpha cell, or perhaps an effect of insulin, which is known to dampen glucagon release.
What are the effects of somatostatin, produced by D cells in the pancreas, on other hormones produced by the pancreas (ie., insulin & glucagon)?
Somatostatin appears to act primarily in a paracrine manner to inhibit the secretion of both insulin and glucagon.
It also has the effect in suppressing pancreatic exocrine secretions, by inhibiting cholecystokinin-stimulated enzyme secretion and secretin-stimulated bicarbonate secretion.
What other types of hormone-secretion are inhibited by somatostatin? Remember it is a hypothalamic hormone secreted by the anterior pituitary, but it is also synthesized & secreted in the pancreas, GIT (epithelium & neurons of the enteric nervous system) and regions of the central nervous system outside the hypothalamus
Growth Hormone (anterior pituitary somatotroph cells)
Insulin & Glucagon (pancreatic beta & alpha cells, respectively; endocrine pancreas)
Cholecystokinin-stimulated enzyme secretion & secretin-stimulated bicarbonate secretion (exocrine pancreas)
Gastrin, cholecystokinin, secretin and vasoactive intestinal peptide (GIT)