* Catecholamines Epinephrine and Norepinephrine
2010Prof. H.D.El-Yassin (Ph.D.,Post Doctorate)
* Synthesis of catecholamines begins with the amino acid tyrosine, which is taken up by chromaffin cells in the medulla and converted to norepinephrine and epinephrine through the above steps:
* Adrenergic Receptors and Mechanism of Action
The physiologic effects of epinephrine and norepinephrine are initiated by their binding to adrenergic receptors on the surface of target cells. These receptors are prototypical examples of seven-pass transmembrane proteins that are coupled to G proteins which stimulate or inhibit intracellular signalling pathways.* There are two major classes of adrenergic receptors these are:α adrenergic receptor (epinephrine and norepinephrine)α1α2β adrenergic receptor (epinephrine )β1β2
* Metabolic
glycogenolysis to provide extra sources of glucose Stimulation of lipolysis in fat cells to provided fatty acids for energy production in many tissues and aids in conservation of dwindling reserves of blood glucose. Increased metabolic rate due to increased oxygen consumption and heat production increase throughout the body in response to epinephrine binding beta receptors. Increased breakdown of glycogen in skeletal muscle to provide glucose for energy production.* Water and electrolyte metabolism Decreased sodium excretion and glomerular filtration due to direct effects on the kidney effects on renin secretion leads to increased aldosterone production with effects on distal sodium handling Serum potassium may be increased
Catecholamine Degradation
All catecholamines are rapidly eliminated from target cells and the circulation by three mechanisms: reuptake into secretory vesicles uptake in non-neural cells (mostly liver) degradation.
Degradation relies on two enzymes:
catechol O-methyltransferase (COMT) in non-neuronal tissues and monoamine oxidase (MAO) within neurons. to produce metabolites (metanephrines and vanillylmandelic acid (VMA)) from free catecholamines.Metabolites and free catecholamine are eliminated by direct filtration into the urine and excreted as:
free norepinephrine (5%); conjugated norepinephrine (8%); metanephrines (20%) and VMA (30%).
Phaeochromocytoma
Catecholamine-secreting tumors arise from the chromaffin cells of the adrenal medulla.The most widely used screening test is urinary metanephrines. Measurement of fractionated metanephrines (metadrenaline and normetadrenaline) has a sensitivity of 97% and a specificity of 69% for the diagnosis of phaeochromocytoma.
Plasma free metaphrine and normetanephrine measurement has a sensitivity approaching 100% and specificity of 90%. Plasma catecholamine measurements should be undertaken in the resting state through an indwelling cannula.
Biochemistry and Disorders of Hormones of the Pancreas
ObjectivesList the hormones synthesized and secreted from the pancreas and state their functions and clinical significance Understand the mechanism of synthesis and release of insulin and glucagon Understand the mechanism of interaction of insulin with its receptor which is the platform for developing medications for type 1 and type 2 DM Understand the mechanism of interaction of glucagon with its receptor define insulinoma and the laboratory results obtained in the assessment of the disease
* The bulk of the pancreas is an exocrine gland secreting pancreatic fluid into the duodenum after a meal.
In 1869, however, a German medical student named Paul Langerhans described some unusual clusters of cells scattered throughout the pancreas; these clusters came to be called islets of Langerhans.
These islets are endocrine tissue containing four types of cells
In order of abundance, they are: Beta cells, which secrete insulin, preptin and amylin. Alpha cells, which secrete glucagon; Delta cells, which secrete somatostatin, and Gamma cells, which secrete pancreatic polypeptide (PP).
Alpha Cells : glucagon
Is , a polypeptide of 29 amino acids. It acts principally on the liver where it stimulates the conversion of glycogen into glucose ("glycogenolysis") and fat and protein into intermediate metabolites that are ultimately converted into glucose ("gluconeogenesis") In both cases, the glucose is deposited in the blood.Glucagon secretion is stimulated by low levels of glucose in the blood; inhibited by high levels of glucose in the blood, and inhibited by amylin. The physiological significance of this is that glucagon functions to maintain a steady level of blood sugar level between meals.
Beta Cells: 1. Insulin
Is a small protein consisting of an alpha chain of 21 amino acids linked by two disulfide (S—S) bridges to a beta chain of 30 amino acids.Beta cells have channels in their plasma membrane that serve as glucose detectors. Beta cells secrete insulin in response to a rising level of circulating glucose ("blood sugar").Beta Cells: 2. Amylin
Is a peptide of 37 amino acids, which is also secreted by the beta cells of the pancreas. Some of its actions: inhibits the secretion of glucagon; slows the emptying of the stomach; sends a satiety signal to the brain. Amylin (IAPP) was identified independently by two groups as the major component of diabetes-associated islet amyloid deposits in 1987Beta Cells: 3. Preptin
Preptin is a peptide of 34 amino acids co-secreted with insulin and amylin. Some of its actions: Stimulates proliferation of primary fetal osteoblast Reduces osteoblsat apoptosis
Delta Cells: somatostatin
This consists of two polypeptides, one of 14 amino acids and one of 28. Somatostatin has a variety of functions. Taken together, they work to reduce the rate at which food is absorbed from the contents of the intestine. Somatostatin is also secreted by the hypothalamus and by the intestine.Gamma Cells: PP
is a 36-amino-acid polypeptide. Its function is to self regulate the pancreas secretion activities . it also has effects on hepatic glycogen levels and gastrointestinal secretions. Its secretion human is increased after a protein meal, fasting, exercise and acute hypoglycemia and is decreased by somatostatin.* Synthesis and secretion of Insulin
Insulin, is synthesized as a preprohormone that is converted in (RER) to proinsulin. The "pre" sequence, a short hydrophobic signal sequence at the N-terminal end, is cleaved as it enters the lumen of the RER.Proinsulin folds into the proper conformation and disulfide bonds are formed between the cysteine residues. It is then transported in microvesicles to the Golgi complex. It leaves the Golgi complex in storage vesicles, where a protease removes the C-peptide (a fragment with no hormonal activity) and a few small remnants, resulting in the formation of biologically active insulin. Zinc ions are also transported in these storage vesicles. Cleavage of the C-peptide decreases the solubility of the resulting insulin, which then coprecipitates with zinc.
*
Quick quiz: The metal ion required during crystalizatio of inulin is:
Zinc Calcium Copper Chromium* Stimulation and inhibition of insulin release
The release of insulin occurs within minutes after the pancreas is exposed to a high glucose concentration. The threshold for insulin release is approximately 80 mg/glucose /dL. Above 80 mg/dL, the rate of insulin release is not an all-or-nothing -response but is proportional to the glucose concentration up to approximately 300 mg/dL glucose. As insulin is secreted, the synthesis of new insulin molecules is stimulated, so that secretion is maintained until blood glucose level fall. Insulin is rapidly removed from the circulation and degraded by the liver and to a lesser extent by kidney and skeletal muscle) so that blood insulin levels decrease rapidly*
* A number of factors other than the blood glucose concentration can modulate insulin such as: neural signals certain amino acids gastric inhibitory polypeptide (GIP, a gut hormone released after the ingestion of food) epinephrine secreted in response to fasting, stress, trauma and vigorous exercise decrease the release of insulin
* Actions of Insulin
GluconeogenesisGlucogenolysis
Lipolysis
Ketogenesis
Proteolysis
Uptake of ions (especially K+ and PO4-3
Protein synthesis
Glycogen synthesis
Glycolysis
Glucose uptake in muscle and adipose tissue
Insulin
* Synthesis and secretion of Glucagon
Glycogenolysis Gluconeogenesis KetogenesisGlycogenolysis Gluconeogenesis Ketogenesis
Insulin Glucagon Epinephrine
* Glucagon a polypeptide hormone, is synthesized in the α cells of the pancreas by cleavage of the much larger preproglucagon, a160 amino acid peptide. Like insulin preproglucagon is produced on the rough endoplasmic reticulum and is converted to proglucagon as it enters the ER lumen. Proteolytic cleavage at various sites produce the mature 29-amino acid glucagon and larger glucagon-containing fragments (named glucagon-like peptides I and 2). Glucagon is rapidly metabolized, primarily in the liver and kidneysIts plasma half-life is only about 3 to 5 minutes.
Glucagon secretion is regulated principally by circulating levels of glucose and insulin. Increasing levels of each inhibit glucagon release. Glucose probably has both a direct suppressive effect on secretion of glucagon from the α cell as well as an indirect effect, the latter being mediated by its ability to stimulate the release of insulin.
* Certain hormones stimulate glucagon secretion. :
catecholamines (epinephrine) cortisol gut hormones Many amino acids also stimulate glucagon release.Quick quiz: Most effective stimulation factor to the secretion of glucagons is:
High carbohydrate diet Hyperglycemia Hypoglycemia High fat diet* Metabolic effects of glucagon
1. Effects on carbohydrate metabolism: The intravenous administration of glucagon leads to an immediate rise in blood glucose. This results from an increase in the breakdown of liver (not muscle) glycogen and an increase in gluconeogenesis. 2. Effects on lipid metabolism: Glucagon favors hepatic oxidation of fatty acids and the subsequent formation of ketone bodies acetyl CoA. The lipolytic effect of glucagon in adipose tissue is minimal in humans. 3. Effects on protein metabolism: Glucagon increases uptake of amino acids by the liver, resulting in increased availability of carbon skeletons for gluconeogenesis. As a consequence plasma levels of amino acids are decreased.
Quick quiz: All the statements are true for glucagons EXCEPT
Its secretion is inhibited by hyperglycemia It will stimulate only glycogenolysis in muscle It ill bind to membrane receptors in liver and adipose tissue It will stimulate lipolysis with the help of hormone sensitive triacylglycerol (TAG) lipaseInsulin and Glucagon receptors
How insulin binds to its receptor, was not yet known until recently (Jan 013). They described it as resembling the "handshake" For more than 20 years, scientists have been trying to solve the mystery of how insulin binds to the insulin receptor. The generation of new types of insulin have been limited by our inability to see how insulin interacts with its receptor in the body.Quick quiz: : the interaction of insulin with its receptor
cause a conformational change in the receptor only cause a conformational change in the hormone only cause a conformational change in both hormone and receptor. cause no conformational changeThe importance of this finding is that:
insulin is a key therapy for type 1 and type 2dm diabetes mellitus and pharmaceutical industries are interested in making insulin that have varying properties so that: people might not have to inject insulin quite often or might ingest insulin in different ways or might be interested in making insulin that can be stored in normal temps.
Quick quiz: How can this finding benefit diabetics
by providing more injected insulin by curing their damaged B cells generating new properties to the insulin molecule that shall be used theraputicaly will have no benefit at allIn this example glucagon binds to its' cell-surface receptor, thereby activating the receptor. Activation of the receptor is coupled to the activation of a receptor-coupled G-protein (GTP-binding and hydrolyzing protein) composed of 3 subunits. Upon activation the α-subunit dissociates and binds to and activates adenylate cyclase. Adenylate cylcase then converts ATP to cyclic-AMP (cAMP). The cAMP thus produced then binds to the regulatory subunits of PKA leading to dissociation of the associated catalytic subunits. The catalytic subunits are inactive until dissociated from the regulatory subunits. Once released the catalytic subunits of PKA phosphorylate numerous substrate using ATP as the phosphate donor
Clinical cases and correlations
InsulinomaA 36-year-old woman was referred to a university hospital for evaluation of spells of dizziness and weakness. These spells typically lasted for 10 min and were occurring with increasing frequency. The spells usually came on after a large meal and could be terminated by her eating candy or drinking fruit juice. After each episode the patient was hungry and tired, and her memory was blurred. The patient's physical examination was within normal limits except for mild obesity. She claimed to have gained 20 kg during the preceding 2 yr. After a 13-hr fast her blood glucose concentration was 2.1 mmollL. After a 5-hr glucose tolerance test, her blood glucose was 2.6 mmol/L. Celiac angiography revealed an abnormality in the body and tail of the pancreas. The patient developed one of her spells while a medical student was in her room, and he was able to obtain a blood sample during the episode. This sample contained 1.1mmol/L of glucose. The patient was transferred to the surgical service, and an insulin-secreting pancreatic adenoma (tumor) was removed, requiring resection of 90% of the pancreas.
Biochemical questions
The insulinoma was producing insulin. Because of the excessive amount of insulin- secreting tissue, too much insulin was released after dietary carbohydrate intake. This caused hypoglycemia during the 5-hr glucose tolerance test and after meals, producing the spells of weakness and dizziness. In addition, to this normal insulin release when carbohydrate was ingested, the tumor also was secreting some insulin continuously. This inappropriate insulin release caused the low blood glucose concentration during prolonged fasting.An insulinoma is an insulin-secreting tumor. How did the presence of such a tumor explain the patient's symptoms?
2. Proinsulin was found in large quantities in this patient's plasma. What is the relationship of proinsulin to insulin? What is preproinsulin?
Proinsulin is the prohormone form of insulin that is made in the β-cells of the pancreatic islets. It has no insulin-like action. After synthesis on the ribosomes, the initial precursor, preproinsulin, penetrates through the endoplasmic reticulum into the lumen of this organelle. The leader sequence is removed in this process, forming proinsulin, which is transported to the Golgi apparatus and stored in granules.Proinsulin is converted to insulin in these granules by proteolytic cleavage, but the conversion is incomplete. When insulin is discharged from the β-cell, some proinsulin that remains in the granule also is released. Likewise, C-peptide that is split out in the conversion of proinsulin to insulin is released during insulin secretion, but it too, has no insulin-like activity.
3. What effects of increased insulin secretion might have predisposed this woman to obesity?
Insulin acts on adipocytes, enhancing fatty acid storage as triglyceride. It binds to specific receptors on the cell surface and facilitates glucose entry into the adipocyte, increasing the availability of the triose backbone, glycerol 3-phosphate, needed for triglyceride synthesis. This also provide glucose carbon atoms for fatty acid synthesis. In addition, it increases the content of lipoprotein lipase in the adipose tissue. This enzyme catalyzes the hydrolysis of chyromicron and VLDL triglycerides, a step that is required to transfer their fatty acids into the adipocytes for resynthesis into triglyceride. Much of the fatty acid stored in the adipose tissue is delivered to the adipocytes in the form of lipoprotein triglycerides, either VLDL from the liver or chylomicrons from the intestine. Therefore the elevated lipoprotein lipase activity also favors triglyceride formation in the adipose tissue. Those adipose tissue effects that were mediated by the excessive insulin production could have contributed to he recent weight gain noted by this patient.
4. What digestive problems might result from excision of 90% of the pancreas?
These include amylase for dietary starches, lipase for triglycerides, chymotrypsin and trypsin for proteins, as well as several others. Since 90%, of the pancrease was excised, the remaining 10% may not produce sufficient amounts of these enzymes to adequately digest large meals. This might lead to malnutrition and weight toss in spite of an adequate diet. Because of this possibility, six or more smaller meals rather than three regular meals each day might be recommended.