1. The Endocrine System as a Communicator
1.1 Why do we need the Endocrine System?
In the evolutionary development of metazoans, multicellularity led to a division of labour in which cells carry out particular functions assembled into coherent associations known as tissues. As such, the homeostatic integration and coordination of the activities of the various tissues need to come under the control of the nervous system and of the chemical messengers – the hormones, which are synthesized and released by the cells of the endocrine system.
The endocrine and nervous system, both of which act to integrate the activities of diverse parts of the organism, are clearly coordinated in function. Hormones of many endocrine glands have an effect on the nervous system, and several endocrine organs are stimulated or inhibited by neural mechanisms.
1.2 What makes up the endocrine system?
The endocrine system consists of endocrine glands that secrete specific chemical regulatory substances known as hormones. These products of the endocrine glands are not secreted through ducts but are released into the extracellular space of bloodstream and transported. Generally, hormones exert their effects at a distance from their site of their secretion. The tissues and organs on which the hormones act are called target organs.
The endocrine system differs from most other systems in the body in that the various endocrine glands are not in anatomical continuity with each other. However, they do form a system in the functional sense, with the pituitary gland (master gland) producing trophic hormones that regulate the activities of most other glands.
The major endocrine glands in humans include the pituitary gland, the thyroid gland, the parathyroid gland, the adrenal gland, the pancreatic islets and the gonads (i.e. the testes and the ovaries). The thymus gland, the pineal gland and the kidneys are sometimes considered as endocrine organs. In addition to the cells that carry out the organ’s other functions, the organ also contains cells that secrete hormones.
The endocrine glands can sometimes be considered as effectors, since they are differentiated structures performing specific reactions relative to the environment in response to a stimulus from the nervous system.
2. Hormones – Workhorses of the endocrine system
2.1 What are hormones?
It comes from the Greek word “hormone” which means to excite or to urge on. It is a specific chemical substance secreted by one part of the body and which evokes a response in another part (i.e. the target organ). It is secreted by an endocrine (ductless) gland. It is transported via the bloodstream to the target organ which may be a distance from the endocrine gland. It exerts a profound effect on the target organ in minute quantities.
The amounts of hormones released are regulated by feedback mechanisms, which depend on the interactions between the endocrine glands, the blood level of various hormones and the activities of the target organs.
Hormones are specific chemical substances. They only exert their effect on target cells possessing specific protein or lipoprotein receptors that can interact with the hormone. These receptor cells respond in specialized ways to the minute quantities of the hormonal message. Some hormones, such as thyroxine (T4) from the thyroid gland (which regulates metabolism), affect nearly all body cells whilst others, such as progesterone from the female ovary (which regulates the uterine lining), affect only a single organ.
2.2 What can Hormones do?
Hormones exert their effect on the target cells in 3 basic ways. They control the rates of enzymatic reaction. E.g. glucagon activates glycogen phosphorylase enzyme in glycogenolysis. They control the transport of molecules across the cell membranes. E.g. insulin binds to a receptor site on the cell membrane, altering membrane permeability to glucose. They control gene expression and protein synthesis. E.g. Triiodothyronine (T3), thyroxine (T4) and somatomedin have a joint stimulatory effect on protein synthesis leading to an increase in growth rate.
2.3 Synthesis, Chemical Structure and Classification of Hormones
Hormones fall into 3 major classes based on their chemical structures.
2.3.1 Amine Hormones
The amine hormones are all derivatives of the amino acids tyrosine and tryptophan. They include the thyroid hormones, adrenaline and noradrenaline (produced by the adrenal medulla) and dopamine (produced by the hypothalamus and posterior pituitary).
2.3.2 Peptide Hormones
The great majority of hormones are either peptides of proteins. They range in size from small peptides having only 3 amino acids to small peptides. We shall follow the common practice of all endocrinologists and refer to these hormones as peptide hormones. In many cases, peptide hormones are initially synthesized on the ribosomes of the endocrine cells as larger proteins known as preprohormones. These are then cleaved to prohormones by proteolytic enzymes in the glandular ER of the cell. The prohormone is then packaged into secretory vesicles by the Golgi apparatus. In this process, the prohormone is cleaved to yield the active hormone. Examples are insulin, glucagon and antidiuretic hormone (ADH).
2.3.3 Steroid Hormones
Cholesterol is the precursor of all steroid hormones. The many biochemical steps in steroid synthesis beyond cholesterol involve small changes in the molecule and are mediated by specific enzymes. Examples are aldosterone, androgens, estrogens and progesterone.
2.4 Mechanisms of Hormone Action
Hormones are transported in the bloodstream, thus they reach every cell in the body. The effects of hormones are to alter the metabolic reactions only in the target cells which possess specific receptor molecules on their surfaces. If a cell lacks an appropriate receptor site, it will not respond to the hormone. The response of the target cell to the hormonal message is only the final event in a sequence that begins when the hormone binds to specific target cell receptors.
2.4.1 How do Steroid Hormones Work?
As steroid hormones are lipid soluble, the readily cross the plasma membrane and activate their specific intracellular receptors, particularly those receptors in the nucleus.
The hormone-receptor complex has the proper conformation to bind to another specific protein, an acceptor protein that recognizes certain regions of the DNA. This acceptor protein is probably a transcription factor that stimulates the transcription of specific genes by binding to enhancer sequences along the DNA.
The mRNA molecules thus produced are processed and transported to the cytoplasm, where they direct the synthesis of new proteins.
2.4.2 How do Amine and Peptide Hormones Work?
Amine and peptide hormones are usually water-soluble and cannot penetrate the phospholipid bilayer of the plasma membrane. They bind to specific receptors on the plasma membrane of target cells and rely on second messenger molecules that will be produced on the cell in response to the binding of the hormone on the receptor. Thus, the hormone is viewed as the first messenger. The best known second messenger is probably cyclic AMP.
The second messengers will then activate one or more enzymes in an enzyme cascade that will catalyze subsequent desired physiological processes, resulting in an amplification of the initial hormonal message. In this sense, the organism can use a single basic mechanism to mediate the responses of diverse cell types to many different hormones.
3. Pancreas as an Endocrine Gland
3.1 Pancreatic Anatomy and Histology
The pancreas is a mixed exocrine and endocrine gland that produces digestive enzymes and hormones respectively. The enzymes are secreted by the pancreatic acinar cells (F cells), which make up the bulk of the pancreas. The hormones are synthesized in clusters of cells known as the islets of Langerhans, which make up less than 2% of the entire pancreas. These islets are the multihormonal endocrine microorgans of the pancreas; they appear as rounded clusters of cells embedded within the exocrine pancreatic tissue. Using immunocytochemical methods, 3 endocrine cell types – alpha, beta and delta cells – have been identified.
3.2 Secretion of Insulin and Glucagon – homeostatic regulation of blood glucose concentration
The pancreatic islets secrete at least 4 hormones: insulin, glucagon, somatostatin and pancreatic polypeptide. The hormones are released into the pancreatic vein, which empties into the hepatic portal vein – a convenient arrangement, since the liver is the primary site of action of insulin and glucagon.
Insulin and glucagon are chiefly involved in regulating carbohydrate metabolism but affect many other processes. Insulin and glucagon are antagonistic in action and they help to maintain blood glucose concentration at approximately 90mg/dl.
Somatosatin, first identified in the hypothalamus as the hormone that inhibit growth hormone secretion, is present in higher concentration in the pancreatic islets than in the hypothalamus. In the pancreas, somatostatin is involved in the local regulation of insulin and glucagon secretion.
3.2.1 Insulin – a peptide hormone activated in the Fed state
3.2.1.1 Structure
It has a molecular mass of 5734 kDa covering 51 amino acids. It is a heterodimeric polypeptide consisting of 2 chains – A and B – that are linked by 2 interchain disulphide bridges connecting A7 to B7 and A20 to B19. A third intrachain disulphide bridge connects residues 6 and 11 of the A chain. The locations of the 3 disulphide bridges are invariant and the A and B chains have 21 and 23 amino acids respectively, in most mammalian species. The conserved amino acid sequence implied that diabetics could use bovine or porcine insulin with little immunological side effects.
3.2.1.2 Stimulus for insulin secretion – simple endocrine reflex
When blood glucose concentration rises above 90 mg / dl, (can reach 500 mg / dl) after a carbohydrate-rich meal had been ingested, this leads to hyperglycaemia. Glucose combines with a receptor, possibly on the beta cell membrane, which activates the secretion mechanism. On top of simple endocrine reflex, insulin secretion might be promoted by autonomic activity (parasympathetic division). This closed system of regulation employs a negative feedback loop.
3.2.1.3 Mode of Insulin Action
Being a peptide hormone, insulin binds to receptor proteins on the target cell membranes. Such binding heads to an activation of the 2nd messenger, cAMP, which activates kinases that attaches phosphate groups to intracellular enzymes. Activation of intracellular enzymes via phosphorylation then produces the primary and secondary effects in the cell.
3.2.1.4 Effects of Insulin – Down-regulation of blood glucose concentration and increased anabolism
3.2.1.4.1 Accelerated conversion of glucose into glycogen (glycogenesis)
After a carbohydrate-rich meal has been digested, an excess of glucose is taken into the bloodstream at the ileum. Blood leaving the ileum contains an excess of glucose above the norm of 90 mg / dl. From the ileum, the blood first goes to the liver via the hepatic portal vein.
In the liver, the excess glucose is absorbed and concerted to glycogen. Up to 100 g of glycogen can be stored in the liver. In this case, insulin stimulates glycogenesis by activating the enzyme glycogen synthase.
At the meantime, insulin inhibits enzymes involved in glycogenolysis (such as glucose-6-phosphatase) and gluconeogenesis to prevent further increase in blood glucose concentration.
3.2.1.4.2 Accelerated uptake of glucose into cells from blood
Insulin circulates in the blood throughout the body and promotes the uptake of glucose by almost all its cells, particularly muscle cells. Glucose is then stored as glycogen via glycogenesis. Insulin does not accelerate glucose entry into the kidney and brain tissues, all of which have an easy access to blood glucose regardless of insulin levels.
Insulin, once bound to its receptors on target cells, makes the target cells more permeable to glucose by increasing the number of active glucose transporter molecules in the cell membrane. In doing so, insulin enhances facilitated diffusion of glucose into the target cell down a glucose concentration gradient. ATP is not required.
3.2.1.4.3 Acceleration of glycolysis and enhanced ATP production
When more glucose is being taken in by the cells, more of it is being used in glycolysis i.e. rate of glucose utilization is proportional to glucose availability. 2nd messengers activate key enzymes involved in the initial steps of glycolysis, such as glucokinase and phosphofructokinase. Phosphorylated glucose can also be incorporated into glycogen, thereby decreasing the intracellular glucose concentration.
3.2.1.4.4 Stimulation of amino acid uptake and protein synthesis
Insulin stimulates the uptake of neutral amino acids into the muscle. It also stimulates enzymes involved in the transcription and translation process.
3.2.1.4.5 Stimulation of lipogenesis
Insulin stimulates the conversion of excess glucose into fatty acids and glycerol which are stored as triglycerides in the adipose tissue. Insulin inhibits intracellular lipase that hydrolyses triglycerides to release fatty acids and glycerol (lipolysis).
3.2.2 Glucagon – a peptide hormone activated in the fasting state
3.2.2.1 Structure
It has a molecular mass of 3,485 kDa covering 29 amino acids. It is a single chain polypeptide. Its amino acid sequence is highly conserved in mammals.
3.2.2.2 Stimulus for Glucagon secretion – Simple endocrine feedback
When blood glucose concentration falls below 90 mg / dl (can reach 60 mg / dl) during fasting, it is called hypoglycaemia. The alpha cells in the islets of Langerhans detect the falling blood glucose concentration and glucagon secretion is stimulated. This closed system of regulation employs a negative feedback loop.
3.2.2.3 Mode of Glucagon Action
Being a peptide hormone, glucagon binds to receptor proteins on the target cell membrane. Such binding leads to the activation of the second messenger cAMP which activates kinases that attaches phosphate groups to intracellular enzymes. Activation of intracellular enzymes via phosphorylation then produces the primary and secondary effects in the cell.
3.2.2.4 Effects of Glucagon – up regulation of blood glucose concentration
3.2.2.4.1 Stimulation of glycogen breakdown (glycogenolysis)
In the liver, glucagon activates enzymes involved in glycogenolysis (such as phosphorylase). Glycogen is converted to glucose which can be metabolized for energy or released into the bloodstream. In the meantime, in the liver, glucagon inhibits enzymes involved in glycogenesis (such as glycogen synthase). In the muscle cells, glucagon does not cause glycogenolysis. Glucose-6-phosphate will be metabolized for energy only.
3.2.2.4.2 Stimulation of glucose production from non-carbohydrate sources (gluconeogenesis)
In the liver, glucagon activates enzymes involved in gluconeogenesis. Amino acids, fatty acids and glycerol are absorbed from the bloodstream and are converted to glucose. In the adipose tissues, glucagon stimulates the breakdown of triglycerides into fatty acids and glycerol , which are released into the circulation for use by other tissues.
