Unit 2: The Endocrine II

Calcium and Phosphate Regulation

 Three hormones in the regulation of calcium and phosphate are Calcitonin, from the Thyroid Gland,
Parathyroid Hormone, from the Parathyroid Gland, and the steroid 1,25-dihydroxyvitamin D3 (or 1,25-
dihydroxycholecalciferol), from the Kidneys.
 Calcium is poorly absorbed from the intestinal tract whereas phosphate is easily absorbed - except when
there is excess calcium in the diet.
 Vitamin D has a potent effect on the absorption from the Gl tract and on bone deposition and bone
reabsorption, though, it must be first converted to 1,25-dihydroxycholecalciferol in the kidney.
 The parathyroid hormone is necessary for the formation of 1,25-dihydroxycholecalciferol.
 When the plasma calcium concentration is too high, the formation of 1,25-dihydroxycholecalciferol is
depressed which then decreases the absorption of calcium from the intestines, from the bones and from
the kidney tubules.
 1,25-dihydroxycholecalciferol promotes calcium absorption from the intestines by increasing the calcium-
binding protein, which is a Ca2+ ATPase pump in the intestinal epithelial cells.
 Ca2+ ATPase pump transports Ca2+ into the cytoplasm from the intestine and then it moves through
the basolateral membrane of the cell by facilitated diffusion to be taken up by the blood.
 The plasma concentration of calcium is regulated within a narrow range (~ 2.4 mMol/L), primarily by
the parathyroid hormone.
 The plasma calcium is present in three different forms:
1. ~1.0 mMol/L is combined with plasma proteins, and can’t diffuse through the capillary membrane.
2. 0.2 mMol/L is diffusible, non-ionized calcium.
3. 1.2 mMol/L is both diffusible and ionized – majority
Abnormal Levels of Calcium and Phosphorus
 The effects of increasing the phosphorous level in the extracellular fluid, by 3-4-fold above or below
normal, has little effect on body functions – however the increase or decrease of calcium does.
 In humans, hyper/hypocalcaemia is associated with abnormal hormone levels.
 Hypocalcaemia, having low Ca+2, results in spontaneous action potentials in peripheral nerves to muscles
because neuronal membrane permeability to Na+ increases allowing easy initiation of action potentials.
 Ca2+ is also involved in the regulation of Na+ permeability - low extracellular Ca2+ will allow an influx
of Na+ through channels in the Sarcolemma, which will depolarize the muscle cell directly.
 The muscles begin to twitch and at about an extracellular concentration of 50% of normal - Tetany will
develop (muscular spasms) – occurs in human patients and small postpartum dogs.
 In cows, twitching phase is short, often not observed, and restricted to muscles over the shoulders.
 In cows, Milk Fever is associated with Paralysis - possibly because Ca2+ isnt available at the
neuromuscular junction for neurotransmitter release, and if not released the tone in muscles is lost.
 Even in voluntary muscles, like the skeletal muscles, there is tone due to the activity of muscle
spindles and due to unconscious activity in the extra pyramidal tracts.
 Hypercalcaemia (high Ca+2) result is a depressed nervous system and reflex activation becomes slow.
 The heart rate slows, and the QT segment is prolonged; eventually it will stop in contraction - the
slowing is due to a prolonged plateau phase of the action potential; is repolarization is delayed, the
heart cannot maintain the normal rhythm.
 In the brain, the high Ca+2 levels likely have a similar effect by preventing normal repolarization.
Hormone Effect on Intestine Effect on Kidney Effect on Bone
2+ 3-
PTH N/a Ca reabsorption; and inhibits PO 4 Resorption
2+ 3- 2+ 3-
Vitamin D Absorption of Ca & PO 4 Ca & PO 4 reabsorption Resorption
2+; 3-
Calcitonin N/a Inhibits Ca and PO 4 reabsorption Deposition
 Parathyroid Hormone
 There are four small, yellowish-brown, flattened parathyroid glands that are embedded in the posterior
surface of the lateral lobes of the thyroid gland – a superior pair and an inferior pair
 Increased parathyroid hormone causes hypercalcemia, while a deficiency results in hypocalcaemia.
 Parathyroid hormone is also important in phosphate metabolism by decreasing phosphate levels
 The rise in calcium is due to the absorption from the bone and due to decreased excretion by the
kidneys – phosphate is also released in the bone but due causes it to be excessively excreted.
 Parathyroid hormone can cause the rapid removal of Ca2+ and PO3-4 from the bone by Osteolysis – not
well understood but it involves the activation of a pump that removes Ca2+ and PO3-4 from the bone.
 It can also cause the slow releases of the minerals from bone – classical role.
 Osteoclasts, which break down bone, are activated and formed – though it takes months of excessive
stimulation for bones to weaken.
 Weakening then stimulates the osteoblasts, which deposit bone, but the hormone effect is greater.
 Also stimulates reabsorption of Ca2+ into blood from the ascending limb, distal tubule & collecting ducts.
 Calcium is filtered at the Glomerulus and ~60% is reabsorbed in the proximal tubules – remaining 40% is
reabsorbed under the influence of the parathyroid hormone.
 Decreases PO3-4 reabsorption into the blood from the kidney, which is usually 85-90%, but the hormone
inhibits the active transport in the proximal tubule.
 Also increases the rate of reabsorption of Mg ions and H ions, while it decreases the reabsorption of Na+,
K+, and amino acids by inhibition their transport mechanisms.
 Administration of large quantities of Vitamin D causes resorption of bone in the same way quantities
parathyroid hormone does because increases Ca2+ transport through cellular membranes.
 In small quantities, it promotes bone calcification by increasing both Ca2+ and PO3-4 absorption from
intestines, but even without increased absorption, there is increased mineralization of bone.
Control of Parathyroid Hormone Secretion
 A slight decrease in the extracellular concentration of Ca2+ will stimulate the parathyroid glands to
increase their rate of hormone secretion.
 If the deficiency persists, the glands will undergo hypertrophy, which is an enlargement.
 Hypertrophy occurs in pregnancy and lactation because of a slight decrease in plasma calcium
 If there is too much extracellular Ca2+ due to excess Ca2+ or vitamin D in the diet, or bone reabsorption
caused by disuse, parathyroid hormone secretion decreases, and the glands undergo hypotrophy.
Bone Diseases – Hypoparathyroidism
 This condition exists when the parathyroid glands do not secrete a sufficient amount hormone.
 Calcium reabsorption from the bones is depressed causing plasma calcium to decrease, though the
strength of bone doesn’t decrease.
 If the glands are surgically removed and replacement therapy is not initiated, the Ca2+ deficiency results in
tetany and eventually, death.
 Replacement therapy with parathyroid hormone is not practical because of its cost and the
development of immune bodies against it.
 Extremely large doses of vitamin D along with an intake of 1-2 g of calcium per day will maintain the plasma
calcium levels in the normal range.
Bone Diseases – Hyperthyroidism
 Occurs when the glands produce an excess of hormone – usually occurs in women and is caused by a tumor
 When mild, bone can be deposited rapidly enough to compensate for increased osteoclastic reabsorption.
 Kidney stones are common because of the excess Ca2+ and PO3-4.
 When severe, the osteoclastic absorption of bone outstrips osteoblastic deposition and the bones are
weakened and break – also increases plasma calcium and causes effects described earlier.
Bone Diseases – Rickets
 Rickets occurs primarily in children due to a deficiency of calcium or phosphate in the plasma by a dietary
deficiency of vitamin D.
 The plasma level of calcium is only slightly depressed because the parathyroid glands prevent the calcium
level from falling by promoting bone resorption every time the calcium level begins to fall.
 Phosphate level is greatly depressed because there is not an ideal regulatory system for preventing the fall
and the increased parathyroid hormone increases the excretion of phosphates in the urine.
Bone Diseases – Adult Rickets
 The deficiency of vitamin D and calcium occurs because of a failure to absorb fat.
 Vitamin D is fat-soluble, and calcium tends to form insoluble soaps with fat - both tend to be lost in feces.
 Adult rickets can be caused by excess intake of castor oil, a laxative favoured by some of the elderly.
 Renal Rickets results from prolonged kidney damage, which may cause the kidney to fail to produce 1,25-
dihyroxycholecalciferol, which is the active form of vitamin D.
Bone Disease – Osteoporosis
 Osteoporosis results from diminished organic bone matrix rather than abnormal bone calcification.
 Osteoblastic activity in the bone is less than normal which results in depressed bone deposition rate.
 It is usually caused by:
1. A lack of physical stress on the bones because of inactivity
2. Malnutrition to the extent that sufficient protein matrix can not be formed
3. Lack of vitamin C which is necessary for secretion of intercellular substances by all cells
4. Postmenopausal lack of estrogen secretion because they have an osteoblast stimulating activity
5. Old age, where GH and growth factors diminish; plus, many proteins anabolic functions become poor.
6. Cushing's disease, due to massive quantities of glucocorticoids which cause decreased protein
deposition, increased catabolism of proteins, and specific depressing osteoblastic activity.
 The Adrenal Glands
The adrenal glands are paired organs that cap in the superior borders of the kidneys
 Each consist of an Outer Cortex and an Inner Medulla that function as separate glands.
The difference between the Cortex and the Medulla are related to their embryonic derivation
 The Medulla derives from an embryonic neural crest called the ectoderm, which is the same tissue that
produces the Sympathetic Ganglia.
 The Cortex derives from an embryonic tissue called the mesoderm.
Hormones of the Cortex
The Cortex secretes a group of hormones known as the Corticosteroids or Corticoids and they are all synthesized
from cholesterol.
There are three main categories of corticosteroids:
 Mineralocorticoids, which regulate Na+ and K+ balance
 Produced by the Zona Glomerulosa
 An example is Aldosterone, and it is the most potent
 Glucocorticoids, which regulate glucose metabolism
 Produced mostly by the Zona Fasciculata and sometimes by the Zona Reticularis
 Example: Cortisol
 Androgens, which supply the sex steroids produced by the gonads.
 Produced by the Zona Reticularis
 Examples: DHEA and Androstenedione, which is weak
Function of Aldosterone
 The most important function of Aldosterone is the promotion of Na+ absorption into the blood and K+
secretion into Kidneys through the wall of the distal tubule and collecting duct of the nephron.
 The concentration of potassium in the extracellular fluid is normally about 4.5 mMol/L.
 A doubling of this concentration can be lethal, so it must be regulated within narrow limits.
 The potassium ion is freely filtered at the glomerulus and is virtually all reabsorbed.
 The amount of potassium ions lost in the urine depends upon secretion, which is regulated by aldosterone.
 Reabsorption of Na+ has little effect on the concentration of Na+ in extracellular fluid because of the
osmotic reabsorption of water.
 When glomerular filtrate reaches the distal tubule, most of the Na+ has already been reabsorbed.
 Aldosterone regulates about 2% of Na+ reabsorption, but sometimes, this 2% can be critical due to
the possibility of reduced body Na+ causing lowering blood pressure – activates hormones release,
 This then stimulates sodium and water reabsorption.
 The mechanism by which aldosterone stimulates Na+ reabsorption and K+ secretion is partly understood.
1. Aldosterone is lipid soluble, so it diffuses across the membrane and combines with a cytoplasmic
receptor protein when then diffuses into the nucleus where it induces mRNA formation.
2. mRNA diffuses back into the cytoplasm where it causes formation of enzymes, receptors, &
membrane transporters for Na, K, & H – includes enzyme Na/K ATPase at the basolateral membrane
3. Channel proteins increase at the luminal membrane of the same tubular cell that permits the rapid
diffusion of Na+ from the tubular lumen into the cell and K+ from the cell into the lumen.
4. Sodium is then pumped out the basolateral membrane in exchange for potassium.
 Although aldosterone causes potassium secretion into the lumen, it also causes a small amount of
hydrogen ion secretion into lumen.
 Since new RNA must be formed, the effects of aldosterone on sodium transport begins after 45 minutes
and will take hours to reach a maximum effect.
Release of Aldosterone
 Aldosterone secretion is regulated by four factors in the following order of importance:
1. Increases in the potassium ion concentration of the extracellular fluid
2. The Renin-Angiotensin system
3. Decrease in sodium ion concentration in the extracellular fluid
4. Adrenocorticotropic hormone (ACTH)
 A very small change in the extracellular concentration of potassium can cause a several-fold change in
aldosterone secretion.
 The Renin-Angiotensin system is activated by a reduction in blood flow to the kidneys due to a reduced
blood volume.
 Angiotensin II, a peptide that causes vasoconstriction, stimulates the release of Aldosterone from the
Adrenal Cortex, which increases sodium and water reabsorption as well as potassium secretion.
 A low concentration of sodium in the extracellular fluid has a direct weak stimulatory effect on Aldosterone
secretion.
 The effect of ACTH is small, but a total absence of ACTH can significantly reduce aldosterone secretion.
Functions of Cortisol
 Cortisol will stimulate the rate of gluconeogenesis, which is the formation of glucose from amino acids, in
the liver by up to 10-fold by acting on the liver cell nuclei to activate DNA transcription leading to the
formation of the enzymes required for gluconeogenesis.
 Also mobilizes amino acids from the muscle that can be used by the liver in gluconeogenesis.
 Cortisol causes a moderate decrease in the rate of glucose utilization in cells – not known why.
 Both increased gluconeogenesis and reduced cellular utilization of glucose leads to elevated blood glucose.
 This is called Adrenal Diabetes; like pituitary diabetes.
 Cortisol reduces the protein stores in all the cells of the body except in the liver due to the increased
catabolism of the protein already in the cells and to decreased protein synthesis – not understood
 Partly due to a decreased amino acid transport into extra hepatic tissues, and the depression of RNA
formation in muscle and lymphoid tissue.
 If Cortisol is excess, muscles become very weak and immunity functions of lymphoid tissue is decreased
 However, liver proteins are increased and since the plasma proteins are produced in the liver, they
too increase – may be due to enhanced amino acid transport into the cells
 Decreased amino acids transportation into muscle and extrahepatic cells, decreases their availability for
protein synthesis.
 At the same time, catabolism of cellular protein increases the release of amino acids from the cell
into the plasma - becomes available to the liver cells for protein synthesis and gluconeogenesis.
 Enhances the mobilization of fatty acids from adipose tissue, which increases the concentration of free
fatty acids in the plasma where they’re used for energy – partly due to reduced glucose uptake into cells.
 Increases oxidation of fatty acids in cells - from reduced availability of glycolytic products for metabolism.
 Increased mobilization of fats and oxidation of fatty acids in cells shifts the metabolic systems in times of
starvation or prolonged stress from using glucose to using fatty acids – requires several hours to fully occur
 Persons with excess Cortisol have excess deposition of fat in the chest and head regions of the body.
Release of Cortisol in Stress
 All types of stress such as examinations, emotional turmoil, trauma, infection, or temperature extremes
will cause the release of cortisol.
 Cortisol makes glucose, amino acids and free fatty acids available as sources of energy, but its specific role
in stress is unknown.
Anti-inflammatory Effects of Cortisol
 Cortisol is very effective as an anti-inflammatory drug and recent work suggests that the injection into the
area of a spinal cord injury can reduce the chance of permanent paralysis.
 Cortisol works by blocking the early stages of inflammation; if it has already begun, it will cause rapid
resolution of the inflammation and increase the rapidity of healing.
 The anti-inflammatory effects are due to the following effects:
1. It stabilizes lysosomal membranes and prevents the release of proteolytic enzymes that are
released by damaged cells and contribute to the inflammation.
2. It decreases the permeability of the capillaries caused by the proteolytic enzymes or histamine
thereby preventing the leaking of plasma out of the vessels.
3. It decreases migration of WBCs into the inflamed area and decreases phagocytosis of damaged cell
4. It suppresses the immune system by reducing the number of T lymphocytes which then lessen the
tissue reactions that cause inflammation
5. It lowers fever by reducing the release of interleukin-1 from leucocytes which then also reduces
the degree of vasodilation
 Although cortisol appears to be a wonder drug that prevents or reverses inflammation, it does not correct
the basic disease condition - in some cases, the inhibition of the immune system may be deleterious.
 Cortisol is usually combined with antibiotics, especially in treating respiratory infections.
Cortisol and Allergy
 Cortisol does not affect the basic allergic reaction between antigen and antibody, but it does block the
potentially lethal inflammatory response by preventing shock or death in anaphylaxis
 In asthma, cortisol prevents the release of histamine by mast cells.

Regulation of Cortisol Release

 The release of cortisol is almost entirely controlled by adrenocorticotropic hormone (ACTH) that is secreted
by the anterior pituitary.
 In addition, vasopressin, also known as Anti-diuretic hormone (ADH), also increases the production of ACTH
by corticotropes.
 The hypothalamus releases corticotrophin-releasing factor (CRF) and ADH, which enters the portal system
and is carried to the anterior pituitary.
 ACTH activates adenyl cyclase in the cell membrane of the adrenocortical cells which induces the formation
of cAMP causing it to activate the intracellular enzymes necessary to produce cortisol.
 Cortisol has a direct negative feedback effect on the hypothalamus to decrease the formation of CRF and
on the anterior pituitary to decrease the formation of ACTH.
 Hormones of the Medulla
The hormones secreted by the inner part of the adrenal gland, the Medulla, are Adrenaline and Noradrenaline
which are catecholamines – they are said to have a synergistic additive affect
 Their effects are similar to the stimulation of the sympathetic nervous system, like the sympathetic
ganglion, except that it lasts about 10x longer and secretions go into the blood
 Secrete at a 4:1 (80%/20%) ratio, but in some animals its closer to 50:50.
Adrenal medulla effects include increased cardiac output and heart rate, dilation of coronary blood vessels,
Increased mental alertness, elevated metabolic rate, and increased respiratory rate.
Specifically, the effects related to metabolism include increased blood glucose levels, increased basal metabolic
rate (BMR), increased glucose release from the liver, and increased glycolysis in the liver and muscle.
The adrenal medulla is innervated by preganglionic sympathetic axons and secretes its hormones whenever the
sympathetic nervous system is activated during a fight or flight response.
 This is supported by a rise in blood glucose due to stimulation of Heptic Glycogenolysis and a rise in blood
fatty acids due to stimulation of lipolysis
Stress and Memory
 Parts of the brain, such as the prefrontal cortex, hippocampus, and amygdala, have receptors for stress
hormones, such as glucocorticoids, epinephrine, and CRH.
 This has shown to promote or suppress long term potentiation (LTP) and long-term depression (LTD).
 Glucocorticoids and epinephrine can enhance LTP and memory formation during acute stress
 High levels of glucocorticoids released during chronic stress inhibit LTP in these parts of the brain.
 These changes may relate to the disruption of working memory, in the prefrontal cortex, and the
declarative memory, in the hippocampus, by stress
 Stress hormones may also act on the amygdala, where fearful memories are stored, and other brain
regions to contribute to anxiety and depression with prolonged negative stress.
Medulla Hormone Response
 There are three stages in the response to stress:
1. The alarm reaction, when adrenal glands activated.
2. Stage of resistances, when readjustments occur.
3. Stage of exhaustion, only occurs if stage 2 doesn’t complete - may lead to sickness and death.
 Different responses of the pituitary-adrenal axis and sympathoadrenal system to different stressors are
coordinated by the higher brain regions such as the prefrontal cortex, amygdala, and hippocampus, and
through the synapses in the hypothalamus, medulla oblongata, and spinal cord
 After epinephrine is released, it binds to adrenergic receptors in the plasma membrane of its target cells.
 The stimulation of the beta-adrenergic receptors results in activation of adenylate cyclase and the
production of cAMP
 The stimulation of the alpha1-adrenergic receptors activates the target cell by activating an enzyme
in the plasma membrane called Phospholipase C via G proteins – produces a Ca2+ second messenger
system
 The substrate of this enzyme is then split by the active enzyme into inositol triphosphate (IP3)
and diaglycerol (DAG), which both serve as second-messengers
 IP3 carries hormone messages and acts to increase cytoplasmic Ca+2 - it leaves the membrane
and transports to the endoplasmic reticulum which then binds to the IP3 receptors.
 Ca+2 then enters the cytoplasm and binds to a protein called Calmodulin which causes it to
become active calmodulin which then causes activated protein kinase enzymes to modify the
actions of enzymes in the cell
 Sympathetic nerves, acting through norepinephrine, can stimulate B3-adrenergic receptors in brown
adipose tissue, which contains an uncoupling protein that dissociates electron transport from the
production of ATP – resulting in a very high rate of energy expenditure by epinephrine.
 The Pancreas
The pancreas is a gland that consists of two parts: the endocrine pancreas and the exocrine pancreas.
The exocrine pancreas secretes products through a duct into the outside of an epithelial membrane or to the
external environment.
 Known to secrete pancreatic juices.
The endocrine pancreas contains three types of endocrine cells called the pancreatic islets or islets of Langerhans
 Alpha cells, compose 35-40% of pancreatic cells, secretes glucagon which raises blood glucose levels
 Beta cells, compose 50% of pancreatic cells, secretes insulin which lowers blood glucose levels
 Delta cells, compose 10-15% of pancreatic cells, secrete somatostatin which depresses insulin and glucagon
These three cells are close in proximity in the islets of Langerhans and have direct control over the secretion of
each other.
The islets of Langerhans receive both parasympathetic and sympathetic innervation.
Mechanisms and actions that regulate Insulin and Glucagon secretion prevent the plasma glucose concentration
from rising above 170mg/100ml after a meal or from falling below about 50mg/100ml between meals.
 Fasting plasma glucose is in the range 65-106mg/dl
Insulin
Insulin is produced by proinsulin, who derives from a precursor called preproinsulin.
The parasympathetic division of the autonomic system is activated during meal and stimulates both GI function
and the secretion of insulin from the beta cells – due to a neurotransmitter, called Acetylcholine (Ach),
stimulating muscarinic ACh receptors to cause a depolarization.
Insulin promotes glucose and amino acid transport and stimulates glycogen, fat, and protein synthesis in its target
organs which are primarily the liver, skeletal muscles, and adipose tissue.
 Acts similar to growth factors such as Epidermal Growth Factor (EGF), Platelet Derived Growth Factor
(PDGF), and Insulin Like Growth Factor (IGF)
Regulation of Insulin
 Not only does blood glucose levels regulate Insulin secretion, but also blood amino acids, gastrointestinal
hormones, glucagon, GH, cortisol, progesterone and estrogen – too a small extent, and the stimulation of
sympathetic and parasympathetic nerves to the pancreas.
 After a meal, the plasma level of insulin rises 10-fold within 3-5 min.
 However, within 5-10 min, the secretion decreases to about 5-fold.
 After ~15 min, insulin increases and a gradual plateau of about 15x control level is reach after 2 hrs
 Blood glucose provides a rapid feedback mechanism to the pancreas for regulating insulin release.
Insulins Receptors
 The receptors on the target cell that Insulin binds to are homodimers have for separate subunits that are
bound together by a disulfide bond.
 Two alpha subunits that lie entirely outside the cell membrane – where Insulin binds to.
 Two beta subunits that penetrate through the membrane with ends that protrude into the cytoplas
 In the case of many growth factors, the binding of the ligand to its receptor causes the receptors to form
dimers that allow one member to phosphorylate the other in a process called autophosphorylation.
 This activates the tyrosine kinase portion on the cytoplasmic side of the receptor
 The receptor forms the shape of an inverted V with an insulin binding site on its extracellular surface
that when bonded to it causes a portion of the polypeptide to move
 This change results in the autophosphorylation of the receptor, activating its tyrosine activity
 The activated insulin receptor then phosphorylates insulin receptor proteins, which provides an
enzymatic docking station that activates a variety of other signaling molecules
 These signalling molecules cause the insertion of transport carrier proteins into the plasma
membrane that’s used in the facilitated diffusion of glucose into the cells
Secretion of Insulin
 When the plasma glucose level is low, ATP gated K+ channels in the beta cell plasma membrane open.
 This allows the efflux of K+ and keeps the membrane hyperpolarized which then causes the entry of
more glucose into the beta cells by facilitated diffusion through GLUT1 carriers
 Glucose then undergoes aerobic respiration, leading to an increase of ATP.
 This then causes the closing of ATP gated K+ channels in the plasma membrane, producing a
depolarization that can reach a threshold and produce an action potential
 At the peak of the action potential, Ca2+ channels open in the plasma membrane and the Ca+2
enters the cell and stimulates the exocytosis of Insulin
 The Oral Glucose Tolerance Test is a measure of the ability of the beta cells to secrete Insulin and of the
ability of Insulin to lower blood glucose.
 In the procedure, a person drinks a glucose solution and then a blood sample is taken periodically for
plasma glucose measurements.
 Insulin secretion increases more rapidly when glucose is taken orally rather than injected intravenously
 The intestine secretes hormones that stimulate Insulin secretion before glucose has even been
absorbed.
 These intestinal hormones are Incretins and they include the Glucagon-Like Polypeptide 1 (GLP-1),
which is secreted by Ileum, and the Glucose-Dependent Insulinotropic Polypeptide (GIP), which is
secreted by Duodenum
 Glycogen is less efficient as an energy reserve, and less is stored in the body, about 100g of glycogen stored
in the liver and 375-400g is stored in the skeletal muscles.
 Insulin promotes the conversion of glucose into glucose-6-phosphate, which then is converted into glucose-
1-phosphate, in the liver and muscles – this is a precursor for glycogen
Insulins Effect on Carbohydrate Metabolism
 Insulin is the only hormone that acts to lower blood glucose concentrations
 It binds to receptors on the targets membrane and through the action of signalling molecules it
causes intracellular vesicles containing GLUT4 carrier proteins to translocate to the membrane.
 GLUT4 promotes the facilitated diffusion of glucose into Insulins target organ cells.
 It also indirectly stimulates the activity of the enzyme glycogen synthetase in the skeletal muscles and liver,
which promotes the conversion of intracellular glucose into glycogen for storage.
 Thereby causes glucose to leave the plasma and enter the targets, where its converted into the
energy storage molecules of glycogen, in skeletal muscles and liver, and fat, in adipose tissue.
 It also promotes anabolism
 Important because the brain uses plasma glucose as its primary energy source – about 60% when resting.
 The brain doesn’t require Insulin to transport glucose due to its permeability.
 Insulin causes the rapid uptake, storage and use of glucose by almost all tissues, but especially by the
muscles, liver and adipose tissue – resting muscles are only slightly permeable to glucose without insulin
 The storage of glucose by the liver is dependent on the inhibition of a liver enzyme, called phosphorylase,
which splits liver glycogen into glucose – prevents a decrease in liver glycogen levels.
 Low Insulin levels, along with high levels of Glucagon, causes Phosphorylase to activate.
 Insulin enhances the uptake of glucose by liver cells by increasing the activity of the enzyme Glucokinase,
which initiates the phosphorylation of glucose after it diffuses into the liver cells.
 Once phosphorylated, the glucose is temporarily trapped inside the cell and cannot diffuse out
 Insulin also increase the activity of the Phosphofructokinase, which causes the second stage in the
phosphorylation of the glucose molecule, and Glycogen Synthase, which causes the polymerization of the
monosaccharide units to form the glycogen molecules.
 Glucose phosphatase, which is inhibited by Insulin, becomes activated and causes the phosphate radical to
split away from the glucose, which allows free glucose to diffuse back into the blood.
Glucose Uptake in Between Meals
 Between meals, the Insulin level is too low for glucose uptake, so instead, the muscles use fatty acids.
 In moderate-heavy exercise, glucose uptake increases between meals - not due to Insulin.
 The cause of the increased uptake in not known.
 During exercise, muscle uptake is increased for a few hours after a large meal because Insulin levels
are high – glucose is utilized preferentially over fatty acids because the flow of fatty acids from the
adipose tissue is strongly inhibited by Insulin.
 Between meals, the blood glucose level falls, and the liver glycogen is converted back into glucose and
released into the blood stream.
 If the muscles are not exercising after a meal, the glucose is stored as glycogen for later use.
 Glycogen is used for energy and especially during bursts of intense exercise when the oxygen supply to the
muscle is inadequate and anaerobic conditions exist - glycogen breaks down into lactic acid.
Insulin Effects on Fat Metabolism
 Insulin enhances fat storage in adipose tissue and spares stored fat by increasing glucose utilization
 When glucose exceeds glycogen storage, Insulin promotes fatty acid synthesis in the liver cells that are
then released into the blood steam where they are transported as VLDLs to the adipose tissue.
 At the adipose tissue, Insulin inhibits the action of hormone-sensitive lipase, which causes the
hydrolysis of the triglycerides already stored in the fat cell - inhibits the release of fatty acids.
 In addition, Insulin promotes glucose transport through the cell membrane into the fat cell.
 Some glucose is used to synthesize bits of fatty acids, but most goes to forming α-glycerophosphate which
supply’s the glycerol that combines with fatty acids to form triglycerides that are the storage form of fat.
 In Insulin deficiency, fat doesn’t take up the fatty acids transported from the liver in lipoproteins.
 Therefore, blood of a diabetic patient often appears to be "milky".
 Its derived from glucose, and is required for both deposition of and maintenance of triglycerides in
these cells - In its absence, fat cells release fatty acids
 Between meals, low levels of Insulin enhance the breakdown and usage of fat as a source of energy
because the enzyme hormone-sensitive lipase in the fat cells becomes activated
 This hormone causes the hydrolysis of the stored triglycerides, releasing large quantities of fatty
acids and glycerol into the circulation – fatty acids then become the main energy source.
 The excess of fatty acids in the plasma promotes liver conversion of some of the fatty acids into
phospholipids and cholesterol.
 These two substances and excess triglycerides in the liver are released into the blood in lipoproteins
 This leads to the development of atherosclerosis in patients with serious diabetes.
 Insulin lack causes excessive amounts of acetoacetic acid to be formed in the liver cells and depresses the
utilization of acetoacetic acid in the peripheral tissues.
 Since it cant be utilized, ß-hydroxybutyric acid and acetone, also called ketone bodies, are produced,
leading to the condition known as ketosis – gives your breath a “sweet” smell
Effects on Protein Metabolism
 Insulin causes the active transport of many amino acids into cells.
 Growth hormone also has this function, but the amino acids are not necessarily the same.
 For normal growth to occur, there must be both growth hormone and insulin.
 Evidence indicates that they act synergistically to promote growth
 Insulin also has a direct effect in turning on the ribosomal machinery for the translation of mRNA and the
formation of new proteins - without this hormone, the ribosomal machinery is not activated.
 Over time, insulin increases the rate of transcription of selected DNA genetic sequences in the cell
nuclei thus forming increased quantities of RNA and more protein/enzyme synthesis for storage of
carbohydrates, fats, and proteins.
 In the liver, Insulin depresses the rate of Gluconeogenesis by decreasing the activity of the enzymes that
promote Gluconeogenesis.
 Because plasma amino acids are the substrates used for the synthesis of glucose in gluconeogenesis,
insulin conserves these amino acids.
 Insulin promotes protein formation and prevents the degradation of the proteins.
 In Insulin deficiencies, all protein storage comes to a complete halt.
 The catabolism of proteins increases, protein synthesis stops, and large quantities of amino acids are
released into the plasma.
 Plasma amino acids rise, and the excess are used directly for energy or as substrates for
gluconeogenesis which leads to the enhanced urea excretion in the urine.
 The loss of protein results in extreme muscle weakness and deranged functions of the organs.
Insulin Diseases – Type 1 Diabetes Mellitus
 Type 1 diabetes mellitus, or Juvenile Onset Diabetes, is an autoimmune disease that is usually diagnosed in
people under 20 – it is characterized by increase blood glucose and glucose appearing in the urine
 In most patients, diabetes mellitus is a diminished secretion of insulin by the beta cells of the pancreas.
 This deficiency may be associated with heredity, damage of beta cells by viral infections, autoimmune
antibodies against the beta cells, or an abnormality in the secretion of a hormone beta cell desensitizing.
 Risk of diabetes mellitus increase to about 65% between identical twins of a patient with the disease.
 Glucose is reabsorbed by active transport in the proximal tubule of the nephron, so none usually appears in
the urine - since a transport protein is involved there’s a maximum amount that the kidney can reabsorb.
 When glucose is excreted in the urine, the glucose has an osmotic effect and water that would
normally be reabsorbed is carried out with the glucose – causes polyuria and polydipsia
 This leads to dehydration, a reduction in blood volume and potentially circulatory shock.
 A loss of body weight and lack of energy, despite polyphagia, are other symptoms which are due to
failure of glucose utilization and loss of body proteins.
 The shift from glucose to fat metabolism results in the production of the acids, acetoacetic acid and ß-
hydroxybutyric acid, which leads to a lowering of the blood pH - acidosis
 These acids are excreted by the kidney with Na+ causing extracellular Na+ concentration to fall and
the positive charges are replaced by hydrogen ions - worsens the acidosis.
 To correct the acidosis, the patient can increase their respiratory rate, known as hyperventilation,
and plasma bicarbonate is used up to buffer the hydrogen ions.
 If the condition is severe enough, the patient will enter an acidotic coma that can lead to death.
 Other complications include Atherosclerosis, increased susceptibility to infections, Diabetic retinopathy,
Cataracts – the clouding of the eye, Hypertension, and Chronic renal disease
 These conditions are more associated with the levels of blood lipids than blood glucose.
 Thus, its equally important to control the patient's fat intake, as it is the carbohydrate intake.
Insulin Diseases – Type 1 Diabetes Mellitus
 Because type 1 diabetes is increasing it appears that environmental factors play triggering role in
genetically susceptible people.
 Viruses are prominent and may trigger an autoimmune attack of the islet beta cells
 Autoreactive T lymphocytes, helper and killer T cells, are believed to be the most important in the
progressive destruction of the insulin secreting beta cells
 Exercise increases insulin sensitivity and obesity decreases insulin sensitivity of the target tissues.
 Insulin resistance refers to a reduction in the target tissues sensitivity to insulin.
 Its promoted by fatty acids and diacylglycerol from ectopic fat, and by adipokines released by
adipocytes
 Can be associated with hypertension, and dyslipidemia
 Weight reduction, entailing a shrinking of viscera adipocytes, reduces insulin resistance.
 Diets enriched in fiber help decrease insulin resistance – including soluble fibers, such as fructose
and galactose, and insoluble fibers, such as cellulose and lignin.
 Exercise is beneficial in two ways:
1. Increases calorie expenditure - helps people lose weight and decreases the size of the adipocytes,
making them more sensitive to insulin
2. Improves sensitivity of skeletal muscle fibers to insulin – partly because muscle contraction during
exercise, which is independent of insulin, increases the amount of GLUT4 carriers in the plasma
membrane that are needed for the facilitative diffusion of glucose into the skeletal muscle fibers.
 Also enhances the ability of insulin to stimulate skeletal muscle glucose uptake and utilization
in other ways, making the skeletal muscles better able to remove glucose from the blood.
Insulin Diseases – Type 2 Diabetes Mellitus
 Type 2 Diabetes, also called Maturity Onset Diabetes, is usually diagnosed in people over 40 and is more
common and they don’t usually develop ketoacidosis
 Plasma insulin levels are normal, but insulin's target cells don’t respond to insulin - maybe due to
insufficient insulin receptors on the targets or issues in the intracellular process after receptor activation.
 Type 2 diabetes may coincide with overeating and obesity resulting in large and frequent release of insulin
 Over time, elevated insulin levels induce a reduction in the number of insulin receptors resulting in the
glucose levels remaining high and stimulating even more insulin secretion, which worsens the problem.
 The insulin hypo-responsiveness can be completely reversed if the person reduces his/her caloric intake.
 Exercise increases the number of insulin receptors independent of changes in weight gain.
 The number and secretory ability of beta cells diminishes, resulting in failure to overcome the resistance
 There’s a strong heritable component; identical twins have ~70% risk and patients will have a 70% risk is
both parents have it - this increases with obesity, more so if they have large adipocytes in the omentum
 Visceral obesity, and the accumulation of ectopic fat, which is fat that’s deposited in the skeletal
muscles and the liver, an opposed to subcutaneous adipose cells, are associated with insulin
resistance, type 2 diabetes, and metabolic syndrome.
 Diabetes is a major cause of kidney failure and limb amputations, and is the second leading cause of
blindness since its associated with metabolic syndrome - high blood triglycerides and low HDL cholesterol
increases risk of atherosclerosis, leading to a significant contributor to CVD.
 People with diabetes frequently have circulatory problems that increase the tendency to develop
gangrene and increase the risk of atherosclerosis – also causes damage to the retina and lens.
 Due to a long-term exposure to high blood glucose.
 Glycated hemoglobin (hemoglobin A1c) test measures blood glucose over a few months – no fasting
 Alc measurement of ~5% is normal, whereas an A1c of 5.7-6.4% indicates prediabetes
 An Alc above 6.5% indicates diabetes
Diabetes Comparison
Feature Type 1 Type 2
Age of onset Under 20 years Over 40 years
Development of symptoms Rapid Slow
% of diabetes population 5% 95%
Ketoacidosis Common Rare
Obesity Rare Common
Beta Cells Destroyed Intact
Insulin Secretion Decreased Normal or Increase
Autoantibodies to Islets cells Present Absent
Associations to MHC antigens Yes Unclear
Treatment Insulin Injection Diet and exercise; oral stimulators of insulin sensitivity

Insulin Diseases – Hyperinsulinism

 Hyperinsulinism can result from a tumour of the islets of Langerhans or from an overdose of exogenous
insulin.
 The blood glucose level falls too low and "insulin shock" can occur.
 As blood sugar level falls, neuronal activity increases, and the patient may appear nervous, tremble
all over, sweat, and very rarely hallucinate.
 As blood glucose levels drop further, the patient will convulse and eventually enter a coma.
 It is possible to differentiate clinically between diabetic coma and insulin shock
 A patient in a diabetic coma will have acetone breath and deep breathing
 A patient in insulin shock will not exhibit these symptoms.
 Glucagon
 Glucagon functions are opposite to those of insulin.
 Glucagon stimulates glycogenolysis, which is the breakdown of liver glycogen, by activating an enzyme
cascade where each step is more potent than the previous one.
 Glucagon stimulates gluconeogenesis in the liver by activating enzymes.
 Also increases the extraction of amino acids from the blood by liver cells and making more available for
conversion to glucose
 Glucagon is secreted during hypoglycaemia to increase the blood glucose levels.
 However, glucagon secretion also increases after a meal high in protein – same effect as insulin
 This is due to the increased levels of amino acids in the blood.
 Glucagon blood levels rise in exhaustive exercise even though the blood glucose is normal - not known why
 Glucagon and other hormones promote other catabolic effects which include lipolysis, the hydrolysis of
stored fat, and ketogenesis, the formation of ketone bodies from free fatty acids by the liver.
 These serve as energy sources for cell respiration during fasting
 Glucagon and epinephrine are both are mediated by cAMP
 Free fatty acids are made available by the action of glucagon which activates an enzyme in adipose tissue
called Hormone Sensitive lipase.
 This enzyme catalyzes the hydrolysis of stored triglycerides and release free fatty acids and glycerol
into the blood.
 Glucagon also activates enzymes in the liver that convert some of these fatty acids into ketone bodies,
which are secreted into the blood.
 Several organs in the body can use ketone bodies, as well as fatty acids, as a source of acetyl CoA in
aerobic respiration.
 Free fatty acids reduce the activity of muscles to utilize glucose for energy so more is available for the brain
 Somatostatin
Somatostatin is stimulated by increased blood glucose, amino acids, fatty acids, and several of the
gastrointestinal hormones released in response to the ingestion of food.
Somatostatin acts locally within the islets of Langerhans to depress the secretion of both insulin and glucagon
 it decreases the motility of the stomach, duodenum and the gall bladder
 it decreases both secretion and absorption in the gastrointestinal tract.
 Its functions appear to be to prolong the availability of nutrients that are ingested.
Somatostatin is the same compound as growth hormone inhibitory hormone (GHIH), which is secreted in the
hypothalamus and suppresses secretion of growth hormone by the anterior pituitary gland.
 The Pineal Gland
The Pineal Gland is a small cone-shaped gland located on the roof of the third ventricle of the diencephalon
where its encapsulated by the meninges covering the brain
 It regresses in size at about age 7; in the adult, it appears as a thickened strand of fibrous tissue
 It lacks direct nervous connections to the rest of the brain, and it is highly innervated by the sympathetic
nervous system from the superior cervical ganglion
 Secretes melatonin, which is an indoleamine neurohormone derived from 5-HT (5-hydroxytryptophan)
The Suprachiasmatic Nucleus (SCN) of the hypothalamus regulates the pineal secretion of melatonin through
hypothalamic control of the sympathetic neurons that innervate the pineal gland
 Its also the primary center for regulations of the body’s circadian rhythms
Most of the neurons of the SCN produce action potentials starting at dawn and increases toward the middle of
the day and decreases to become mostly silent at night
 Light acts through the retinohypothalamic tract to synchronize this spontaneous circadian rhythm to the
light/dark cycle; activation of rhodopsin and photopsins also influence the retina to regulate these rhythms
 The regulatory effect of light on the SCN appear to require the retinal pigment Melanopsin, which is found
in a population of ganglion cells
Melatonin
 Melatonin is derived from a nonpolar amino acid is orally effective due to its ability to pass through plasma
membranes – it also has some polar similarities due to its effect on cells
 Secretion is affected by a circadian rhythm, with light inhibiting secretion – peaks in the middle of the night
 Melatonin has a role in helping time the births of seasonally breeding animals by influencing the pituitary-
gonad axis – stimulates it in short day breeders, like sheep, and inhibits in long day breeders, like voles
 In humans, excessive production of melatonin is associated with delayed onset of puberty.
 Evidence suggests that exogenous consumption of melatonin could be beneficial in dealing with jetlag.
 Paracrine and Autocrine
All paracrine/autocrine regulators control gene expression in their target cells to some degree
 This occurs with various growth factors including Platelet Derived Growth Factor, Epidermal Growth Factor,
and Insulin-Like Growth Factor – stimulate cell division and proliferation of their target cells
Paracrine regulators are locally acting chemicals that regulate neighbouring cells within an organ
 Known as Cytokines if they regulate cells of the immune system, and as Growth Factors if they promote
growth and cell division in any organ.
Cytokines produced by adipose tissue are called Adipokines and are produced by muscle tissue called myokines.
Cytokines produced by lymphocytes are known as lymphokines, and molecules involved are called interleukins.
Blood vessel walls have different tissue layers and the endothelial layer produces several regulators for the
smooth muscle layer
 Produces regulators that include Endothelin’s, such as endothelin-1, which directly promote
vasoconstriction, and Bradykinin which promotes vasodilation – important for blood flow and pressure
Autocrine regulators act on the same cell and cell type that produced them
 Neurons and neuroglia release neurotrophins, such as the nerve growth factor.
The most diverse group of paracrine/autocrine regulators is the Prostaglandins – a 20-C long fatty acid that
contains a 5 membered C ring from the family Eicosanoids which are derived from the precursor Arachidonic Acid
 Produced in almost every organ and has a wide variety of regulatory functions
 Upon stimulation by hormones, Arachidonic Acid is released from phospholipids in the plasma membrane
and may then enter one of two possible pathways
1. Arachidonic acid is converted by Cyclooxygenase into a Prostaglandin which can be changed by other
enzymes into other prostaglandins
2. Arachidonic acid is converted by Lipoxygenase into leukotrienes, which are eicosanoids that are
closely related to prostaglandins and largely responsible for the symptoms of Asthma.
 Prostaglandins
Blood platelets produce Thromboxane A2, which is a prostaglandin that promotes clotting by stimulating platelet
aggregation and vasoconstriction.
Endothelial cells of blood vessels produce a different prostaglandin, known as PGI2 or Prostacyclin, whose effects
it inhibits platelet aggregation and causes vasodilation.
Some regulatory functions proposed for prostaglandins in different systems of the body are:
1. Immune System; promotes many aspects of the inflammation, including the development of pain and fever
 Drugs that inhibit prostaglandins synthesis help to alleviate these symptoms
2. Reproductive System; role in ovulation and corpus luteum in the ovaries and contraction of the uterus.
o Excessive PGE2 and PGI1 may be involved in premature labor, endometriosis, dysmenorrhea - painful
menstrual cramps, and other gynecological disorders.
3. Digestive system; inhibits gastric secretions and influence motility and fluid absorption
4. Respiratory system; constriction or dilation of blood vessels in the lungs and bronchiolar smooth muscle
o Leukotrienes are potent Broncho-constrictors, and these compounds, together with PGF2, may cause
respiratory distress and contribute to bronchoconstriction in asthma
5. Circulatory system; vasoconstrictors or vasodilators depending on the hormone.
o Thromboxane A2, a vasoconstrictor, and prostacyclin, a vasodilator, play a role in blood clotting.
o PGE2 is believed to promote dilation of the ductus arteriosus, which is a short vessel that connects
the pulmonary artery with the aorta
o After birth, the ductus arteriosus normally closes because of a rise in blood oxygen when the baby
breaths – if not, it’s closed by the administration of drugs that inhibit prostaglandin synthesis
6. Urinary system; produced in the renal medulla and causes vasodilation resulting in an increased renal
blood flow and increased excretion of water and electrolytes in the urine
Drugs and Cyclooxygenase
There are two major isoenzyme forms of cyclooxygenase:
1. Type 1 COX-1, which is produced by the cells of the stomach and kidneys, and by blood platelets
2. Type 2 COX-2, which is induced in many cells in response to cytokines that are involved in inflammation
causing prostaglandins to be produced and promote this inflammatory condition.
 COX-2 selective inhibitors produce a significant increase in the risk of myocardial infarction, also
known as heart attack, and thrombotic stroke after a year or more of treatment.
 The benefits of the selective COX-2 inhibitors for GI protection may outweigh the increased risk of
cardiovascular disease in some patients.
Aspirin is a member of a class of drugs known as Nonsteroidal Anti-Inflammatory drugs (NSAIDs); other members
include indomethacin and ibuprofen
 Specifically inhibit a Cyclooxygenase that’s needed for prostaglandin synthesis therefore inhibiting
inflammation – may produce side effects like gastric bleeding, kidney issues, and prolonged clotting time
When aspirin and indomethacin inhibit COX-1, they reduce the synthesis of prostacyclin, also known as PGI2, and
PGE2 in the gastric mucosa
 Inhibition of the COX-1 isoenzyme may cause serious Gl and renal toxicity in long-term use
 Newer COX-2 selective drugs, including celecoxib and rofecoxib, can inhibit inflammation while producing
fewer negative side effects in the gastric mucosa
Acetaminophen doesn’t greatly inhibit either COX-1 or COX-2 and is not effective in anti-inflammatory agent
 Though it does reduce fever and relieve pain
Drugs that are anti-leukotrienes have recently become available and can aid in asthma treatment.
 Some work by inhibiting the enzyme 5-lipoxygenase that forms leukotrienes
 Others can block the leukotriene receptor.