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Adrenal glands

The adrenal glands consist of an outer cortex and inner medulla. The cortex secretes mineralocorticoids like aldosterone and glucocorticoids like cortisol. The medulla secretes epinephrine and norepinephrine. Adrenal insufficiency can be primary, secondary, or tertiary and results in low cortisol levels. Addison's disease is primary adrenal insufficiency caused by destruction of the adrenal cortex. It causes symptoms like fatigue, weight loss, and hypoglycemia due to low cortisol and mineralocorticoid deficiencies.

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adrenal glands • Two adrenal glands • Each weighs 4 grams • Lie at the superior poles of the two kidneys • Two distinct parts, adrenal medulla and adrenal cortex Adrenal medulla, central 20 % of the gland, is functionally related to the sympathetic nervous system • It secretes epinephrine and norepinephrine in response to sympathetic stimulation Adrenal cortex secretes corticosteroids.
Adrenocortical hormones: Mineralocorticoids Glucocorticoids Androgens (small amounts) • Mineralocorticoids: affect electrolytes (“minerals”) of extracellular fluids -sodium and potassium, in particular • Glucocorticoids : important effects that increase blood glucose concentration + additional effects on protein and fat metabolism • More than 30 steroids have been isolated from the adrenal cortex • Aldosterone principal mineralocorticoid • Cortisol principal glucocorticoid.
Adrenal Cortex • Three Distinct Layers 1. Zona glomerulosa, 15% of the adrenal cortex • A thin layer of cells that lies just underneath the capsule • Secrete aldosterone • Secretion is controlled by ECF concentrations of angiotensin II and potassium, which stimulate aldosterone secretion. 2. Zona fasciculata, 75% of the adrenal cortex • Middle and widest layer • Secretes glucocorticoids cortisol, corticosterone, and small amounts of adrenal androgens and estrogens. • Secretion is controlled by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).
• Zona reticularis, deep layer of cortex • Secretes adrenal androgens, dehydroepiandrosterone (DHEA) and androstenedione, small amounts of estrogens and glucocorticoids. • ACTH regulates secretion of these cells • Cortical androgen-stimulating hormone, released from the pituitary, may also be involved.
Adrenal Gland
Adrenocortical Hormones Are Steroids • Derived from Cholesterol • Cholesterol is provided by LDL in the circulating plasma. • Transport of cholesterol is regulated by feedback mechanisms • For example, ACTH increases the number of adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL. • Cholesterol enters cell, delivered to mitochondria, cleaved by enzyme cholesterol desmolase to form pregnenolone • This initial step in steroid synthesis is stimulated by the different factors that control secretion of the major hormone
Synthesis of Adrenal Steroids • Synthesis occur in two of the organelles of the cell, mitochondria and endoplasmic reticulum • Each step is catalyzed by a specific enzyme system.
MSc Essex University March 2010 Adrenal Steroids and Pathways Pregnenolone Progesterone Deoxycorticosterone Cotricosterone Aldosterone Mineralocorticoids 17-Hydroxypregnenolone 17-Hydroxyprogesterone Deoxycortisol Cortisol Glucocorticoids Dehydroepiandrosterone Androstenedione Testosterone Oestrone Androgens Cholesterol 17a 17a 3 21 11 18 3 21 11 L 3 17ß A
MSc Essex University March 2010 Enzymes in Steroid Biosynthesis • Side-chain cleavage enzyme; desmolase • 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) • 17 alpha-hydroxylase. • 21-hydroxylase . • 11 beta-hydroxylase . • 18 hydroxylase (aldosterone synthase . • 17 beta-hydroxysteroid dehydrogenase • Aromatase . • Mutation or failure of any of these genes can lead endocrine disease
More Important Glucocorticoid Hormones including Synthetic ones: 1. Mineralocorticoids - Aldosterone (very potent, accounts for 90% of all mineralocorticoid activity - Desoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted - Corticosterone (slight minralocorticoid activity) - 9a-Fluococortisol (synthetic, slightly more potent than aldosterone) - Cortisol (very slight mineralocorticoid activity, but large quantity secreted - Cortisone (synthetic, slight mineralocorticoid activity)
2. Glucocorticoid - Cortisol (very potent, accounts for about 95% of all glucocorticoid activity - Corticosterone (provides 4% of total glucocorticoid) activity, much less potent than cortisol) - Cortisone (synthetic, almost as potent as cortisol) - Prednisone (synthetic, four times as potent as cortisol) - Methyprednisone (synthetic, five tmes as potent as cortisol) - Dexamethasone (synthetic, 30 times as potent as cortisol)
The Intense Glucocorticoid Activity of Dexamethasone, has almost zero mineralocorticoid activity, thus is important drug for stimulating specific glucocorticoid activity
Relative Steroid Potencies Glucocorticoid Mineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 - Dexamethasone 25-50 - Fludrocortisone 15-20 +++++
Biochemical actions of adrenocorticosteroids A. Mineralocorticoids: aldosterone It promotes Na+ reabsorption at the distal convoluted tubules of kidney. Na+ retention is accompanied by corresponding excretion of K+,H+ and NH4 + ions.
1. Effects on glucose metabolism: They promote gluconeogenesis. They work in tandem with insulin from the pancreas to maintain blood glucose levels in the proper balance. 2. Effects on lipid metabolism: They increase lipolysis in adipose tissue and reduce synthesis of triglyceride 3. Effects on protein and nucleic acid metabolism: They promote transcription and protein synthesis in liver. They also cause catabolic effects in extrahepatic tissues results in enhanced degradation of protein. B. Glucocorticoids: Cortisol
4. Effects on water and electrolyte metabolism: Deficiency of them cause increased production of ADH which can decrease glomerular filtration rate causing water retention in the body. 5. Effects on immune system: Cortisol suppress the immune response directly and indirectly by affecting most cells that participate in immune reactions and inflammatory reactions. It is powerful anti-inflammatory even when secreted at normal levels. This is one of the reasons why strong corticosteroids (prednisone, prednisolone, etc.) are used with all diseases involving inflammatory processes, including auto-immune diseases.
6. Effects on cardiovascular system: Cortisol could control the contraction of the walls of the mid-sized arteries in increasing blood pressure, but this hypertensive effect is moderated by calcium and magnesium. It also directly affects the heart by regulating sodium and potassium in the heart cells and increasing the strength of contraction of the heart muscle. 7. Effects on central nervous system: The changes of behavior, mood, excitability and even the electrical activity of neurons in the brain frequently occur in cases of excess and deficient cortisol levels. Many signs and symptoms of adrenal fatigue involve moodiness, decreased tolerance, decreased clarity of thought and decreased memory. These occur because the brain is affected by both too little and too much cortisol.
Adrenal Medullary Hormones •Cells in the adrenal medulla synthesize and secrete epinephrine and norepinephrine. •The ratio of these two catecholamines differs considerably among species: in humans, roughly 80, of the catecholamine output is epinephrine. •Following release into blood, these hormones bind adrenergic receptors on target cells, where they induce essentially the same effects as direct sympathetic nervous stimulation
Synthesis and Secretion of Catecholamines 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 following steps: Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP and several neuropeptides. Secretion of these hormones is stimulated by acetylcholine release from preganglionic sympathetic fibers innervating the medulla. Many types of "stresses" stimulate such secretion, including exercise, hypoglycemia and trauma. Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.
Complex physiologic responses result from adrenal medullary stimulation because there are multiple receptor types which are differentially expressed in different tissues and cells. The alpha and beta adrenergic receptors and their subtypes were originally defined by differential binding of various agonists and antagnonists and, more recently, by analysis of molecular clones.
Effects of Medullary Hormones In general, circulating epinephrine and norepinephrine released from the adrenal medulla have the same effects on target organs as direct stimulation by sympathetic nerves, although their effect is longer lasting. •Increased rate and force of contraction of the heart muscle: •this is predominantly an effect of epinephrine acting through beta receptors. •Constriction of blood vessels: norepinephrine, in particular, causes widespread vasoconstriction, resulting in increased resistance and hence arterial blood pressure. •Dilation of bronchioles: assists in pulmonary ventilation •. •Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many tissues and aids in conservation of declining reserves of blood glucose.
•Increased metabolic rate: oxygen consumption and heat production increase throughout the body in response to epinephrine. • Medullary hormones also promote breakdown of glycogen in skeletal muscle to provide glucose for energy production. •Dilation of the pupils. •Inhibition of certain "non-essential" processes: an example is inhibition of gastrointestinal secretion and motor activity. Common stimuli for secretion of adrenomedullary hormones include exercise,hypoglycemia, hemorrhage and emotional distress.
Regulation of glucocorticoids The Secretion of glucocorticoids from the adrenal cortex is regulated by negative feedback involving the CRH secretion by the hypothalamus. CRH then acts on the anterior pituitary to stimulate ACTH secretion, which then stimulates the adrenal cortex into cortisol secretion. About 70% of blood cortisol is bound to a carrier protein called corticosteroid- binding globulin. Another 15% is bound to albumin, the remaining 15% exists free in solution.
The HPA axis or HPA system, a negative feedback system, is one of the most important elements of homeostasis, the process that maintains a steady internal biochemical and physiological balance in your body. The HPAAxis adjusts cortisol level according to the needs of the body, under normal and stressed conditions, via ACTH. ACTH is secreted from the pituitary gland in response to orders form the hypothalamus and travels in the bloodstream to the adrenal cortex. ※ The Hypothalamus/Pituitary/Adrenal (HPA) Axis
Stress: During stress cortisol must simultaneously provide more blood glucose, mobilize fats and proteins for a back-up supply of glucose, modify immune reactions, heartbeat, blood pressure, brain alertness and nervous system responsiveness. If cortisol level cannot rise in response to these needs, maintaining your body under stress is nearly impossible.
Higher brain centers Hormonal Limbic system Hypothalamus Pituitary CRF Adrenal ACTH ACTH Stress Diurnal rhythm Cortisol - - negative feedback Mineralocorticoids Androgens/Estrogens The hypothalamic-pituitary-adrenal axis
Renin-angiotensin-aldosterone (control system) •Renin, a proteolytic enzyme, secreted by juxtaglomerular cells (JG) of the juxtaglomerular apparatus (JGA) •Baroreceptors and chemoreceptors of JGA are sensitive to: - hypovolemia renin - concentration of Na renin •The renin-angiotensin system is also stimulated by: - sympathetic nervous system renin •Hypotension renin •Aldosterone secretion is controlled by: ECF volume BP or Na renin (JGA) angiotensin (plasma) angiotensin I angiotensin II aldosterone (zona glomerulosa) *“converting enzyme” converts ANG I to ANG II] • K adrenal zona glomerulosa aldosterone
Adrenal gland disorders
MSc Essex University March 2010 Adrenal gland disorders • Disorder of adrenal cortex 1-Adrenal Insufficiency (Hypoadrenalism) Addison disease Congenital adrenal hyperplasia (CAH) 2--Adrenal over production(Hyperadrenalism) • Cushing’s syndrome • Conn’s syndrome • Disorder of adrenal medulla • Phaeochromocytoma
Adrenal Insufficiency (AI) • Impairment in synthesis and/or release of adrenocortical hormones • Classified as: – Primary AI  results from disease intrinsic to the adrenal cortex – Secondary AI  results from impaired release or effect of adrenocorticotropic hormone (ACTH) from the pituitary gland – Tertiary AI  results from the impaired release or effect of corticotropin releasing hormone (CRH) from the hypothalamus
Adrenal Insufficiency hypothalamicCRH pituitary ACTH adrenalcortisol adrenal defect 1ºadrenal insufficiency pituitary defect 2ºadrenal insufficiency hypothalamic defect 2ºadrenal insufficiency + + - - adrenal aldosterone
Addison disease is adrenocortical insufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.
Addison’s Disease • Failure of the adrenal cortices to produce adrenocortical hormones • Most frequently caused by primary atrophy of the adrenal cortices, caused by autoimmunity against the cortices. • Also caused by tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer. • These processes usually are gradual, leading to a progressive reduction in glucocorticoid and mineralocorticoid function. • As a result of the decreased cortisol secretion, there is a compensatory increase in ACTH secretion, which produces hyperpigmentation.
• Mineralocorticoid Deficiency • Excessive loss of sodium, hypovolemia, hypotension, and increased plasma renin activity • Excessive potassium retention and hyperkalemia • Mild acidosis • Glucocorticoid Deficiency • Abnormal carbohydrate, fat, and protein metabolism resulting in muscle weakness, fasting hypoglycemia, and impaired utilization of fats for energy • Loss of appetite and weight loss • Poor tolerance to stress. • The inability to secrete increased amounts of cortisol during stress leads to an Addisonian crisis that may end in death if supplemental doses of adrenocortical hormones are not administered.
Acute adrenal (addisonian) crisis • Clinical features – fever, dehydration, nausea, vomiting, hypotension, that evolves rapidly to circulatory shock.
Clinical presentation: • The onset of symptoms most often is insidious and nonspecific. • Hyperpigmentation of the skin and mucous membranes vitiligo:Dizziness , Myalgias and flaccid muscle paralysis may progressive weakness, fatigue, poor appetite, and weight loss. • gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea.
Laboratory Investigations … • Synacthen stimulation test – Measuring levels of cortisol in blood before and 30 and 60 minutes after an injection of 250µg synthetic ACTH • If the adrenal glands are functional - cortisol levels will rise in response to the ACTH stimulation If they are damaged or non-functional - response to ACTH will be minimal. • ACTH - baseline test to evaluate whether or not the pituitary is producing appropriate amounts of ACTH. – low ACTH levels indicate secondary adrenal insufficiency – high levels indicate primary adrenal insufficiency (Addison’s disease).
• Congenital adrenal hyperplasia (CAH) • is a group of inherited autosomal-recessive disorders in which a genetic defect results in the deficiency of an enzyme essential for synthesis of cortisol and, at times, aldosterone. There are several forms of CAH, the most common of which is 21-hydroxylase (21-OH) deficiency, occurring in over 90% of all cases
Some autosomal recessive mutations in biosynthetic enzymes responsible for converting cholesterol to androgens generally lead to partial male-to-female sex reversal. CAH is a deficiency of 21-hydroxylase enzyme ( most common) causing a decrease in synthesis of steroid hormones,leading to overproduction of ACTH. When this occurs adrenal steroid synthesis is stimulated and 17-hydroxyprogesterone is converted to androstenedione and further to testosterone, leading to severe virilization of the female fetus. This disorder is known as CAH which disrupts the synthesis of all adrenal and gonadal steroids. Affected genetic males are born with normal female external genitalia. congenital adrenal hyperplasia CAH :
Presentations of CAH • Ambiguous genitalia in girls • Dehydration • Shock • Salt-loss presentations with electrolytes imbalance – Hyponatremia – Hyperkalaemia • Hypoglycemia • Hyperpigementations
Hyperadrenalism • Hypersecretion by the adrenal cortex causes a complex cascade of hormone effects called Cushing’s syndrome. • Hypercortisolism can occur from multiple causes: 1) adenomas of the anterior pituitary ACTH adrenal hyperplasia cortisol secretion 2) abnormal function of the hypothalamus CRH ACTH release 3) “ectopic secretion” of ACTH by a tumor in the body 4) adenomas of the adrenal cortex 5) by administration of large amounts of exogenous glucocorticoids. • When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this is referred to as Cushing’s disease.
• Cushing’s syndrome is caused by prolonged exposure of the bodies’ tissue to high levels of the hormone cortisol • Cushing syndrome is also called hypercortisolism.
Etiology • ACTH dependent : - pituitary corticotrophic adenoma *Cushing’s disease - extrapituitary tumor (ectopic ACTH tumor secreting CRH • ACTH independent : - adrenocortical tumors adrenal hyperplasia or dysplasia
Symptoms • Upper body obesity (moon face, increased neck fat buffalo hump) • Thinning around the arms and legs • Delayed growth • Easy bruising of skin • Purplish-pink stretch marks on the abdomen, thigh, buttocks, arms, and breasts
Symptoms • High blood sugar, high blood pressure • Depression and anxiety • Increased hair growth in women • Irregular menstrual cycles • Bones are fragile, susceptible to fractures easily
Conn’s syndrome • Characterized by excessive secretion of aldosterone from the adrenal glands. • Also referred to as primary hyperaldosteronism • Excessive aldosterone is produced by One or more benign adrenal tumours • Commonly occurs in adults between the ages of 30 and 50 (although it can be in anyone) • Most common cause of secondary hypertension • More common in women than men • Presence of hypokalemia with hypertension - suggests possible primary hyperaldosteronism.
Primary Aldosteronism or Conn’s Syndrome • Excessive aldosterone secondary to adrenal tumor • retain sodium and excrete potassium • Results in alkalosis • Hypertension—universal sign of hyperaldosteronism • Inability of kidneys to concentrate the urine • Serum becomes concentrated • Excessive thirst • Hypokalemia interferes with insulin secretion thus will have glucose intolerance as well
phaeochromocytoma (PCC) a neuroendocrine tumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually adrenaline (epinephrine) if in the adrenal gland and not extra-adrenal, and noradrenaline (norepinephrine).
Adrenals-Pheochromocytoma • Usually benign tumor • Originates from the chromaffin cells of the adrenal medulla • Any age but usually. Between 40-50 years old • Can be familial • May be associated with thyroid carcinoma or parathyroid hyperplasia or tumor
Clinical Manifestations • Headache, diaphoresis, palpitations, hypertension • May have hyperglycemia related to excess epinephrine secretion • Tremors, flushing and anxiety as well • Blurring of vision • Feeling of impending doom • BPs exceeding 250/150 have occurred
Pancreatic hormones
Pancreas • Digestive functions • Secretes two important hormones Insulin Glucagon Secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide
Physiologic Anatomy of the Pancreas  Two major types of tissues 1) The acini,which secrete digestive juices into duodenum (exocrine) 2) The islets of Langerhans, which secrete insulin and glucagon into blood(endocrine).  1 to 2 million islets of Langerhans, organized around small capillaries into which its cells secrete their hormones.  The islets contain three major types of cells alpha, beta, delta cell  The beta cells 60 % of all the cells of the islets, lie mainly in the middle of each islet and secrete insulin and amylin,  The alpha cells, 25 % of the total, secrete glucagon  The delta cells, about 10 %, secrete somatostatin.  One other type of cell, the pancreatic polypeptide PP cell, is present in small numbers in the islets and secretes pancreatic polypeptide.
The endocrine cells of the pancreas are localized in the islets of Langerhans and constitute only 2% of the mass of the pancreas. The human pancreas contain about 1 million islets of Langerhans which are distributed throughout the organ, but more commonly found in the tail.
Hormones  Both insulin and glucagon are synthesized as large preprohormones. • In Endoplasmic reticulum, the prohormones are formed. • Most of this is further cleaved in the Golgi apparatus to form hormone and peptide fragments before being packaged in the secretory granules.  In the case of the beta cells, insulin and connecting (C) peptide are released into the circulating blood in equimolar amounts.  Insulin is a polypeptide containing two amino acid chains A and B(21 and 30 amino acids, respectively) connected by disulfide bridges.  Glucagon is a straight-chain polypeptide of 29 amino acid residues.  Both insulin and glucagon circulate unbound to carrier proteins and have short half-lives of 6 minutes.  Approximately 50% of the insulin and glucagon in blood is metabolized in the liver; most of the remaining hormone is metabolized by the kidneys.
Structure of Insulin • Insulin is a polypeptide hormone, composed of two chains (A and B) • Both chain are derived from preproinsulin, then proinsulin. • The two chains are joined by disulfide bonds.
Physiologic Effects of Insulin The Insulin Receptor (IR) and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane ( PM). The IR is composed of 2 alpha subunits and 2 beta subunits linked by S-S bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the PM.
Actions of Insulin • To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein • The insulin receptor is a tetramer made up of two α-subunits that lie outside the cell membrane and two β-subunits that penetrate the cell membrane and protrude into the cytoplasm • When insulin binds with the alpha subunits on the outside of the cell, portions of the beta subunits protruding into the cell become autophosphorylated.
Thus, the insulin receptor is an example of an enzyme-linked receptor Autophosphorylation of the beta subunits of the receptor activates a local tyrosine kinase, which in turn causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS). The net effect is to activate some of these enzymes while inactivating others. In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein metabolism.
Insulin Is a Hormone Associated with Energy Abundance • When there is great abundance of energy-giving foods in the diet, especially excess amounts of carbohydrates, insulin is secreted in great quantity. • Insulin plays an important role in storing the excess energy. • In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles. • Excess carbohydrates is also converted under the stimulus of insulin into fats and stored in the adipose tissue. • Insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. • In addition, it inhibits the breakdown of the proteins that are already in the cells.
Specific Targets of Insulin Action: Carbohydrates Activation of glycogen synthetase. Converts glucose to glycogen. Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis. Increased activity of glucose transporters. Moves glucose into cells.
Specific Targets of Insulin Action: Lipids  Activation of acetyl CoA carboxylase. Stimulates production of free fatty acids from acetyl CoA. Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell.
Role of Insulin in Storage of Fat in the Adipose Cells • Insulin has two other essential effects that are required for fat storage in adipose cells: 1. Insulin inhibits the action of hormone-sensitive lipase. This is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells. 2. Insulin promotes glucose transport through the cell membrane into the fat cells. Some of this glucose is then used to synthesize minute amounts of fatty acids, but forms large quantities of a-glycerol phosphate. This substance supplies the glycerol that combines with fatty acids to form the triglycerides that are the storage form of fat
Effect of Insulin on Protein Metabolism and on Growth • Insulin Promotes Protein Synthesis and Storage • During the few hours after a meal proteins are also stored in the tissues by insulin 1. Insulin stimulates transport of many of amino acids into the cells, eg valine, leucine, isoleucine, tyrosine, and phenylalanine. 2. Insulin increases the translation of mRNA, thus forming new proteins 3. Over a longer period of time, insulin also increases the rate of transcription of selected DNA, forming increased quantities of RNA and still more protein synthesis
4. Insulin inhibits the catabolism of proteins 5. In the liver, insulin depresses the rate of gluconeogenesis, this suppression of gluconeogenesis conserves the amino acids in the protein stores of the body. • In summary, insulin promotes protein formation and prevents the degradation of proteins • Lack of Insulin causes protein depletion and increased plasma amino acids • The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus. • It can lead to extreme weakness as well as many deranged functions -of the organs.
Insulin and Growth Hormone Interact Synergistically to Promote Growth • Because insulin is required for the synthesis of proteins, it is as essential for growth as growth hormone is. • A combination of these hormones causes dramatic growth. • Thus, it appears that the two hormones function synergistically to promote growth each performing a specific function that is separate from that of the other.
Insulin: Summary and Control Reflex Loop
Glucagon •Glucagon is a catabolic peptide hormone secreted by α cells of the pancreatic islets Regulation of secretion •Glucagon secretion is directly stimulated by: - low blood glucose concentration - high levels of circulating amino acids •Somatostatin glucagon secretion •Insulin & secretin glucagon secretion •Sympathetic stimulation glucagon secretion (ß-receptor mechanism) •Vagal stimulation glucagon secretion •All forms of physical stress glucagon secretion
Targets of Glucagon Action • Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen. • Inactivates glycogen synthase by phosphorylation (less glycogen synthesis). • Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis • Activates lipases, breaking down triglycerides. • Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA • Result: more production of glucose and substrates for metabolism
Glucagon Action on Cells: Dominates in Fasting State Metabolism
 A few hours after a meal (active): - blood glucose levels decrease - insulin secretion decreases - increased secretion of glucagon, cortisol, GH, epinephrine - glucose is released from glycogen stores (glycogenolysis) - increased lipolysis (beta oxidation) - glucose production from amino acids increases (oxidative deamination; gluconeogenesis) - decreased uptake of glucose by tissues - blood glucose levels maintained Hormonal Regulation of Nutrients
Somatostatin •Somatostatin is a peptide hormone secreted by δ cells of the pancreatic islets (also produced in the hypothalamus) in response to: - blood glucose - plasma amino acids - fatty acids •Somatostatin decreases gastrointestinal functions by: - motility - secretion - absorption •Somatostatin release of: - insulin - glucagon
Diabetes Mellitus • Diabetes mellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin • Two forms of diabetes mellitus • Type I diabetes mellitus, also called insulin- dependent diabetes mellitus (IDDM), is caused by impaired secretion of insulin. • Type II diabetes mellitus, also called non–insulin- dependent diabetes mellitus (NIDDM), is caused by resistance to the metabolic effects of insulin in target tissues.
Type I Diabetes • Caused by Impaired Secretion of Insulin by the Beta Cells of the Pancreas • Often, type I diabetes is a result of autoimmune destruction of beta cells, but it can also arise from the loss of beta cells resulting from viral infections. • Because the usual onset of type I diabetes occurs during childhood, it is referred to as juvenile diabetes. • Pathophysiological features: • Hyperglycemia as a result of impaired glucose uptake into tissues and increased glucose production by the liver (increased gluconeogenesis)
• Depletion of proteins resulting from decreased synthesis and increased catabolism • Depletion of fat stores and increased ketosis • As a result of these fundamental derangements: • Glucosuria, osmotic diuresis, hypovolemia • Hyperosmolality of the blood, dehydration, polydipsia • Hyperphagia but weight loss; lack of energy • Acidosis progressing to diabetic coma; rapid and deep breathing • Hypercholesterolemia and atherosclerotic vascular disease
Type II Diabetes Mellitus • Insulin Resistance Is the Hallmark of Type II Diabetes Mellitus • Type II diabetes is far more common than type I diabetes (accounting for approximately 90% of all cases of diabetes) • Usually associated with obesity. • This form of diabetes is characterized by impaired ability of target tissues to respond to the metabolic effects of insulin, which is referred to as insulin resistance. • In contrast to type I diabetes, pancreatic beta cell morphology is normal throughout much of the disease, and there is an elevated rate of insulin secretion.
• Type II diabetes usually develops in adults and therefore is also called adult-onset diabetes. • Caloric restriction and weight reduction usually improve insulin resistance in target tissues • Drugs that increase insulin sensitivity, such as metformin, or drugs that cause additional release of insulin by the pancreas, such as sulfonylureas, may also be used. • In the late stages of the disease when insulin secretion is impaired, insulin administration is required.
Glucose Tolerance Test •when a normal, fasting person ingests 1 gram of glucose per kg of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours. •In a person with diabetes, this test is always abnormal

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Adrenal glands

  • 1.
    adrenal glands • Twoadrenal glands • Each weighs 4 grams • Lie at the superior poles of the two kidneys • Two distinct parts, adrenal medulla and adrenal cortex Adrenal medulla, central 20 % of the gland, is functionally related to the sympathetic nervous system • It secretes epinephrine and norepinephrine in response to sympathetic stimulation Adrenal cortex secretes corticosteroids.
  • 2.
    Adrenocortical hormones: Mineralocorticoids Glucocorticoids Androgens (smallamounts) • Mineralocorticoids: affect electrolytes (“minerals”) of extracellular fluids -sodium and potassium, in particular • Glucocorticoids : important effects that increase blood glucose concentration + additional effects on protein and fat metabolism • More than 30 steroids have been isolated from the adrenal cortex • Aldosterone principal mineralocorticoid • Cortisol principal glucocorticoid.
  • 3.
    Adrenal Cortex • ThreeDistinct Layers 1. Zona glomerulosa, 15% of the adrenal cortex • A thin layer of cells that lies just underneath the capsule • Secrete aldosterone • Secretion is controlled by ECF concentrations of angiotensin II and potassium, which stimulate aldosterone secretion. 2. Zona fasciculata, 75% of the adrenal cortex • Middle and widest layer • Secretes glucocorticoids cortisol, corticosterone, and small amounts of adrenal androgens and estrogens. • Secretion is controlled by the hypothalamic-pituitary axis via adrenocorticotropic hormone (ACTH).
  • 4.
    • Zona reticularis,deep layer of cortex • Secretes adrenal androgens, dehydroepiandrosterone (DHEA) and androstenedione, small amounts of estrogens and glucocorticoids. • ACTH regulates secretion of these cells • Cortical androgen-stimulating hormone, released from the pituitary, may also be involved.
  • 5.
  • 6.
    Adrenocortical Hormones AreSteroids • Derived from Cholesterol • Cholesterol is provided by LDL in the circulating plasma. • Transport of cholesterol is regulated by feedback mechanisms • For example, ACTH increases the number of adrenocortical cell receptors for LDL, as well as the activity of enzymes that liberate cholesterol from LDL. • Cholesterol enters cell, delivered to mitochondria, cleaved by enzyme cholesterol desmolase to form pregnenolone • This initial step in steroid synthesis is stimulated by the different factors that control secretion of the major hormone
  • 7.
    Synthesis of AdrenalSteroids • Synthesis occur in two of the organelles of the cell, mitochondria and endoplasmic reticulum • Each step is catalyzed by a specific enzyme system.
  • 8.
    MSc Essex UniversityMarch 2010 Adrenal Steroids and Pathways Pregnenolone Progesterone Deoxycorticosterone Cotricosterone Aldosterone Mineralocorticoids 17-Hydroxypregnenolone 17-Hydroxyprogesterone Deoxycortisol Cortisol Glucocorticoids Dehydroepiandrosterone Androstenedione Testosterone Oestrone Androgens Cholesterol 17a 17a 3 21 11 18 3 21 11 L 3 17ß A
  • 9.
    MSc Essex UniversityMarch 2010 Enzymes in Steroid Biosynthesis • Side-chain cleavage enzyme; desmolase • 3 beta-hydroxysteroid dehydrogenase (3 beta HSD) • 17 alpha-hydroxylase. • 21-hydroxylase . • 11 beta-hydroxylase . • 18 hydroxylase (aldosterone synthase . • 17 beta-hydroxysteroid dehydrogenase • Aromatase . • Mutation or failure of any of these genes can lead endocrine disease
  • 10.
    More Important GlucocorticoidHormones including Synthetic ones: 1. Mineralocorticoids - Aldosterone (very potent, accounts for 90% of all mineralocorticoid activity - Desoxycorticosterone (1/30 as potent as aldosterone, but very small quantities secreted - Corticosterone (slight minralocorticoid activity) - 9a-Fluococortisol (synthetic, slightly more potent than aldosterone) - Cortisol (very slight mineralocorticoid activity, but large quantity secreted - Cortisone (synthetic, slight mineralocorticoid activity)
  • 11.
    2. Glucocorticoid - Cortisol(very potent, accounts for about 95% of all glucocorticoid activity - Corticosterone (provides 4% of total glucocorticoid) activity, much less potent than cortisol) - Cortisone (synthetic, almost as potent as cortisol) - Prednisone (synthetic, four times as potent as cortisol) - Methyprednisone (synthetic, five tmes as potent as cortisol) - Dexamethasone (synthetic, 30 times as potent as cortisol)
  • 12.
    The Intense GlucocorticoidActivity of Dexamethasone, has almost zero mineralocorticoid activity, thus is important drug for stimulating specific glucocorticoid activity
  • 14.
    Relative Steroid Potencies GlucocorticoidMineralocorticoid Hydrocortisone 1 ++ Prednisone/ Prednisolone 3-5 + Methylprednisone 5-6 - Dexamethasone 25-50 - Fludrocortisone 15-20 +++++
  • 15.
    Biochemical actions ofadrenocorticosteroids A. Mineralocorticoids: aldosterone It promotes Na+ reabsorption at the distal convoluted tubules of kidney. Na+ retention is accompanied by corresponding excretion of K+,H+ and NH4 + ions.
  • 16.
    1. Effects onglucose metabolism: They promote gluconeogenesis. They work in tandem with insulin from the pancreas to maintain blood glucose levels in the proper balance. 2. Effects on lipid metabolism: They increase lipolysis in adipose tissue and reduce synthesis of triglyceride 3. Effects on protein and nucleic acid metabolism: They promote transcription and protein synthesis in liver. They also cause catabolic effects in extrahepatic tissues results in enhanced degradation of protein. B. Glucocorticoids: Cortisol
  • 17.
    4. Effects onwater and electrolyte metabolism: Deficiency of them cause increased production of ADH which can decrease glomerular filtration rate causing water retention in the body. 5. Effects on immune system: Cortisol suppress the immune response directly and indirectly by affecting most cells that participate in immune reactions and inflammatory reactions. It is powerful anti-inflammatory even when secreted at normal levels. This is one of the reasons why strong corticosteroids (prednisone, prednisolone, etc.) are used with all diseases involving inflammatory processes, including auto-immune diseases.
  • 18.
    6. Effects oncardiovascular system: Cortisol could control the contraction of the walls of the mid-sized arteries in increasing blood pressure, but this hypertensive effect is moderated by calcium and magnesium. It also directly affects the heart by regulating sodium and potassium in the heart cells and increasing the strength of contraction of the heart muscle. 7. Effects on central nervous system: The changes of behavior, mood, excitability and even the electrical activity of neurons in the brain frequently occur in cases of excess and deficient cortisol levels. Many signs and symptoms of adrenal fatigue involve moodiness, decreased tolerance, decreased clarity of thought and decreased memory. These occur because the brain is affected by both too little and too much cortisol.
  • 19.
    Adrenal Medullary Hormones •Cellsin the adrenal medulla synthesize and secrete epinephrine and norepinephrine. •The ratio of these two catecholamines differs considerably among species: in humans, roughly 80, of the catecholamine output is epinephrine. •Following release into blood, these hormones bind adrenergic receptors on target cells, where they induce essentially the same effects as direct sympathetic nervous stimulation
  • 20.
    Synthesis and Secretionof Catecholamines 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 following steps: Norepinephine and epinephrine are stored in electron-dense granules which also contain ATP and several neuropeptides. Secretion of these hormones is stimulated by acetylcholine release from preganglionic sympathetic fibers innervating the medulla. Many types of "stresses" stimulate such secretion, including exercise, hypoglycemia and trauma. Following secretion into blood, the catecholamines bind loosely to and are carried in the circulation by albumin and perhaps other serum proteins.
  • 21.
    Complex physiologic responsesresult from adrenal medullary stimulation because there are multiple receptor types which are differentially expressed in different tissues and cells. The alpha and beta adrenergic receptors and their subtypes were originally defined by differential binding of various agonists and antagnonists and, more recently, by analysis of molecular clones.
  • 22.
    Effects of MedullaryHormones In general, circulating epinephrine and norepinephrine released from the adrenal medulla have the same effects on target organs as direct stimulation by sympathetic nerves, although their effect is longer lasting. •Increased rate and force of contraction of the heart muscle: •this is predominantly an effect of epinephrine acting through beta receptors. •Constriction of blood vessels: norepinephrine, in particular, causes widespread vasoconstriction, resulting in increased resistance and hence arterial blood pressure. •Dilation of bronchioles: assists in pulmonary ventilation •. •Stimulation of lipolysis in fat cells: this provides fatty acids for energy production in many tissues and aids in conservation of declining reserves of blood glucose.
  • 23.
    •Increased metabolic rate:oxygen consumption and heat production increase throughout the body in response to epinephrine. • Medullary hormones also promote breakdown of glycogen in skeletal muscle to provide glucose for energy production. •Dilation of the pupils. •Inhibition of certain "non-essential" processes: an example is inhibition of gastrointestinal secretion and motor activity. Common stimuli for secretion of adrenomedullary hormones include exercise,hypoglycemia, hemorrhage and emotional distress.
  • 24.
    Regulation of glucocorticoids TheSecretion of glucocorticoids from the adrenal cortex is regulated by negative feedback involving the CRH secretion by the hypothalamus. CRH then acts on the anterior pituitary to stimulate ACTH secretion, which then stimulates the adrenal cortex into cortisol secretion. About 70% of blood cortisol is bound to a carrier protein called corticosteroid- binding globulin. Another 15% is bound to albumin, the remaining 15% exists free in solution.
  • 25.
    The HPA axisor HPA system, a negative feedback system, is one of the most important elements of homeostasis, the process that maintains a steady internal biochemical and physiological balance in your body. The HPAAxis adjusts cortisol level according to the needs of the body, under normal and stressed conditions, via ACTH. ACTH is secreted from the pituitary gland in response to orders form the hypothalamus and travels in the bloodstream to the adrenal cortex. ※ The Hypothalamus/Pituitary/Adrenal (HPA) Axis
  • 26.
    Stress: During stresscortisol must simultaneously provide more blood glucose, mobilize fats and proteins for a back-up supply of glucose, modify immune reactions, heartbeat, blood pressure, brain alertness and nervous system responsiveness. If cortisol level cannot rise in response to these needs, maintaining your body under stress is nearly impossible.
  • 27.
    Higher brain centers HormonalLimbic system Hypothalamus Pituitary CRF Adrenal ACTH ACTH Stress Diurnal rhythm Cortisol - - negative feedback Mineralocorticoids Androgens/Estrogens The hypothalamic-pituitary-adrenal axis
  • 28.
    Renin-angiotensin-aldosterone (control system) •Renin,a proteolytic enzyme, secreted by juxtaglomerular cells (JG) of the juxtaglomerular apparatus (JGA) •Baroreceptors and chemoreceptors of JGA are sensitive to: - hypovolemia renin - concentration of Na renin •The renin-angiotensin system is also stimulated by: - sympathetic nervous system renin •Hypotension renin •Aldosterone secretion is controlled by: ECF volume BP or Na renin (JGA) angiotensin (plasma) angiotensin I angiotensin II aldosterone (zona glomerulosa) *“converting enzyme” converts ANG I to ANG II] • K adrenal zona glomerulosa aldosterone
  • 30.
  • 31.
    MSc Essex UniversityMarch 2010 Adrenal gland disorders • Disorder of adrenal cortex 1-Adrenal Insufficiency (Hypoadrenalism) Addison disease Congenital adrenal hyperplasia (CAH) 2--Adrenal over production(Hyperadrenalism) • Cushing’s syndrome • Conn’s syndrome • Disorder of adrenal medulla • Phaeochromocytoma
  • 32.
    Adrenal Insufficiency (AI) •Impairment in synthesis and/or release of adrenocortical hormones • Classified as: – Primary AI  results from disease intrinsic to the adrenal cortex – Secondary AI  results from impaired release or effect of adrenocorticotropic hormone (ACTH) from the pituitary gland – Tertiary AI  results from the impaired release or effect of corticotropin releasing hormone (CRH) from the hypothalamus
  • 33.
  • 34.
    Addison disease is adrenocorticalinsufficiency due to the destruction or dysfunction of the entire adrenal cortex. It affects both glucocorticoid and mineralocorticoid function. The onset of disease usually occurs when 90% or more of both adrenal cortices are dysfunctional or destroyed.
  • 35.
    Addison’s Disease • Failureof the adrenal cortices to produce adrenocortical hormones • Most frequently caused by primary atrophy of the adrenal cortices, caused by autoimmunity against the cortices. • Also caused by tuberculous destruction of the adrenal glands or invasion of the adrenal cortices by cancer. • These processes usually are gradual, leading to a progressive reduction in glucocorticoid and mineralocorticoid function. • As a result of the decreased cortisol secretion, there is a compensatory increase in ACTH secretion, which produces hyperpigmentation.
  • 36.
    • Mineralocorticoid Deficiency •Excessive loss of sodium, hypovolemia, hypotension, and increased plasma renin activity • Excessive potassium retention and hyperkalemia • Mild acidosis • Glucocorticoid Deficiency • Abnormal carbohydrate, fat, and protein metabolism resulting in muscle weakness, fasting hypoglycemia, and impaired utilization of fats for energy • Loss of appetite and weight loss • Poor tolerance to stress. • The inability to secrete increased amounts of cortisol during stress leads to an Addisonian crisis that may end in death if supplemental doses of adrenocortical hormones are not administered.
  • 37.
    Acute adrenal (addisonian)crisis • Clinical features – fever, dehydration, nausea, vomiting, hypotension, that evolves rapidly to circulatory shock.
  • 38.
    Clinical presentation: • Theonset of symptoms most often is insidious and nonspecific. • Hyperpigmentation of the skin and mucous membranes vitiligo:Dizziness , Myalgias and flaccid muscle paralysis may progressive weakness, fatigue, poor appetite, and weight loss. • gastrointestinal symptoms may include nausea, vomiting, and occasional diarrhea.
  • 39.
    Laboratory Investigations … •Synacthen stimulation test – Measuring levels of cortisol in blood before and 30 and 60 minutes after an injection of 250µg synthetic ACTH • If the adrenal glands are functional - cortisol levels will rise in response to the ACTH stimulation If they are damaged or non-functional - response to ACTH will be minimal. • ACTH - baseline test to evaluate whether or not the pituitary is producing appropriate amounts of ACTH. – low ACTH levels indicate secondary adrenal insufficiency – high levels indicate primary adrenal insufficiency (Addison’s disease).
  • 40.
    • Congenital adrenalhyperplasia (CAH) • is a group of inherited autosomal-recessive disorders in which a genetic defect results in the deficiency of an enzyme essential for synthesis of cortisol and, at times, aldosterone. There are several forms of CAH, the most common of which is 21-hydroxylase (21-OH) deficiency, occurring in over 90% of all cases
  • 41.
    Some autosomal recessivemutations in biosynthetic enzymes responsible for converting cholesterol to androgens generally lead to partial male-to-female sex reversal. CAH is a deficiency of 21-hydroxylase enzyme ( most common) causing a decrease in synthesis of steroid hormones,leading to overproduction of ACTH. When this occurs adrenal steroid synthesis is stimulated and 17-hydroxyprogesterone is converted to androstenedione and further to testosterone, leading to severe virilization of the female fetus. This disorder is known as CAH which disrupts the synthesis of all adrenal and gonadal steroids. Affected genetic males are born with normal female external genitalia. congenital adrenal hyperplasia CAH :
  • 42.
    Presentations of CAH •Ambiguous genitalia in girls • Dehydration • Shock • Salt-loss presentations with electrolytes imbalance – Hyponatremia – Hyperkalaemia • Hypoglycemia • Hyperpigementations
  • 43.
    Hyperadrenalism • Hypersecretion bythe adrenal cortex causes a complex cascade of hormone effects called Cushing’s syndrome. • Hypercortisolism can occur from multiple causes: 1) adenomas of the anterior pituitary ACTH adrenal hyperplasia cortisol secretion 2) abnormal function of the hypothalamus CRH ACTH release 3) “ectopic secretion” of ACTH by a tumor in the body 4) adenomas of the adrenal cortex 5) by administration of large amounts of exogenous glucocorticoids. • When Cushing’s syndrome is secondary to excess secretion of ACTH by the anterior pituitary, this is referred to as Cushing’s disease.
  • 44.
    • Cushing’s syndromeis caused by prolonged exposure of the bodies’ tissue to high levels of the hormone cortisol • Cushing syndrome is also called hypercortisolism.
  • 45.
    Etiology • ACTH dependent: - pituitary corticotrophic adenoma *Cushing’s disease - extrapituitary tumor (ectopic ACTH tumor secreting CRH • ACTH independent : - adrenocortical tumors adrenal hyperplasia or dysplasia
  • 46.
    Symptoms • Upper bodyobesity (moon face, increased neck fat buffalo hump) • Thinning around the arms and legs • Delayed growth • Easy bruising of skin • Purplish-pink stretch marks on the abdomen, thigh, buttocks, arms, and breasts
  • 47.
    Symptoms • High bloodsugar, high blood pressure • Depression and anxiety • Increased hair growth in women • Irregular menstrual cycles • Bones are fragile, susceptible to fractures easily
  • 51.
    Conn’s syndrome • Characterizedby excessive secretion of aldosterone from the adrenal glands. • Also referred to as primary hyperaldosteronism • Excessive aldosterone is produced by One or more benign adrenal tumours • Commonly occurs in adults between the ages of 30 and 50 (although it can be in anyone) • Most common cause of secondary hypertension • More common in women than men • Presence of hypokalemia with hypertension - suggests possible primary hyperaldosteronism.
  • 52.
    Primary Aldosteronism orConn’s Syndrome • Excessive aldosterone secondary to adrenal tumor • retain sodium and excrete potassium • Results in alkalosis • Hypertension—universal sign of hyperaldosteronism • Inability of kidneys to concentrate the urine • Serum becomes concentrated • Excessive thirst • Hypokalemia interferes with insulin secretion thus will have glucose intolerance as well
  • 53.
    phaeochromocytoma (PCC) a neuroendocrinetumor of the medulla of the adrenal glands (originating in the chromaffin cells), or extra-adrenal chromaffin tissue that failed to involute after birth and secretes excessive amounts of catecholamines, usually adrenaline (epinephrine) if in the adrenal gland and not extra-adrenal, and noradrenaline (norepinephrine).
  • 54.
    Adrenals-Pheochromocytoma • Usually benigntumor • Originates from the chromaffin cells of the adrenal medulla • Any age but usually. Between 40-50 years old • Can be familial • May be associated with thyroid carcinoma or parathyroid hyperplasia or tumor
  • 55.
    Clinical Manifestations • Headache,diaphoresis, palpitations, hypertension • May have hyperglycemia related to excess epinephrine secretion • Tremors, flushing and anxiety as well • Blurring of vision • Feeling of impending doom • BPs exceeding 250/150 have occurred
  • 56.
  • 57.
    Pancreas • Digestive functions •Secretes two important hormones Insulin Glucagon Secretes other hormones, such as amylin, somatostatin, and pancreatic polypeptide
  • 58.
    Physiologic Anatomy ofthe Pancreas  Two major types of tissues 1) The acini,which secrete digestive juices into duodenum (exocrine) 2) The islets of Langerhans, which secrete insulin and glucagon into blood(endocrine).  1 to 2 million islets of Langerhans, organized around small capillaries into which its cells secrete their hormones.  The islets contain three major types of cells alpha, beta, delta cell  The beta cells 60 % of all the cells of the islets, lie mainly in the middle of each islet and secrete insulin and amylin,  The alpha cells, 25 % of the total, secrete glucagon  The delta cells, about 10 %, secrete somatostatin.  One other type of cell, the pancreatic polypeptide PP cell, is present in small numbers in the islets and secretes pancreatic polypeptide.
  • 59.
    The endocrine cellsof the pancreas are localized in the islets of Langerhans and constitute only 2% of the mass of the pancreas. The human pancreas contain about 1 million islets of Langerhans which are distributed throughout the organ, but more commonly found in the tail.
  • 61.
    Hormones  Both insulinand glucagon are synthesized as large preprohormones. • In Endoplasmic reticulum, the prohormones are formed. • Most of this is further cleaved in the Golgi apparatus to form hormone and peptide fragments before being packaged in the secretory granules.  In the case of the beta cells, insulin and connecting (C) peptide are released into the circulating blood in equimolar amounts.  Insulin is a polypeptide containing two amino acid chains A and B(21 and 30 amino acids, respectively) connected by disulfide bridges.  Glucagon is a straight-chain polypeptide of 29 amino acid residues.  Both insulin and glucagon circulate unbound to carrier proteins and have short half-lives of 6 minutes.  Approximately 50% of the insulin and glucagon in blood is metabolized in the liver; most of the remaining hormone is metabolized by the kidneys.
  • 63.
    Structure of Insulin •Insulin is a polypeptide hormone, composed of two chains (A and B) • Both chain are derived from preproinsulin, then proinsulin. • The two chains are joined by disulfide bonds.
  • 64.
    Physiologic Effects ofInsulin The Insulin Receptor (IR) and Mechanism of Action Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane ( PM). The IR is composed of 2 alpha subunits and 2 beta subunits linked by S-S bonds. The alpha chains are entirely extracellular and house insulin binding domains, while the linked beta chains penetrate through the PM.
  • 65.
    Actions of Insulin •To initiate its effects on target cells, insulin first binds with and activates a membrane receptor protein • The insulin receptor is a tetramer made up of two α-subunits that lie outside the cell membrane and two β-subunits that penetrate the cell membrane and protrude into the cytoplasm • When insulin binds with the alpha subunits on the outside of the cell, portions of the beta subunits protruding into the cell become autophosphorylated.
  • 66.
    Thus, the insulinreceptor is an example of an enzyme-linked receptor Autophosphorylation of the beta subunits of the receptor activates a local tyrosine kinase, which in turn causes phosphorylation of multiple other intracellular enzymes including a group called insulin-receptor substrates (IRS). The net effect is to activate some of these enzymes while inactivating others. In this way, insulin directs the intracellular metabolic machinery to produce the desired effects on carbohydrate, fat, and protein metabolism.
  • 69.
    Insulin Is aHormone Associated with Energy Abundance • When there is great abundance of energy-giving foods in the diet, especially excess amounts of carbohydrates, insulin is secreted in great quantity. • Insulin plays an important role in storing the excess energy. • In the case of excess carbohydrates, it causes them to be stored as glycogen mainly in the liver and muscles. • Excess carbohydrates is also converted under the stimulus of insulin into fats and stored in the adipose tissue. • Insulin has a direct effect in promoting amino acid uptake by cells and conversion of these amino acids into protein. • In addition, it inhibits the breakdown of the proteins that are already in the cells.
  • 70.
    Specific Targets ofInsulin Action: Carbohydrates Activation of glycogen synthetase. Converts glucose to glycogen. Inhibition of phosphoenolpyruvate carboxykinase. Inhibits gluconeogenesis. Increased activity of glucose transporters. Moves glucose into cells.
  • 71.
    Specific Targets ofInsulin Action: Lipids  Activation of acetyl CoA carboxylase. Stimulates production of free fatty acids from acetyl CoA. Activation of lipoprotein lipase (increases breakdown of triacylglycerol in the circulation). Fatty acids are then taken up by adipocytes, and triacylglycerol is made and stored in the cell.
  • 72.
    Role of Insulinin Storage of Fat in the Adipose Cells • Insulin has two other essential effects that are required for fat storage in adipose cells: 1. Insulin inhibits the action of hormone-sensitive lipase. This is the enzyme that causes hydrolysis of the triglycerides already stored in the fat cells. 2. Insulin promotes glucose transport through the cell membrane into the fat cells. Some of this glucose is then used to synthesize minute amounts of fatty acids, but forms large quantities of a-glycerol phosphate. This substance supplies the glycerol that combines with fatty acids to form the triglycerides that are the storage form of fat
  • 73.
    Effect of Insulinon Protein Metabolism and on Growth • Insulin Promotes Protein Synthesis and Storage • During the few hours after a meal proteins are also stored in the tissues by insulin 1. Insulin stimulates transport of many of amino acids into the cells, eg valine, leucine, isoleucine, tyrosine, and phenylalanine. 2. Insulin increases the translation of mRNA, thus forming new proteins 3. Over a longer period of time, insulin also increases the rate of transcription of selected DNA, forming increased quantities of RNA and still more protein synthesis
  • 74.
    4. Insulin inhibitsthe catabolism of proteins 5. In the liver, insulin depresses the rate of gluconeogenesis, this suppression of gluconeogenesis conserves the amino acids in the protein stores of the body. • In summary, insulin promotes protein formation and prevents the degradation of proteins • Lack of Insulin causes protein depletion and increased plasma amino acids • The resulting protein wasting is one of the most serious of all the effects of severe diabetes mellitus. • It can lead to extreme weakness as well as many deranged functions -of the organs.
  • 75.
    Insulin and GrowthHormone Interact Synergistically to Promote Growth • Because insulin is required for the synthesis of proteins, it is as essential for growth as growth hormone is. • A combination of these hormones causes dramatic growth. • Thus, it appears that the two hormones function synergistically to promote growth each performing a specific function that is separate from that of the other.
  • 78.
    Insulin: Summary andControl Reflex Loop
  • 80.
    Glucagon •Glucagon is acatabolic peptide hormone secreted by α cells of the pancreatic islets Regulation of secretion •Glucagon secretion is directly stimulated by: - low blood glucose concentration - high levels of circulating amino acids •Somatostatin glucagon secretion •Insulin & secretin glucagon secretion •Sympathetic stimulation glucagon secretion (ß-receptor mechanism) •Vagal stimulation glucagon secretion •All forms of physical stress glucagon secretion
  • 81.
    Targets of GlucagonAction • Activates a phosphorylase, which cleaves off a glucose 1-phosphate molecule off of glycogen. • Inactivates glycogen synthase by phosphorylation (less glycogen synthesis). • Increases phosphoenolpyruvate carboxykinase, stimulating gluconeogenesis • Activates lipases, breaking down triglycerides. • Inhibits acetyl CoA carboxylase, decreasing free fatty acid formation from acetyl CoA • Result: more production of glucose and substrates for metabolism
  • 82.
    Glucagon Action onCells: Dominates in Fasting State Metabolism
  • 83.
     A fewhours after a meal (active): - blood glucose levels decrease - insulin secretion decreases - increased secretion of glucagon, cortisol, GH, epinephrine - glucose is released from glycogen stores (glycogenolysis) - increased lipolysis (beta oxidation) - glucose production from amino acids increases (oxidative deamination; gluconeogenesis) - decreased uptake of glucose by tissues - blood glucose levels maintained Hormonal Regulation of Nutrients
  • 85.
    Somatostatin •Somatostatin is apeptide hormone secreted by δ cells of the pancreatic islets (also produced in the hypothalamus) in response to: - blood glucose - plasma amino acids - fatty acids •Somatostatin decreases gastrointestinal functions by: - motility - secretion - absorption •Somatostatin release of: - insulin - glucagon
  • 86.
    Diabetes Mellitus • Diabetesmellitus is a syndrome of impaired carbohydrate, fat, and protein metabolism caused by either lack of insulin secretion or decreased sensitivity of the tissues to insulin • Two forms of diabetes mellitus • Type I diabetes mellitus, also called insulin- dependent diabetes mellitus (IDDM), is caused by impaired secretion of insulin. • Type II diabetes mellitus, also called non–insulin- dependent diabetes mellitus (NIDDM), is caused by resistance to the metabolic effects of insulin in target tissues.
  • 87.
    Type I Diabetes •Caused by Impaired Secretion of Insulin by the Beta Cells of the Pancreas • Often, type I diabetes is a result of autoimmune destruction of beta cells, but it can also arise from the loss of beta cells resulting from viral infections. • Because the usual onset of type I diabetes occurs during childhood, it is referred to as juvenile diabetes. • Pathophysiological features: • Hyperglycemia as a result of impaired glucose uptake into tissues and increased glucose production by the liver (increased gluconeogenesis)
  • 88.
    • Depletion ofproteins resulting from decreased synthesis and increased catabolism • Depletion of fat stores and increased ketosis • As a result of these fundamental derangements: • Glucosuria, osmotic diuresis, hypovolemia • Hyperosmolality of the blood, dehydration, polydipsia • Hyperphagia but weight loss; lack of energy • Acidosis progressing to diabetic coma; rapid and deep breathing • Hypercholesterolemia and atherosclerotic vascular disease
  • 89.
    Type II DiabetesMellitus • Insulin Resistance Is the Hallmark of Type II Diabetes Mellitus • Type II diabetes is far more common than type I diabetes (accounting for approximately 90% of all cases of diabetes) • Usually associated with obesity. • This form of diabetes is characterized by impaired ability of target tissues to respond to the metabolic effects of insulin, which is referred to as insulin resistance. • In contrast to type I diabetes, pancreatic beta cell morphology is normal throughout much of the disease, and there is an elevated rate of insulin secretion.
  • 90.
    • Type IIdiabetes usually develops in adults and therefore is also called adult-onset diabetes. • Caloric restriction and weight reduction usually improve insulin resistance in target tissues • Drugs that increase insulin sensitivity, such as metformin, or drugs that cause additional release of insulin by the pancreas, such as sulfonylureas, may also be used. • In the late stages of the disease when insulin secretion is impaired, insulin administration is required.
  • 92.
    Glucose Tolerance Test •whena normal, fasting person ingests 1 gram of glucose per kg of body weight, the blood glucose level rises from about 90 mg/100 ml to 120 to 140 mg/100 ml and falls back to below normal in about 2 hours. •In a person with diabetes, this test is always abnormal