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131 Cards in this Set

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What substances are secreted by the endocrine pancreas?
The pancreatic islets are composed of:
➣ insulin-secreting β cells (the majority),
➣glucagon-secreting α cells, ➣somatostatin-secreting δ cells, ➣pancreatic polypeptide (PP)-secreting cells.
Describe the structure of Insulin and its function.
Insulin is a major glucoregulatory, antilipolytic, antiketogenic, and anabolic hormone.

It consists of two straight-chain peptides held together by disulfide bonds, and it is synthesized from a single-chain precursor (proinsulin).
What stimulates the release of insulin and what are its effects?
Insulin secretion is stimulated primarily by glucose and food intake, but also by other fuels, gastrointestinal peptides, and cholinergic and β-adrenergic stimuli. Release is decreased during fasting and by exercise, both circumstances that require fuel mobilization.
Insulin promotes fuel storage.
HOW?
Its effects in the order of increasing insulin doses required are:
➣ inhibition of adipose tissue lipolysis and of ketogenesis;

➣ inhibition of hepatic glycogenolysis, gluconeogenesis, and glucose release;

➣inhibition of muscle proteolysis;

➣stimulation of muscle glucose uptake and storage as glycogen.
How does insulin affect metabolites and amino acids?
Insulin also stimulates cellular uptake of amino acids, potassium, phosphate, and magnesium, as well as synthesis of numerous proteins.
How is insulin regulated?
➣ Insulin acts through a plasma membrane receptor
➣ phosphorylates itself via tyrosine residues
➣ acquires external tyrosine kinase activity
➣ activated receptor phosphorylates 4 insulin receptor substrates
➣ a cascade of modulation of the activities of enzymes involved in glucose and FA metabolism

➣ gene trxn of numerous enzymes and proteins essential to cell growth is induced or repressed
Insulin ________ plasma levels of glucose, free fatty acids (FFAs), ketoacids, glycerol, and branched-chain and other amino acids.
Insulin deficiency leads to ____glycemia, _____ of lean body and adipose tissue mass, growth retardation, and ultimately metabolic keto____osis.
Insulin decreases plasma levels of: glucose,

free fatty acids (FFAs),

ketoacids,

glycerol,

branched-chain and other amino acids.

➣Insulin deficiency leads to: hyperglycemia,
loss of lean body
adipose tissue mass,
growth retardation,
ultimately metabolic ketoacidosis.
When is Glucagon released and what is its effect?
Glucagon is a straight-chain peptide released in response to hypoglycemia and to amino acids.

Its secretion is suppressed by glucose, FFAs, and insulin. Glucagon secretion increases during prolonged fasting and exercise.
Describe the antagonistic effects of Insulin.
Glucagon is an insulin antagonist that promotes mobilization of glucose

acts primarily on the liver to stimulate glycogenolysis and gluconeogenesis, as well as FA oxidation and ketogenesis

cAMP is its second messenger, and covalent modification of enzyme activities by phosphorylation is the main mechanism of action.

Glucagon increases the plasma levels of glucose, FFAs, and ketoacids, but it decreases amino acid levels.
Give an example of how glucagon and insulin have antagonistic effect.
insulin:glucagon ratio controls the relative rates of glycolysis and gluconeogenesis by altering hepatic fructose-2,6-BP levels

➣ regulates the rate and direction of flow between F-1-P and F-1,6-BP.

The two hormones have antagonistic effects at numerous other liver enzyme steps in glucose and fatty acid metabolism.
What type of hormone is Somatostatin and what does it do?
SS is a neuropeptide of delta islet and intestinal cell origin.

It decreases the motility of the GI tract, GI secretions, digestion and absorption of nutrients, and secretion of both insulin and glucagon.

SS is secreted in response to meals; its actions, along with those of insulin and glucagon, probably coordinate nutrient input with substrate disposal.
What is the difference between endocrine, neurocrine and paracrine/autocrine?
Hormones are signaling molecules that are conveyed by the bloodstream (endocrine), by neural axons and the bloodstream (neurocrine), or by local diffusion (paracrine, autocrine).
Describe protein and peptide processing.
How is it different from steroid and thyroid hormones.
Protein and peptide hormone synthesis involves gene transcription, primary mRNA splicing and excision, translation, and further processing of a primary gene product, called a prohormone.

Such further processing includes proteolytic cleavage, glycosylation, and phosphorylation.

Thyroid and steroid hormones, catecholamines, and prostanoids are synthesized from precursors by multiple enzyme reactions.
How are
peptide, protein and catecholamines stored
thyroid stored
steroid stored

How are they released?
Peptide and protein hormones and catecholamines are stored in granules and secreted by exocytosis.

Thyroid hormone is stored within protein molecules in large quantities;

steroid hormones are not stored at all.

Both are released by diffusion.
Proteins, peptides, catecholamines, prostanoids act on __________ via _________ receptors located in the ____________. The _________-_______ complex ________ signals through ______ ________.
Proteins and peptides, catecholamines, and prostanoids act on target cells via specific protein receptors located in the plasma membranes. The hormone-receptor complexes transduce signals through second messengers.
Stimulatory or inhibitory G-proteins often link the receptor to membrane mechanisms that generate cAMP, Ca2+, diacylglycerols, and inositol trisphosphate. These molecules act intracellularly to increase or decrease enzyme activities. Other receptors activate tyrosine kinase sites that subsequently phosphorylate enzymes and other key molecules.
All of these effects are rapid.
Where do thyroid, steroid hormones and vitamin D act? How? Fast or slow?
Thyroid and steroid hormones and vitamin D act by means of specific protein receptors located in the cell nucleus. The hormone-receptor complex interacts with promoter/ elements or inhibitory elements in DNA molecules, and with transcription factors to induce or repress expression of target genes. This leads to increases or decreases in the concentration of enzymes and other cell proteins. These effects are slower than those of hormones interacting with plasma membrane receptors.
What is hormone sensitivity?
What influences hormone sensitivity?
The sensitivity of an organism to hormone action is expressed as the hormone concentration that produces half-maximum activity.
The sensitivity can be influenced by changes in receptor number, affinity, hormone degradation rate, or competitive antagonists.

The maximum effect produced by saturating concentrations of hormone can be influenced by
the number of target cells,
receptor number,
concentration of target enzymes,
or
noncompetitive antagonists.
Where does Vitamin D come from?
Where is it modified?
Vitamin D is a steroid molecule

synthesized from cholesterol in the skin in the presence of UV light or is absorbed from the diet.

The basic structure is modified successively in the liver and kidney to 1,25-(OH)2-D, the active metabolite.
How does Vitamin D act?

Vitamin D acts via its _______ receptor to ___________ _________ absorption from the GI tract. The hormone is __________ to maintaining the supply of _________ for _______ formation and growth.
PTH ___________ bone resorption
Vitamin D _________ plasma Calcium and plasma phosphate concentrations.
1,25-(OH)2-D acts via its NUCLEAR receptor to INCREASE CALCIUM AND PHOSHPATE absorption from the GI tract. The hormone is therefore CRITICAL to maintaining the supply of CALCIUM for BONE formation and growth.

PTH ENHANCES bone resorption.

Overall, 1,25-(OH)2-D INCREASES plasma calcium and plasma phosphate concentrations.
PTH is a __________ _______ synthesized from a ___________ in the 4 PTH glands.

PTH is released by ________ in response to a _______ in plasma ________ concentration that is sensed by the calcium recepter in the parathyroid cell.

PTH synthesis and secretion and parathyroid gland mass are _________ by Calcium and Vitamin D.
Parathyroid hormone (PTH) is a straight-chain peptide synthesized from a prohormone in the four parathyroid glands.

PTH is released by exocytosis in response to a decrease in plasma calcium concentration that is sensed by the calcium receptor in the parathyroid cell.

PTH synthesis and secretion and parathyroid gland mass are suppressed by calcium and 1,25-(OH)2-D.
PTH acts via a plasma membrane _______ and _____ to
1) to _______ osteoclastic bone resorption
2) to _______ renal tubular reabsorption of Ca2+
3) to ________ Vitamin D synthesis in the kidney
4) to ________ renal tubular phosphate reabsorption and _______ urinary excretion of phospate.
Overall, PTH ______ plasma Calcium and _______ plasma phosphate concentrations.
PTH acts via a plasma membrane receptor and cAMP (1) to increase osteoclastic bone resorption, (2) to increase renal tubular reabsorption of calcium, (3) to increase 1,25-(OH)2-D synthesis in the kidney, and (4) to decrease renal tubular phosphate reabsorption and increase urinary excretion of phosphate.

Overall, PTH increases plasma calcium and decreases plasma phosphate concentrations.
Calcium deficiency evokes a synergistic sequence that increases PTH and Vitamin D.

The combined actions of these 2 hormones ______ the inflow of Ca and restore plasma concentrations to _____.

They simultaneously dispose of the inflow of extra phosphate by enhancing its renal excretion.
Calcium deficiency evokes a synergistic sequence that increases PTH and 1,25-(OH)2-D secretion. The combined actions of these two hormones increase the inflow of calcium and restore plasma concentrations to normal. They simultaneously dispose of the inflow of extra phosphate by enhancing its renal excretion.
Phosphate deprivation evokes synergistic sequence that ___________ Vitamin D secrtion but __________ PTH secretion.

The result is to _______ the plasma phosphate concentration toward normal while disposing of the inflow of extra calcium by _________ its renal excretion.
In contrast, phosphate deprivation evokes a synergistic sequence that increases 1,25-(OH)2-D secretion, but reduces PTH secretion.

The result is to restore the plasma phosphate concentration toward normal while disposing of the inflow of extra calcium by increasing its renal excretion.
Calcitonin is synthesized in the _ cell within the ________ ______.

It is a PTH _________ in bone, and it is secreted in response to hypercalcemia.

Thus, it acts to lower the plasma concentration of calcium.
Calcitonin is a peptide hormone synthesized in C cells within the thyroid gland. It is a PTH antagonist in bone, and it is secreted in response to hypercalcemia. Thus, it acts to lower the plasma concentration of calcium.
What is BMR?
Basal or resting metabolic rate (BMR or RMR) amounts to an average daily expenditure of 20 to 25 kcal (84 to 105 kjoules)/kg body weight
(or 1.0 to 1.2 kcal/min)
it requires the use of approximately 200 to 250 ml oxygen/min.
Which organ systems use up large amounts of the average daily energy expenditure?
About 40% of the BMR is accounted for by the central nervous system and 20% to 30% by the skeletal muscle mass.
What is diet-induced thermogenesis?
Ingestion of food causes a small obligate increase in energy expenditure, referred to as diet-induced thermogenesis.

This is partly explained by the cost of digestion and the increased rate of rxns involved in the disposition of the ingested calories, such as storage of glucose in the large molecule, glycogen, or as degradation of amino acids to urea.
What is nonshivering thermogenesis?
Nonshivering thermogenesis refers to energy expended for the purpose of producing heat: in an obligatory manner to maintain a constant thermoneutral state, or in a facultative manner when an individual is acutely exposed to cold. All tissues contribute to the obligatory thermogenic process.

Such energy expenditure may also be evoked and may increase to compensate for prolonged exposure to caloric excess, as a means of limiting weight gain.
How much eneryg is contained in the two terminal P-O bonds of ATP?
The two terminal P-O bonds of ATP each contains about 12 kcal of potential energy per mole under physiological conditions.
Describe the energy consumption of energy.
They are generated by oxidative reactions and are consumed as the energy is either
(1) transferred into other high-energy bonds involved in synthetic reactions (e.g., amino acid + ATP → amino acyl AMP)
(2) expended in creating lower-energy phosphorylated metabolic intermediates (e.g., glucose + ATP → glucose-6-phosphate)
or
(3) converted to mechanical work (e.g., propulsion of spermatozoa).
Describe the path of fatty acid to release energy.
The combustion of FA begins with their activation to palmitoyl-CoA.

To enter the mitochondria, palmitoyl-CoA is converted to palmitoyl-carnitine by CPT-1 and reconverted to palmitoyl-CoA in the IM of mitochondria by CPT-2.

The palmitoyl-CoA is then oxidized by β-oxidation.

This process releases 2C at a time as acetyl-CoA -> enters TCA Cycle.

Some of FA oxidat 4 C and yields acetoacetic and β-hydroxybutyric acids.
Fat carries more caloric energy than protein. How are carbs converted to fats?
Fat stores can supply energy needs for up to 2 months in totally fasted individuals of normal weight.

TAGs are formed by esterification of free FA (largely derived from the diet) with α-glycerol phosphate derived from glucose. However, free FAs can also be synthesized from acetyl-CoA derived from oxidation of glucose. Thus, carb can be converted to fat in liver and adipose tissue, and its energy can be stored in that more efficient form.
In humans, however, this process accounts for very little glucose use and no more than 10 to 12 g of fat is synthesized from glucose in 24 hours.
Where is leptin made?
What are leptin levels are measure of?
Leptin is made in adipose tissues

plasma leptin level and mRNA content of leptin in fat correlates well with the BMI amd estimated fat mass of humans.
Where are the receptors for leptin?
Leptin reacts with a plasma membrane receptors in Hypothalamic and other brain cells

it releases a jak-STAT-3 tyrosine kinase intracellular second messenger.
How does leptin get to receptors on brain cells?
leptin must first cross the blood-brain-barrier. It has a transporter that is alternatively spliced, shortened product of the leptin receptor gene present in brain endothelial cells.
How is leptin deficiency expressed?
If leptin is absent an organism is extremely obese, overeats. has low BMR and body temp and is physically very inactive.
Can leptin replacement therapy be used to treat obesity and low BMR?
Yes if the receptors are normal. Therapy with leptin causes weight loss, decreases food consumption and increaes energy expenditure and body temperature.

If leptin receptors are mutated/nonfx

obesity and a similar abnormal metabolism, but the plasma leptin levels are high. In this mouse, treatment with leptin is ineffective.
What are the major hormones involved in body fuel homeostasis?

Fuel = carbohydrates
Hormones that regulate carbohydrate metabolism
anabolic: Insulin, Glucocorticoid, GH

catabolic: Glucagoon (liver), Catecholamines
What are the major hormones involved in body fuel homeostasis?

Fuel = lipids
Anabolic: Insulin

Catabolic: Catecholamines, GH, Glucocorticoid, Glucagon (liver)
What are the major hormones involved in body fuel homeostasis?

Fuel = protein
Anabolic: Insulin, GH

Catabolic: Glucocorticoid, Glucagon (liver), Catecholamines
What are the major processes and hormones involved in regulation of blood glucose concentrations?
Insulin
GH
Cortisol
Glucagon
Epinephrine
How doe insulin regulate blood glucose?
During a fed state when insulin is high glucose output from the liver to the blood is inhibited and breakdown of TAGs in adipocytes to free fatty acids is inhibited. Insulin stimulates Glucose uptake by muscle and adipocytes.
How does GH regulate blood glucose?
Decrease in blood glucose (fasting) triggers GH which
1) stimulate glucose output from the liver (gluconeogenesis, glycogenolysis) to the blood.
2) inhibit glucose uptake by the muscles and adipocytes
3) stimulates breakdown of TAGs from adipocytes to generate free FAs.
How does cortisol regulate blood glucose?
same as GH
Cortisol increases glucose output by the liver into the blood.
Inhibits glucose uptake by the muscle and adipocytes.
Stimulates TAG breakdown into free fatty acids.
How does glucagon regulate blood glucose?
Glucagon stimulates glucose output by the liver.
stimulates glycogen breakdown by the liver.
How does epinephrine regulate blood glucose?
Epinephrine stimulates glucose output and stimulates free fatty acid from TAGs.
Fatty acids increase glucose output from the liver. Fatty acids are used in gluconeogenesis.
Compare and contrast the endocrine effects of glucagon vs. insulin.
Gluconeogenesis and glucose export → ↓insulin activity and insulin gene express
→ ↑glucagon activity and ↑ gene expression
↑ G-6-Phosphatase
↑ F-1,6-Bisphosphatase
↑ PEP Carboxykinase
Pyruvate → ↑insulin activity and gene expression and ↓ glucagon activity and gene expression
↓ Glucokinase
↓ 6-Phosphofructo-1-kinase
↓ Pyruvate kinase
Glycolysis and glucose oxidation
How does Glucagon promote glucose output from the liver?
Glucagon binds to a hepatic plasma membrane glycoprotein receptor →signal transduction cascade → adenylyl cyclase → cAMP → PKA → converts inactive phosphorylase kinase to active phosphorylase kinase → the rate of glycogenolysis increases
Describe the effect of Glucagon on the liver.
Glucagon →glycogenolytic effect by ⊕ glycogen phosphorylase → G-1-P → glycogen resyn blocked by inhibition of glycogen synthase.

Glucagon ↑ alanine and ↓ glycolysis
How is the bifunctional enzyme regulated?
Insulin causes dephosphorylation, making it a kinase, which raises the level of F-2,6-BP. This intermediate stimulates the activity of 6-PFK and shifts metabolism toward pyruvate (glycolysis).

Glucagon phosphorylates the bifunctional enzyme, making it a phosphatase, which lowers the level of F-2,6-BP, thereby increasing the activity of F-1,6-BPase and shifting metabolism toward glucose (gluconeogenesis).
What is the bifunctional enzyme? Why is it important?
6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase IS THE BIFUNCTIONAL DOMAINS.

They are important because they determine the direction and magnitude of the flow between F-6-P and F-1,6-BP, and therefore the relative rates of glycolysis and gluconeogenesis.

This enzyme either catalyzes synthesis of F-2,6-BP from F-6-P, or catalyzes hydrolysis of F-2,6-BP to F-6-P.
How do the hormones of the islet of pancreas regulate each other?
Somatostatin inhibits Insulin and Glucagon and causes decrease glucose influx and amino acid influx.

Somatostatin is inhibited by insulin and stimulated by glucagon.

Insulin inhibits glucagon and glucagon stimulates insulin ? huh? why?
The role of entero-pancreatic axis in insulin secretion
In response to carbs, aa, FA, H+
substrate stimulation
endocrine transmission
neuro transmission
stimulates the islet cells of pancreas
releasing insulin which inhibits the gut activity and decreases motility and inhibits secretion of islet pancreas.
How is glucose regulated during GI Glucose Flux?
GI Glucose Flux
GI hormones, cholinergic and perhaps peptidergic NT reach the islets of Langerhans and elicit anticipatory response of insulin secretion. This avoids major shift in the 6 g/h glucose supply to the brain by increasing the amt of glucose to liver, muscle and fat cells. So if after a big meal 50g/h of glucose is absorbed by gut, 6g/h goes to brain and 44 g/h to muscles, liver and fat.
How is glucose regulated during resting state-post absorptive?
If 10g/h of glucose is absorbed by the liver during resting state, only 4g/h goes to liver, muscle and fat. A constant 6g/h goes to the brain.

In resting state, insulin and glucagon maintain equality btwn rate of glucose utilization an dthat of hepatic glucose prod. 75% of glucose prod is estimated to be glucagon mediated.
How is glucose regulated during Sympathetic NS Activation (Fight or Flight)?
When running from a bear adrenergic NT reach the islet of Langerhans to cause decrease insulin and increase glucagon. Glucagon leads to increase glycogenolysis and gluconeogenesis to lead to glucose release into blood. Insulin inhibition leads to ↓ uptake of endogenously prod. glucose by tissues other than exercising muscles and brain.

If 46g/h glucose is prod. the brain gets 6g/h and the muscles get 40g/h.
How is glucose regulated during severe injury/trauma?
Adrenergic receptors/NT from CNS leads to increase glucagon and decrease insulin. This causes stimulation of gluconeogenesis and minimizes glucose utilization by insulin responsive tissue. Stress hormones also stimulate glucagon secretion.

So if 10g/h is made by the liver gluconeogenesis the brain uses 6g/hr and the liver muscle and fat ONLY uses 1g/h because we are not using our muscles.
What factors lead to diabetes type 2?
- β cell decompensation: is both a genetic disposition and an environmental factor.
Causes
Excessive food intake and inadequate exercise
Results of β cell decompensation
Type 2 Diabetes (adult-onset, ketosis-resistant, NIDDM)
-Obesity
Causes: genetic disposition and excessive food intake + inadequate exercise (compensatory hyperinsulinemia).
Obesity leads to insulin resistance which leads to Beta cell decompensation and compensatory hyperinsulinemia (causes obesity)
What is the treatment of diabetes Type 2 (aka disease of excess)
Dietary restrictions to produce weight loss
insulin releasing drugs - sulfonylurea drugs
promotes insulin action in target cells
corrects sluggish response of β-cells to glucose.
What factors lead to diabetes type 1?
β cell injury caused by:
genetic disposition
beta cytotrophic viruses and chemical toxins
islet antibodies

Leads to type I diabetes
-juvenile, ketosis-prone, IDDM, ~20% of diabetics
What is the treatment of diabetes Type 1?
Long term control of IDDM requires balance btwn
-insulin injections
-diet
-exercise which promotes uptake of glucose by muscle
What is the effect of insulin lack on carbohydrate metabolism?

diabetic state
insulin lack causes hyperglycemia

glycosuria, osmotic diuresis & dehydration

decrease fluid concentration, hypotension

decrease renal blood flow

anuria

coma and death
What is the effect of insulin lack on fat metabolism?

diabetic state
insulin lack

decreases lipogenesis and mobilization depot of fat

lipemia

incr. ketogenesis in the liver

ketonemia which causes metabolic acidosis

ketonuria and loss of Na
What is the effect of insulin lack on protein metabolism?

diabetic state
insulin lack

increase protein breakdown (catabolism)

increase gluconeogenesis

increase urinary nitrogen

cellular dehydration and loss of K

Net loss of K from body
Adrenal Androgens
from zona reticularis

DHEA, DHEA Sulfate and androstenedione

weak androgens

their metabolism in periphery is major source of T in females
Glucocorticoid
from zona fasciculata
cortisol
contra-insulin or counter-regulatory hormone
Mineralocorticoid
from zona glomerulosa

Aldosterone

regulates plasma osm by promoting kidney Na and water retention, K excretion and increase blood pressure
What is the role of ACTH in corticoid biosythesis in adrenal cortex
In adrenal cortex fasciculata the hormone is ACTH which binds its membrane receptor.

the receptor is ACTH receptor coupled to Gs/cAMP and PLC/IP3 pathways and the steroid hormone cortisol.
What is the role of Angiotensin II in glomerulosa layer?
In glomerulosa layer the hormone/receptor is mainly angiotensin II/angiotensin receptor

the hormone is aldosterone
What is the function of cyp450 Enzyme?
Cytochrome P-450 is a hydroxylase enzyme in mitochondria and ER

Critical to all steroid hormone biosynthesis

Conversion of cholesterol to pregnenolone via side chain cleavage enzyme (cyp450scc) specifically stimulated by ACTH is rate controlling for cortisol and DHEA production.
Describe ACTH's key immediate biochemical and physiological events stimulated by ACTH on adrenal cortex.
When ACTH acts on its receptor it stimulates cAMP and activates peptide proteins near mitochondria to move cholesterol into mitochondria

↑synthesis of cholesterol esterase ↑cholesterol transport into mitochondria
↑cholesterol binding to P-450scc
↑increase prenenolone production
Describe ACTH's key subsequent biochemical and physiological events stimulated by ACTH on adrenal cortex.
increase gene trxn of P-450scc and other P-450 and LDL receptor
increase peptide synthesis of peptides responsible for synthesis of the hormone
Describe ACTH's key long-term biochemical and physiological events stimulated by ACTH on adrenal cortex.
increase size and fx and complexity of organelles
increase size and number of cells due to increase growth factors
Describe role and site of production of Cortisol
Cortisol is product of zona fasciculata

causes - FB on ACTH at pituitary and hypothalamic levels

11-OH group from cyp450c11 required for FB and glucocorticoid activity

limited conversion in adrenal to cortisone
Describe the differential processing of the Pituitary cells on POMC.

Pro-OpioMelanoCortin
ACTH produced mainly in the anterior pituitary under CRH control. ACTH from POMC gene product.

products of corticotrophic cell of anterior pit under control of CRH to drive molecule to be proteolyzed to a product that is secreted

In intermediary lobe of pituitary gland there is differential processing and POMC forms endorphin and MSH peptides.
in rested, relatively healthy and unstressed individuals
cortisol secretion is in ________ and ________ bursts
burst frequency ______ in ____ _____ driven by a more prominent ______ rhythm.

Determines ______ rhythm
in rested, relatively healthy and unstressed individuals
cortisol secretion is in frequent and pulsatile bursts
burst frequency increases in early morning, driven by a more prominent ACTH rhythm.

Determines CIRCADIAN rhythm

Stressors and pathophysiologies can readily override and obliterate/flatten the normal cortisol rhythm
Describe Congenital adrenal hyperplasia

CAH driven by dysregulated ____
_____ cortisol, mostly becaues of deficient _______

steroid intermediates from blocked cortisol and aldosterone pathways are driven into reticularis pathway to androgens.
CAH driven by dysregulated ACTH
DECREASES cortisol, mostly becaues of deficient cyp450c21 (21-hydroxylase in fasciculata layer)

P450c21 catalyzes hydroxylation of progesterone to 11-deoxycortisol (occurs in SER)

steroid intermediates from blocked cortisol and aldosterone pathways are driven into reticularis pathway to androgens.
How is cortisol transported in plasma?
Cortisol ~95% bound (mostly to cortisol-binding globulin ~ 80% and a little to albumin) in plasma

with 5% "free" biologically active
How is aldosterone transported in plasma?
Aldosterone is more water-soluble, has no specific transport globulin but ~60% bound to albumin
aldosterone turnover is faster and half-life is shorter than cortisol
Cortisol excretion can be measured by....
17-OHcorticoids is an index of cortisol secretion
Name the major effects of cortisol on body fuels
Essential for life
catabolic and anti-anabolic on muscle
stimulates liver gluconeogenesis
fat lipolysis
protein catabolism
induces liver gluconeogenic enzyme levels over the long term
while blocking insulin's action on substrate storage
cortisol increases liver glycogen stores
is a permissive hormone it maximizes the effects of other hormones by providing glycogen and inducing enzymes EPI AND GLUCAGON
Contra-insulin actions of coritsol on glucose production and glucose utilization
Cortisol increases glucose production and decreases glucose utilization
Name the activities and enzyme levels that are increased by cortisol.
Cortisol induces G-6-phosphatase which increase release of glucose
increases conversion of pyruvate to glycogen by inducing Pyruvate carboylase, PEP Carboxykinase, gylcogen synthase, F-1,6-BP

Provides carbon precursors
alanine and tyrosine transaminase etc.
Cortisol
decrease connective tissue
decrease bone formation and increase bone resorption
maintain muscle fx and decr. muscle mass
modulate emotions, wakefulness
increase glomerular filtration and free water clearance
facilitate maturation of the fetus
maintain CO, incr. arteriolar tone, decr. endothelial permeability
inhibt inflammatory and immune response
How does cortisol block the inflammatory response?
cortisol blocks IL1,2,6 and blocks fever T cell proliferation is blocked

blocks PLA2 and so inhibits formation of Arachidonic acid and so COX (prevents inflammation) AND Lipooxygenase is blocked

Blocks platelet activating factor and NO.
How does cortisol work
has nuclear receptors and has zinc fingers
DNA-vinding domain: pair of zinc finers governing binding to HREs in enhancer regions of susceptible genes
Primary Cushing's syndrome
due to excess cortisol from adrenocorticoal (micro) adenoma or carcinoma which also suppresses circulating ACTH
Secondary Cushing's syndrome (Cushing's disease)
due to excess pituitary ACTH output

~ 3-fold more common than primary Cushing's
Ectopic ACTH syndrome
due to production of ACTH or ACTH-like proteins from non-pituitary and non-adrenal tumors
What is the cause for Cushingoid syndromes?
Because anti-inflammatory coriticoid medication is widespread, excessive glucocorticoid intake (iatrogenic Cushing's) is a comon reason for Cushingoid syndromes
What is Addison's Syndrome?
Adrenal insufficiency
depressed cortisol output due to:
❅ primary adrenocortical failure, usually autoimmune cause, termed Addison's disease

❅ secondary (pituitary) or tertiary (hypothalamic) deficiency (rare)

❅ iatrogenic adrenal insufficiency due to HPA axis suppresion by prior pharmaco therapy.
What are the metabolic actions of EPI?
Carbohydrate metabolism → increase muscle glycogenolysis, providing glucose for energy metabolism and lactate gluconeogenesis

Lipid metabolism → stimulates HSTL in adipose tissue to provide free FA. Inhibits Insulin
What are the two types of cells of the adrenal medulla? How are they released?
Adrenal Medulla: two types of chromaffin cells in adrenal medulla (most are EPI secreting)

Both chromaffin granules that store release CAs upon neuronal and hormonal stimulation

CA release by exocytosis involves Ca2+ dependent fusion of granules with inner membrane and release of granule contents into ECS and bloodstream

EPI and or NE with ATP
Regulation of adrenal catecholamine synthesis and secretion
Regulation of EPI production is both neuronal and hormonal

Neuronal: peripheral cholinergic nerves synapse on chromaffin cells induce TH and DBH levels/activities, causing exocytosis

Hormonal: cortisol perfusing medulla from cortex induces DBH nd especially PNMT, thus sustaining EPI synthesis and secretion.
EPI converted by MAO to Dihydroxymandelic acid which is converted by COMT to Vanillylmandelic Acid

Same for NE
EPI is converted by COMT (Catecol-O-methyl transferase) to Metanephrine

Metanephrine is converted by MAO (Monoamine oxidase) to VMA, Vanillymandelic acid

MAO is a mitochondrial enzyme used to treat depression
Explain Aldosterone's mechanism of action on kidney in terms of its physiological effects, and why cortisol is normally blocked from exerting a similar effect.
Aldosterone works thru binding MR- (mineralocorticoid receptor) that allows it to enter the nucleus

Aldosterone increases bp via Na-water retention, increases renal K secretion and increases renal H secretion

This restores ECF volume while the K secretion is useful for dealing with hyperkalemia.

Cortisol is a MR ligand but is normally blocked from exerting a similar effect to aldosterone by the BODYGUARD ENZYME - 11-β-hydroxysteroid dehydrogenase, type 2 (11β-HSD)

The BODYGUARD ENZYME, 11β-HSD, inactivates and prevents cortisol from binding to the MR (in the kidney) by changing it to cortisone.

Glycyrrhetinic acid (GA) is a 11β-HSD inhibitor which allows cortisol to interact with the MR and have the same effects as aldosterone (Na retention and hypertension)
What would happen in the absence of BODYGUARD ENZYME, 11β-HSD, on renal cells?
increased bp

via Na-water retention, ↑ renal K secretion and ↑ renal H secretion
What are the clinical manifestations of Cushing's Dx?

Secondary Cushing's Syndrome
moon face
purple striae
poor wound healing buffalo hump
excessive weight gain (esp. in torso)
What are the metabolic actions of EPI?
EPI
increases muscle glycogenolysis - glucose and lactate
increases hepatic glycogenolysis and gluconeogenesis
stimulates triglyceride lipolysis via HSTL
inhibits insulin secretion
Describe the Catecholamine biosynthesis pathway of DA, NE and EPI
Tyr

↓TH

Dopa

↓DDC + Vit B6

DA

↓DβH + (Vit C; Cu)

NE

↓PNMT (w/ SAM)

Epi
TH is modulated by __________.
DβH is modulated by _________.
PNMT is modulated by __________.
TH is modulated by sympathetic stimulation.
DβH is modulated by sympathetic stimulation.
PNMT is modulated by cortisol stimulation.
Describe the two main enzymatic pathways in EPI and NE catabolism.
EPI and NE

↓ COMT

(NOR)METANEPHRINE

↓MAO + AldDH

VMA
---------------------------

EPI and NE

↓MAO and AldDH

DMA

↓COMT

VMA
What is the fx of MAO?
What is the fx of AldDH?
What is the fx of COMT?
What is the fx of VMA and metanephrines?
MAO removes amine groups
AldDH converts aldehydes to acids
COMT converts catechols to inactive phenols by O-methylation using SAM cofactor
VMA and metanephrines are useful clinical assays of catecholamine-related pathological conditions
α1

equally responsive to EPI and NE

causes PIP turnover to IP3/DAG/Ca2+

Ca2+ binds calmodulin

activates PLC and Gαq

What are the biological effects?
vasoconstriction
uterine contraction
pupil dilation
GI muscle relaxation
α2 receptors

responds more to NE than EPI

inhibits AC via Gαi

inhibits cAMP

What are the biological effects?
Increase platelet aggregation

decrease presynaptic NE release
β1

responds more to EPI than NE

stimulates AC

increase cAMP

What are the biological effects?
Cardiac stimulation

GI muscle relaxation
β2

responds more to EPI than NE

stimulates up to adenylate cyclase

increase cAMP

What are the biological effects?
Bronchodilation
vasodilation
uterine relaxation
Parasympathetic = Long Preganglionic,
short postganglionic → long arms, short fingers

Sympathetic = short preganglionic, long postganglionic → short arms, long fingers
Adrenal medullary discharge of EPI
Diffuse discharge of NE from sympathetic nerves
RAPID RESPONSE
Pheochromocytoma is
nonmalignant chormaffin cell tumor

secreting excess EPI and often NE that can cause up to 5% hypertension

detected by VMA and Metanephrine exretion.

Why is it called the ten percent tumor?
10% Malignant
10% Bilateral
10% In Children
10% Familial
10% Recur
10% Associated with MEN
10% Present with Stroke
10% Extra-adrenal
Describe the differences in plasma EPI and NE levels in response to stresses.

resting supine
standing
hypoglycemia
Mild exercise
Heavy exercise
Pheochromocytoma
The threshold for is low ~50pg/mL

resting supine: low NE; EPI at threshold levels
standing: low NE; threshold EPI
hypoglycemia: low NE; HIGH EPI
Mild exercise: low NE; exceeds EPI threshold
Heavy exercise: high NE; high EPI
Pheochromocytoma: NE and EPI exceeds threshold
Where is melatonin synthesized
When is melatonin secreted
Melatonin made and secreted mainly by the pineal gland

Melatonin has a marked circadian synthesis/secretion pattern driven by NE nerve release and receptors

high at night, low in light

no melatonin at noon when N-acetyl transferase is low
Melatonin synthesis via tryptophan-serotonin pathway

Starts with Tryptophan
Intermediate is Serotonin
End Product is Melatonin
Tryptophan catalyzed by Tryptophan hydroxylase and aromatic amino acid decarboxylase

Serotonin

↓N-Acetyl transferase

N-acetyl-serotonin

↓HIOMT, SAM

Melatonin

(N-acetyltransferase activated by phosphorylation due to night time release of synaptic NE and β receptor activation)
Sleep regulation

Regulation of reproduction
Large doses

Inhibits gonadotropin secretion in animal models- premature pineal destruction may cause premature puberty and nocturnal melatonin secretion declines with age
Explain the physiological importance of thyroid hormones in overall development and metabolism.
TH stimulates carbohydrate absorption from small intestine and fatty acid release from adipocytes

stimulate Na/K ATPase

calorigenic = consumes ATP at a high rate to give off heat

permissive effects on Epi and NE and upregulates β-adrenergic receptors

essential for normal growth and development particularly of nervous system (def causes cretinism)
what is the importance of dietary iodide

its thyroid gland uptake for adequate thyroid biosynthesis
Thyroid gland traps ~20% of iodide intake

Iodide is a critical component in thyroid synthesis
What is the Wolff-Chaikoff effect?
a means of autoregulation

when Iodide doses are high it rejects large quantities which prevents the thyroid from synthesizing large quantities of thyroid hormones

large amts of thyroid hormones causes the thyroid gland to shut down
What is the fx of TSH on T3 and T4 biosynthesis in the thyroid follicle?
TSH from the anterior pituitary goes to the thyroid gland

TSH is a dimer with two subunits- α and β

β TSH subunit binds the membrane receptor and increases cAMP

Increases Ca, IP3 and DAG, and Growth Factors

this causes increased
increase follicle formation
I trapping,
iodination,
endocytosis of colloid,
proteolysis of TGB
Describe the HPT axis
Hypothalamus releases TRH from arcuate nucleus and median eminence

Pituitary releases TSH due to TRH
Thyroid gland releases T4/T3 due to TSH

T4/T3 negative FB on Pituitary and hypothalamus

TSH shuts off TRH release

Hypothalamic Dopamine and Somatostatin has tonic inhibition of TSH release
Describe the role of Thyroglobulin and thryoperoxidase in T4/T3 biosynthesis
TGB and thryoid peroxidase are found in the colloid

TGB is a carrier of Iodide and thyroid peroxidase is the enzyme that attaches them to tyrosines on TGB.

MIT= 1 Iodide attached
DIT= 2 Iodide attached

When thyroid hormones is needed the follicle is endocytosed and MIT and DIT is deiodized by enzyme called iodotyrosine deiodinase.

I- is reutilized and T4, T3 is released into the blood
Albumin has the largest ___________ to bind T4 and can bind most T4 before becoming _______________.

TBG has highest ______________ for T4
Albumin has the largest capacity to bind T4 and can bind most T4 before becoming staurated.

TBG has highest affinity for T4.
What are the similarities and differences between thryroid hormone receptors and steroid hormone receptors?
similarities: lipophilic, intracellular receptor of the steroid hormone superfamily

TRs have 2 genes for TRs: (α and β) with alternate splicing

TRs comtain key cysteines in DNA binding domain forming zinc fingers which promote TR binding with chromatin thyroid response elements (TREs)

TRα2 has no carboxy region so it can't bind T3 and transactivate → inactive
TRα1, TRβ1, β2 can bind T3 and transactivate.

TR are different from steroid hormone receptors because
they dimerize as heteromers with nuclear retinoic acid receptor
T3-occupied TR dimerized with occupied RR activates TRXN.
Unoccupied TR dimerized with occupied RR represses TRXN
How is gene expression regulated through TR and RR receptors?
Unoccupied TR/RXR heterodimer on TRE recruits co-repressor HDAC which closes chromatin structure and represses TRXN

T3-occupied TR/RXR heterodimer on TRE recruits co-activator complex with HAT which opens chromatin structure and activates TRXN.
How does T4/T3 levels affect behavior?
Hypothyroidism causes mental retardation, cretinism, cold sensitivity

Hyperthyroidism causes mental quickness, restlessness, irritability, anxiety, wakefulness, sensitivity to heat and sweating.
How does T4/T3 levels affect cardiovascular?
Hypothyroidism causes decreased cardiac output, weak heartbeat

Hyperthyroidism causes increased cardiac output, tachycardia, palpitations
How does T4/T3 levels affect muscles?
Hypothyroidsim
causes muscle weakness, hypotonia

Hyperthyroidism
Fibrillary twitching, tremors
How does T4/T3 levels affect the whole individual?
hypothyroidism
deficient growth- dwarfism
LOW BMR
hypercholesterolemia
myxedema

hyperthyroidsim
negative nitrogen balance
HIGH BMR
hypocholesterolemia
exothalalamos
Hyperthyroidism

what are the clinically symptoms
what assay should be used
Hyperthyroidism is commonly ~65-80% due to Graves dx.
Graves dx is an autoimmune dx which is causes by TSA- thyroid stimulating antibodies overstimulating receptors and causing excessive Thyroid hormone release

Serum TSH determination is the single best test of thyroid state

Normal TSH levls are 0.5-4.5mU/L
Hypothyroidism

what are the clinical symptoms
Elevated TSH and low serum T4/T3 are the most common clinical proglmes in overt cases, indicates primary thyroid problem.

Hashimoto's dx - T cells attack and destroy thyroid tissues causing increased TSH levels due to the negative feedback

Treatment is with artifical T4
Genetic sex
Male
Y chromosome
SRY sex determining region of Y chromosome
X chromosome
carries androgen receptors

Female
Ovary development depends on the presence of 2X and no Y chromosome

AHC- adrenocortical hypoplasia congeital

Loss of one X chromosome results in Turner Syndrome (ovarian dysgenesis) but not loss of female ducts
Gonadal Sex
Genetic sex dictates Gonadal sex and Gonadal sex is not dependent on hormone

development of testis not hormone dependent
development of the ovary is not hormone dependent
Phenotypic Sex
involves internal and external structures

if not male then female