What are endocrines secreted by?
Ductless glands
What are endocrines?
Chemical messengers that coordinate activities at cell, tissue, organ, and systemic levels
What is classic endocrine signaling?
Hormones travel to distant organs to regulate target organs function
What is an intracrine?
Endocrine that has effect on cell that produces it WITHOUT secretion
What is an autocrine?
Endocrine has effect on cell that secretes it
What is a paracrine?
Endocrine that has effect on neighboring cells
What is a hormone?
Endocrine that has effect on cell in different location
What is a neuroendocrine?
Endocrine secreted by neuron and delivered to another location
What makes an endocrine a cytokine?
If it is secreted into ECF and establishes a gradient - can act as paracrine, autocrine, or hormone
How do chemical messengers maintain homeostasis?
Change in environment -> hormone secretion -> action on target cell -> restoration of normal environment
What are the three general classes of endocrines?
- Proteins/polypeptides
- Steroids (cholesterol backbone)
- Amine derivatives (tyrosine, tryptophan)
What is the solubility of protein hormones?
Water soluble
What is the precursor and production of protein hormones?
Synthesized as larger precursors, undergo proteolytic cleavage into a pro hormone, then are cleaved again into biologically active hormone
How are protein hormones stored?
In secretory vesicles in cells
Examples of protein hormones?
TSH, ADH, insulin, PTH
What is the solubility of steroid hormones?
Lipid soluble
What is the precursor/production of steroid hormones?
All synthesized from cholesterol - differ in ring structure and side chains
How are steroid hormones stored?
Usually not - large stores of cholesterol in cytoplasmic vacuoles, stimulus causes them to be synthesized into steroid
What are some types of steroid hormones?
Glucocorticoids (cortisol) Mineralcorticoids (aldosterone) Androgens (testosterone, DHEA) Estrogens (estradiol, estrone) Progestins (progesterone)
When are steroid hormones synthesized?
On an as needed basis for immediate release
Where are steroid producing enzymes located?
Mitochondria and ER
What is a secosteroid?
Cholesterols with a broken ring
What is solubility of a secosteroid?
Lipid soluble
Example of secosteroid?
Vitamin D
What are the two groups of hormones derived from tyrosine?
Thyroid hormones and catecholamines
What is the solubility of thyroid hormones?
Lipid soluble
What is the structure of thyroid hormones?
“Double” tyrosine with incorporation of 3 or 4 iodine atoms
What is the structure of catecholamines?
“Single” tyrosine
What is the solubility of catecholamines?
Water soluble
What are examples of catecholamines?
Neurohormones (epinephrine, norepinephrine)
Neurotransmitters
What hormones are synthesized from tryptophan?
Serotonin and melatonin
What hormone is synthesized from glutamic acid?
Histamine
What other hormone is synthesized from tyrosine?
Dopamine
What are eicosanoids?
Signaling molecules derived from polyunsaturated fatty acids (omega 3 or omega 6 fats)
Which eicosanoids are pro-inflammatory?
Omega 6 derivatives
Which eicosanoids are anti-inflammatory?
Omega 3 derivatives
What is the most abundant eicosanoid precursor?
Arachidonic acid
How long are eicosanoids active?
Only a few seconds
What are the 4 main eicosanoids?
Prostaglandins, prostacyclins, leukotrienes, thromboxanes
What do anti inflammatory drugs do to eicosanoid synthesis?
Down regulate
Why is a cell called a target?
It has a specific receptor for a particular hormone
How are endocrines regulated using receptors?
Target cell receptors decrease in number if there is an excess of hormone in blood
What do physiologic effects of hormones depend on?
Their concentration in blood and ECF and number of receptors present on target cells
Why is precise control over hormone circulation crucial?
Hormone concentrations that are too high or too low can lead to disease
How is hormone secretion regulated?
Most commonly: Negative feedback loop
Less commonly: positive feedback loop
What is the most highly regulated aspect of endocrine control?
Synthesis/secretion of hormones
What are 4 ways hormones are metabolized and excreted?
- Metabolic destruction by tissues
- Binding to tissue and subsequently “recycled”
- Excretion by liver into bile
- Excretion by kidney into urine
What is the link between nervous system and endocrine system?
Hypothalamus
How does chronotropic control work?
Works in conjunction with neural control
Superimposed on negative/positive feedback control systems
What is circadian rhythm?
Hormones released at set interval everyday
What are diurnal rhythms?
Biological circadian rhythms that synchronize with day/night cycle
What is the sleep-wake cycle?
Can be different than diurnal rhythm in people with sleep problems or who work late night shifts
What is circhoral release of hormones?
Release frequency of about 1 hour
What is ultradian release of hormones?
Episodic release of longer than an hour but less than 24 hours
When is episodic secretion of hormones considered circadian?
If the periodicity is approximately 24 hours
What controls the circadian rhythm?
Suprachiasmatic nucleus in hypothalamus
Why is pulsatile release of GnRH important?
Slower frequency will not maintain gonadal function, faster or continuous release will inhibit gonadotropin secretion and block gonadal steroid production
Down regulation: What does an increased hormone concentration and receptor engagement lead to
- Functionally?
- Structurally?
- Decreased sensitivity of target tissue (inactivation of Receptor molecules, inactivation of intercellular signaling)
- Decrease in number of receptor sites (temporary removal of receptor or receptor destruction)
What is hormone up regulation?
Decreased hormone concentration and receptor engagement leads to increased sensitivity of target tissue to stimulating effects of hormone - same mechanisms as down regulation
Where are receptors for water soluble hormones found?
Surface of target cell
What are water soluble hormone receptors coupled to?
Second messenger systems
Where are receptors for fat soluble hormones located?
In the nucleus of target cell
What happens when a hormone binds an enzyme linked receptor?
Conformational change, usually involving phosphorylation of a tyrosine
What does phosphorylation of a tyrosine do?
May activate/inactivate intercellular enzymes, may catalyze second messenger, may generate new protein => change cell function
How do G protein linked receptors work?
Hormone binds to receptors -> conformational change in receptor -> intracellular G protein recruited to receptor -> alpha subunit has GTPase activity -> cellular change (open/close ion channels, activate adenyl Cyclase, change other enzyme activity)
What do second messengers do?
Amplify hormone signal
What does generation of second messengers and activation of specific protein kinases result in?
Changes in activity of target cell
How fast are changes invoked by second messengers?
Rapid
Three examples of second messenger systems?
- Cyclic nucleotides (cAMP)
- Calcium and calmodulin
- Phospholipase C
What does activated G protein complex recruit?
Adenyl Cyclase
What does adenyl Cyclase do?
Converts ATP to cAMP
What does cAMP do?
Activates protein kinase
What does activated protein kinase do?
Phosphorylates specific proteins that trigger cellular response to hormone
Hormones using adenyl Cyclase/cAMP system?
ACTH, angiotensin II, calcitonin, catecholamines, CRH, FSH, glucagon, HCG, LH, PTH, secretin, somatostatin, TSH, vasopressin
What does phospholipase C do?
Breaks down membrane phospholipids into IP3 and DAG
What does IP3 do?
Mobilizes mitochondrial/ER calcium to cause smooth muscle contraction and cell secretion
What does DAG do?
Activates protein kinase C that promotes protein phosphorylation and arachidonic acid conversion to prostaglandins
Hormones using phospholipase C system?
Angiotensin II, catecholamines, GnRH, GHRH, oxytocin, TRH, vasopressin
What does calcium entry into cells cause?
Binds calmodulin -> activation/inhibition of protein kinases
How do lipid soluble hormone receptors work?
Hormones diffuse through lipid bilayer, bind to receptor (in cytoplasm or nucleus), undergoes conformational change -> binds specific DNA sequence called “response elements in the nucleus”
What do steroid hormones cause in target cells?
Protein synthesis (enzymes, transport proteins, structural proteins)
How fast are responses evoked by lipid soluble hormones?
SLOW due to transcription/translation mechanism
What is an agonist ligand?
Binds to receptor -> hormone response
What is an antagonist ligand?
Binds to receptor and inhibits hormone response
What is a partial agonist/partial antagonist?
Binds receptor -> hormone response < full agonist
If concentration high enough can act as antagonist
What is a mixed agonist-antagonist?
Compounds that act in different ways through same receptor depending on context
What is hormone deficiency usually due to?
Destructive process at gland where hormone produced
What are two other ways to cause hormone deficiency?
Genetic defects in hormone production, inactivating mutations of receptors
How does hormone excess happen?
May be overproduced by gland, or by tissue that is not endocrine organ
Endocrine gland tumors
What does overproduction of tropic hormones lead to?
Overstimulation of target gland
Example of overstimulated target gland disease?
Cushing’s
What does activating mutations of cell surface receptors cause?
Aberrant stimulation of hormone production by endocrine gland
Example of activating mutation disease?
McCune-Albright syndrome
What does malignant transformation of non-endocrine tissue cause?
Lack of differentiation -> ectopic production of hormones
What do anti-receptor antibodies do?
Stimulate receptor instead of block it
What do alterations in receptor number and function result in?
Endocrine disorders
What will an aberrant increase in level of specific hormones most commonly cause?
Decrease in available receptors => down regulation (eg type II diabetes)
What can ingestion of exogenous hormone cause?
Hormone excess
Which hormones does the pancreas secrete?
Insulin, glucagon, amylin, somatostatin, pancreatic polypeptide
Which hormones are secreted by beta cells?
Insulin and amylin
Which hormone is secreted by alpha cells?
Glucagon
Which hormone is secreted by delta cells?
Somatostatin
What is insulin?
- Energy abundance hormone
- Energy storage hormone
- Hypoglycemic hormone
What is the dominant hormone in regulation of blood sugar?
Insulin
How is insulin synthesized?
As preprohormone after translation of insulin RNA
Cleaved in ER to proinsulin
What happens to proinsulin?
Cleaved in Golgi to insulin
-packaged in secretory granules and secreted into blood
How long does insulin circulate in blood?
Cleared in 10-15 minutes
How is insulin degraded?
By insulinase to allow rapid “turn off”
What happens with a lack of C peptide?
Neuropathy, cardiovascular disease, kidney issues
What does C peptide do in nervous system?
Promotes axonal repair
What does C peptide do in cardiovascular system?
Promotes micro vascular blood flow by stimulating Na+/K+ pump and release of NO
What does C peptide do in urinary system?
Promotes glomerular filtration
What happens with too much C peptide?
C peptide deposits on endothelia cause inflammation
- macrophages become foam cells
- T cell mediated inflammation
- smooth muscle proliferation
What is the primary factor that stimulates beta cells?
Increased blood glucose
Which transporter is on beta cells?
GLUT2
How does glucose get into beta cell?
Diffusion using GLUT2 transporter
How is insulin secreted?
Glucose uptake into beta cells using GLUT2
Glucokinase makes G6P
Glycolysis products NADH and ATP close K+ channels
Ca2+ channels open
Preformed vesicles bind Ca2+ and release insulin to blood
What other factors increase Ca2+ influx and therefore insulin secretion in the presence of glucose?
Glucagon Arginine Lysine GI hormones Acetylcholine Sulfonurea drugs
What is the effect of insulin on carbohydrates?
Increased glucose uptake
Increases glycogenesis
Decreased gluconeogenesis
What is the effect of insulin on fat?
Increased triglyceride synthesis
Decreased triglyceride breakdown
What is the effect of insulin on protein?
Increased synthesis
Decreased breakdown
What type of receptor does insulin bind to?
Enzyme linked receptor
What are the end effects of insulin binding?
- Within seconds, 80% of body’s cells increase glucose uptake by mobilizing GLUT4
- Phosphorylation of glucose allows it to be substrate for CHO metabolic functions
What happens to cell membrane under influence of insulin?
Becomes permeable to amino acids, K+ and phosphate
What does insulin do to Na/K pump activity?
Increases activity
What happens after a high CHO meal?
Increased glucose -> increased insulin -> rapid uptake, storage and use
Why is it important To have low serum insulin between meals?
So glucose can go preferentially to brain
What does insulin do in liver?
Stimulates glycogen synthetase and inhibits glycogen phosphorylase
What happens to most glucose after a meal?
Stored immediately in liver as glycogen
What enzyme does insulin increase to promote glucose uptake by liver?
Glucokinase
What does decreased glucose between meals lead to?
Less insulin
- activates phosphorylase and induces glycogenolysis
What is insulin’s effect on
- glucose storage/utilization enzymes?
- glucose mobilization/synthesis enzymes?
- activates
- inactivates
What does resting muscle preferentially use for energy?
Fatty acids
Two conditions where muscle uses glucose?
- Exercise
2. After meal - blood glucose high, insulin is high= rapid transport of glucose into muscle
What happens to glucose transported into muscle cell after a meal if not exercising?
Store as glycogen
What does insulin do to muscle amino acids?
Inhibits release so not available for gluconeogenesis
What does insulin do to fat?
Increase fat synthesis, decrease fat breakdown
What happens when liver glucose storage reaches limit?
Conversion of excess sugar into fatty acid by liver
What is insulin’s action on adipose?
Inhibits hydrolysis of TG, preventing free fatty acids from getting to blood. Increases use of glucose for energy and decreased use of fat
When insulin is low, what is preferentially used for energy?
Fat
What is the signal for switching from fat to CHO for energy use?
Blood glucose
- low BG = low insulin = FAT use
- high BG = high insulin = CHO use
Other hormones that play a role in switching from fat to CHO use?
Growth hormone, cortisol, glucagon
What effect does insulin have on amino acid uptake?
Promotes it
What effect does insulin have on protein catabolism?
Inhibits catabolism via inhibition of normal degradation
What is insulin’s effect on potassium?
Promotes K+ uptake to decrease serum [K+]
Inhibits K+ efflux
What effect does insulin have on phosphate?
Promotes phosphate uptake
What happens if insulin or growth hormone is absent?
Leads to decreased growth
What type of hormone is glucagon considered?
Hyperglycemic
What is the most important action of glucagon?
To increase blood glucose
What are the two main effects of glucagon on glucose metabolism?
- Glycogenolysis
2. Gluconeogenesis
What increases secretion of glucagon?
- Low blood glucose
- Exercise
- High serum amino acids
What decreases glucagon secretion?
High blood glucose, somatostatin
What is the solubility of amylin?
Can be chemically modified to be water soluble or insoluble
What does amylin do if insoluble?
Forms fibrils, induces apoptosis of pancreatic beta cells, therefore inhibiting insulin secretion
What does amylin do if water soluble?
Decreases blood glucose
- synergizes with insulin
- decrease glucagon
What does somatostatin do?
Inhibits glucagon and insulin
What increases somatostatin secretion?
Ingestion of food
What is the main goal of somatostatin?
Extend period of time over which food/nutrients are assimilated, decreases use of absorbed nutrients by tissues
What does somatostatin secreted by the hypothalamus do?
Suppress secretion of GH by anterior pituitary
What happens to proteins with lack of insulin?
Protein storage and synthesis slows down dramatically, increased catabolism of protein in muscle
What happens with use of fat for energy with lack of insulin?
Increased use by all tissues except brain - causes lipolysis
Increased FFA in blood leads to liver conversion of FA into phospholipids, TG, and cholesterol => atherosclerosis
What is diabetes mellitus?
Syndrome of impaired CHO, PRO, FAT metabolism
Two causes of DM?
- Lack of insulin secretion
2. Decreased insulin sensitivity of tissues
What are the 2 main types of DM?
Type I - overt beta cell failure
Type II - loss of insulin sensitivity
What is insulin dependent DM?
Type I
Genetic predisposition
Pancreatic beta cells fail
What is non-insulin dependent DM?
Type II
Body responds poorly to insulin
Pancreatic beta cells begin to fail
When does type I generally onset?
Childhood to early adolescence
How quickly does type I DM develop?
Abruptly
- increased BG
- increased use of fats for energy
- depletion of protein
What are symptoms of type I DM?
High BG
Polyuria/increased thirst => dehydration
Osmotic diuresis causes decreased electrolytes
Polyol pathway is stimulated - “sugar coated proteins”
What effect does chronic high blood glucose have on
- vascular system?
- nerves?
- Arteriosclerosis, renal disease, retinopathy, blindness, ischemia, gangrene, hypertension, atherosclerosis
- Peripheral neuropathy, impaired CV reflexes, impaired bladder function
What happens to metabolism in type I DM?
Shift from CHO to fat metabolism
What are the effects of fat metabolism?
Hyperventilation increased for expiration of co2
Increased cholesterol in circulation cause arteriosclerosis
Depletion of protein stores causes weight loss, fatigue, polyphagia, severe wasting, death
When is typical onset of type II DM?
Usually >30
How fast does type 2 DM develop?
Gradually
What is the greatest risk factor for type 2 DM?
Obesity
What happens in type II DM?
Decreased sensitivity to insulin so beta cells increase insulin secretion
=> impaired CHO use, increased BG, increased insulin secretion
Warning signs of type II DM?
Obesity Reactive hypoglycemia Insulin resistance Fasting hyperglycemia Lipid abnormalities Hypertension
Causes of insulin resistance?
Chronic insulin exposure Obesity Excess cortisol Excess GH Pregnancy/ gestational DM Polycystic ovarian syndrome Hemochromatosis Genetic causes of obesity
What happens in the later stages of insulin resistance?
Pancreatic beta cells burn out, no longer able to produce insulin => IDDM
Testing for DM - what will be found in UA?
Type I
Type II
Type I - high glucose, high ketones
Type II - high glucose, low ketones
Testing for DM - what will be seen on oral glucose/ tolerance test?
Type I vs type II
Both DM types - BG does not return to normal for 4-6 hrs
Type I - insulin low or undetectable
Type II - insulin high in early stage (low in late stage)
What does insulinoma cause?
Hypersecretion of insulin
What can happen if insulinoma untreated?
Can lead to insulin shock due to hypoglycemia
Causes of fasting hypoglycemia?
Drugs
Hormone deficiencies (hyperglycemic hormones)
Liver failure
Critical illness
Endogenous hyperinsulinisn (insulinoma)
Autoimmune - insulin or insulin receptor antibodies
Causes of postprandial hypoglycemia?
Congenital deficiency of enzyme of CHO metabolism
Gastrointestinal