Endocrinology 01
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- leptin
- satiety hormone secreted by adipose tissue
- ghrelin
- satiety hormone secreted by stomach
- atrial natiuretic peptide
- hormone that affect renal sodium excretion, secreted by the heart
-
G-protein coupled receptor
- basic structure - 7-pass membrane receptor associated with G-proteins
- what occurs after ligand binding to a G-protein coupled receptor?
- G-proteins undergo conformational changes and associated with an effector molecule (adenylate cyclase or phospholipase C) causing production of a 2nd messenger
- what is the classic example of receptor with tyrosine kinase activity?
- INSULIN
- basic structure of classic steroid hormones
- based on 17 carbon aromatic rings -- most derived from cholesterol
- name 5 classic steroid hormones
- testosterone, estrogen, progesterone, aldosterone, cortisol
- do steroid hormones bind to extracellular receptors?
-
NO, rather they bind to an intracellular receptor
THEN . . .
steroid-receptor complex goes to nucleus and binds to HRE on DNA altering gene transcription -
thyroid hormones
- derived from
- general MOA - derived from tyrosine but have mechanism of action similar to other steroid hormones by binding to nuclear receptors and altering gene transcription
- regulation of levels of active vitamin D occurs how?
- via regulation of production of the active form of vitamin D (1,25-dihydroxyvitamin D)
- what type of receptor does vitamin D bind to to exert its action?
- nuclear receptor
- what is the most common example of resistance to a hormone?
- Type 2 diabetes mellitus
- adrenal adenoma
- Cushing's syndrome
- parathyroid adenoma
- Hyperparathyroidism
- Do we maintain our body weight in a relatively narrow range?
- YES
- after eating a meal when do serum glucose levels peak?
- 1 hour after initiation of meal
- after eating a meal how long until serum glucose returns to its pre-meal levels?
- 3-5 hours
- The serum level of glucose is very tightly regulated. What are the normal fasting glucose levels?
- 60-100 mg/dL, avg. 80 mg/dL
- When serum glucose levels decline below normal we secrete counter-regulatory hormones. Give 4 examples
- glucagon, catecholamines, cortisol, and GH
- Which cells sense a rise in glucose and secrete insulin?
- Beta cells within the pancreatic Islets of Langerhans
- what is the basic mechanism for beta cells in pancreatic islets of langerhans?
-
FASTING: on cell surface of beta cells are ATP sensitive K+ channels which are open during fasting --> resting voltage w/in beta cell is negative
AFTER MEAL: glucose metabolized within beta cell and intracellular ATP conc INC --> ATP binds to sulfonylurea subunit of K+ channel --> beta cell depolarizes --> transmembrane calcium channels open --> INC intracellular Ca2+ conc --> exocytosis of insulin-containing vesicles - Once glucose is transported to cytoplasm of beta cell via GLUT2, what must happen before insulin secretion stimulation?
- glucose must be metabolized through the glycolytic pathway
- what percentage of glucose that circulates after a meal is delivered to muscle?
- approx 80%
- T/F muscle contains high numbers of protein receptors that specifically bind insulin
- T
- GLUT4
- after insulin binding to insulin receptor, there is a phosphorylation cascade which results in GLUT4 being translocated from cytoplasm to PM via vesicles, where they aid in transporting glucose
- T/F Liver produces and secretes glucose into the circulation in the absence of insulin.
- T; Insulin inhibits the liver from secreting glucose
- HSL
-
Hormone Sensitive Lipase
catalyzes the breakdown of triglyceride to diacylglycerol (DAG) - ATGL
- catalyzes the breakdown of triacylglycerol and DAG to glycerol and free fatty acids
- catecholamines, cortisol, and GH
-
are the counter-regulatory hormones
counter insulin action, inc the function of HSL & ATGL - what happens to intrahepatic fatty acids?
- fatty acids are esterified into triacylglycerides, which are packaged with apoproteins and secreted into the circulation as VLDL
- after lipids are absorbed in the intestinal brush border, what happens next?
-
lipids are packaged with apoproteins, particularly apoprotein CII, into a lipoprotein particle called a chylomicron
chylomicrons leave the intestine with the lymph, primarily via the thoracic duct, and are dumped into the venous circulation - desc interaction b/t LPL and chylomicron
-
LPL is activated by attaching to apoprotein CII molecule that is part of the chylomicron; LPL hydrolyzes the trigrlycerides into free fatty acids and glycerol
(tissues absorb the free fatty acids and re-esterify them into triglycerides) - desc relationship b/t LPL and insulin
-
insulin INC synth of LPL and the translocation of LPL from the adipocyte to the endothelial surface
without insulin, or in states of insulin resistance, LPL activity on the endothelial surface and the clearance of chylomicrons is reduced - fasted state
- In this state, most of our tissues oxidize fatty acids to provide the energy necessary to power our vital functions
- does the brain oxidize fatty acids in the fasted state?
- NO, the CNS is an obligate glucose consumer and is the single largest consumer of this fuel in the fasted state
- in prolonged fasting and type 1 diabetes mellitus, what fuel is used by the brain?
- 4-carbon by-products of fatty acid metabolism -- acetoacetate and hydroxybutyrate (ketoacids)
- which is the main organ involved in lysing glycogen stores and in synth'ing glucose from smaller C precursors?
- liver
-
glucagon
- secreted when
- by what
- does what -
secreted as serum glucose and insulin levels dip below normal
secreted by alpha cells in the islets of langerhans
stimulates hepatic glycogenolysis and gluconeogenesis (prevents hypoglycemia) - does glucagon stimulate or inhibit glycogen synthesis?
- inhibits
- glucagon kits
-
for unconscious diabetic
IM injection of glucagon, quickly breaks down liver glycogen stores, converts glucose-6-P to glucose and restores circulating glucose levels (within seconds or minutes) - basic three step process of gluconeogenesis
-
(1) gluconeogenic substrates (lactate, alanine, glycerol) must be delivered to the liver
(2) substrates (fatty acids) which produce the energy necessary to drive gluconeogenesis must be delivered to the liver
(3) enzymes in the gluconeogenic pathway need to be stimulated - T/F During fasting, both free fatty acids and glycerol concentrations INC in the serum
- T
- Can fatty acids be used for fuel by liver during fasting state?
- YES, fatty acids can be transported into mitochondria by the carnitine system and be oxidized --> inc ATP
- what are the four factors required by the liver for VLDL synth?
-
(1) apo B
(2) cholesterol
(3) triglycerides
(4) MTP (microsomal triglyceride transfer protein) - what is the proportion of triglyceride to cholesterol in VLDL?
- 5:1
- how is VLDL metabolized?
-
contains apo B-100 and apo CII and apo E
Apo CII binds LPL and coactivates the enzyme; LPL will then hydrolyze the triglyceride content of VLDL, releasing the free fatty acids that can then be transported into tissues for energy or fat storage - IDL
- triglycerides in VLDL particle are hydrolyzed by LPL on vascular surface --> resultant particle, called an intermediate density lipoprotein (IDL), has LESS TG and is cholesterol enriched
- what happens to IDL
-
(1) 50% is degraded by liver
(2) IDL stripped of TG component --> LDL -
LDL
- where does it go? -
LDL receptors bind to apo B of LDL --> particles are internalized into tissues and cholesterol is released into cytosol
liver --> CE returns to intrahepatic pool
macs --> CE results in formation of lipid streaks and beginning of atherosclerosis - what is the highest appetite center in the hypothalamus?
- the lateral nucleus
- neurons in the lateral nuclei are stimulated or inhibited by lower-order neurons located in the ________ of the hypothalamus
- arcuate nucleus
- the stimulatory neurons in the arcuate nucleus contain which neurotransmitters?
- neuropeptide Y (NPY) and agouti-related peptide (AGRP)
- the inhibitory neurons in the arcuate nucleus contain which neurotransmitters?
- melanocyte stimulating hormone alpha (MSH-alpha) and cocaine and amphetamine-regulated transcript (CART)
- MSH-alpha action
-
binds to a receptor called melanocortin receptor 4 (MCR4) to inhibit appetite
Note: AGRP is a competitive inhibitor for this receptor and therefore stimulates appetite - T/F genetic mutations in MCR4 are responsible for about 10% of all subjects with morbid obesity
- T, according to one study
- rimonabant
- currently being tested, competitively blocks endocannabinoid function and inhibits appetite; also appears to help smoking cessation!
- what are the three components of the total daily energy expenditure?
- basal metabolic rate, thermal effect of food, and activity
- what percentage of total energy expenditure is BMR?
- approx 60%
- thermal effect of food (TEF)
- energy we expend to digest our meals
- two hormones that sense body fat and signal the hypothalamus to regulate appetite and energy expenditure
- insulin and leptin
- T/F Fasting and postprandial serum conc of insulin DEC in proportion to the amount of body fat.
- F, proportional INC
- what does insulin do to the appetite-controlling neurons within the arcuate nucleus of the hypothalamus?
- insulin inhibits the appetite-stimulating NPY/AGRP neurons and stimulates the appetite-suppressing POMC/CART neurons
- T/F Leptin is a protein that is secreted by fat cells in proportion to the amount of fat
- T
- what does leptin do to the appetite-controlling neurons within the arcuate nucleus of the hypothalamus?
- leptin inhibits NPY/AGRP neurons and stimulates POMC/CART neurons
- ghrelin / arcuate nucleus
- ghrelin, secreted by stomach, INC activity of the appetite stimulating neurons (NPY/AGRP)
- protein YY (PYY)
- secreted by L cells in the distal GI tract, signals satiety
- what does AMPKinase do to glycolysis / fatty a oxidation / gluconeogenesis / glycogen synth / fatty acid synth?
-
INC glycolysis
INC fatty acid oxidation
DEC gluconeogenesis
DEC glycogen synthesis
DEC fatty acid synthesis - consequences of insufficient insulin secretion or action on muscle
- inadequate glucose uptake; protein degradation --> release of amino acids, lactate, and alanine into the circulation
- consequences of insufficient insulin secretion or action on fat
- breakdown of intra-adipocyte trigelycerides and release of free fatty acids and glycerol into the circulation; inability to clear chylomicrons and VLDL in circulation
- consequences of insufficient insulin secretion or action on liver
-
liver secretes more glucose due to enhanced gluconeogenesis and glycogenolysis
delivery and oxidation of enhanced levels of free fatty acids provides the energy to drive gluconeogenesis and the substrate for ketone production - in insufficient insulin secretion, why (2) does bood glucose rise?
-
(1) inability to transport glucose into cells (particularly muscle)
(2) inc hepatic glucose output - what are three big clinical consequences of insufficient insulin secretion?
-
(1) inc blood glucose
(2) inc blood ketones
(3) dyslipidemia - name 3 big acute clinical consequences of diabetic state?
-
(1) osmotic diuresis
(2) ketosis
(3) coma (diabetic ketoacidosis or non-ketotic, hyperglycemic, hyperosmolar coma) - compare DKA and non-ketotic coma with regards to glucose, pH, and HCO3
-
DKA
glucose > 300
pH < 7.3
HCO3 < 18
Non-ketotic
glucose > 600
pH > 7.3
HCO3 > 15 - diagnostic criteria for diabetes mellitus
-
(1) presence of classic symptoms (polyuria, polydipsia, unexplained weight loss, plus casual plasma glucose concentration of >= 200 mg/dL
(2) fasting plasma glucose >= 126 mg / dL
(3) 2-hour plasma glucose >= 200 mg / dL during an oral glucose tolerance test - what is the best clinical parameter for differentiating type 1 and type 2 diabetes?
- Type 1 are ketoacidosis prone
- what accounts for 45% of genetic susceptibility for type 1 diabetes?
- MHC HLA class II region genes
- what is insulitis (type 1 DM)
- chronic inflammatory infiltrate consisting of mostly CD8 cells with near total lack of insulin-secreting beta cells
- 4 major risk factors for type 2 diabetes
-
(1) heredity
(2) obesity (particularly central)
(3) age
(4) inactivity - coexistence of hyperglycemia or normolgycemia with hyperinsulinemia suggests what?
- that insulin resistance is present