Endo 4: Peripheral glands part 2 Flashcards
Ghrelin
“hunger hormone” secreted by stomach. Stimulates appetite and feeding
GLP-1 (Glucagon-Like Peptide-1)
EXERTS ANTI-HYPERGLYCEMIC EFFECT:
- Stimulates pancreas to secrete insulin
- Causes decreased glucagon secretion
- Inhibits gastric emptying
- Signals satiety to brain-↓food intake,wt loss
What happens following gastric bypass?
Less ghrelin is secreted leading to satiety sooner.
Fewer calories are eaten, less carbs/sugar.
6 wks after surgery, increased GLP-1 secreted as a result of shunting food directly to mid-intestine.
Insulin resistance disappears w/in few wks.
Endocrine Pancreas
Continuous regulation of nutrient metabolism depends on the ratio of insulin to glucagon.
Alpha cells of pancreas
Glucagon-increase blood glucose. 20%
Beta cells
Insulin, increase uptake of glucose into cells, thereby decreasing blood glucose levels. 65%
Delta cells
Somatostatin-inhibits/modulates insulin and glucagon secretion. 10%
Remainder of pancreatic cells secrete ..
pancreatic peptide-regulates exocrine & endocrine secretions; secreted in response to food intake; may diminish appetite, regulate food food intake.
Islets of Langerhans
ANS innvervation, Beta cells connected by gap jxns and influenced by paracrines (i.e. somatostatin)
Insulin and glucagon are present in plasma at all times, but . . .
concentrations vary depending on food intake.
Insulin
anabolic
fed state
storage of carbs, fats, proteins
Glucagon
Promotes glycogenolysis & GNG
Fasting state->increase plasma glucose-> breakdown triglycerides to increase plasma FA’s & glycerol.
Glycerol can be used in GNG, producing glucose.
Amylin
co-secreted with insulin by beta cells 100:1.
Slows gastric emptying thereby preventing spikes in plasma [glucose]. Glycemic control.
Contributes to satiety.
Somatostatin (pancreatic)
also derived from PreProSomatostatin (28) as the intestinal(14) and hypothalamic(14) somatostatin.
Factors STIMULATING Insulin secretion
FA’s and AA’s
Glucagon
GIP-Glucosedependent Insulinotropic peptide
Cortisol
Parasympathetic stimulation (ANS)
Sulfonylurea drugs->close ATP dependent K+ channels->insulin release
Factors DECREASING insulin secretion
Decreased blood glucose Fasting Exercise Somatostatin Epi/NorEpi (sympathetic stimulation)
What kind of receptors do beta cells express?
GLUT 2, a transporter that brings glucose into the cell via facilitated diffusion when extracellular [glucose] is high. Glucose goes thru CAC producing ATP->triggers opening of voltage gated-Ca sensitive channels->Ca ions enter the cell and facilitate exocytosis of insulin.
What kind of receptor does glucagon act through?
GPCR-PLC-> IP3/Ca
Where is GLP-1 synthesized?
Cells of the small intestine and secreted in the presence of nutrients.
How does somatostatin antagonize the ACTION of glucagon?
by inhibiting the production of IP3/Ca.
What is the action of GIP? “Gastric Inhibitory Peptide” Glucose-dependent Insulinotropic Peptide
stimulates the beta cells to secrete insulin.
Secreted by cells of small intestine when glucose is consumed, thus->FEED-FORWARD EFFECT, getting to the beta cells before substantial glucose is absorbed.
Sulfonylurea drugs
stimulate insulin secretion by closing ATP dependent K+ channels.
Also used to treat Type II DM
What type of receptor does insulin bind to?
Dimeric tyrosine kinase receptor-> Binds to α-subunit & triggers the tyrosine kinase of the β-subunit to autophosphorylate. Having phosphorylated itself, the β-subunit kinase phosphorylates other proteins in the cell to carry out the specific functions of the target cell.
What happens to the insulin receptors in Obesity and Type II DM?
The insulin receptor is down regulated in target cells, and the cells become less sensitive to insulin (insulin resistant)
How does insulin lower plasma glucose?
Increasing glucose transport into insulin-sensitive cells.
Enhancing glucose utilization (glycolysis) and storage (glycogenesis) & inhibiting glycogenolysis & GNG.
Incorporating aa’s into proteins & inhibiting protein breakdown.
Promoting fat synthesis (lipogenesis) & inhibiting lipolysis.
ANABOLIC EFFECTS!
Insulin triggers intracellular cascades in target cells via . . .
- Insulin binds to tyrosine kinase receptor
- Receptor phosphorylates Insulin-Receptor Substrates
- 2nd messenger pathways alter protein synthesis & existing proteins
- Membrane transport is modified
- Cell metabolism is changed
How does insulin affect adipose tissue and RESTING skeletal muscle?
promotes incorporation of GLUT 4 transporters, moving glucose into cell via facilitated diffusion. In the absence of insulin, these transporters are not expressed in the target cell membrane. Exercising skeletal muscle via contraction, triggers incorporation of GLUT 4 receptors in the ABSENCE of insulin and takes up glucose.
What kind of receptors do liver cells have?
Constitutive GLUT 2, brings glucose into cells in fed state via facilitated diffusion.
How does the diffusion gradient stay favorable?
Insulin stimulates kinases
(glucokinase/hexokinase) that phosphorylate glucose, keeping free glucose low in the cell.
In the fasting state, glucose (eg from GNG) leaves the cell by facilitated diffusion through same GLUT 2, now following it’s conc. grad out of cell.
Insulin stimulates enzymes for glucose utilization/storage . . .
glycolysis-utilization, glycogen synthesis,lipogenesis, and protein synthesis.
In the absence of insulin, are GLUT 4 transporters expressed in the cell membrane? (adipose, resting sk. m)
No, insulin signals the cell to incorporate (via exocytosis) GLUT 4 transporters into the membrane.
What have recent studies shown for GLUT 4 transporters?
contractions induced translocation of specific sk. m. v-Snare isoforms from intracellular compartments to cell surface membranes together with GLUT 4. Isoforms may participate in the docking and fusion of GLUT 4 to the surface membrane.
Don’t need insulin! Sk. muscle contractions will insert GLUT 4.
Ketoacids/ketone bodies are strong metabolic acids used when?
Used by the brain and peripheral tissues when glucose is not available for ATP synthesis.
What happens when there is an increase in ketoacids?
Strong metabolic acids such as Acetoacetic and hydroxybutyric acid are filtered at the glomerulus and appear in urine.
What are Fatty acids?
Biochemical precursors or ketoacids, produced in the liver, filtered at glomerulus, and excreted in urine.
What does glucagon prevent?
Hypoglycemia. Secreted by α cells when blood glucose is low and when protein is ingested.
What is glucagon’s mechanism of action?
Glucagon acts on liver cell. Binds to GPCR triggers a response via cAMP->PKA->
↑glucose, FA’s, Ketoacids via glycogen break down, GNG, lipolysis.
What STIMULATES/↑ Glucagon secretion?
Fasting ↓blood glucose ↑blood aa's CCK E,NE Ach
What inhibits/↓ glucagon secretion?
↑ blood glucose Insulin Somatostatin ↑blood fatty acid and ketoacids GLP-1
What happens after subjects ate a high protein meal?
Simultaneous secretion of glucagon and insulin to ensure that both glucose and aa’s are available to peripheral tissues.
Which organs control glucose homeostasis?
Liver, pancreas, and skeletal muscle
GLP-1 has a half-life of 2 mins. What is the enzyme that rapidly inactivates it?
DPP4-Dipeptidyl peptidase 4. Researchers are interested in its powerful anti-hyperglycemic effects in treating type 2 DM. But half-life is so short due to DPP4, need to develop drugs that serve as agonist to GLP-1 receptor or that inhibit DPP4.
What stimulates nerve input to CNS?
Nutrients and GLP-1.
CNS sends out commands to regulate:
Liver glucose production & storage
Pancreatic insulin secretion
Skeletal muscle glucose uptake
When a person consumes a meal, absorbed nutrients and GLP-1 stimulate afferent nerves to provide input to the CNS. Both afferent nerve input and humoral signals(circulating nutrients and hormones) are integrated in the CNS. Based on these summed inputs, how does the CNS react?
CNS sends out efferent nerve activity that directly regulates glucose in the liver, insulin and glucagon secretion from the pancreas, and skeletal muscle glucose uptake.
Somatostatin 28 of the small intestine inhibits:
Gastrin
CCK(cholecystokinin)
Secretin
VIP-vasoactive intestinal peptide
Somatostatin 14 of the pancreas inhibits:
Insulin
Glucagon
SS 14 is secreted by the delta cells and functions as a paracrine to inhibit secretion of both insulin and glucagon.
Somatostatin of the hypothalamus inhibits:
Growth Hormone
Type I DM?
Inadequate secretion of insulin due to destruction of beta cells.
Tx: insulin replacement therapy.
Type II DM?
“Insulin resistant diabetes”-abn responsiveness to target cells.
May become insulin deficient.
Often associated with obesity
Caused by down regulation of insulin receptors
Tx: Sulfonylurea drugs
Up-reg insulin receptors using BIGUANIDE drugs
Supress liver output of glucose (metformin)
Block enzymes that digest carbs and slow surge of glucose absorption (alpha-glycosidase inhibitors)
Weight reduction
Along with metabolic abnormalities, chronic hyperglycemia is associated with . ..
damage to blood vessels, eyes, kidneys, and nervous system.
How do the liver metabolic pathways metabolize glucose?
Liver metabolic pathways do not metabolize glucose; instead turn on glycogenolysis and GNG to pour more glucose into the bood.
Neurons in the brain are not sensitive to insulin, except for neurons in the ?
Satiety Center(ventromedial nucleus of hypothalamus), which perceives lack of glucose (due to absence of insulin) and inappropriately stimulates feeding.
Why is glucose inappropriately secreted in DM?
SGLT transporters in the renal proximal tubule become saturated, and glucose is excreted in the urine. Glucose exerts an osmotic effect and “holds” water in tubule lumen, so that large volumes of urine are excreted. Dehydration and its consequences results from loss of large volumes of urine.
Why does metabolic acidosis develop in DM?
ketone body production, causing hyperventilation, acidification of the urine, and hyperkalemia.
What are the acute effects of DM?
Decreased aa uptake by cells.
Increased protein degradation.
Decrease K+ uptake by cells leading to hyperkalemia (depolarized)
What are the consequences of prolonged exposure to excess glucose?
Degenerative complications and decreases life expectancy. Heart disease and stroke Kidney failure Blindness Gangrenous extremities Neuropathies
Decreased glucose uptake by cells (DM) inappropriately stimulates appetite and increased food intake. Why is it inappropriate?
Only neurons in VentroMedial Nucleus-satiety center, are sensitive to insulin. In the absence of insulin, they wrongly “sense” low glucose in plasma and stimulate eating.
What does accumulation of FA’s in blood lead to?
Leads to liver using FA’s and releasing excessive ketone bodies. Leads to metabolic acidosis-> hyperventilation to compensate and get rid of CO2. Exhales ketones have a fruity smell.
What does the net break down of proteins lead to?
muscle wasting, wt loss, and weakness. In children, leads to reduced growth. Excess aa’s in blood are taken up by hepatocytes for GNG, and increased lipolysis produces glycerol, also used in GNG, all further aggravating hyperglycemia.
How does hyperkalemia impact insulin?
Hyperkalemia stimulates insulin secretion
What promotes K+ entry into cells?
Insulin and beta-adrenergic catecholamines promote K entry into cells.
What promotes K+ secretion at nephron?
Aldosterone via Angio II promotes K secretion at nephron.
What effect do beta blockers have on extracellular [K+] ?
Increases EC [K+] stimulating insulin secretion
What effect to beta-agonist have on EC [K+] ?
decrease EC [K+] thereby decreasing insulin secretion.
How does insulin binding to TK receptors and E/NE binding to beta receptors stimulate K uptake?
By stimulating the Na/K ATP-ase pump.
How insulin secretion regulated?
negative feedback.
Hyperkalemia stimulates insulin secretion, which stimulates cellular uptake of K+ and hypokalemia inhibits insulin secretion.
Why might hyperthyroid patients have hypokalemia?
may be due to thyroid hormone’s stimulation of synthesis of the Na/K ATP-ase.
What effect does aldosterone have on hyperkalemia?
Hypekalemia stimulates aldosterone secretion in order to promote K+ secretion and excretion. Conversely, hypokalemia inhibits aldosterone secretion.
Why do exercise and adrenergic catecholamines inhibit insulin secretion?
By reducing plasma insulin to ensure reduced glucose uptake by cells and sufficient circulating glucose to support cell functions. Contracting muscle does not require insulin for glucose uptake
What type of transport is GLUT, SGLT, AND Na/K ATPase?
GLUT is facilitated diffusion, uses carrier, no ATP used
SGLT is 2ndary active transport, using concentration gradient created by the Na/K ATPase.
Na/K ATP-ase is primary active transport.
Insulin resistance appears to contribute to kidney failure in Type II DM, suggesting . . .
that insulin resistance contributes to diabetic nephropathy. ie not caused by high glucose, its due to insulin resistance because lack of insulin receptors.
Calcium homeostasis is finely controlled. What are the 3 hormones and 3 organ systems involved?
PTH-parathyroid gland
Active Vitamin D (1,25-dihydroxycholecalciferol)-diet & skin+UV
Calcitonin-“C” cells of thyroid gland.
Organ systems: Bone, Kidney, Intestine
When total Ca is found to be high or low, why is it necessary to check serum albumin levels?
Because albumin binds Ca ions. If albumin is normal then one can conclude that the measured Ca is an accurate reflection of the free biologically active Ca in the serum.
↓ EC calcium leads to . . .
Hyperexcitability:
Sensory neurons-tingling/numbness
Motor neurons and muscle- muscle twitches.
↑ EC calcium leads to . . ..
Constipation Polyuria Polydipsia Lethargy Hyporeflexia Coma Death
What are the forms of Ca in the blood?
50%-IONIZED-Only Biologically active form: controlled w/in narrow range.
40%-Protein bound: ↑ or ↓ plasma proteins → slow effects on EC [Ca]
10%-complexed to anions such as phosphate, sulfate, citrate. ↑ or ↓ anions alters EC [Ca]
What is Hypocalcemia?
Decreased EC [Ca] affects the fxns of membranes of excitable cells, causing them to have lower thresholds for firing APs→Hyperexcitability
What is the Chvostek sign?
A clinical test for hyperexcitability in which tapping the facial nerve causes facial muscles to twitch.
What is the Trousseau sign?
A clinical test for hyperexcitability in which inflation of a bp cuff causes carpopedal spasm.
What is hypercalcemia?
Increased EC [Ca] produces neurological symptoms that result from lower excitability of neurons to produce hyporeflexia, lethargy and coma. In addition, hypercalcemia causes polyuria and polydipsia which lead to dehydration and constipation (likely due to dehydration and depressed action of ANS).
Blood pH influences EC [Ca]. Acidemia? Alkalemia?
Acidemia→ ↑ ionized Ca b/c H+’s bump off Ca2+’s from the albumin.
Alkalemia→ ↓ ionized Ca b/c less H+ attached to albumin so more Ca is bound.
How is PTH synthesized?
Parathyroid glands, on the dorsal aspect of thyroid gland, contain Chief cells which synthesize PTH form PreproPTH→ProPTH→PTH packaged in secretory granules. PTH is continuously produced with little stored.
How is PTH transported?
Dissolved in plasma and half life <20 mins. Onset of action is within minutes in kidney, 2-3 hours in bone, 1-2 days to influence intestinal absorption of Ca (indirect via Vit D)
When PTH binds to its target cell receptor, how does it illicit a cellular response?
It acts via Adenyl cyclase and cAMP->PKA. It’s whole body effect is increase plasma [Ca].
PTH has a whole body effect of increasing plasma [Ca]. It does so by . . ..
Converting inactive Vit D to ACTIVE Vit D.
Renal absorption of Ca ions
Renal excretion of phosphate anions
Bone resorption.
Chief cells have a cell membrane Ca-sensing receptor (CaSR). How does CaSR work?
This GPCR activates PLC to INHIBIT secretion of PTH. Thus, when plasma [Ca] is high, little PTH is secreted, when its low, the inhibition is lifted and PTH is secreted by exocytosis.
Small decreases in plasma [Mg] also stimulate the secretion of PTH, however when [Mg] is chronically low as in alcoholism, PTH is inhibited. What can this effect lead to?
This hypoparathyroid effect can lead to hypocalcemia and the neurological sxs of of hyperexcitability of nerve and muscle cells.
Explain the action of PTH on Bone.
In BONE, PTH works synergistically with Vit D to stimulate OSTEOCLASTS and ↑ BONE RESORPTION. Both Ca and phosphate are released from bone into ECF. By itself, this effect on bone would not increase serum ionized [Ca] because the phosphate released from bone complexes with Ca.
Ca and phosphate are the main components of hydroxyapetite, primary mineral in bone.
Explain the effect of PTH on the kidney/nephron.
PTH has 2 actions, both of which are mediated by the action of adenyl cyclase and production of cAMP.
- In PT, PTH inhibits the Na/phosphate cotransporter which is responsible for phosphate reabsorption, promoting excretion of phosphate anion which ensures an ↑ in free ionized Ca/biologically active.
- PTH stimulates Ca reabsorption in the DT.
Explain the effect of PTH on the intestine.
PTH stimulates 1α-hydroxylase in the PT to convert 25-hydroxycholecalciferol to the active form 1,25-dihydroxycholecalciferol→active Vit D stimulates absorption of Ca by the intestinal epithelium via the action of calbindin D-28k.
High Levels of ALP (alkaline phosphatase)
Associated with ↑ osteoblastic activity & high bone turnover(1º hyperparathyroidism). Synthesized in liver, bone, placenta. ALP is normally high in growing bone and bile. Abnormally high levels may indicate disease in bone or liver, bile duct obstruction, or certain malignancies.
PTH, active Vit. D, and Calcitonin finely regulate Ca in the ECF. These hormones also regulate EC phosphate.
- When EC ca is low, secretion of PTH and Active Vit D ↑ → ↑ EC Ca.
- When EC Ca is high, calcitonin secretion increases and PTH, Vit D secretion ↓. Calcitonin acts at its target tissue to ↓ EC Ca.
Calcitonin- secreted when plasma Ca is high.
inhibits bone resorption and reabsorption of Ca in the kidneys.
Intestinal Ca absorption is decreased in the absence of Vit D-Vit D is NOT converted to active form when plasma Ca is high.
What type of receptors to C cells have?
Thyroid C cells which secrete calcitonin have GPCR membrane Ca-sensing receptor similar to that in PTH cells. When plasma [Ca] is high, the sensor STIMULATES calcitonin release! (unlike the PTH CaSR which leads to inhibition of PTH when plasma [Ca} is high.
PTH promotes phosphate excretion at proximal tubule . .
Na/phosphate cotransporter is inhibited→phosphate is not reabsorbed→PHOSPHATURIA
1. PTH binds to GPCR→Gs→AC→ATP converted to cAMP→protein kinases phosphorylating proteins leading to the inhibition of Na/phosphate co-transport. ↓ Na and phosphate reabsorbed, and ↑ phosphate excreted=phosphaturia. (↑ urinary cAMP)
Active Vit. D exerts its effects at the intestine (stimulate absorption of dietary Ca), kidney (to reabsorb both Ca and phosphate), bone (to stimulate osteoclast activity and bone resorption, a prerequisite to to bone formation). How is Active Vit D synthesized?
synthesis is regulated by changing activity of 1α-hydroxylase. 1α-hydroxylase is increased in response to PTH and Low plasma Ca and phosphate.
25-OH-cholecalciferol is converted by 1α-hydroxylase in the kidney to active vit. D.
What stimulates 1α-hydroxylase?
↑ PTH
↓[Ca]
↓[phosphate]
What is the difference b/w the actions of PTH and Vit D in the kidney?
Vit D increases BOTH Ca and Phosphate reabsorption.
PTH stimulates ONLY Ca reabsorption, INHIBITS phosphate reabsorption.
Clinically, what is measured to check for calcium deficiency?
25-OH-D3
D3 and metabolites are transported in the plasma bound to carrier proteins. D bing protein? (DBP)
DBP has lower affinity for 1,25 (OH)2D3→frees it to bind to receptors in target cells. At target, enters nucleus→binds to VDR→Vit D response elements. Because it is fat soluble, it is absorbed by chylomicrons in the small intestine. Vit D plays a role in cardiac health.
Active vit D stimulantes synthèses of Calbindin D-28K. What are the actions of Calbindin D-28K?
Ca ions bind to Calbindin D-28K which maintains conc gradient for Ca entry into cell, buffers [Ca]i from reaching toxic levels and facilitates its passage through cell.
Loss of Calcitonin→No major defect!
Calcitonin exerts effects on . . ..
PTH exerts effects on . . .
Calcitonin exerts effects on ostetoclasts
PTH exerts effects on osteoblasts
Calcitonin summary
Secreted when Ca is high-opposite PTH, vit D
Inhibits bone resorption by direct action on osteoclasts.
Promotes excretion of BOTH Ca and phosphate at nephron.
Clinically used to treat hypercalcemia, osteoporosis, Paget’s disease-excessive bone resorption by over active osteoclasts.
Relate PTH (peptide) to 1,25(OH)2D (steroid):
Both stimulate bone resorption→ ↑ plasma Ca & phosphate.
Both stimulate Ca reabsorption in nephron.
PTH decreases phosphate reabsorption in nephron, but Vit D increases it!
Both lead to Ca absorption in intestinal epithelium:
-PTH stimulates Vit D synth (indirect effect)
-Vit D induces calbindin-28K synth (direct effect)
What is Pseudohypoparathyroidism? PHP
genetic disorder
Patient shows hypocalcemia and hyperphosphatemia, skeletal abns.
↓[Ca]→ ↑PTH secretion (gland fxns normally)
But! Target tissues unresponsive/Kidney cells do not respond: α-subunit of GPCR is non-fxnl→no cAMP produced, and cells do not perform their fxns.
No Ca reabsorption at DTs→ hypocalcemia
No phosphate excretion at PT→hyperphosphatemia
No stimulation of α1-hydroxylase→ No active Vit D formed.
What disorders result from Vit. D deficiency?
Rickets(children) and Osteomalacia(adults)
Often caused by lack of Vit D, obtained from diet or sunlight. Afflicted suffer from diffuse pains, weak muscles, fragile bones.
What is Vit D resistance?
Results from inability to produce the active form of Vit D. Either the renal enzyme 1α-hydroxylase is lacking(i.e. congenital condition), or it is nonfunctional( i.e. renal failure)
