Exam 2 master file Flashcards
extracellular concentration of calcium
Total 2.5 x 10’-3 M; Free 1.2 x 10’-3 M
extracellular concentration of phosphate
Total 1.00 x 10’-3M;Free 0.85 x 10’-3 M
extracellular function of calcium ion
bone mineral; blood coagulation; membrane excitability
extracellular function of phosphate
bone mineral
how might anticoagulants work
against calcium ion
how does calcium ion affect membrane excitability
calcium channels, binding proteins, depolarization
intracellular calcium concentration
very low 10’-7 M
intracellular phosphate concentration
1.2 x 10’-3 M
intracellular calcium ion function
neuronal activation; hormone secretion; muscle contraction in all muscle types
why is intracellular calcium kept low
calcium can activate neurons and cause unwanted muscle contractions if unchecked
what is intracellular phosphate role
buffering; structure role; higher energy bonds (GTP, ATP); regulation of proteins by phosphorylation
where is 99% of calcium ion
in bone
how is calcium ion found in blood
50% is blood bound to albumin and globulins
what major hormones regulate Ca2+
PTH, vitamin D, and calcitonin
Where is calcium from
diet; GI tract is major source;
how does calcium travel from GI tract
half excreted; half absorbed in blood; 10 mmol travel back and forth between blood and bone; 240 mmol are sent from blood to kidney; 233 mmol go back to blood
what is grab and release
what bone does with calcium from blood; sends it back; in adults it is balanced because there is no bone growth
major glands in charge of calcium regulation
thyroid and parathyroid
cells in thyroid gland
follicular and parafollicular cells
what is important about parafollicular cells
involved in secreting calcitonin; AKA “C-cells”
how does parathyroid present
at least four of these glands in one person. Tiny, from 30-50 mg. Sometimes parathyroid sits with thymus, which happens during embryogenesis.
what is calcitonin
a peptide
what do calcitonin and PTH have in common
a precursor. But then it is cleaved. PTH precursor is made in thyroid. Calcitonin precursor is made in brain.
CGRP
calcitonin gene related peptide
cells of parathyroid
chief cells and oxyphil cells
what do chief cells secrete
PTH
what is parathyroid related hormone (PTHrP)
a hormone that is a precursor to PTH, related, but PTH is cleaved from PTHrP
how does serum calcium affect PTH
if calcium goes up, PTH goes down and vice versa. Inverse relationship.
what is calcium sensor
7TM domain
7TM domain
large; changes conformation on the basis of calcium levels in serum
what does calcium activate if there are high levels of it
phospholipase. Inhibits PTH secretion and synthesis.
what does calcium activate if there are low levels of it
adenylate cyclase cyles. Increases PTH secretion and synthesis.
How is either calcium pathway chosen
chosen by sensor and G protein has to be chosen that will activate each specific pathway.
PTH receptor
G protein linked
what binds to PTH receptor
both PTH and PTHrP
How does PTH regulate calcium
PTH activates adenylate cyclase, which activates cAMP production in kidney, which causes retention of Ca in distal convoluted tubule and inhibition of phosphate reabsorption in proximal tubule. Clinically, see more cAMP and phosphate in urine.
what is source of vitamin D, besides sunlight
diet
what is vitamin D
a classical steroid hormone
transcalciferin
Vitamin D transporter
good source of vitamin D
fish, because they consume plankton
why do we need to consume vitamin D in an oil
it is hydrophobic. Will go right through consumer if taken with water.
what is VDRE
vitamin D response element
where is VDRE
in promoter domain. Receptor binds to the sequences on VDRE, right?
How does PTHR activate adenylate cyclase
Gs activates AC
how deos PTHR activate phospholipase
Gq
target tissue of vitamin D
Gi tract, bone and kidney
effects of vitamin D
uptake of calcium in GI tract because vitamin D increases production of calbindin via gene transcription
calbindin
protein that binds to calcium in cytoplasm
what are the two calcium pathways in GI tract
active and passive
active pathway for calcium in GI tract
specialized transporter with pumps pumps calcium into cell. Calcium binds to calbindin, which shuttles it to other side of cell and pushes it out of cell.
passive pathway for calcium in GI tract
calcium travels between cells. Works well when there are large amounts of calcium consumed.
why might it be good to upregulate active transport of calcium
to prevent osteoporosis
how does calcium travel in kidney
similar pathway to GI tract. Reuptake in distal tubule and upregulation of calcium binding protein.
what is the calcium depot in the body
bone(storage and relase system)
what cells make up bone
osteoblasts, osteocytes, and osteoclasts
osteoblast function
secrete osteoid to form bone, calcify, help with remodeling
osteocyte function
made from osteoblasts; hardened in mineral; responsible for blood maintenance like toxin removal and nutrient uptake
osteoclast function
responsible for bone degradation
mesenchymal cells
differentiate and form osteoblasts
how do osteoblasts become osteocytes
osteoblasts become trapped in matrix and cant divide
how do osteoclasts raise blood calcium levels
they digest bone and release calcium from bone
what receptors are on osteoblasts
alkaline phospholypase, PTHR, IGF-1R
what do osteoblasts produce
Type 1 collagen and various noncollagenous proteins
what are noncollagenous proteins
osteocalcin, osteonectin, osteopontin, bone sialoprotein, osteoprotegerin, macrophage-colony, stimulating factor
osteocalcin
regulated by Vitamin D; has high binding affinity to hydroxyapatite Ca5(PO4)3(OH)
how do osteocytes work
sit in bone; interact by projections; close to blood vessels; excrete toxins/take up nutrients from blood
where are osteoclasts located
in concave ares called resorption cavities or Howship’s Lacunae
what does osteoclast secrete
protons and lysosomal enzymes that mediate osteolysis
what do calcitonin receptors do on osteoclasts
they inhibit degradation of bone
Vitamin D formation cycle
start with a cholesterol – 7-dehydrocholesterol/ irradiate with UV light (skin) → one of the rings breaks –> chelecalciferol (vitamin D3) –> suffers 25-hydroxylation in liver –> becomes 25 hydroxychotecalciferol (25-COH)D3 → treated with either 1. hydroxylation or 24. hydroxylation in kidney → becomes 1,25-dyhydroxycholescalciferol or 24,25-dihydroxycholescalciferol
mechanism of vitamin D in target cells
enters nucleus → in nucleus is VDRE, TATA and ATG → at VDRE is bound heterodimer RXR/VDR (coinhibitors are available) → D binds to its receptor on VDRE → string of coactivators complex binds to D and connects it to RNA polymerase II on TATA box(initiation complex)→ transcribes mRNA –> ATG is methionine start codon, which waits in nucleus
how do osteoclasts form? What is their function?
fusion of macrophages to form large multinucleated cells. They break down bone matrix.
where do osteoblasts come from?
from mesenchymal cells. Make protein matrix -osteoid and calcification hydroxyapatite
how do osteocytes form
osteoblasts trapped in matrix. Concerned with bone maintenance.
what parts of osteocytes do the work
canaliculi and gap junctions
howship’s lacunae
invaginations in bone to which osteoclasts attach and release enzymes and H+ and Cl-
what does calcitonin do to bone
it has receptors on osteoclasts and inhibits secretory and digestive properties of osteoclasts
how do osteoclasts work
form ruffled border between itself and invagination; pump in Cl- and H+; makes more acidic; lysosomal enzymes
how does PTH elevate calcium levels in blood
recruits precursors of macrophages that become osteoclasts; indirectly activates osteoclasts by stimulating osteoblasts; upregulates M-CSF and down regulates osteoprotegerin
what does osteoprotegerin do
it blocks RANKL from binding with its receptor on macrophage that will become osteoclast
how does M-CSF work
binds with macrophage that becomes osteoclast
steps of osteoclast differentiation
first, monocyte; second, becomes macrophage and binds M-CSF, which makes it express RANK receptor; third, binds RANKL and is bound to osteoblast; fourth; disassociates from osteoblast but is inactive; fifth, becomes inactive when ruffle forms and and sealing zone form
what is alpha v beta 3 integrin
binds to osteoclasts to form sealing zone
How does vitamin D affect calcium ion?
Vitamin D increases Ca; it increases Ca ion transport in intestine and kidney by upregulating transcription and translation of calcium binding protein; 2. regulates osteoclast activity in the bone
How does PTH regulate calcium
- increases retention of calcium by kidney and decreases retention of phosphate 2. increases production of calcitriol (active Vitamin D) by kidney 3. osteoclast upregulation, albeit indirectly
how does calcitonin work
calcitonin decreases Ca 1. direct inhibition of osteoclast activity in bone 2. increased loss of calcium and phosphate in the kidney filtrate
how does prostaglandin E2 affect calcium
increases osteoclast activity
what does mechanical stress do
signals need for bone remodeling
what does thyroid do to calcium
stimulates osteoclast activity
how does bone immobilization affect calcium homeostasis
it increases bone resorption and decreases bone formation ; it increases serum Ca, which decreases PTH. Both increase urine Ca. Decrease in PTH causes decrease Vitamin D, which causes decrease in intestinal calcium absorption
how does exercise affect calcium homeostasis
it decreases bone resorption and increases bone formation; it decreases serum Ca, which increases PTH; both lead to decrease in urine Ca. Increase in PTH causes increase in vitamin D; which causes increase in intestinal Ca absorption
growth hormone and calcium
mechanism: signals somatomedin C (IGF-1) release from liver; effect: increases bone and cartilage growth
thyroid hormones and ca
mechanism: secretions from thyroid gland follicular cell; increases bone and cartilage growth
PTH
low blood ca signals relase from parathyroid gland; PTH signals osteoblasts to stimulate osteoclast activity; stimulates osteoclast line development from CFU-GM and bone resporptive activity; inhibits alkaline phosphatase of osteoblast
calcitonin
high blood ca signals thyroid c-cell to secrete it; directly inhibits osteoclasts
sex hormones
estradiol and testosterone affect cartilage and bone growth; complex actions: stimulate bone growth; leads to closing of growth plate; too much; dwarfism, too little: gigantism, osteoporosis
vitamin A
binds to receptors on osteoclasts and releases proteases from chondrocytes; signals bone resorption; signals cartilage resorption
vitamin C
cofactor for proline hydroxylase in collagen synthesis; supports collagen formation
vitamin D
stimulates ca uptake from gut; stimulates production of osteonectin by osteoblast; stimulates osteoclast development from CFU-MG stem cell; supports mineralization of bone and cartilage; stimulates bone turnover
bone growth promoters
insulin, somatomedins, vitamin K
bone grrowth inhibitors
sglucocorticoids
how do PTH, vitamin D and FGF23 interact
PTH to kidney; upregulate vitamin D; Vitamin D to PT gland; down regualte PTH; vitamin D to bone; upregulate FGF23; bone to kidney, down regulate vitamin D
integrated response to hypocalcemia
four responses: calcium sensor taks to PT gland; increase PTH; increase D; increase gut absorption; calcium sensor talks to thyroid c-cells – decrease calcitonin – increase bone resorption (PTH does this as well); ca sensor talks to kidney – increase renal ca absorption (PTH) and decrease urinary ca excretion; renal ca filtration decreases, which decreases ca in urine
integrated response to hypercalcemia
foru responses: calcium sensor talks to PT gland – down PTH – down D-down gut absorption; sensor talks to c-cells – up calcitonin – down bown resporption (PTH as well causes this); sensor talks to kidney – down renal ca reabsorption – increase ca in urine – up renal ca filtration, which increases ca urine
how does vitamin D affect bone, kidney, gut, blood calcium
bone: up o/c activity, up bone resorption; kidney: up ca reabsorption, up phosphate reabsorption; gut: up calcium absorption, up phosphate absorption; blood: up calcium and phosphate
how does PTH affect bone, kidney, gut, blood calcium
bone: down o/b activity, up bone resorption; kidney – up 1alpha hydroxylase synthesis, up ca reabsorption, down phosphate reabsorption; gut – up ca absorption, up phosphate absorption by indirect action only; blood – up ca and down phosphate
how does calcitonin affect bone, kidney, gut, blood calcium
bone: down o/c activity, down bone res.; kidney – down ca reab, down p reab; gut – nothing; blood – down ca and p
symptoms of hypocalcemia 4
muscle cramps, numbness, parasthesia, mood swings and depression
signs of hypoclacemia 5
tetany, carpopedal spasm, neuromuscular activity, convulsions, cardiac arrhythmias, cataract
symptoms of hypercalcemia 8
bony pain, abdominal pain from peptic ulceration, acute pancreatitis or constipation, anorexia and nausea, thirst and polyuria, muscle weakness, headache and confusion, palpitations through cardiac arrhythmias, tiredness and fatigue
signs of hypercalcemia 5
renal stones, bone fractures, convulsions and coma if severe, corneal calcification, hypertension
what can cause bone changes by hyperparathyroidism
many tumors secrete PTH or PTHrP and thus cause generalized demineralization as seen in phalanges of the hand
rickets and osteomalacia
disorders of mineralization of organic matrix (D deficiency)
osteoporosis
metabolic bone disease with decreased bone mass
paget’s disease
uncontrolled, large osteoclasts cause bone demineralization
osteopetrosis
high density bone with occlusion of marrow spaces and subsequent anemia due to lack of osteoclastic activity
jensen’s disease or metaphysial chondrodysplesia
causes dwarfism due to deficiency in PTH or PTHrP or its respective receptors
symptoms of vitamin D deficiency
pains and aches; severe pain, weakness; osteomalacia; bone pains (hips, ribs, feet, pelvis and thighs)
adult vitamin d deficiency symptoms
poor immune system, osteoporosis, mood changes, heart problems and high BP, chronic diseases like crohn’s disease and MS, dental problems like gum disease, asthma, bone disease development called osteomalacia
How is energy stored in body?
as glycogen and fat
how often does fuel metabolism change
several times a day, between catabolic and anabolic phases
how are higher brain centers stimulated to influence the gut
taste, smell, sight, thought, etc.
What does higher brain send signals to
hypothalamus
what does hypothalamus send signals to?
it sends signals back to higher brain and it sends hunger or satiety signals to the gut
what signals does the gut send?
the gut stimulates the vagus (SNS) catabolic process and releases CCK in the short term. In the long term, the gut releases hormones that are substrates to the pancreas, which in turn produce insulin, which helps build WAT, and which releases leptin, which also stimulates the SNS anabolic pathway
what signals does the SNS send?
it signals the pancreas to produce insulin, which help add WAT and leptin. It also stimulates BAT and heat production.
catabolism
tears down molecules
anabolism
builds up molecules
what makes up the oral cavity? What is it responsible for?
mouth and pharynx, salivary glands; chewing begins, initiation of swallowing
what are the exocrine secretions of the salivary glands
salt and water – moisten food; mucus – lubrication; amylase – polysaccharide-digesting enzyme
what is role of esophagus
moves food to stomach by peristaltic waves
what are esophagus exocrine secretions
mucus for lubrication
role of stomach
store, mix, dissolve and continue digestion of food; regulates emptying of dissolved food into small intestine
exocrine secretions of stomach
HCL – solubilization of food particles, kill microbes, activation of pepsinogens to pepsins; Pepsins – protein-digesting enzyme; mucus – lubricate and protect epithelial surface
role of pancreas
secretion of enzymes and bicarbonate; also has nondigestive endocrine functions
exocrine secretions of pancreas
Enzymes – digest carbs, fats, proteins and nucleic acids; bicarbonate – neutralize HCL entering small intestine from stomach
liver role
secretion of bile; many other nondigestive functions
exocrine secretions of liver
bile salts – solubilize water – insoluble fats; bicarb – neutralize HCL entering small intestine from stomach
role of gallbladder
store and concentrate bile between meals
role of small intestine
digestion and absorption of most substances, mixing and propulsion of contents
exocrine secretions of small intestine
Enzymes – food digestion; salt and water – maintain fluidity of luminal contents; mucus - lubricataion
role of large intestine
storage and concentration of undigested matter; absorption of salt and water; mixing and propulsion of contents; defecation
exocrine secretions of large intestine
lubrication
anatomical features of gut in order from inside to out
lumen, mucosa, submucosa, submucosal nerve plexus, circular muscle, myenteric plexus, longitudinal muscle, serosa. There is sympathetic and parasympathetic input to gut
will myenteric plexus move on its own
it is autonomic; will contract without attachment to body. It is a network of mesh.
how do enteroendocrine cells present in gut
they are present in most of GI tract distributed as single cells throughout gastrointestinal epithelium
largest endocrine “organ”
enteroendocrine cells
does enteroendocrine cell reach epithelial surface
no
what are the two types of enteroendrocrine cells
lingual taste-receptor cell and intestinal enteroendocrine cell
what is ligand that signals enteroendocrine cells
food
How does a lingual taste receptor cell work
G protein activates phospholipase Cbeta2; which makes IP3, which increases Ca2+ in cytoplasm, which causes release of neurotransmitters that stimulate afferent nerve
what three channels exist on lingual taste receptor
Sodium /transient receptor potential channels’ de;ayed-rectifying K+ channels; calcium voltage gated channels
how does intestinal enteroendocrine cell work
via nutrient ligand, binds to receptor, activates Galpha protein that activates phospholipase, which synthesizes IP3, increases intracellular calcium, and secretes GLP1 into bloodstream and vagal or spinal nerve
what channels live on intestinal enteroendocrine cell
sodium/TRPMS
model to increase ghrelin secretion
bitter tastants bind to taste receptors on ghrelin cell or on the brush cells in the GI tract, and couple via alpha-gustducin to increase ghrelin secretion
what does increased ghrelin secretion result in
short term increase in food intake and accelerated grastric emptying; followed by a prolonged decrease in food intake
what does decrease in food intake correlate with
delay in grastric emptying
what does alpha-gustducin do?
it is involved in sensing the medium chain fatty acid (MCFA) octanoic acid in the diet
what is octanoic acid necessary for in diet
the octanoylation of ghrelin
what receptor may play a role in the lipid sensing cascase in ghrelin-producing cells
GPR120
what two hormones are produced in the pyloric antrum?
gastrin and glucagon
gastrin function
stimulates release of HCL and pepsinogen
glucogen function
promotes conversion of glycogen to glucose in the liver
what four hormones are produced in the duodenum and jejunum?
cck, gastric inhibitory peptide, motilin, and secretin
cholecystokinin
stimulates pancreatic enzyme release and elicits gallbladder contraction
gastric inhibitory peptide
stimulates insulin secretion
motilin
stimulates gastrointestinal motility
secretin
stimulates bicarbonate and water secretion by pancreatic duct cells
what hormone does the ileum produce?
neurotensin
neurotensin
inhibits GI motility
what hormone does large intestine make?
glicentin
glicentin
promotes conversion of glycogen to glucose in liver
what hormones are produced in stomach, small intestine and large intestine?
somatosatin, serotonin, substance P
somatostatin
inhibits local secretion of gastrin, motilin, secretin, and gastric inhibitory peptide + other actions
serotonin
stimulates gastrointestinal motility
substance P
stimulates intestinal motility
where is gastrin released in large intestine? By when does it diminish?
antrum/ ileum
order of large intestine parts
fundus, antrum, duodenum, jejunum, ileum, colon
where is CCK release in large intestine? By where does it diminish?
duodenum/colon
where is secretin released in large intestine? By where does diminish?
duodenum/colon
where is GIP secreted in large intestine? By where does it diminish?
duodenum/ileum
Are VIP, Motilin or somatostatin secreted in large intestine?
no, but they are present still
what stimuli in cephalic phase control HCL secretion during a meal? What pathway is used?
sight, smell, taste, chewing ; parasympathetic nerves to ENS
what stimuli in gastric phase control HCL secretion during a meal? What pathway is used?
distension, increase in peptides, decrease in proton concentration; long and short neural reflexes and direct stimulation of gastrin secretion
what stimuli in intestinal phase control HCL secretion during a meal? What pathway is used?
distension, increase in proton concentration, increase in osmolarity, increase in nutrient concentrations; long and short neural reflexes; secretin, CCK, and other duodenal hormones
three phases of digestion
cephalic, gastric and intestinal
what sphincter is next to esophagus at entrance to stomach
cardiac sphincter
what sphincter is at end of stomach
pyloric sphincter
layers of stomach wall from luminal to basolateral
glands that secreted gastric juice, gastric glands, circular muscle, longitudinal muscle
through what is gastric released into lumen
the gastric fundic region
what makes up gastric fundic region, from luminal to basolateral
pit, isthmus, neck, and base
what cells line the gastric fundic region?
mucous neck cells (in neck), parietal cells, enteroendocrine cells, chief (zymogenic cells)
what are the two secretory cells of the stomach
chief cell and parietal cell
what makes up inside of chief cell?
zymogen granules, and extensive rER
what makes up inside of parietal cell?
tobulovesicular system, intracellular calaliculus, few ribosomes and lysosomes
what does chief cell produce?
precursor enzyme of the gastric secretion; pepsinogen and lipase
what does parietal cell produce?
HCL and intrinsic factor for vitamin B12
what is at luminal side of both chief and parietal cells
junctional complexes
what three receptors does parietal cell have?
histamine H2, acetylcholine, and gastrin
what secretes gastrin? How does it get to parietal cell?
G cell. Through the bloodstream.
what secretes histamine?
ECL cell
What stimulates G cell to secrete gastrin?
vagus nerve stimulates post synaptic neuron, which releases gastrin releasing peptide
what stimulates ECL cell to release histamine?
postganglionic cholinergic nerve releases neurotransmitters that bind with receptor on ECL cell
what secretes acetylcholine?
a neuron
What hormones regulate the parietal cell?
gastrin, histamine, acetylcholine, somatostatin, gastrin releasing peptide
how is acetylcholine a major secretagogue?
it stimulates secretion of pepsinogen by chief cells of stomach
is gastrin an important secretagogue
it is only effective in vitro and at high concentration
what kind of secretory cells do pancreas have?
exocrine and endocrine
which pancreatic cells secrete enzymes?
exocrine cells
which pancreatic cells secrete bicarbonate?
duct cells
what runs along length of pancreas
pancreatic duct
what role do pancreas play
main digestive gland in our body
what enzymes do the pancreas secrete?
trypsin, chymotrypsin, steapsin, carboxypeptidase, elastases, nucleases, and pancreatic amylase
trypsin
protease that cleaves proteins at the basic amino acids
chymotrypsin
protease that cleaves proteins at the aromatic amino acids
steapsin
degrades triglycerides into fatty acids and glycerol
carboxypeptidase
protease that takes off the terminal acid group from a protein
elastase
degrades the protein elastin and some other proteins
nucleases
degrade nucleic acids, like DNAase and RNAase
pancreatic amylase
degrades starch, glycogen and most other carbohydrates
bicarb regulation cycle
increase in acid from stomach; increase in secretin secretion in small intestine; increase in plasma secretin; the Panceas increase bicarb secretion, which increases flow of bicarb into small intestine, which neutralizes the intestinal acid put there by stomach. Once pH goes up, this provides negative feedback to small intestine’s secretin secretion.
fatty acid and amino acid digestion cycle between SI and pancreas
increase in intestinal fatty acids and amino acids; increase in CCK secretion in small intestine; increase in plasma CCK; stimulates pancreas to increase enzyme secretion; increases flow of enzymes into small intestine, which leads to increase in digestion of fats and proteins in SI
what part of SI is ileum?
Last part before colon
portal vein flows from small intestine to?
liver
bile flows from and to?
liver and gallbladder to small intestine
what are six main ingredients of bile?
bile salts; lecithin; bicarb ions and other salts; cholesterol; bile pigments and small amounts of other metabolic end-products; protein (IgA) and peptides, and trace metals
how do gallstones form?
when concentration of cholesterol in the bile becomes high in relation ot the concentrations of phospholipids and bile salts, cholesterol crystallizes out of solution and causes gallstones
enterohepatic circulation of bile salts
bile salts are secreted into bile and enter the duodenum through the common bile duct. Bile salts are reabsorbed from the intestinal lumen into hepatic protal blood. The liver reclaims bile salts from hepatic portal blood.
what is preprograstrin
precursor to gastrin
what do the structures of gastrin and cck both contain
sulfated tyrosine residue
which adiposity signals work straight with hypothalamus (3)
adiponectin, insulin, and leptin
Which gut hormones act directly with hypothalamus (3)
PYY, OXM, Ghrelin
Which gut hormones act directly with brainstem?
PP, GLP-1, CCK
which gut hormones and adipose signals influence vagus?
adiposity signals: leptin; gut: ghrelin, PP, GLP-1, and CCK
what does antral mucosa secrete?
gastrin
what do pancreas secrete?
insulin, glucagon, somatostatin, pancreatic polypeptide
what does upper small intestine secrete?
secretin, CCK, GDIP, motilin
what does lower small intestine secrete?
neurotensin, enteroglucagon
what do pancreatic islets of langerhans secrete?
insulin, glucagon, and somatostatin
what do pancreatic endocrine cells secrete?
pancreatic polypeptides
role of CCK in digestion
slows down emptying of the stomach by acting on pyloric sphincter; stimulates bile release from the galbladder and the secretion of pancreatic enzymes
role of secretin in digestion
stimulates pancreatic bicarb secretion; enhances insulin secretion by B cells of the islets of langerhans
role of gastrin in digestion
stimulates HCL secretion in parietal cells; stimulates insulin secretion by B cells of islets of langerhans; stimulates gastric motility and growth of mucosal cell
digestion
breaking proteins, fats and carbs into absorbable units (principally in small intestine)
absorption
products of digestion and vitamins, minerals and water cross the mucosa and enter lymph or blood
how do mixed amino acids reach the liver?
via the portal vein
what are branched amino acids used for?
protein synthesis under influence of insulin
how are amino acids and di and tripeptides absorbed?
across symporter channels together with Na+. The transport is active.
where does protein digestion start?
in the stomach, in the presence of pepsin.
what is pepsin derived from?
precursor pepsinogen secreted by chief cells
where does pepsin activity end?
in alkaline environment of duodenum.
what pancreatic proteases continue proteolysis?
endopeptidases and exopeptidases
what activates trypsinogen? Where?
enterokinase turns trypsinogen to trypsin on the microvilli. Trypsin in turn activates the bulk of trypsinogen.
what activates chymotrypsinogen and proelastase?
chymotrypsin and elastase, respectively
what are carboxypepsidasea A and B derived from?
procarboxypeptidase A and B precursors
in what does trypsin play a significant role?
it activates and inactivates pancreatic proenzymes.
how are tripeptides in cytosol digested?
by cytoplasmic peptidases into amino acids
what is daily protein requirement for adults?
0.8 g/kg body weight. Higher in pregnant women, postsurgical patients and athletes.
why must nine essential amino acids be in diet?
because body cannot synthesize them.
in what two ways does glucose from diet enter hepatic glycogen?
a. 50% glycogen formed from ingestd glucose directly, without degradation; remainder is converted to lactate in peripheral and splanchnic tissues
how is glucose converted to lactate in peripheral and splanchnic tissues?
15-20% of glucose converted to lactate in subcutaneous adipose tissue and CNS and RBC; lactate returns to liver and is coverted to G-6-phosphate via gluconeogenesis; lactate also from intestinal metabolism of either circulating or newly absorbed glucose.
what are the main dietary carbs?
starch, sucrose, lactose and maltose
starch?
amylose and amylopectin
sucrose?
glucose, fructose disaccharide
lactose?
Galactose-glucose disaccharide
maltose?
glucose dimer
what initiates digestion of starch?
salivary alpha-amylase in the mouth
what completes starch digestion?
pancreatic alpha-amylase in small intestine
oligosaccharidases
(sucrase, lactase, isomaltase), hydrolyze major dietary sugars; present in PM of microvilli
why is cellulose not digested by humans?
cellulase is not present. Cellulose accounts for undigested dietary fiber.
what is bile salt?
glycocholic acid
what is fat emulsified by?
bile salts and phospholipids
what is emulsification?
fat globule and bile salt and phospholipid
what do fat droplets become with bile salt and phospholipids?
emulsion droplets
add bile salts and pancreatic lipase to emulsion droplets and get?
micelles
what happens to emulsion micelles once they are formed?
they become free molecules of fatty acids and monoglycerides that can diffuse through lipid bilayer. They are treated by triglyceride synthetic enzymes in endoplasmic reticulum and become chylomicrons
chylomicron
droplets of triglyceride enclosed by membrane from the endoplasmic reticulum
where are lipids stored?
adipose tissue
what is the purpose of adipose tissue?
adaptation to famine
how do lipids travel in circulation?
dietary lipids cross through intestinal cell; become chylomicrons; enter capillaries; are treated by lipoprotein lipase; chylomicron remnants go to liver and are received by remnant receptors
what induces the phosphorylation of lipase?
epi, glucagon and ACTH
what does phosphorylation of lipase result in?
mobilization of triglyceride pool/ lypolytic effect
what inhibits lipase activity?
insulin and prostaglandins
what does lipase inhibition cause?
lipid storage, or antilypolytic effect
two clinical conditions associated with adipose tissue
obesity and diabetes
leptin is produced by?
white adipose tissue
leptin provides what?
information about fat mass and nutritional status to neural centers regulating appetite, energy balance and feeding
GLUT-4
glucose transporter protein; produced by adipocyte; facilitates entrance of glucose to the cell
lipoprotein lipase synthesized by? Transferred to?
synthesized by adipose cell and transferred to endothelial cell
catabolism: how does liver produce glucose?
via glycogen breakdown and via gluconeogenesis
what is glucose preserved for?
CNS
what do tissues besides CNS preferentially use for energy?
long chain fatty acids and their derivative products – ketone bodies
what can brain also use, besides glucose
ketones
what does lipolysis release?
glycerol
where does pyruvate lactate come from?
muscle glycogen
where do amino acids come from?
proteolysis
what are three additional gluconeogenesis substrates?
glycerol, pyruvate/lactate, amino acids
where do hunger and satiety originate?
from afferent neuronal and humoral signals from the GI tract, adipose tissue, and other peripheral organs to the brain
from where do hypothalamus and brainstem receive signals to coordinate feeding and metabolic adaptations?
nutrients, GI hormones, adipokines, and vagal afferents
when are peripheral stimuli and inhibitors to digestion released?
in anticipation or response to food
what can peripheral stimuli and inhibitors cross?
blood brain barrier
what is role of peripheral stimuli and inhibitors?
activate/release/synthesize central factors in the hypothalamus that either increase or decrease subsequent food intake
where do executive functions originate?
frontal cortex
central inhibitors (5)
POMC, CART, CCK, NE, CRH
central stimuli (3)
NYY, orexin-A, cannabinoids
when stomach releases ghrelin and cortisol, what do they stimulate?
they cross the BBB and stimulate NYY, orexin-A and cannabinoids
list peripheral inhibitors (7)
glucose/AA/FFA, CCK, PYY, insulin, leptin
how is ghrelin initially synthesized?
as a preprohormone
how is ghrelin processed?
proteolytically processed to yield 28 aa peptide
when is ghrelin produced and secreted?
by stomach as early response to food
in the brain, what is source of ghrelin?
hypothalamus
where else, other than hypothalamus and stomach, is ghrelin made?
placenta, kidney and pituitary gland
What 3 major regions of brain does ghrelin stimulate?
hindbrain, hypothalamus, mesolimbic reward system in midbrain
role of hindbrain
controls automatic processes
role of hypothalamus
regulates metabolism
when does ghrelin spike?
before routine meal times.
when does ghrelin spike for grazing animals?
they have little spikes all day
from what are glucagon, oxyntomodulin, NPGF and glicentin derived?
from a larger, common precursor that has 158 aa
what does oxyntomodulin do?
it acts to suppress appetite
what were results of parabiosis study of Ob/Ob and Db/Db mice?
Ob and WT – slimmer OB, normal WT; Db and WT – normal Db and slimmer WT; Ob and Db – slimmer Ob and normal Db.
how big is leptin?
16 Kda protein hormone
where is leptin made?
synthesized and secreted by adipose tissue and the placenta
of what gene is leptin a product?
Ob gene, on chromosome 7q31.3-32
what is main target of leptin?
hypothalamus
what kind of receptor does leptin have?
cytokine receptor group of cell surface receptors
what is intracellular signaling apparatus of leptin receptor?
JAK-STAT
leptin binding protein
soluble isoform of ectodomain of leptin receptor forms a binding protein in circulation
main actions of leptin
suppress appetite; increases energy expenditure
leptin and fasting
plasma leptin is very low, so stored energy is conserved
nonfasting and leptin
circulating leptin increases with adiposity
rhythm of circulating leptin
exhibits circadian rhythm; highest around midnight with nadir around middday
relative levels of plasma leptin throughout life in newborn, childhood, puberty and adulthood?
Newborn – high; childhood – low; puberty – leptin increases early in puberty. In boys, increase is only transient. In girls, sustained. ; adulthood – leptin higher in women than men
how do environment and lifestyle influence food intake and energy expenditure in brain?
cognition; reward; choice; mood; stress
how does brain respond to environmental stimuli?
energy intake or expenditure
cycle of energy intake?
GI, liver, to adipose tissue and muscle tissue, where there is nutritional partitioning
what three things influence individual predisposition to digestion?
genetics, early life events and epigenetics
what neurotransmitters decrease food intake (3)
Norepi – Beta receptor; dopamine; serotonin
what hypothalamic peptides decrease food intake (4)
Cordicotropin-releasing factor (CRF); urocortin; glucagon-like peptide I (GLP-I); cholecystokinin (CCK)
peripheral factors that decrease food intake? 3
leptin, CCK, and insulin
when are peripheral factor effects observed, that decrease food intake?
Leptin – long term signal; CCK – meal-related signal; insulin – effect observed after central administration
central factors that increase food intake (6)
Norepi – alpha receptor; neuropeptide Y (NPY); melanin concentrating hormone (MCH); galanin; growth hormone-releasing hormone (GHRH); opioid peptides
pereipheral factor that increases food intake (1)
hypoglycemia
pathologies associated with food intake
obesity, anorexia nervosa, bulimia nervosa
what fuels anabolism?
diet
what processes happen during anabolism?
glycogen, triglyceride and protein synthesis
what is anabolism?
making and storing compounds
hormone profile of anabolism
insulin increase, glucagon decrease, GI peptide increase, leptin increase
what fuels catabolism?
glycogen, fat deposits, muscle protein
what processes happen during catabolism?
glycogenolysis, gluconeogenesis, lypolysis, ketogenesis, proteolysis
catabolism hormone profile
insulin decrease, glugacon increase, catecholamines increase
what two processes make glucose in liver?
glycogenolysis and gluconeogenesis
what do muscles feed into gluconeogenesis?
amino acids and glycogen
what does adipose tissue contribute to liver?
fatty acids
what does liver do with fatty acids?
ketogenesis
what is the result of ketogenesis?
ketones headed for nonCNS and CNS
what is destination of glucose?
CNS
What fuels CNS?
glucose
most glucose transporters work by
facilitated diffusion
why does glucose concentration outside of brain need to remain high?
because of concentration gradient needed for facilitated diffusion into brain
what can be used by brain besides glucose
ketones
name three substrates for glucogenesis
glycerol from lipolysis, pyruvate-lactate from muscle glycogen, amino acids from proteolysis
where does glucose go once past the gut? (postmeal)
blood
from blood where does glucose go?
muscle, liver, adipose tissue and nerve and other tissues
what does blood glucose become in muscle?
glycogen
what does blood glucose become in liver?
glycogen and triglycerides
what does blood glucose become adipose tissue?
triglycerides
how does glucose get to blood during fasting?
muscle and adipose tissue send amino acids, glycogen, and fatty acids to liver to become glucose through gluconeogenesis
what do fatty acids become in liver?
ketones
three types of cells in pancreas islets of langerhans
beta, alpha and delta cells
beta cells
synthesis and secretion of insulin. Are in center of islet.
alpha cells
25% of cell content in islets – make glucagon, periphery of islet
delta cells
somatostatin producers in periphery of islet
how are pancreas vascularized?
arterioles feed into center of islet so beta cells get exposed to high glucose concentration. Arterioles supply capillaries that drain into venules that drain out of islets.
how are cells connected to one another in islets of langerhans?
by gap junctions so they can signal each other
acinear cells
smaller than islet of langerhans cells (release into duodenum?)
what is inside beta cells
high density of granules with insulin inside
what increases insulin secretion?
amino acids, raised blood glucose, glucagon, gastrin, secretin, cck, GIP, sympathetic innervation (alpha-receptors), parasympathetic (cholinergic) innervation
GIP
glucose dependent insulinotrophic peptide
what is insulin secretion decreased by?
somatostatin, blood glucose, sympathetic innervation of beta receptros , stress (exercise, hypoxia, hypothermia, surgery, severe burns)
how is response to orally administered glucose different from that delivered via IV?
greater insulin stimulating effect.
how is response to orally administered aa different from that delivered via IV?
greater insulin stimulating effect.
do peptides secreted by GI endo cells stimulate insulin secretion?
yes
how does GLP-1 regulate insulin secretion and blood glucose levels?
Incretin and GLP-1 stimulate insulin release and inhibit glucagon release, both of which lower blood glucose
what inactivates GLP-1?
DPP-4 enzyme
what inhibits DPP-4? To what end?
drugs block DPP-4 and decrease glucose levels in blood
where is GLP-1 secreted?
L-cells of GI
how is an increase in blood glucose regulated?
- release of insulin 2. insulin binds to membrane receptors in liver cells, adipocyte and muscle cells 3. in liver, increase activity of glycogen synthase (stores glucose) and adypocyte and muscle, exocytosis and activation of glucose transporters (so glucose has where to go) 4. removal of glucose from blood and is stored as glycogen
hos is decrease in blood glucose regulated?
- release of glucagon 2. glucagon binds to membrane receptor 3. activation of adenylyl cyclase 4. increase in cAMP, activation of cAMP-dependent kinase 5. activation of glycogen phosphorylase and inhibition of glycogen synthase 6. degradation of glycogen to glucose, release of glucose into blood
subcellular sites of insulin biosynthesis in beta cells
- rough ER 2. microvesicles 3. golgi 4. early granules 5. mature granules 6. plasma membrane
proinsulin to insulin process
86 aa proinsulin goes through protease and becomes 21 aa A-chain, 30 aa B-chain and C peptide
what happens to glucagon in anticipation of oral glucose load?
its concentration initially increases, but then is suppressed by increase in insulin
how does insulin react to oral glucose load?
rise in insulin lags behind glucose peak
how does high glucose affect GH release?
high glucose suppresses basal GH release initially, but there is a surge after 2-3 hours. This is a response to falling glucose concentration.
how do elevated insulin levels affect lipogenesis?
stimulate lipogenesis because it cases a decrease in circulating free fatty acids
what does GH to to free fatty acids?
causes their release from adipose tissue for use by muscle and liver cells
How does Glut2 transporter work?
- glucose enters cell via glut2 transporter 2. glucose metabolism produces ATP as it becomes pyruvate 3. ATP levels increase in cytoplasm and closes K+ channels 4. membrane depolarization follows causing step 5 5. opening of voltage gated Ca2+ channels 6. elevation oin cytosolic Ca2+ stimulates secretion of insulin.
how does insulin receptor work?
- conformation change leads to receptor autophosphorylation and tyrosine phosphorylation of intracellular protein substrates 2. insulin activates 2 main branching pathways
what two pathways does insulin receptor stimulate?
Ras-MAP kinase and IRS pathways
Ras-MAP kinase pathway
- receptor binds Shc, which binds Grb2 ans SOS. 2. SOS binds Ras and Ras binds Raf 3. Raf activates MEK. 4 MEK activates Erk1/2, which causes cell proliferation and antiapoptosis
what is Ras-MAP kinase pathway known as?
growth signal
IRS pathway
actiavates kinase dependent on heterodimeric (p85/p110) p12K (protein kinase B). this modulates enzyme activities that control glucose, lipid and protein metabolism and affect NO generation and apoptosis. Also known as metabolic signal.
how does insulin receptor signal transduction lead to metabolic changes
insulin binds and activates protein kinase B. protein kinase B activates Glut4 translocation and inactivates GSK3, which inhibits glycogen synthase
what is insulin receptor like?
dimeric receptor tyrosine kinase
what are two roles of insulin receptor?
Ras-MAP kinase pathway and glucose levels in circulation regulation
What is IR made up of?
2 extracellular alpha subunits that bind insulin and 2 transmembrane beta-subunits that contain tyrosine kinase domain
what mediates insulin effects on metabolism?
protein kinase B
what does insulin result in with blood glucose?
increase of glucose transport from blood, translocation of glucose transporters to plasma membrane I fat and muscle, activation of glycogen synthase.
how does glucose enter intestines and kidney?
secondary active transport with Na+
how does insulin stimulate glucose entry into muscle, adipose and other cells?
upregulates no of glucose transporters in cell membrane
where is Glut4 stored?
in muscle and adipose cells in vesicles in cytoplasm
what happens to glut4 vesicles after insulin binds cell?
vesicles fuse with plasma membrand and increase no. of Glut4 on cell surface
how does insulin affect liver catabolic pathways?
inhibits glycogenolysis, conversion of fatty acids and aa to keto acids and conversion of aa to glucose
how does insulin affect liver anabolic pathways?
promotes glucose storage as glycogen (induces glucokinase and glycogen synthase, inhibits phosphorylase), increases triglyceride synthesis and VLDL formation
how does insulin affect muscle protein synthesis?
increases aa transport, and ribosomal protein synthesis
how does insulin affect muscle glycogen synthesis?
increases glucose transport, induces glycogen synthase, inhibits phosphorylase
how does insulin affect adipose tissue triglyceride storage?
a. lipoprotein lipase is induced by insulin to hydrolyze triglycerides in circulating lipoproteins for delivery of fatty acids to adipocytes b. glucose transport nto cell provides glycerol phosphate to permit esterification of fatty acids supplied by lipoprotein transport c. intracellular lipase is inhibited by insulin
how does insulin affect brain?
decreases appetite. Increases energy expenditure.
how does insulin affect K+?
causes K+ to enter cells – lowers extracellular K+ concentration. Infusions of insulin and glucose lower plasma K+ level in normal individuals. Very effective for temporary relief of hyperkalemia in patients with renal failure. Increases activity of Na/K ATPase in cell membrane, so more K+ is pumped into cells
how is glycogen synthesized?
UDP-glucose plus glycogen in residues , through glycogen synthase, results in glycogen (n + 1 residues) and UDP
how is glycogen degraded?
glycogen (in residues) through glycogen phosphorylate and Pi becomes glucose-1-phosphate and glycogen (n-1 residues)
how does increased cAMP regulate glycogen levels?
stimulates glycogen breakdown and inhibits glycogen synthesis. Inactive cAPK phosphorylates GPK, which phosphorylates GP, which breaks down into glycogen (n+1 residues) plues glucose. Inactive cAPK phosphorylates GS
how does decreased cAMP regulate glycogen levels?
inhibits glycogen breakdown and stimulates glycogen synthesis. Active PP dephosphorylates GPK and GP and GS, which leads to UDP glucose becoming glycogen and UDP
At what plasma glucose level does insulin secretion get inhibited?
Approx 80 mg/dL
At what plasma glucose level do glucagon, epi, and GH get secreted?
Approx 68 mg/dL
At what plasma glucose level is there cortisol secretion due to stress?
Approximately 55 mg/dL
At what plasma glucose level is there cognitive dysfunction?
Approx 50 mg/dL
At what plasma glucose level is there a coma?
30 mg/dL
At what plasma glucose level are there convulsions?
20 mg/dL
At what plasma glucose level is there permanent brain damage or death?
Under 15 mg/dL
What is human proglucagon precursor to in alpha cells?
GRPP, glucagon, hexapeptide and major proglucagon segment.
What is human proglucagon precursor to in small intestine?
Glincentin, Truncated GLP-1 and GLP-2
What is Glincentin a precursor to?
GRPP and Oxyntomodulin
What are steps of glucagon/receptor G-alpha-s pathway?
Glucagon binds with G protein 7 transmembrane domain. G alpha-s dissociates from Beta and gamma, loses GDP and gains GTP, and activates adenylate cyclase, which makes cAMP in cytoplasm. cAMP increases active PKA, which increases active phosphorylase kinase, which phosphorylates Phosphorylase, which increases glycogenolysis. Increase in active PKA also uses PGC-1, PEPCK and G-6-Pase to increase gluconeogenesis, which increases glucose.
What are steps of glucagon/receptor G-q pathway?
G-q activates phospholipase C, which makes PiP2 and IP3, which leads to release of Ca2+ in cytosol, which leads to decrease in glycolysis and glycogenesis.
What are the steps of glycogenolytic response stimulated by glucagon?
Glucagon activates adenylate cyclase, which makes cAMP, which activates phosphorylase kinase, which activates phosphorylase b to make it phosphorylase a, which accelerates the production of glucose-1-phosphate from glycogen.
What regulates glycogen mobilization from the liver?
Glucagon
By how much does glucagon accelerate production of glucose-1-phosphate from glycogen?
1000 fold
is glycogen synthetase active or inactive in the phosphorylated form?
Inactive
What does glucagon action on liver or epinephrine action on muscle stimulate?
Adenylate cyclase
What kind of proteins are capable of phosphorylating glycogen synthetase?
Two protein kinases. One is cAMP dependent and the other cAMP independent.
Glycogen synthetase regulation via glucagon and adreline.
Glucagon acts on liver. Adrenaline acts on muscle. Both hormones stimulate adenylate cyclase. Adenylate cyclase makes cAMP. cAMP activates cAMP-dependent protein kinase, which phosphorylates glycogen synthetase and renders it inactive.
Glycogen synthetase regulation via insulin.
Insulin inhibits (somehow) cAMP-independent protein kinase, which makes it stop phosphorylating glycogen synthetase, so glycogen synthetase is activated because it has not be phosphorylated.
How does insulin regulate glycogen synthetase via factor Fa?
Insulin activates Fa, which reacts with an inactive form of phosphoprotein phosphatase to produce the active form of the phosphatase. Phosphatase dephosphorylates glycogen synthetase, rendering it active.
Percentage of adults in US with diabetes? Prediabetes?
11.3%/ 35%
How does diabetes rank as cause of death in the US?
7th leading cause
Insulin-dependent diabetes mellitus (IDDM)
Low or absent levels of circulating endogenous insulin; dependent on injected insulin to prevent ketosis and sustain life. Onset predominantly in youth but can occur at any age. Associated with certain HLA and GAD antigens. Abnormal immune response; islet cell antibodies are frequently present at diagnosis.
Non-insulin-dependent diabetes mellitus (NIDDM)
Insulin levels may be normal, elevated, or depressed; hyperinsulinemia and insulin resistance characterize most patients and insulinopenia may develop as the disease progresses. Not insulin dependent or ketosis prone under normal circumstances but may require insulin for treatment of hyperglycemia. Onset predominantly after age 40 years but can occur at any age. Approximately 50% of men and 70% of women are obese. Cause probably strongly genetic; 60-90% of monozygotic twins are concordant for NIDDM.
Gestational diabetes
Glucose intolerance that has its onset or recognition during pregnancy. Associated with older age, obesity, family history of diabetes. Conveys increased risk for the woman for subsequent progression to NIDDM. Associated with increased risk of macrosomia.
Glucose pathway
Diet to intestine to plasma glucose. From blood goes to liver, muscle, adipose, brain and kidney. From kidney, glucose leaves through urine.
Glycosuria
Glucose in urine
What type of disease is Type 1 diabetes?
An autoimmune disease
Pancreas/lymph node Type 1 diabetes pathway
Viral attack on pancreas, which release insulin pieces and other cell protein fragments that are taken to lymph nodes. Autorreactive T cells attack islet cells. Islet cells are killed.
What happens to diabetics who have inherited DR3 (but not DR4)?
Tend to develop diabetes earlier in life and have an immune reaction against insulin.
What happens to diabetics who inherit both DR3 and DR4?
They develop diabetes at the youngest age and have the highest levels of antibodies against insulin.
Risk levels of HLA-DR allele 1-9
DR1 slight risk, DR2 protective, DR3 significant risk, DR4 significant risk, DR5 slight risk, DR6 neutral/protective, DR7 protective/risk in African descent, DR8 neutral/slight risk, DR9 risk in Chinese, Japanese, Korean descent
What leads to type 2 diabetes?
Too much food/animal fat, not enough exercise, one set of genes inherited from parents make you hungry, another set of genes cause greater insulin resistance, being overweight, which makes body resistant to insulin, making it produce more
How do genes affect pancreas directly in type 2 diabetes?
Make islet cells wear out early and one can’t make enough insulin.
What do fatty deposits from being overweight do to pancreas?
Damage islet cells
What is the cause of type 2 diabetes, insulin wise?
Body needs more insulin but can’t produce it
How does body develop insulin resistance in type 2 diabetes?
Decrease in insulin receptor number, change in receptor signaling (from insulin R to GLUT4), decrease in the glucose transport
How does abdominal adipose tissue change in obesity?
Macrophages and other immune cells change in obese fat tissue, and release elevated amounts of cytokines leading to metabolic disease. Immune cells cause low-grade inflammation, insulin resistance, and metabolic disease.
How do insulin deficiency and glucagon excess contribute to underutilization of glucose?
Insulin very much. Glucagon zero.
How do insulin deficiency and glucagon excess contribute to overproduction of glucose?
Insulin + Glucagon ++++
How do insulin deficiency and glucagon excess contribute to increased glycogenolysis?
Insulin + Glucagon ++++
How do insulin deficiency and glucagon excess contribute to increased gluconeogenesis?
Insulin + Glucagon ++++
How do insulin deficiency and glucagon excess contribute to increased release of aa?
Insulin very much. Glucagon zero.
How do insulin deficiency and glucagon excess contribute to increased release of aa?
Insulin very much. Glucagon zero.
How do insulin deficiency and glucagon excess contribute to increased lipolysis?
Insulin ++++ Glucagon +
How do insulin deficiency and glucagon excess contribute to increased hepatic ketogenesis?
Insulin + Glucagon ++++
How does insulin deficiency lead to ketone acidosis?
Increase in lipolysis, increase in plasma free fatty acids, increase in ketone synthesis, increase in plasma ketones, increase in plasma H+ (acidosis), which leads to impaired brain function and death
How does insulin deficiency lead to decrease in brain blood flow?
Decrease in glucose uptake by cells, increase in glycogenolysis and gluconeogenesis. Increase in plasma glucose. Increase in renal filtration of glucose and ketones. Osmotic diuresis. Increase in sodium and water excretion. Decrease in plasma volume. Decrease in arterial bp. Decrease in brain blood flow, which leads to impaired brain function and death.
How does diabetes affect the vascular system?
Through atherosclerosis and arteriolosclerosis.
Atherosclerosis
Of the aorta and large and medium-sized blood vessels leads to myocardial and brain infarctions and gangrene of the lower extremities.
Arteriolosclerosis
Thickening of the wall of the arterioles; associated with hypertension
How does diabetes affect the bladder?
Urinary bladder neuropathy (alteration in the autonomic nervous system)
How does diabetes cause eye complications?
Total blindness. Retinopathy, cataract, glaucoma.
Retinopathy
Damage of retina
Cataract
Opacity of lens
Glaucoma
Impaired drainage of the aqueous humor is frequently observed
How does diabetes affect kidneys?
Glomerulosclerosis, aerteriosclerosis, pyelonephritis, and diffuse thickening of the basal lamina of the glomerular capillaries and proliferation of mesangial cells, or Kimmelstiel-Wilson lesion
Gangrene
Caused by blood vessel obstruction as a consequence of vascular arteriosclerosis
What causes osmotic damage in diabetes?
Increased activity of the sorbitol and glycogenic pathways
What do glycosylation reactions in diabetes lead to?
Alterations in the eye and basement membranes of cells, which in turn affect permeability and transport mechanisms
What does increase of glycogen in kidney and leucocytes cause?
Osmotic damage
What kind of glycosylation of proteins happens in diabetes because of high circulating levels of glucose?
Non-enzymatic glycosylation
Which amino acids are primarily glycosylated?
Lysine and valine
What damage does diabetes do to eye?
Microaneurysms, “cotton wool” spots, hemorraghes, exudates and abnormal blood vessels.
Difference between healthy and diabetic retinal capillaries.
Diabetic retinal capillaries – some are closed off, others form dilated segments “microaneurysms”
What happens to basal lamina in diabetic kidney
Thickening
What leads to neuropathy in diabetes?
Changes in nerve bundles (NB)
Diabetes treatment options
Insulin pump, islet transplantation
How does islet transplantation work?
Donor pancreas, isolate islets, use syringe to put islets in portal vein
