1 - endocrine Flashcards
list and describe the glucose transporter family
transported via facilitated diffusion (down concentration gradient)
GLUT-1:
- found in most mammalian tissues
- involved in basal glucose uptake and maintaining blood brain barrier
GLUT-2:
- found in liver and pancreatic beta cells
- involved in regulation of insulin
GLUT-3:
- found in most mammalian tissues
- involved in basal glucose uptake and neurones
GLUT-4:
- found in muscle and fat cells
- traffics glucose in response to insulin
GLUT-5:
- small intestine
- primarily fructose transporter
how is glucose homeostasis achieved in the pancreas?
pancreatic beta cells:
- produce insulin –> induce anabolic reactions
- increases storage of glucose, fatty acids & amino acids
- signal peptide removed from linear preproinsulin
to give proinsulin –> moves from ER to golgi –> C-peptide removed to give insulin
- insulin binds to extracellular binding dimers —> activates receptor —> conformational change —> auto-phosphorylation of tyrosine kinase domain —> tyrosine kinase activated —> phosphorylates proteins (*IRS = insulin receptor substrate) —> activated IRS activates/deactivates enzymes and induces/suppresses gene expression —-> glucose homeostasis and other metabolic functions
preatic alpha cells:
- functional antagonist to beta cells
- produce glucagon –> catabolic reactions
- mobilises glucose, fatty acids and amino acids from stores to blood
what is the absorptive state and how is glucose homeostasis achieved in this state?
absorptive state = following a meal
increase in glucose = increase in insulin
insulin promotes glucose uptake out of circulation and into cells/storage
decrease in blood glucose = decrease in insulin
how does insulin activate/stimulate glucose uptake through GLUT4?
are there other mechanisms for glucose uptake?
GLUT-4 stored in cytoplasmic vesicles in muscle/fat cells
insulin stimulates these vesicles to travel to membrane
vesicles under exocytosis (SNARE proteins), and GLUT-4 embeds in membrane ready to transport glucose
when GLUT-4 genes knocked out, there is still some glucose uptake into cell —> insulin can also have enzymatic effects which induces glucose uptake from other transporters - GLUT-1/3
what pathway does insulin activate to activate GLUT-4?
PI3kinase/AKT(PKB) pathway
insulin binds to tyrosine kinase receptor –> phosphorylation pathway –> PKB activates GLUT-4
how does insulin stimulate glucose uptake in the liver?
GLUT-2 found in liver but not insulin sensitive –> insulin uses enzymes such as glucokinase to stimulate glucose uptake
glucose crosses from blood stream to IS space —> then trafficked into hepatocyte via GLUT2 transporter
insulin promotes activity of glucokinase, converting glucose to glucose-6-phosphate (inhibits reconversion)
insulin promotes activity of glycogen synthase, converting glucose-6-phosphate to glucose-1-phosphate to glycogen for storage
insulin enhances enzyme activity to convert glucose-6-phosphate to pyruvate to acetyl CoA to ATP (citric acid cycle)
insulin promotes lipogenesis (acetyl CoA –> fatty acids –> triglycerols –> lipid droplets) and protein synthesis
- draw diagram
how does insulin stimulate glucose uptake in muscle?
glucose crosses from blood stream to IS space —> then trafficked into myocyte via GLUT4 transporter
insulin promotes activity of hexokinase, converting glucose to glucose-6-phosphate (inhibits reconversion)
insulin promotes activity of glycogen synthase, converting glucose-6-phosphate to glucose-1-phosphate to glycogen for storage
insulin enhances enzyme activity to convert glucose-6-phosphate to pyruvate to acetyl CoA to ATP (citric acid cycle)
minor component: insulin promotes lipogenesis (acetyl CoA –> fatty acids –> triglycerols –> lipid droplets)
myocytes not good for fat storage
major component: protein synthesis
*draw diagram
how does insulin stimulate glucose uptake in fat cells?
glucose crosses from blood stream to IS space —> then trafficked into adipocyte via GLUT4 transporter
insulin promotes conversion of glucose to glucose-6-phosphate (inhibits reconversion)
insulin enhances enzyme activity to convert glucose-6-phosphate to pyruvate to acetyl CoA to ATP (citric acid cycle)
insulin promotes lipogenesis (acetyl CoA –> fatty acids –> triglycerols –> lipid droplets)
note: adipocytes do not store glycogen
* draw diagram
how is insulin secretion controlled?
1) pancreatic beta-cells
- control secretion for insulin, but also act as a sensor of insulin-levels
- high glucose in ECF —> glucose trafficked into cell via concentration gradient —> insulin released in cell
- insulin stimulates glucokinase: glucose —> glucose-6-phosphate —> ATP (oxidation) —> closure of K+ channel —> depolarisation (buildup of intracellular K+)
- calcium induces vesicle fusion to release insulin (SNARE proteins)
2) autonomic ns:
- sympathetic ns inhibits insulin—> don’t want glucose stored —> want high blood glucose levels
- parasympathetic ns promotes —> store glucose during digestion
3) glucagon/somatostatin:
- glucagon is a function antagonist to insulin i.e. stimulates catabolism to increase blood glucose
- stimulates insulin to maintain glucose homeostasis
- somatostatin inhibits
4) gastrointestinal hormones
- released in response to nutrients in lumen —> switch on insulin during digestion
describe the function of glucagon on carbs, fats and proteins.
CARBS: 1. Inhibits glycogen synthesis 2. Promotes glycogenolysis 3. Stimulates gluconeogenesis Overall glucagon increases hepatic glucose production & release, thus increasing blood glucose
FATS: 1. Promotes lipolysis 2. Inhibits TG (triglycerol) synthesis 3. Enhances ketogenesis Overall glucagon increases blood FAs & ketone bodies
PROTEINS:
1. Inhibits hepatic protein synthesis
2. Promotes degradation hepatic protein
3. Stimulates gluconeogenesis (uses aa’s to produce glucose)
Overall no significant effect on blood AA levels
how is glucagon secretion controlled?
1) blood glucose
- hypoglycaemia stimulates
- hyperglycaemia inhibits
2) beta-cells
- beta-cells stimulate insulin which in turn stimulates glucagon
3) blood AA and FA
- high blood AA increase glucagon and insulin
- high protein —> don’t want all glucose stored —> glucagon counter-balances insulin action
4) sympathetic NS
- adrenaline stimulates
5) hormones
- cortisol stimulates
- somatostatin inhibits
6) infection and exercise
- stimulate glucagon to release glucose into blood
relationship between glucose and insulin/glucagon release
at low glucose levels:
- high glucagon to mobilise glucose stores
- low insulin
as glucose increases:
- insulin increases for storage / utilisation in cells
at high glucose levels:
- both insulin and glucagon increase
- paracrine infuence from beta-cells causes insulin to stimulate glucagon
describe what happens to insulin/glucose levels during exercise
during exercise, lower blood glucose inhibits insulin and stimulates glucagon secretion
sympathetic NS active:
- noradrenaline inhibits insulin release
- adrenaline stimulates glucagon release
acute muscle contraction stimulates GLUT-4 translocation to membrane
chronic (endurance) muscle contraction increases GLUT-4 expression
calmodulin and AMP kinase pathways also stimulate GLUT-4 translocation to membrane
symptoms and effects of diabetes mellitus
describe the difference between type I and type II
disease of impaired carbohydrate, fat and protein metabolism - characterised by HYPERGLYCEMIA
causes:
- glucosuria (glucose in urine)
- polyuria (frequent urination)
- polydipsia (frequent hunger)
- polyphagia (frequent thirst)
TYPE I:
- —-> insulin dependent diabetes mellitus (IDDM) i.e. inadequate insulin secretion / destruction of beta cells
- —-> early onset
- —-> symptoms develop rapidly
- —-> treated using insulin injections and diet management
TYPE II:
- —-> non-insulin dependent diabetes mellitus (NIDDM) i.e. insulin resistance / insensitivity
- —-> adult onset
- —-> symptoms develop slowly
- —-> treated using oral hypoglycemics, weight reduction, exercise, diet management
severe type II can lead to type I
how can diabetes mellitus be tested for?
oral glucose tolerance test
patient fasts then ingest 75g of glucose (via sugar water). plasma glucose levels are recorded to see if insulin is acting to restore homeostasis
plasma glucose levels are extremely high because insulin cannot induce uptake of glucose into storage
more insulin is required for the same glucose uptake
- —-> pancreas forced to pump out insulin to overcome sensitivity
- —-> pancreatic beta-cells can become damaged and fail in a chronic situation
what are the long term effects of diabetes mellitus?
chronic complications of diabetes mellitus can lower life expectancy
hyperglycaemia leads to excessive glycosylation of proteins causing:
- —-> damage in blood vessels (atherosclerosis in peripheral vessels)
- —-> damage kidney
- —-> damage retina
- —-> neuropathy in ANS fibres
glycolysis process
note which enzymes are regulated by insulin
1 glucose + 2ADP + 2Pi + 2NAD+ —-> 2 pyruvate + 2ATP + 2NADH + 2H+ + 2H2O
aerobic: 2NADH —–> 3-5 more ATP molecules in mitochondria
anaerobic: pyruvate —-> lactate
enzymes regulated by insulin:
1) hexokinase/glucokinase = glucose to gluco-6-phosphate
2) phosphofructokinase (PFK)
3) pyruvate kinase (PK)
gluconeogenesis process
note which enzymes are activated by glucagon
2 pyruvate + 4ATP + 2GTP + 2NADH + 6H2O —–> 1 glucose + 4ADP + 2GDP + 6Pi + 2H+
key products during process include glycerol and oxaloacetate
enzymes activated by glucagon:
- phosphoenolpyruvate carboxykinase (PEPCK)
- pyruvate carboxylase
- oxaloacetate
compare the regulation of glycolysis vs gluconeogenesis
glycolysis occurs in cytosol
gluconeogenesis in mitochondria and ER
glycolysis = allosteric regulation i.e. regulated by ATP, not just hormones
e.g. high levels of AMP stimulate phosphofructokinase (PFK) and therefore glycolysis
high levels of ATP inhibit phosphofructokinase (PFK)
transcriptional regulation of enzymes:
- –> insulin STIMULATES key enzymes of glycolysis (PFK / PK)
- –> insulin INHIBITS key enzymes of gluconeogenesis (PEPCK)
- –> glucagon INHIBITS key enzymes of glycolysis (PFK / PK)
- –> glucagon STIMULATES key enzymes of gluconeogenesis (PEPCK)
gluconeogenesis process
note which enzymes are activated by glucagon
2 pyruvate + 4ATP + 2GTP + 2NADH + 6H2O —–> 1 glucose + 4ADP + 2GDP + 6Pi + 2H+
key products during process include glycerol and oxaloacetate
enzymes activated by glucagon:
- phosphoenolpyruvate carboxykinase (PEPCK)
- pyruvate carboxylase
- oxaloacetate
how is fatty acid synthesised in the liver?
the liver can convert glucose and amino acids into fatty acids
- amino acids deaminated to acetyl coA and pyruvate
- acetyl coA and pyruvate create citrate in mitochondria
- citrate can travel into cytoplasm, therefore is converted to malonyl coA
- condensation, reduction and dehydration give palmitate (precursor for longer fatty acids)
how are proteins stored after a meal?
how dos insulin stimulate this process?
- high protein meal
- digested in gut, amino acids absorbed through gut wall into hepatic portal vein (INSULIN STIMULATED)
- some amino acids oxidised (pyruvate —> citric acid cycle —> G6P —> glycogen) (INSULIN STIMULATED)
- aa spillover into ECF
- aa travel into muscle to turn into protein (INSULIN STIMULATED)
how are fats stored after a meal?
how dos insulin stimulate this process?
- fatty meal
- fats broken down in gut and absorbed through lymphatics into blood (bypass liver)
- in blood, free fatty acids or LPL breaks down fats (INSULIN STIMULATED)
- these products taken up into adipocytes to create triacylglycerides —> fat storage (INSULIN INHIBITS HSL i.e. fat breakdown)
describe how glycogenolysis occurs in THE LIVER via the adenylate cyclase/cAMP/PKA pathway
- glucagon binds to glucagon receptor on hepatocyte
- Gs proteins stimulate adenylate cyclase
- AMP —> cAMP
- activates PKA
- PKA phosphorylates PK
- PK phosphorylates glycogen phosphorylase (GP)
- active GP catalyses breakdown of glycogen to G1P
- G1P converted to G6P
- G6P converted to glucose by G6Pase
- glucose released to blood
describe how glycogenolysis occurs in MUSCLE via the adenylate cyclase/cAMP/PKA pathway
- adrenaline binds to adrenoreceptor on myocyte
- Gs proteins stimulate adenylate cyclase
- AMP —> cAMP
- activates PKA
- PKA phosphorylates PK
- PK phosphorylates glycogen phosphorylase (GP)
- active GP catalyses breakdown of glycogen to G1P
- G1P converted to G6P
- G6P not converted to glucose, but is oxidised via glycolysis into pyruvate —> ATP —> energy for local use
describe how lipolysis occurs in FAT via the adenylate cyclase/cAMP/PKA pathway
- adrenaline binds to adrenoreceptor on adipocyte
- Gs proteins stimulate adenylate cyclase
- AMP —> cAMP
- cAMP activates hormone-sensitive lipase (HSL)
- HSL releases stored TAGs via hydrolysis to give fatty acids and glycerol
- fatty acids transported to liver and muscle