hormonal regulation of intermediary metabolism Flashcards
glucose homeostasis
maintenance of concetrations within 60-150 mg/ml range is critical to survival
glucose is predominant fuel utilized by the CNS
hormones involved in glucose homeostasis (list)
insulin glucagon catecholamines growth hormone hormones of the gut
what does insulin control (generally)
initiates events that promote removal of glucose
also fatty acids and amino acids from blood, preventing hyperglycemia
what do all of the glucose homeostasis hormones except for insulin control (generally)
all regulate biochemical processes which help to elevate the plasma glucose levels to prevent hypoglycemia
structure of insulin
2 peptide chains held together by S-S bridges
MW 6000
entire molecule needed for activity
synthesis of insulin
in beta cells of islets of langerhans
initial product of mRNA translation is pre-proinsulin
enzymatically cleaved to proinsulin
proinsulin cleaved to insulin and C-peptide
products secreted by beta-cells of islets of langerhans
insulin
c-peptide (in approximately equal amounts to insulin)
proinsulin
how does proinsulin compare with insulin in terms of reactivity?
50% of immunoreactivity of insulin
5% of its biological activity
how is human insulin made?
with recombinant DNA techniques
control of insulin secretion (summary card)
high blood glucose level is primary stimulus
modulating factors: certain AA, espec. arginine; ketones; glucagon; gut peptide hormones (stimulator); beta adrenergic receptor activation
inhibitory: catecholamines (on alpha adrenergic receptors), sympathetic nervous system, somatostatin
involves glucokinase (glucose sensor, glucose metabolism, and coupling of glucose metabolism via the ATP/ADP ratio - results in ionic events governing insulin secretion
key factor for insulin secretion is calcium ion concentration
stimulatory factors for insulin production
certain amino acids (esp. arginine) ketones glucagon gut peptide hormones Increased plasma K Obesity Vagal stimulation via Ach Beta adrenergic receptors
inhibitory factors for insulin production
catecholamines
sympathetic nervous system
somatostatin
key factor in insulin secretion
calcium ion concentration
inactivation of insulin and proinsulin
half life of insulin = ~10 minutes - degraded by hepatic proteolytic enzymes
halflife of proinsulin = 20 minutes - degraded by kidney enzymes
insulin mechanism of action
binds to cell surface receptor (TM protein)
receptor functions as tyrosine kinase
=> autophosphorylation
=> phosphorylation of docking proteins (IRS, Shc)
=> activation of series of parallel downstream events that involve cascade of covalent phos reactions and protein-protein interactions
=> modulation of specific cell functions including glucose transport, glycogen and protein synthesis and mitogenesis
insulin actions on muscle
1: stimulation of glucose transport into cell
2: enhancement of glycogen synthesis
3: stimulation of amino acid uptake
4: stimulation of protein synthesis
5: inhibition of proteolysis
note: exercise also stimulates glucose transport into muscle cells
insulin actions on adipose tissue
1: stimulation of glucose uptake into the cells
2: promotion of fat synthesis
3: activation of lipoprotein lipase
4: inhibition of hormone-sensitive lipase
5: enhancement of glycogen synthesis
6: enhancement of AA uptake and protein synthesis
insulin actions on liver
1: stimulation of glucokinase and glycogen synthetase activity
2: stimulation of activities of key rate limiting glycolytic enzymes (glucokinase, phosphofructokinase, pyruvate kinase, pyruvate dehydrogenase)
3: inhibition of activities of key rate-limiting gluconeogenic enzymes (glucose-6-phosphatase, fructose-1,6-diphosphate phosphatase, phosphoenolypyruvate carboxykinase, pyruvate carboxylase)
4: stimulation of FA synthesis and increase in activities of key lipogenic enzyme
structure of glucagon
29 AA polypeptide chain
MW 3485
synthesis of glucagon
in alpha-cells of islets of langerhans
initial product is pre-proglucagon
stimuli for glucagon release
primary stimulus = low blood glucose level others = AA gut hormones catecholamines
degradation of glucagon
degraded rapidly in liver - questionable whether any normally reaches peripheral circulation
proglucagon degraded in kidney - biological activity minimal
glucagon receptors
cell surface receptors in liver, fat, myocardial cells, pancreatic islet beta-cells
physiological actions of glucagon
1: stimulates hepatic glycogenolysis (most powerful hyperglycogenolytic agent known)
2: inhibits glycogen synthetase
3: stimulates gluconeogenesis
4: stimulates hepatic lipolysis
5: inhibits FA synthesis
6: increases hepatic ketogenesis
note: all of these effects are mediated via cAMP
catecholamine synthesis
from tyrosine in the adrenal medulla, which primarily secretes epi
in postganglionic sympathetic nerve endings, primarily secrete norepi
regulation of catecholamine synthesis
tonic inhibition by NE in cytosol - removed when nerve stimulation releases this NE
chronic nerve stimulation induces the enzymes tyrosine hydroxylase and dopamine-beta-hydroxylase (involved in synthesis)
ACTH and cortisol may enhance synthesis
release of catecholamines
- major stimulus is acetyl choline
- induced by cold, hypoxia, stress
- stimulation releases cat. from both adrenal gland and sympathetic nerve endings
degradation of catecholamines
Degrade (plasma, liver, kidney), recycle (n. endings), or excrete (kidney)
very rapid (half-life in plasma less than one minute)
in plasma, liver, kidney
can be taken up and recycled at nerve terminals
can be excreted unchanged by kidneys
catecholamine receptors
on cell surface of target cells
two categories: alpha and beta
plus lots of subtypes
both E and NE bind to all receptors, but with different affinities
catecholamine beta receptors
implicated in metabolic effects
activation results in synthesis of cAMP
catecholamine alpha receptors
some that release Ca++ may also be involved in metabolic effects
effects of catecholamines on skeletal muscle
1: stimulation of glycogenolysis and lactate production
2: inhibition of glycogen synthesis and glucose uptake
effects of catecholamines in adipose tissue
stimulation of lipolysis via the hormone-sensitive lipase
effects of catecholamines in liver
1: stimulation of glycogenolysis
2: inhibition of glucose oxidation
3: inhibition of glycogen synthesis
4: stimulation of gluconeogenesis
5: stimulation of lipolysis
actions of glucocorticoids in metabolism
protect body from insulin-induced hypoglycemia by:
1: stimulating hepatic gluconeogenesis
2: permissively by enhancing the stimulatory effect of glucagon and catecholamines on gluconeogenesis and glycogenolysis
3: inhibiting peripheral glucose utilization
4: promoting liver glycogen synthesis - thus storing substrate for acute responses to glycogenolytic agents
actions of growth hormone in metabolism
1: stimulates lipolysis
2: inhibits tyrosine-amino transferase
3: stimulates acutely glucose uptake in muscle and fat
protect the body from insulin-induced hypoglycemia
actions of somatostatin (SRIF) in metabolism
protect the body from insulin-induced hypoglycemia
inhibitor of many polypeptide hormones including:
insulin
glucagon
GH
effective as a pharmacological agent
physiological significance is unclear
