week 1, lecture 3 Flashcards
DIAGRAM of the twin cycle hypothesis
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what happens with insulin resitstance and steatosis
increased gluconeogenesis, increased VLDL export, increased blood glucose and increased insulin pancreatic insulin secretion
what receptor does palmitic acid (a FFA) activate?
TLRs –> which exacerbate insulin resistance
how does the liver deal with extra FFA
export energy;; VLDL production –> IDL –> LDL –>deliver to other cells
what cycle increases blood glucose as a result of liver steatosis
inappropriate GNG
which cells of the pancreas are important in adiposity and fibrosis?
acinar cells (and islets)
what does the liver deliver to the pancrease
excess triglycerides (via VLDL)
what FFA accumulates in pancreatic beta cells
palmitic acid
what effect does fatty pancreas have on beta cells
ER stress, ROS, apoptosis of beta cells or de-differentiation (act like alpha cells and secrete glucagon)
what is the positive feedback loop seen in the twin cycle
Insulin resistance→increased hepatic steatosis and VLDL output→TG and FFA accumulation in the pancreas→compromised insulin secretion (impaired ability to secrete large, immediate “pulses of insulin)→ hyperglycemia→conversion to fat, increased circulating FFAs
what is VLDL mainly made of
TGs
what happens if LDL not cleared by hepatocytes
oxidized and becomes a risk factor for atherosclerosis
what does adiponectin help with and where is it stores
from subcutaneous fat to regulate glucose levels and breakdown fatty acids.,.. but cant keep up with leptin
leptin: adiponectin ratio increased in T2DM but become resistant to leptin
what type of receptors do vascular endothelial cells
insulin receptors
–> vasodilator and constrict –> insulin resistance cause more constriction (decreased NO) and increases hypertension and atherosclerosis
insulin resistance impacts on brain
atherosclerosis in vasculature of brain and dementia
Alzheimers from reduced synaptogenesis
and inflammation and glial activation damage neurons
leaky BBB
advanced glycation end products
insulin resistance impact on kidneys
sclerosis of glomeruli- damage filtration, kidney infections, arteriolosclerosis, hypertension
insulin resistance impact on bone
insulin is anabolic for bones and increases osteoblast activity (build bone) and decrease osteoclast (resorb bone) –> resistance does opposite
overweight stressed bones might be good but in T1D have a lower bone mineral density
insulin resistance impact on heart
ER stress, mitochondrial dysfunction, ROS< vascular function, impaired calcium balance effects systole and diastole, angiotensin II, fibrosis, cardiac hypertrophy
advanced glycation end products (from hyperglycemia) impact on arteries
pro inflammatory cytokines, ROS, procoagulant, constrict blood vessels via proliferation of vascular smooth muscle, make resistant to proteolysis
–>decrease large artery elasticity, narrow small arteries, deposit atherosclerotic plaques, increase coagulation (blood clots)
activate PKC pathway
hyaline arteriolosclerosis (diabetes)
small vessels thicken hyaline walls and narrow lumen
diabetic microangiopathy
thicken basement membrane and make capillaries leaky
diabetes- neuropathy
loss axons and myelination
loss of pain sensation
postural hypotension, sex dysfunction, bladder emptying incomplete
skin condition from T2DM
acathosis nigricans (black leathery skin)
also psoriasis and achordons (skin tags)
what are bile acids synthesize from and where?
from cholesterol in hepatocytes
what are primary bile acids and what enzymes are used to make them
hydroxylase enzymes to make cholic acid and chenodeoxycholic acid (which then get conjugated with glycine or taurine) to make bile
where are bile stored
gallbladder (made in liver)
what does bile respond to
CCK and fat/ food in the small intestine
what can secondary acids can bile acid turn into in the large intestine and via what
deoxycholic acid and lithocholic acid via microbiota
what are the main bacterial enzymes in bile acid processes
Bile salt hydrolases – deconjugation of primary BA’s
Hydroxysteroid dehydrogenases – causing oxidation of BA’s
Dehydroxylation of unconjugated BA’s
bile acid effects
reduce TG biosíntesis and promote clearance
reduce hepatic GNG
increase brown adipose tissue and BMR
promote GLP1 and PYY release (reduce food intake and reduce gastric emptying)
promote insulin secretion
