Feeding and Fasting: integration of glucose and fat metabolism Flashcards
Key hormones in short term regulation of blood glucose
insulin (reduce blood sugar – hypoglycemic effect)
glucagon (along w/ epi, GH, cortisol act to increase blood sugar– hyperglycemic effect)
fat metab and rising insulin/falling catecholamines
-inhibition of lipolysis thus reducing fatty acid oxidation and facilitating fatty acid synthesis
very low insulin and high counter regulatory hormones and fat metab
-fatty acids enter ketogenesis pathway (instead of being oxidized to CO2 and water)
When are counter regulatory hormones released?
When glucose FALLS
What fuel do muscles prefer?
fatty acids for fuel preferred, but can consume glucose when insulin rises.
Where are effects of insulin most pronounced? results?
- liver, muscle, and adipose tissue
- effect of insulin is to promote storage of excess glucose as glycogen in liver and muscle and as triglycerides in adipose tissue
insulin release is timulated by:
- increase in blood glucose
- increase in indiv aa (argninie, leucine)
- facilitated by gut hormone GLP-1
Glucagon release stimulated by
-low glucose and increased epi
inhibited by high glucose and insulin
During fasting, primary actor?
- glucagon acts primarily on liver
- promotes glycogenolyis and gluconeogenesis
During exercise/stress: action of epi
- stimulates glycogenolysis in muscle and liver and release of FFA by adipose tissue thru hormone sensitive lipase
- hormone binding–> cAMP–> PKA–> glycogen phosphorylase and hormone sensitive lipase activation (and inactivation of glycogen synthase; acetyl coA carboxylase in fatty acid synthesis)
Fed state: 1-3 hours after ingestion of meal
- high insulin/glucagon ratio
- modest rise in blood glucose
What organ preferentially takes up glucose in post-prandial period?
- liver (using glucokinase to convert glucose from portal v to G6P)
- elevated G6P in liver along with high insulin levels stimulates glycogen synthase
Enzymes favored by high insulin/glucagon ratio
glycogen synthase (active form is dephosphorylated)
pyruvate dehydrogenase (provides lots of acetyl CoA for FFA synthesis, facilitated by activation of acetyl CoA carboxylase (rate limiting step) (Also need NADPH from PPP for fatty acid synthesis by fatty acid synthase)
Muscle metabolism in fed state
high insulin/glucagon ratio:
- increased glucose uptake (Glut-4)
- glucose to G6P by hexokinase
- activation of glycogen synthase
- glucose is primary fuel for muscle in fed state
- increased aa uptake and protein synthesis–> storage of carbon skeletons
- NOT favored: uptake of fat in chylomicrons due to reduction in skel muscle LPL caused by increased insulin levels.
Brain metabolism in fed state
- glucose is EXCLUSIVE fuel for brain tissue (except in extreme starvation: ketone bodies)
- use of insulin dependent glucose transporters (Glut-1, Glut-3)
- brain relies on aerobic metab of glucose
adipose tissue metabolism in fed state
- high insulin/low glucagon and catecholamine levels
- hormone sensitive lipase is NOT active, and rates of lipolysis are LOW
- glucose taken up by adipose tissue can be coverted to fatty acids and into trigylceride by the pathway of fatty acid synthesis (de novo lipogenesis)
- uptake of dietary fat contained in chylomicrons faciliated by increase in adipose tissue lipoprotein lipase
Fasting state
- from 3-4 hours to 32-36 hours after a meal is marked by decreasing levels of absorbed nutrients in the blood stream and a declining insulin/glucagon ratio.
- increased reliance on glycogenolysis and gluconeogenesis
Liver metabolism in the fasting state
Glycogen degradation (glycogenolysis) -stim by glucagon induced activation of glycogen phosphorylase (inhib of glycogen synthase)
Gluconeogenesis:
- reduction in F2,6BP relieves inhibition of fructose 1,6 bisphosphatase and reduces PFK1 activation. NET: increased gluconeogenesis, decreased glycolysis
- inactivation of pyruvate kinase by PKA prevents futile recycling of PEP
- increased levels of circulating free fatty acids that result from increased rates of lipolysis result in increased rate of beta oxidation and increased levels of acetyl CoA in mitochondria (diverts pyruvate to gluconeogenesis)
In liver only: G6P to glucose via Glucose-6-phosphatase. (release glucose into blood)
Muscle metabolism in fasting state
- degradation of muscle proteins provide carbon skeletons for hepatic gluconeogenesis
- FFA are primary fuel source for muscle during fasting
- low insulin and high counter-reg hormones favor increased skel muscle LPL and increased uptake of VLDL triglyceride as another fat fuel source.
- glucose as fuel from glycogen degradation during SHORT exertion.
- glycogen from muscle can go down glycolysis to lactate, be exported to liver, can serve as gluconeogenic precursor (Cori cycle)
Brain metabolism in fasted state
- glucose as fuel
- hepatic gluconeogenesis and glycogenolysis provide glucose source
After 3-5 d of fasting
- increased reliance on ketones and fatty acids for fuel
- maintain bg b/t 60-65 mg/dl
- spares protein for prolonged periods without food
- occurs thru effects mediated by absence of insulin and high level so counterregulatory hormones: glucagon, growth hormone, cortisol, catecholamines
Liver metabolism in starvation state
-rate of gluconeogenesis decreases as rate of aa available from muscle protein catabolism decreases
-glycerol released by lipolysis from adipose tissue –> low lvl gluconeogenesis in liver (only tissue with glycerol kinase)
glycerol–> glycerol 3-P –> DHAP–> Glucose
-fatty acid (from adipose tissue) oxidation at high level in liver (energy for gluconeogenesis)
-Acetyl CoA from beta oxidation accumulates, leads to production of ketone bodies
-ketoacidosis is hallmark of starvation
-acetone (not metabolized) gives a fruity breath
Muscle metabolism in starvation state
- degradation of muscle protein persists but decreases as demand for blood glucose is reduced (catabolism driven by counterregulatory hormones)
- FFA, ketones, triglyc are used as energy sources in starvation
- starvation persists, muscle relies more on FFA, leaving ketone bodies for BRAIN
Brain metabolism in the starvation state
- increasing ketone body use, spares glucose for use by RBCs (rely solely on glucose for energy)
- decreasing glucose use by brain reduces need for hepatic gluconeogenesis and indirectly spares muscle protein
