Chapter 19 Flashcards
What organ is specialized for Gluconeogenesis
Ketogenesis
Urea Production
Liver
Where is glycogen stored
Liver/muscle, when fed
Kidney:
Glutamine –> alpha-ketoglutarate –> glucose
Fasting/Starving: How does liver make ketone bodies?
Triacylglycerols –> acetyl-CoA –> Ketone Bodies
Cori Cycle
Cori cycle transfers free energy from liver to muscles
Waste disposal
Lactate dehydrogenase, reversible
Glucose-Alanine Cycle
transport nitrogen from muscles to liver.
Pyruvate –> Alanine
Why is insulin released?
In response to glucose
Insulin receptor is an
RTK, not a lot of questions, that would be chapter 10 review
Unique about glucokinase (insulin) Glucose –> G6P?
sigmodial curve, yet 1 active site
substrate-induced conformational change: at end of catalytic cycle, enzyme briefly maintains high affinity for next glucose molecule.
Increase glc uptake > insulin release
High Km, sensitive to glc
Glucokinase- pancreatic glucose sensor
Is glucokinase only pancreatic glucose sensor?
Yes → mutations in gene causes rare form of diabetes
No → Other cellular factors:
Mitochondria of beta cells
Mitochondrial NAD+/NADH or ADP/ATP ratios
Insulin action in muscle
+: glucose uptake and glycogen synthesis
-: glycogen breakdown
Insulin action in Adipose tissue
+: extracellular lipoprotein lipase/acetyl-CoA carboxylase
+: triacylglycerol synthesis
-: lipolysis
Insulin in liver
+: glycogen/triacylglycerol synthesis
-: gluconeogenesis
Insulin =
fuel abundance, decreases metabolism of stored fuel, promotes fuel storage
Insulin’s Vmax for glucose increases because…
insulin increases number of transporters at cell surface.
Increase GLUT4 passive receptors
Insulin activates extracellular
lipases, hydrolyze triacylglycerols so fatty acids can be taken up and stored
Glycogen synthase
Homodimer
+: G6P
Phosphorylation deactivates
Dephosphorylation activates
UDP-glucose + glycogen (n residues) → UDP + glycogen (n+1 residues)
Glycogen Phosphorylase: Phosphorolysis
Heterodimer
+: AMP
-: ATP
Phosphorylation activates
Dephosphorylation deactivates
Glycogen (n residues) + Pi → glycogen (n-1 residues) + G1P
(G1P ←PHOSPHOGLUCOMUTASE→ G6P, 1st glycolysis intermediate)
Primary mechanism for regulating glycogen synthase/phosphorylase is through ______________________ (phosphorylation/dephosphorylation) under HORMONE CONTROL. Both enzymes undergo reversible phosphorylation at specific _______
Covalent modification
Serine residues
Insulin activates phosphatases
Dephosphorylation
Activate- glycogen synthase
deactivate- glycogen phosphorylation
`What does liver use to opposed insulin and trigger fuel metabolism?
Norepinephrine/Epinephrine and Glucagon
Glucagon/Epinephrine/Norepinephrine bind to receptors with
7 membrane-spanning segments.
Hormone binds → conformation changes that activates G protein → adenylate cyclase → cAMP → PKA
Glucagon functions
Stimulates liver to generate glucose by glycogenolysis and gluconeogenesis
Stimulates lipolysis in adipose tissue
Muscle cells don’t have glucagon
They do, however, response to catecholamines, which have same overall effects as glucagon.
Epinephrine/Norepinephrine stimulation of muscle cells: activates glycogenolysis, which makes more glucose available to power muscle contraction
PKA phosphorylates hormone-sensitive lipase
Catalyzes rate limited step of lipolysis (triacylglycerols → diacylglycerols → monoacylglycerols → fatty acids)
Hormone stimulation not only increases the lipase catalytic activity, also relocates the lipase from cytosol to the fat droplet of the adipocyte.
Co-localization with substrate (possibly by interactions w/lipid-binding protein) boosts fatty acid mobilization rate.
Adiopectin
Adipose Tissue
Activates AMPK (promotes fuel catabolism)
Resistin
Adipose Tissue
Blocks insulin activity
Leptin
Adipose Tissue
Signals fullness
Amylin
Pancrease
Signals fullness
Neuropeptide Y
Hypothalamus
+Stimulates Appetite
Ghrelin
Stomach
+: Stimulates Appetite
Cholecystokinin/PYY
Intestine
-: Suppresses appetite
Incretin
Intestine
Promotes insulin release, inhibits glucagon release
What do AMP-dependent protein kinases do?
Act as fuel sensor
AMP-dependent protein kinase
REgulated by thronine phosphorylation
If fuel levels insufficient, ATP binds to regulatory component, blocks phosphorylation. Blocks activity
ADP-prevents dephosphorylation
ATP inhibits it. If no ATP, switches on ATP producing pathways
AMP PK effects
hypothalamus- increase food intake
Liver: glycolysis and fatty acid oxidation
No glycogen/gluconeogenesis
Muscle: Fatty acid oxidation/mitochondrial biogenesis
Adipose Tissue:
Increase lipolysis
Decrease fatty acid synthesis
Why does insulin secretion cease with the drop in circulating glucose?
Glucose will be available for brain
How do liver and kidneys respond to continued demand for glucose?
increasing the rate of gluconeogenesis, using noncarbohydrate precursors such as amino acids (derived from protein degradation) and glycerol (from fatty acid breakdown)
Fasting burns more…
Fatty acids
body weight that remains constant and independent of energy intake/expenditure even over many decades.
Set point
Regulated by leptin
named for its high mitochondrial content, is specialized for generating heat to maintain body temperature.
Brown adipose tissue
Norepinephrine- binds to receptors on brown adipocytes, signal transduction to PKA activates lipase that frees f.a. From triacylglycerols.
UCP in brown adipose tissue allows fuel oxidation w/out ATP
More brown=less obese
Type 1 (juvenile or insulin-dependent):
Type 2 (adult or non-insulin-dependent):
Immune system destroys pancreatic beta cells
Insulin resistance- failure of body to respond to normal or even elevated concentrations of the hormone
high levels of glucose in blood. Loss of responsiveness of tissues to insulin = cells fail to take up glucose
Hyperglycemia
Insulin insensitivity
Glucose + NADPH + H⁺ —ALDOSE REDUCTASE→ Sorbitol + NADP⁺
Sorbitol accumulation and disruption of osmotic balance; renal stress; protein precipitation leads to cataracts
Diabetic Ketoacidosis:
Uncontrolled diabetics also metabolics fatty acids instead of carbs, resulting in over production of ketone bodies.
Metabolic syndrome
set of symptoms, including obesity and insulin resistance, that appear to be related.
High proportion of visceral fat
(decreased leptin and adiponectin, increased resistin)
TNFa promotes inflammation, insulin insensitivity
B cell exhaustion from overstimulation
impaired GLUT4 translocation
increase in liver gluconeogenesis
Warburg effect
aerobic glycolysis
Cancer cells have oxidative phosphorylation, but consume glucose and waste is lactate. Why? Make precuors for cell growth
How does glutamine support cancer growth?
Provides the nitrogen
Converts to other stuff
CAC flux increases
What is a control point for cancer metabolism?
Glutamate dehydrogenase
Activated by ADP/Leucine
Inhibited by GTP/Palmitoyl-CoA
Extreme loss of weight/muscle in cancer patients, only cure is food. White fat to brown
Cachexia
