BIOCHEM 2EE3 Lecture Notes - Lecture 12: Adenylyl Cyclase, Diabetes Mellitus Type 1, Cori Cycle
28 Apr 2018
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•"Lactate"transported"via"bloodstream"to"liver,"where"it’s"reconverted"through"
gluconeogenesis
for"glucose"for"return"to"muscle"&"other"tissues"by
the"Cori"cycle
o"Major"fate"of"lactate:"uptake"by"heart"for
use"as"fuel,"via"oxidation"as"CO2
o"Liver"glucose"uptake"mediated"by"hexokinase"IV"(AKA"glucokinase,"which"converts
glucose"to"G6P)"and"GLUT2/"GLUT4"(glucose"transporter)
•"B"cells"(which"synthesize"insulin)"respond"to"increased"blood"glucose"by"taking"it"up"
&
catabolizing"it
o"Increased"ATP"à"closure"of"ATP-gated"K+"channels"à"decreased"K+à"opening"of"Ca2+
channels"à"increased"Ca2+à"membrane"depolarization"à"exocytosis"of"insulin
granules
•"Activation"of"acetyl-CoA"carboxylase"in"liver"also"stimulates"fatty"acid"synthesis
o"Fat"acids"then"transported"to"adipose"tissue"as"triacylglycerols"via"VLDL"(very"
lowdensity
lipoproteins)
o"Glucose"released"into"bloodstream
•"Glucagon"increases"cAMP"in"liver"cells,"leading"to
phosphorylation"of"key"enzymes"that"increase
blood"glucose"levels.
•"Epinephrine"released"from"adrenal"medulla"in
response"to"low"blood"glucose"levels
o"Activates"adenylate"cyclase,"starting
glycogenolysis"&"increasing"blood"glucose
•"Short-lived"metabolic"effects"unlike"glucagon
Diabetes"Mellitus
•"Type"I"diabetes:"insulin-dependent"diabetes
o"Results"from"immune"destruction"of"B-cells
•"
Type"II"diabetes:"dysfunction"in"insulin"signalling
o"Multifactorial
o"Closely"linked"to"metabolic"syndrome"(defined"by"abdominal"obesity,"hypertension,
high"blood"sugar,"and"insulin"resistance)
o"Lipid"overdose"hypothesis:"when"fat"accumulates"in"muscle"cells,"blocks"
insulinsignalling
that"normally"stimulates"GLUT4"(major"glucose"transporter"in"muscle)
o"Inflammation"hypothesis:"adipose"cells" increase"in"size"with"excess"lipids,"secrete
inflammatory"cytokines"that"interfere"with"insulin"signalling
•"As"muscle"occupies"half"our"body"mass,"it’s"a"significant"consumer"of"glucose
o"Regular"exercise"can"help"maintain"healthy"glucose"levels&"prevent"development"of
Type"II"diabetes
•"Essentially"starvation"in"midst"of"plenty:"blood"glucose"levels"don’t"fall,"so"glucose"
isn’t"being
used
o"Leads"to"starvation,"despite"eating"lots.
o"Starvation"àketosis,"ketoacidosis"(from"the"organic"acids),"and"acetone"can"be"
smelled
o"Results"in"sweet"urine"(mellitus)
Starvation"(see"figure"from"textbook)
•"After"half"a"day,"liver"glycogen"stores"are"likely"depleted.
o"Adipose"tissue"fat"stores"can"be"taken"into"bloodstream,"and"converted"to"ketone
bodies"by"liver
o"During"starvation,"brain"&"heart"will"adapt"to"using"ketone"bodies
•"Ketone"bodies
o"Usually"picked"up"by"the"liver"and"made"into"acetyl-CoA
o"Increased"use"of"carbon"for"gluconeogenesisdiminishes"amount"of"oxaloacetate
available"to"combine"with"acetyl-CoA"in"citric"acid"cycle
o"As"fat"breakdown"is"activated,"acetyl-CoA"&"reduced"electron"carriers"accumulate"in
liver
o"Acetyl-CoA"cannot"all"be"oxidized,"soketone"bodies"accumulate"in"the"blood
•"Ketone"bodies"examples:"acetoacetate"and"B-hydroxybutyrate.
•"Final"avenue"of"fuel:"protein
o"Significant"protein"“reserves”"in"the"muscle
o"Protein"broken"down"to"amino"acids
§"Glucogenic"amino"acids"converted"to"glucose
§"Ketogenic"amino"acids"converted"to"ketone"bodies
o"Bodies"will"presence"muscle"mass"until"there"are"no"other"options
§"No"muscle"mass"à"can’t"move"around"to"gather"food
§"Mechanism"of"self-preservation"and"survival
•"Organs"adapt"to"become"increasingly"better"than"using"ketone"bodies"–so"much"so"
that"loss"of
muscle"decreases"late"in"starvation,"allowing"life"to"increase"for"many"weeks"without"
food"intake
o"Total"period"determined"by"size"of"fat"deposits
M12:%Readings%
Friday,"March"30,"2018
9:16"PM
