Glucose Metabolism Flashcards
what are the special features of each of the following glucose transporters?
a. GLUT1
b. GLUT2
c. GLUT3
d. GLUT4
e. GLUT5
a. GLUT1: basal glucose uptake in RBC and brain
b. GLUT2: liver, pancreas (beta cells), kidney, intestines
c. GLUT3: major glucose transporter in neurons
d. GLUT4: responsive to insulin, adipose, muscle (expression increases with endurance training)
e. GLUT5: small intestine, primarily fructose
how does Maturity Onset Diabetes of the Young (MODY-2) develop?
MODY2, aka GCK-MODY: reduced GluCoKinase activity via LOF mutation
heterozygotes - detected in adulthood (~20s)
homozygotes - neonatal diabetes
what causes Hyperinsulinemic Hypoglycemia?
GOF mutation in glucokinase such that it has a higher affinity for glucose —> seizures/coma due to low plasma glucose
what condition is caused by pyruvate kinase deficiency?
RBC have insufficient ATP to maintain membrane pumps —> compromised membrane integrity —> chronic hemolytic anemia
echinocytes/ burr cells (spiky RBC) seen on peripheral smear
pyruvate dehydrogenase complex catalyzes ________ of pyruvate, producing ____, ___ and ____
pyruvate dehydrogenase complex (E1+E2+E3) catalyzes OXIDATIVE DECARBOXYLATION of pyruvate,
producing ACETYL COA, NADH, and CO2
what are the 5 cofactors required for pyruvate dehydrogenase complex? (mnemonic!)
Tender Loving Care For Nancy:
1. Thiamine pyrophosphate (B1/thiamine)
2. Lipoic acid
3. Coenzyme A (B5/ pantothenic acid)
4. FAD (B2/ riboflavin)
5. NAD+ (B3/ niacin)
*note these same cofactors are required for alpha-ketoglutarate dehydrogenase complex (basically same enzyme as PDH complex)
what symptoms do patients with PDH Complex Deficiency (PDCD) experience, and how is it treated?
pyruvate accumulates —> lactic acidosis —> hyperventilation, hypotonia
brain depends on glucose for fuel —> neurodegeneration, seizures
treatment: keto diet (high fat, low carb), dichloroacetate (inhibits PDH kinase, disinhibiting PDH), thiamine supplement (cofactor for PDH)
one turn through TCA cycle produces:
3 NADH
2 CO2*
1 FADH2
1 GTP
*note net carbon yield = 0 because 2 carbons are input as acetyl CoA —> to produce glucose, other anaplerotic reactions must occur
what are the 3 irreversible reactions (enzymes) of the TCA cycle? which is the committed step?
- citrate synthase (acetyl CoA —> citrate)
- isocitrate dehydrogenase (isocitrate —> alpha-ketoglutarate): committed step
- alpha-ketoglutarate dehydrogenase (alpha-ketoglutarate —> succinyl CoA)
what are the common clinical manifestations of mitochondrial diseases (MELAS, Kearns-Sayre, LHON, Leigh Syndrome, MERRF, etc)?
tissues with high energy ed and (brain/nerves, skeletal/cardiac muscle) are effected most
—> seizures, muscle weakness, cardiomyopathy
[recall mitochondrial gene mutations exhibit heteroplasmy]
how can the L:P ratio be used to distinguish between pyruvate dehydrogenase deficiency and inherited disorders of the ETC?
L:P ratio = blood lactate to pyruvate ratio
normal/decreased L:P (higher pyruvate) suggest defect in PDH
elevated L:P (higher lactate) suggested disorders of the ETC
*recall pyruvate can be converted to either lactate or acetyl CoA (—> TCA —> ETC)
what is the effect of atractyloside on the ETC?
atractyloside: plant in mediterranean/northern Africa, can be confused with wild artichoke
inhibits ATP synthase (complex V) via targeting adenine nucleotide translocase
what is the effect of rotenone on the ETC?
rotenone: insecticide
inhibits NADH dehydrogenase (complex I) of ETC
what is the effect of antimycin on the ETC?
antimycin: pesticide
inhibits complex III of ETC —> electron carriers before this step are reduced, those after are oxidized, NO ATP is produced
what is the effect of cyanide (CN) on the ETC? how can CN poisoning be treated?
cyanide: inhibits cytochrome c oxidase (complex IV) via binding to ferric iron (Fe3+) state of cyt a3
—> NO ATP is produced
rx: nitrite (produces large pool of ferric iron via methemoglobin to pull CN away) + thiosulfate (causes CN to be excreted)
note CN has odor of “bitter almonds”
