Carbohydrate Metabolism (3 lectures) (Note: + means induces, - means represses) Flashcards
Standard values for 75 gram oral glucose:
1) Fasting
2) 1 Hour
3) 2 hour
1) 60-100 mg/dL
2) less than 200 mg/dL
3) less than 140 mg/dL
Glycemic index
Indicator of how rapidly glucose levels rise (after eating food)
1) GI of fruit, veggies, milk
2) GI of corn flakes, baked potatoes
1) less than 50
2) greater than 70
Hormones regulating metabolism
Insulin, Glucagon, Epinephrine, and Cortisol
How does insulin regulate metabolism?
Promotes fuel storage after meal, promotes growth
It binds to receptors on muscle, adipose tissue, and stimulates GLUT4 receptors
Where is insulin produced?
It is produced as a pre-pro-hormone in the beta cell of the islets of Langerhans (pancreas) and is stored in vesicles for release. It responds directly to increased intracellular glucose through the GLUT2 receptor
What is the mechanism of the response (of insulin from the GLUT2 receptor)?
Increasing [ATP] in the cell inhibits an ATP dependent potassium channel that depolarizes the cell and allows extracellular calcium to enter
The insulin receptor, ____, is membrane bound and is a ____.
GLUT4,
tyrosine kinase receptor
How does glucagon regulate metabolism?
It mobilizes fuel, maintains blood glucose during fasting
It acts through a glucagon receptor that activates a G-protein, an ATP cyclase, and a cAMP dependent kinase
Where is glucagon produced?
The peptide hormone is produced in a pre-pro form in the alpha cells of the pancreas. It’s release is directly suppressed by glucose and insulin
How does epinephrine regulate metabolism?
It mobilizes fuel during acute stress.
It activates glycogen phosphorylase to release glucose but does not stimulate gluconeogenesis.
In muscle it activates a G protein and an adenylate cyclase to activate protein kinase A (similar to glucagon). In liver it binds alpha-agonist receptor signals through IP3 and calcium to activate multiple kinases
How does cortisol regulate metabolism?
It alters long term metabolism. It binds an intracellular receptor and moves to the nucleus where it controls the gene trascription. It stimulates gluconeogenesis and fatty acid release from adipose tissue (influences long-term fuel mobilization).
Epinephrine is also known as ___.
adrenaline
Cortisol is also known as ___.
Glucocorticoid
The major anabolic hormone in the body
insulin
Insulin stimulates
Protein synthesis, glycogen synthesis, and triglyceride synthesis
Preproinsulin has an ____ that is cleaved when perproinsulin becomes proinsulin.
N-terminal signal peptide
Proinsulin is cleaved in ___ location(s) to form mature insulin (A and B chains). The internal peptide cleaved from insulin is called the ____ and can be measured to distinguish endogenous insulin from injected insulin.
two,
C-peptide
What releases vesicles of insulin?
calcium
____ closes potassium channels and stimulates ___ influx, which is useful with patients that have functional beta cells (type _ diabetes)
Sulfonylureas (glipizide, glyburide),
calcium,
II (two)
Insulin peaks about __ minutes after high carbohydrate meals
45
What does salivary amylase do?
It digests starch to maltose (disaccharide of glucose), trisaccharides, and dextrins (4-9 glucosyl units)
What does stomach acid to?
It inactivates amylase (I’m not positive why but that’s what the slide says)
What occurs in the duodenum?
Neutralization of acid, alpha-amylase from pancreas forms more maltose, ditrisaccharides, dextrins
What enzymes are present in the small intestine brush border complexes?
glucoamylase (cleaves alpha 1-4 glycosidic bonds), sucrase-isomaltase, trehalase (cleaves threhalose found in mushrooms) and lactase (cleaves lactose into glucose, galactose)
What does glucoamylase do?
Cleaves alpha 1-4 glycosidic bonds
What does lactase do?
Cleaves lactose into glucose and galactose
Where are GLUT1 receptors?
RBCs, brain endothelial cells (High affinity for glucose)
Where are GLUT2 receptors?
pancreas, liver (low affinity for glucose)
Where are GLUT3 receptors?
neurons
Where are GLUT4 receptors?
fat, muscle, heart (insulin induced)
Where are GLUT5 receptors?
testis (actually a fructose transporter)
How is glucose absorbed into cells?
Through a GLUT family of transporters
What happens in lactose intolerance?
lactase on the intestinal brush border begins to decrease (which is natural) and lactose is not absorbed and is instead metabolized by colonic bacteria. This causes gas and diarrhea (methane is made, the osmotic effect creates diarrhea)
Some sugars that are undigested
raffinose, soluble fiber (pectin, gums)
What are the fates of glucose-6-phosphate?
lactate, ribose and NADPH, glucose (serum glucose levels), or Co2 and water (TCA cycle). Also glycogen.
a) Function of glycogen
1) in muscle
2) in liver
a) Glucose reserve
1) provides glucose for glycolysis during anaerobic exercise
2) Glycogen is degraded and the glucose released into the blood stream to support serum levels during fasting
What is glycogen?
Branched chain of glucose molecules connected by alpha-1,4 linkages and alpha-1,6 branches
What protein is associated with glycogen synthesis?
Glycogen synthesis initiates on the protein glycogenin (autoglycosylation with UDP-glucose on Tyr)
UDP-glucose is added to the ____ end of the glycogen molecule by ___.
non-reducing,
glycogen synthase
Chains over ___ residues are ____ and attached via ____ to create a branch site. (Glycogen)
11,
hydrolyzed,
alpha-1,6
What vitamin is required to convert glycogen to glucose?
Vitamin B6 (pyridoxine)
Phosphorylase stalls within __ glucose units of a branch. (releasing glycogen)
four
Glycogen degradation II debranching enzyme has both ___ and ___ activity and transfers ___ glucose units.
transferase,
hydrolase,
3
What is McArdle’s disease?
It is a lack of muscle glycogen phosphorylase. It causes rhabdomyolysis and myoglobinuria.
What regulates glycogen phosphorylase?
Phosphorylase-kinase activates/phosphorylates it (glycogen phosphorylase-b). cAMP increases activity and phosphoprotein phosphatase (which is activated by insulin) inactivates or dephosphorylates glycogen phosphorylase-a.
Phosphorylase-kinase ____ phophorylase-b.
Phosphorylates/activates
Phosphorylated glycogen phosphorylase is ____.
The activated form of glycogen phosphorylase
Protein kinase A _____ phosphorylase-kinase, which ____ phosphorylase-kinase.
phosphorylates,
activates
Phosphoprotein phosphatase ____ glycogen phosphorylase
inactivates (removes a phosphate group from glycogen phosphorylase-a)
cAMP ___ phosphoprotein phosphate
inhibits
What inactivates glycogen synthase?
glycogen synthase kinase, protein kinase C (diacylglycerol, Ca++), calmodulin-dependent kinase (Ca++), phosphorylase kinase (Ca++, cAMP), and protein kinase A (Ca++, cAMP) all inactivate glycogen synthase-a
True or False: Glucagon has no effect on muscle.
True
How does glucagon affect the liver?
It causes phosphorylation of glycogen synthase (inactive form) and glycogen phosphorylase (active form)
In muscle, AMP is an ____ of glycogen phosphorylase.
allosteric activator
True or false: AMP has little effect on liver glycogen phosphorylase
True
Glycogen storage disease 1
1) Enzyme affected
2) Name
3) Primary organ involved
4) Symptoms
1) Glucose-6-phosphatase
2) Von-Gierke’s
3) Liver
4) Within a few months of birth: severe hypoglycemia, epinephrine secretion > stimulates fatty acid release > increase VLDL made in liver
Glycogen storage disease 2
1) Enzyme affected
2) Name
3) Primary organ involved
1) Lysosomal alpha-glucosidase
2) Pompe’s disease
3) All organs
Glycogen storage disease 3
1) Enzyme affected
2) Primary organ involved
1) Amylo 1,6-glucosidase (debrancher)
2) liver, skeletal muscle, heart
Glycogen storage disease 4
1) Enzyme affected
2) Primary organ involved
1) Amylo 4,6-glucosidase (debrancher)
2) liver
Glycogen storage disease 5
1) Enzyme affected
2) Name
3) Primary organ involved
4) Symptoms
1) Muscle glycogen phosphorylase
2) McArdle’s disease
3) Skeletal muscle
4) exercise induced cramps, muscle pain. Typically diagnosed in 2nd or 3rd decade of life due to exercise intolerance
Glycogen storage disease 6
1) Enzyme affected
2) Name
3) Primary organ involved
1) Liver glycogen phosphorylase
2) Herr’s disease
3) Liver
Glycogen storage disease 7
1) Enzyme affected
2) Primary organ involved
1) Phosphofructokinase
2) Liver, muscle, RBC
Glycogen storage disease 8
1) Enzyme affected
2) Primary organ involved
1) Phosphorylase kinase
2) Liver
Glycogen storage disease 9
1) Enzyme affected
2) Primary organ involved
1) Protein kinase A (cAMP dependent)
2) Liver
Gluconeogenesis
The pathway used to support serum glucose levels during fasting and starvation particularly for those tissues that cannot switch to ketone bodies (RBCs, renal medulla)
What are the primary sources for glucose production?
Lactate, alanine, and glycerol (minor source: propionate)
Where does gluconeogenesis occur?
Liver
What is the starting point for gluconeogenesis from lactate?
Pyruvate
How much ATP is required to convert pyruvate to glucose?
6
Enzymes used to convert pyruvate to phosphoenol pyruvate
pyruvate carboxylase (in mitochondria) and phosphoenolpyruvate carboxykinase (in cytoplasm)
What vitamin is required for pyruvate carboxylase to function?
Biotin (Vitamin B7)
Fatty acid oxidation coordinates with gluconeogenesis in what ways?
ATP provided for gluconeogenesis; FA oxidation increases acetyl-CoA and NADH, which activate pyruvate DH kinase and inhibit pyruvate DH; High acetyl-CoA activates pyruvate carboxylase to form oxaloacetate; oxaloacetate and acetyl-CoA form citrate which inhibits PFK-1 (glycolysis); High ATP/ADP ratio inhibits PFK and pyruvate kinase
What enzymes does cAMP activate?
G6P-phosphatase, F-1,6-bisphosphatase, and PEP carboxykinase
What enzymes does cAMP inactivate or inhibit?
PFK-1, glucokinase, and pyruvate kinase
What are the regulators for glucose-6-phosphatase?
+cAMP, -insulin
What are the regulators for glucokinase?
+insulin, -cAMP, -Glucose-6-phosphate
What are the regulators for phosphofructokinase-1?
+AMP, +fructose-2,6-phosphate,
-ATP, -cAMP, -citrate
What are the regulators for fructose-1,6-bisphosphatase?
+cAMP, -AMP, -Fructose-2,6-phosphate, (Also +citrate)
What are the regulators for phophoenolpyruvate carboxykinase?
+cAMP (that’s all that’s on the slide)
What are the regulators for pyruvate kinase?
+Fructose-1,6-bisphosphate,
-alanine, -ATP, -citrate, -cAMP
What are the regulators for pyruvate carboxylase?
+acetyl-CoA, -ADP, -insulin
What are the regulators for pyruvate dehydrogenase?
-acetyl-CoA, -NADH
What enzymes are active under fasting conditions?
Glucose-6-phosphatase, Fructose-1,6-bisphosphate phosphatase, Pyruvate carboxylase, Phosphoenolpyruvate carboxykinase (it’s synthesized so I assume it’s activated and it’s going in the right direction?), “phosphorylase” (WHICH FUCKING ONE? IF WE’RE EXPECTED TO BE SPECIFIC WHY ARE YOU NOT?)
Which enzymes are inhibited during fasting?
Glucokinase (sequestered in nucleus), PFK2 (phosphofructokinase-2), PFK-1 (phosphofructokinase-1), pyruvate kinase, PDH (pyruvate dehydrogenase)
There’s a slide marked key regulatory points and I’m just like, no. This was just on the last slide. Put it on the last slide.
Freebie cuz yeah you deserve it. Keep it up mothafuckahs
Substrates required for gluconeogenesis
glycerol (from adipose tissue), lactate from muscle (exercise), red blood cells, amino acids when diet is high in amino acids and low in carbs
So you just answered which enzymes are activated under fasting conditions, so if you can repeat that you’re good. but if not, there’s three you need to know. You also need to know when they’re activated and inhibited. Go. (Slide 25)
“High glucagon inhibits PYRUVATE KINASE due to phosphorylation by protein kinase A (prevents conversion of PEP to pyruvate)
PHOSPHOENOLPYRUVATE CARBOXYKINASE synthesis increases as a result of phosphorylation of transcription factors (CREB - cAMP Response Element - Binding) Also include cortisol by different binding protein.
PYRUVATE DEHYDROGENASE is inhibited by acetyl CoA and NADH. Both are high during beta-oxidation”
Yay. This card is over! But seriously try to know this at least.
Four enzymes are regulated by glucagon and epinephrine. Name those bitches.
pyruvate carboxylase, PEP carboxykinase, Glucose-6-phosphatase, Fructose-1,6-bisphosphatase
Cori cycle in a nutshell
release of lactate from muscles, conversion by liver into glucose and release into bloodstream
Alanine cycle in a nutshell
release of alanine by muscle, conversion by liver into glucose and release into bloodstream
That stupid video we watched, it talked about fructose. What was the gist of what the guy was saying?
Don’t eat fructose because it’s toxic because only the liver can break it down and this guy thinks it’s the primary reason for obesity and insulin resistance
(and Forney gave it the okay and put it in the lecture. I think I’m being judgmental of this guy because he kinda sounded fishy but he’s done more research on this than I have so he knows more.)
Glucose-6-phosphate is converted to ___ to become part of the pentose phosphate pathway.
6-Phosphogluconate
Glucose-6-Phosphate is converted to ___ before becoming glycogen.
UDP-glucose
What does the pentose phosphate pathway create (according to slide 28)?
ribose, NADPH
What is NADPH used for?
fatty acid synthesis, glutathione reductase, cholesterol, and steroid hormone synthesis, p450 detoxification in liver
What enzyme converts glucose-6-phosphate to 6-phophogluconate?
glucose-6-phosphate dehydrogenase
What enzyme converts 6-phosphogluconate to ribose-5-phosphate?
6-phosphogluconate dehydrogenase
What other molecule can be converted to ribose? (techincally ribose-5-phosphate)
fructose-6-phosphate
What molecule is required for the conversion of g-6-p to ribose-5-phosphate? (not the enzyme)
NADP+ (2 of them)
What are the key points of the oxidative phase of the pentose phosphate pathway? (Important card)
generates NADPH (2 per G6P) for biosynthesis or reductive reactions (only source of NADPH for RBC) and ribulose-5-phosphate (1 per G6P) for nucleotides key enzyme: glucose-6-Phosphate dehydrogenase
What are the key points of the nonoxidative phase of the pentose phosphate pathway? (also important card)
Generates different sugars (including ribose-5-phosphate) using transaldolase (transfers 3C keto units) and transketolase (transfers 2C keto units)
Transketolase requires what vitamin?
B1 or thiamine (transketolase uses TPP to transfer 2C)
The most common known enzyme deficiency?
Glucose-6-Phosphate dehydrogenase (It confers resistance to malaria and has the same distribution as sickle-cell)
What are symptoms of Glucose-6-phosphate deficiency?
hemolytic anemia
What can exacerbate hemolytic anemia in patients with glucose-6-phosphate deficiency?
sulfa drugs, antimalarials, antipyretics, certain infections, and fava beans
What are heinz bodies?
They are aggregates of hemoglobin that develop when there is a deficiency of NADPH. NADPH normally reduces glutathione reductase and is part of a pathway that reduces oxidative stress. The development of heinz bodies helps mark the RBCs for degredation
What are some sources of fructose?
Honey, fruit, sucrose
What is a source of galactose?
Lactose (milk)
Where are fructose and galactose metabolized?
only in the liver (though the slide says some digestion is performed in the small intestine and kidney)
What is the first step of fructose metabolism?
Fructokinase uses ATP to convert fructose to fructose-1-phosphate and (ADP).
What happens to fructose-1-phosphate?
It enters the glycolysis cycle when aldolase B converts it to dihydroxyacetone phosphate (or glyceraldehyde, which triose kinase coverts to glyceraldehyde-3-phosphate using ATP)
Fructosuria
fructokinase deficiency (benign)
Fructosemia
Aldolase B deficiency, hypoglycemia results
Only _____ can cleave fructose-1-phosphate.
Aldolase B
What is the rate-determining step of fructose metabolism?
Aldolase B converting fructose-1-phosphate to glyceraldehyde or dihydroxyacetone phosphate
Aldolase B is present in ____ .
Liver, kidneys, and intestine
Fructose-1-phosphate inhibits ____ .
Aldolase A, which is is used in muscle cells but also in liver cells. If aldolase B is not working and fructose is ingested, F-1-P will build up and gluconeogenesis will be prevented and the patient will be hypoglycemic.
What is the first step of metabolism of galactose?
galactokinase uses ATP to convert galactose to Galactose-1-Phosphate (and ADP)
What happens to galactose-1-phosphate?
It is converted to glucose-1-phosphate using galactose-1-phosphate Uridylytransferase (which uses UDP-glucose and creates UDP-galactose)
What is galactosemia?
Deficiency of galactose-1-phosphate uridylytransferase. Galactose appears in urine and it’s symptoms are cataracts and mental retardation
