metabolism midterm

glycolysis

conversion of glucose into 2 pyruvate/lactate

what tissues does glycolysis occur?

everywhere

is glycolysis active in the fed or fasted state?

fed

glycogenesis

glycogen synthesis

is glycogenesis active in the fed or fasted state?

fed --> storing glucose as glycogen

where does glycogenesis occur?

liver and muscle

gluconeogenesis

generation of glucose from non-carbohydrate carbon substrates

Where does gluconeogenesis occur?

liver (majority) & kidneys

is gluconeogenesis activity in the fed or fasted state?

fasted

glycogenolysis

breakdown of glycogen

where does glycogenolysis occur?

liver and muscle

muscle cannot breakdown ________ to _____________

glycogen to glucose

why can't muscle breakdown glycogen to glucose?

no glucose-6-phosphatase --> goes down glycolysis pathway to be oxidized

is glycogenolysis active in the fed or fasted state?

fasted

what are the steps to glucose-stimulated insulin release?

1. glucose transported into the B-cell via GLUT2

2. ATP production from glycolysis

3. K+ channels close --> depolarization of the cell

4. Intracellular concentrations of Ca 2+ increase

5. Insulin secretory vesicles are translocated to the cell membrane

where is glucokinase

liver and pancreatic B-cells

does glucokinase have a low or high affinity for glucose?

low affinity --> more active only after a meal when glucose concentration is high

is glucokinase inhibited by glucose-6-phosphate?

no --> allows for liver to continue taking up glucose from blood

where is hexokinase found

most tissues

does hexokinase have a low or high affinity for glucose?

high affinity --> works efficiently even when glucose concentration is low

is hexokinase inhibited by glucose-6-phosphate?

yes --> prevents continuous glycolysis and conserves energy

rate limiting reactions of glycolysis

glucose --> glucose-6-phosphate (hexokinase/glucokinase) fructose-6-phosphate --> fructose-1,6-phosphate (phosphofructokinase) phosphoenolpyruvate --> pyruvate (pyruvate kinase)

main difference between red blood cells and other tissues for glucose metabolism?

red blood cells lack mitochondria

how many ATPs are produced from one molecule glucose via glycolysis in brain cells and red blood cells?

brain: 6-8 ATP rbc: 2 ATP

where is GLUT2 distributed

pancreas and liver

how does GLUT2 respond to blood glucose and insulin

facilitates the influx of glucose into the beta-cell which triggers insulin release

where is GLUT4 distributed

muscle and adipose tissue

how does GLUT4 respond to blood glucose and insulin

respond to high levels of blood glucose and reduce circulating glucose levels

how does insulin stimulate glucose uptake? in which tissues?

in the 2nd tier response, insulin promotes the uptake of glucose into muscle and adipose tissue via GLUT4

How does insulin regulate GLUT4?

Insulin regulates GLUT4 translocation from the intracellular compartment to the cell surface

How does the pancreas maintain blood glucose levels after a meal?

Islet cells secrete insulin

How does the liver maintain blood glucose levels after a meal?

Makes glycogen from dietary glucose and converts glucose to fatty acids if the amount of absorbed glucose is more than what the body can use and store

How does muscle maintain blood glucose levels after a meal?

Takes up glucose from the circulation in an insulin-dependent manner (via GLUT4), oxidizes it for energy, and makes glycogen from it.

How does adipose tissue maintain blood glucose levels after a meal?

Takes up glucose from circulation in an insulin-dependent manner (via GLUT4)

How does the brain maintain blood glucose levels after a meal?

Primarily uses glucose for energy and takes up glucose from the circulation (22%)

How do other tissues maintain blood glucose levels after a meal?

Take up glucose from the circulation (2-3%)

How does the liver maintain blood glucose levels during starvation?

• Breaks down glycogen and releases glucose to the circulation.

How do the kidneys maintain blood glucose levels during starvation?

Make glucose and release it to the circulation

How does the pancreas maintain blood glucose levels during starvation?

Islet cells stop making and secreting insulin and secrete glucagon

How do muscle and adipose tissue maintain blood glucose levels during starvation?

Slow down taking up glucose from the circulation and GLUT4 actvitiy decreases

First-tier response

high glucose levels stimulate insulin secretion from beta cells in pancreas

What triggers first-tier response?

elevated blood glucose levels

second-tier response

high insulin levels stimulate GLUT4 translocation and activity

what triggers second-tier response?

insulin and it promotes the uptake of glucose into tissues

What happens to glucose homeostasis if GLUT2 and GLUT4 is defective?

• GLUT2: some uptake of glucose into the circulation but no insulin is being produced

  • GLUT4: Insulin and blood glucose are increased leading to insulin resistance

where does glycolysis occur in the cell?

cytoplasm

what is the final product of glycolysis under aerobic and anaerobic conditions?

Aerobic → 2 pyruvate

Anaerobic → 2 lactate

What happens to pyruvate after glycolysis in the liver in the fed and fasted state?

• Fed: pyruvate is decarboxylated to acetyl-CoA and enters the TCA cycle and fatty acid synthesis occurs

• Fasted: pyruvate is used to synthesis glucose via gluconeogenesis and no fatty acid synthesis occurs

at happens to pyruvate after glycolysis in the liver in the fed and fasted state?

pyruvate is reduced to lactate

How is fructose metabolized via glycolytic pathway?

Fructose → Fructose-1-phosphate → Glyceraldehyde + DHAP → Glyceraldehyde-3-phosphate

Why can a high intake of fructose cause an increase in lipogenesis (synthesis of TAGS)?

Increases glycogens and bypasses the rate-limiting reactions that build up acetyl-CoA

Which reaction does pyruvate dehydrogenase (PDH) complex catalyze?

pyruvate → acetyl-CoA

How is PDH activity regulated and what is its significance?

By levels of acetyl-CoA and NADH. If acetyl-Coa and NADH levels are too high, PDH activity will be inhibited and no longer be able to convert pyruvate to acetyl-CoA

What happens to acetyl-CoA from PDH reaction?

Transported to the TCA cycle

TCA cycle function

• oxidation of acetyl-CoA to CO2

• Supplies reducing equivalents for ATP production

How many ATPs are produced directly and indirectly from the TCA cycle?

• Directly: 24

• Indirectly: 6

final products of digestion

glucose, fructose, and galactose

main goals for glucose metabolism

1. to maintain circulating glucose levels

2. to provide sufficient energy substrates to tissues that only or heavily use glucose for ATP production

where does aerobic metabolism occur in the cell?

mitochondria

end products of aerobic metabolism

CO2 + H2O

Where does anaerobic metabolism occur in the cell?

cytosol

what are the end products of anaerobic metabolism?

lactate

glucose uptake facilitated by

glucose transporters

Insulin-independent glucose transporters

GLUT1, GLUT2, GLUT3, GLUT5

Insulin-dependent glucose transporters

GLUT4

during fasting, liver can produce and release

glucose to the circulation when glucose levels are down

does skeletal muscle release glucose into blood?

provides gluconeogenic precursors for synthesis of glucose in the liver during faster

in glycolysis, how many ATPs are produced in aerobic conditions?

6-8 ATP

In glycolysis, how many ATPs are produced in the anaerobic condition?

2 ATP

Fructose doesn’t stimulate ____ secretion and is mainly metabolized by the _______

insulin, liver

why does high fructose consumption increase obesity?

high fructose consumption → lipogenesis in liver → fatty liver + obesity

acetyl-CoA pathways

ATP production from one complete oxidation of one molecule of glucose

36-38 ATP

What physiological conditions and in what tissues does GNG occur?

Fasted state in the liver and kidney

Where does GNG occur in the cell?

Mitochondria and cytosol

What are the precursors for GNG?

pyruvate, lactate, glycerol, propionate

How does pyruvate synthesize glucose in GNG?

Pyruvate → oxaloacetate → PEP → Fructose-1,6-Biphosphate → F6P → G6P → Glucose

How does lactate synthesize glucose in GNG?

Lactate → Pyruvate → Oxaloacetate → PEP → Fructose-1,6-Biphosphate → F6P → G6P → Glucose

How does glycerol synthesize glucose in GNG?

Glycerol → Glycerol-3-Phosphate → DHAP + GADP → F6P → G6P → Glucose

How does propionate synthesize glucose in GNG?

Propionate → Oxaloacetate → PEP → Fructose-1,6-Biphosphate → F6P → G6P → Glucose

Which steps in GNG are regulated? Which enzymes catalyze these steps?

• Pyruvate → Oxaloacetate (pyruvate carboxylase)

• Oxaloacetate → PEP (PEPCK)

• Fructose-1,6-biphosphate → F6P (Fructose-1,6-biphosphatase)

• G6P → Glucose (Glucose-6-phosphatase)

Which tissues are capable of releasing glucose to the circulation during fasting? What enzyme allows tissues to do this?

Liver and skeletal muscle via G6Pase

What is the role of the liver in GNG?

glucose goes to partial oxidation in liver and muscle for sparing carbon backbone (pyruvate & lactate) for GNG in liver

What is the role of the kidneys in GNG?

• GNG occurs during prolonged starvation → the longer starvation, the more active kidney is

• Precursors: mostly glucogenic AAs

In what physiological conditions does insulin increase or decrease?

Fed → increase

Fasted → decrease

In what physiological conditions does glucagon increase or decrease?

Fed → decrease

Fasted → increase

In what physiological conditions does epinephrine increase or decrease?

Fed → decrease

Fasted → increase

Which substrates are involved in regulation of glucose metabolism?

• Fructose-6-Phosphate

• Fructose -1- Phosphate

• Citrate

• ATP / AMP

How do substrates and hormones regulate glucose → G6P?

• + : insulin, Fru 1-P, Glucose

• - : Fru 6-P

What substrates and hormones regulate F6P → F 1,6-BP2

• + : AMP, insulin ↑enzyme ↑ F 2,6-B2

• - : ATP, citrate

What substrates and hormones regulate PEP → pyruvate?

• + : insulin (protein dephosphorylation), ↑enzyme,

• - : alanine, ATP, glucagon (protein phosphorylation)

What substrates and hormones regulate pyruvate → oxaloacetate?

• + : acetyl-CoA

what substrates and hormones regulate oxaloacetate → PEP

• - : insulin ↓ enzyme

what substrates and hormones regulate F 1,6-BP2 → F6P

• - : AMP, insulin ↑ F 2,6-B2

What substrates and hormones regulate G6P → glucose?

• + : glucagon

• - : insulin

Which substrates and hormones are involved in the regulation of glucokinase activity?

• Substrates: Fructose, Fru 1-P, Fru 6-P, Glucose

• Hormones: Insulin

How do the substrates Fru 1-P and glucose regulate glucokinase?

Promote dissociation of GK from GKRP and GK is moved out of the nucleus to the cytosol

How does Fru 6-P regulate glucokinase?

Inhibits the dissociation of GK and GKRP causing GK to go back into the nucleus and rebind with GKRP

How does insulin regulate glucokinase activity?

Promotes GK to phosphorylate glucose

Describe the overall regulation of glucokinase

• GK is bound to GKRP in nucleus

• Once glucose or Fru 1-P are present, GK will dissociate from GKRP

• GK will move to cytol → insulin promotes GK to phosphorylate glucose

• Fru 6-P causes GK to go back into the nucleus and rebinds with GKRP inhibiting GK activity