Metabolism of CHO pt. 1

FED STATE CHO METABOLISM OVERVIEW

ingested CHO from diet gets absorbed as

monosaccharides (glucose, fructose, galactose)

the liver can participate in what CHO pathways when in fed state (6)

• glycolysis

• glycogen synthesis

• pentose phosphate pathway to produce NADPH

• make de novo lipids (lipogenesis/VLDL) and secretion

• conversion of lactate, glycerol, glucogenic AA, and monosaccharides to glycolytic intermediates

• complete oxidation of pyruvate to CO2 and H2O

from liver, what will be released in fed state

glucose (along with TAG from VLDL)

glucose from the liver will go to what main tissues?

brain, erythrocytes, muscle, adipose

in brain, glucose is absorbed via what transporter?

GLUT 1 and 3

in brain, what is the fate of glucose during fed state

complete oxidation

in erythrocyte, glucose is absorbed via

GLUT 1

in erythrocyte, what are the fates of glucose during fed state? (2)

• metabolized to lactate

• oxidized by pentose phosphate pathway

in skeletal muscle, glucose enters cell via

GLUT 4

GLUT4 is dependent on

insulin**

in skeletal muscle, what are the fates of glucose during fed state? (4)

• Completely oxidated

• Metabolized to lactate

• Stored as glycogen

• Used to synthesize glycerol-3-p for TAG synthesis and stored in muscle

in adipose tissue, glucose is absorbed via what transporter?

GLUT 4

GLUT 4 is dependent on

insulin

in adipose tissue, what are the fates of glucose during fed state?

• Completely oxidated

• Metabolized to lactate

• Used to synthesize glycerol-3-p for TAG synthesis and stored

the brain, erythrocyte, skeletal muscle, and adipose tissue all release what into the blood to be taken to liver

lactate

adipose tissue also releases what to be taken to liver

glycerol

why does adipose tissue release glycerol into blood

lacks glycerol kinase, so cannot phosphorylate it and keep it within cell

during fed state, organs consume what % of glucose

• skeletal muscle

• liver

• brain

• skeletal muscle (30-35%)

• Liver (25-30%)

• brain (10%)

OVERVIEW OF GLUCOSE METABOLISM DURING FASTED STATE

what 2 main organs work during fasted state to provide glucose?

liver and kidney (gluconeogenesis)

the kidneys undergo what pathways during fasted state (CHO related) (3)

• Undergo gluconeogenesis

• Convert lactate, glycerol, glutamine carbon into glucose and glycolytic/anaplerotic intermediates

• Release glucose via urine

kidneys will receive what from the blood during fasted state

glycerol, lactate, glutamine

liver will release what to the liver

glucose

glucose will receive what nutrients via the blood

Glycerol, lactate, alanine, and AA's via blood

the liver will undergo what CHO pathways during fasted state (3)

• Degrade glycogen

• Undergo gluconeogenesis

• Release glucose via hepatic duct

• Convert lactate, glycerol, glutamine carbon into glucose and glycolytic/anaplerotic intermediates

the liver will release what via the blood to go to other tissues during fasted state

• Glucose

• VLDLs (TAG)

Glucose released into blood will go what tissues? (4)

brain, erythrocytes, skeletal muscle, and adipose tissue

in the brain, glucose will have what possible fate

completely oxidized

in the erythrocytes, glucose will have what fates (2)

• Metabolized to lactate

• oxidized by pentose phosphate pathway

in the skeletal muscle, during fasted state the muscle will undergo what pathways (3)

• Glycogen breakdown (until stores run out)

• Switch to FA oxidation (from TAG it has stored)

• Proteolysis and release of AA's (glutamine and alanine)

during fasted state, muscle will release what into blood to be taken to liver

lactate and AA’s

in the adipose, during fasted state the muscle will undergo what pathway (1)

Will undergo lipolysis (TAG --> NEFA and glycerol )

during fasted state, what will be released form adipose tissue to the blood

free FA’s and glycerol

SOURCES OF GLUCOSE

what is the CENTRAL organ that controls glucose homeostasis (aprox. 6 mmol)

liver

during fed state, what are the sources of glucose? (3 categories)

• dietary CHO

• excess AA

• glycerol from chylomicrons and VLDL

dietary CHO sources that are sources of glucose (3)

• absorbed glucose

• absorbed fructose and galactose (converted to glucose)

during fasting/starvation, what are the sources of glucose? (5)

• Hepatic glycogenolysis

• Hepatic and renal gluconeogenesis

• Glycerol from TAG

• AA from muscle protein breakdown → gluconeogenic substrates

• Lactate → glucose

GLUT TRANSPORTERS

what are GLUT transporters

 5 Isoforms that differ from tissue to tissue and in kinetic properties

aka glucose transporters

what is a isoform?

transporters that have the same function but differ in location and kinetics

what are the GLUT isoforms (5)

GLUT 1-5

GLUT 1 is found in what organ(s)

RBC (and brain)

GLUT 2 is found in what organ

liver and pancreas

GLUT 3 is found in what organ

brain

GLUT 4 is found in what organ

muscle and adipose

GLUT 5 is found in what organ

small intestines (fructose uptake)

GLUT transporters are what type of transport

facilitative diffusion

facilitative diffusion is dependent on

concentration gradient

how is the concentration gradient for GLUT transport maintained? (2 enzymes)

hexokinase and glucose phosphatase

role of hexokinase in GLUT concentration gradient

hexokinase will phosphorylate glucose taken into the cell, which will decrease glucose concentration in the cell (increase G6P), which allows for more glucose uptake

role of glucose phosphatase in GLUT concentration gradient?

G6P is converted into Glucose, which increases amount of glucose concentration in the cell —→ less uptake

how is glucose absorbed in enterocytes? released into blood?

• absorbed via active transport of sodium-glucose cotransporter 2 (SGLT2)

• released to blood via GLUT 2

GLUT 2 is found in what tissues (3)

liver and kidney and basolateral membrane of enterocyte

GLUT 2 km?

high Km (high affinity)

GLUT 2 having high Km allows for what

uptake of large amounts of glucose into cell

GLUT 2 and insulin

GLUT 2 is insulin independent

GLUT2 response to high glucose in blood

 GLUT 2 brings glucose in liver converts into glycogen or lipid synthesis

GLUT2 response to low glucose in blood

GLUT2 exports de novo glucose / glycogenolysis from liver to other tissues

GLUT 4 is found in what tissues (3)

muscle, adipose, heart

GLUT 4 responds to

insulin (insulin dependent)

GLUT 4 Km

low Km (responds at physiological levels of glucose-lower concentrations)

GLUT 1 and 3 are _________ expressed

widely (many tissues)

GLUT 1 and 3 have what Km

low

GLUT 1 and 3 do what

constantly bring glucose into cells (especially at basal levels)

when we talk about GLUT 4, we refer to its actions in what tissues

skeletal and adipose tissue

GLUT 4 is stored where (not tissue but cell)

within vesicles

what happens to GLUT 4 within cell when insulin is present? not present? (steps)

1. GLUT 4 is stored within cell in membrane vesicles

2. When insulin binds to receptor, vesicle with GLUT 4 will move to the plasma membrane

3. When insulin levels drop, glucose transporters (GLUT 4) are removed from membrane by endocytosis (reform vesicles)

4. The smaller vesicles fuse with larger endosomes

5. Patches of endosomes enriched with GLUT bud off to become small vesicles

6. Cycle starts again when insulin binds to receptor

during FED state, what happens to GLUT 4 synthesis

lots of GLUT 4 is transcribed and translated within the nucleus

GLUT 4 will move to what part of the cell when insulin is present (not cell activated)

cytosol

having lots of GLUT 4 present, will result in what when cell is stimulated by insulin

GLUT 4 moves into membrane and uptakes lots glucose

during fasting state, what happens to GLUT 4 synthesis

transcription and translation of GLUT 4 is decreased (less made)

when insulin stimulates the cell during fasting state, what happens in terms of GLUT 4

GLUT 4 moves into membrane but brings in less glucose

GLUT 4 production is downregulated when?

insulin resistance and prolonged fasting

GLUT 4 production is upregulated when?

CHO feeding and exercise

HEXOKINASE 4

Hexokinase are ______

isozymes

what is an isozyme?

different enzymes that participate in the same reaction but differ in location and kinetics

what is the function of hexokinase?

phosphorylates glucose into Glucose-6-phosphate

hexokinase types

1-4

hexokinase 4 is present in what tissues

liver and pancreas (beta cells)

hexokinase 2 is present in what tissues

muscle and adipose

in the liver, during fed state what brings in glucose?

GLUT 2 (high Km)

once glucose is brought into the cell, what will happen to glucose

hexokinase will phosphorylate it to G6P

hexokinase 4 has ____ km

high (not inhibited by product)

what does the phosphorylation of glucose do (what is the importance)? (3)

• decreases glucose concentration in cell (maintains gradient)

• Traps glucose (as G6P) in cell

• Activates glucose for subsequent reactions

G6P in the cell can undergo what pathways (fed state)

• Glycogen synthesis

• Glycolysis (make 2 pyruvate)

• Pyruvate --> FA synthesis

how can glucose lead to FA synthesis (simple summary)

• glucose —> pyruvate —> acetyl CoA

• Acetyl CoA + OAA —> citrate (citric acid cycle)

• citrate leave cycle—> leave mitochondria—> enter cytosol

• citrate break down to acetyl CoA + OAA

• acetyl CoA —> malonyl CoA via ACC

• malonyl CoA —> FA synthesis

the beta cells of the pancreas serve as a

glucose sensor

glucose enters the pancreatic beta cells via what transporters

GLUT 1,2,3

what happens to glucose absorbed in beta cells?

phosphorylated via Hexokinase 4 to G6P

G6P will undergo what pathway (fed state) in pancreas

glycolysis (produce ATP)

G6P undergoing glycolysis in pancreas will result in

increased ATP:ADP (and AMP) ratio

Increased ATP:ADP(or AMP) ratio will result in

stimulation of insulin secretion via beta cells

hexokinase 4 is upregulated by

insulin**

hexokinase 4 has __Km, which means __ affinity, which results in __ glucose uptake into cell

low, low, high

hexokinase 4 and feedback inhibition

not inhibited by product (G6P)

GLUCOSE METABOLISM IN DIFFERENT CELL TYPES

red blood cells will use glucose how? (2)

• G6P —> pentose phosphate pathway

• G6P —> lactate production