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BIOC/DENT/PHCY 230
LECTURE 7
Fed state characterised by:
increased plasma concentration of fuel molecules
increased rate of uptake of fuel molecules from plasma
increased storage of fuel molecules in appropriate tissues
release of specific hormones to regulate fed state metabolism
Glucose metabolism in the fed state
regulated by insulin
glucose uptake in muscle and adipose tissue
glycogen synthesis
gluconeogenesis
glycogenolysis
Movement of glucose is regulated by specific transporters
Glucose transporters may:
be insulin dependent or independent
have a high or low affinity for glucose
be ubiquitous or restricted in tissue distribution
move glucose up or down its concentration gradient
high affinity
low affinity
Model mechanism for glucose transport
Glucose uptake from small intestine
glc
glc
SGLT1
glc
Na+
enterocyteintestinal lumen
glucose is moved across the enterocyte cell membrane by co-transport with Na+
glc
GLUT2glc
glc
glc
glc
hepatic portal vein
enterocyte
GLUT2 transports glucose out of the enterocyte
Insulin independent
Low affinity, high capacity (KM 7-20mM)
hepatic portal vein
GLUT2
enterocyte
GLUT5fru frufru
fru
fru
Fructose has its own transporter
insulin independent
Stimulation of insulin secretion
there are many stimuli that can promote insulin secretion
pancreatic -cells use GLUT1 and GLUT2 to sense blood glucose levels
GLUT1 has a KM around physiological plasma [glucose]
GLUT2 has a higher KM
insulin secretion is stimulated by glucose concentrations around 8mM
GLUT4 is an insulin sensitive transporter
GLUT4 cycles between the plasma membrane and intracellular vesicles
insulin stimulates the translocation of GLUT4 to the plasma membrane
insulin increases the rate of transport by GLUT4
GLUT1 GLUT3
blood brain
barrier
neuronal cell
membrane
KM ~ plasma [glucose]
low KM
regulates entry into neurons
glc glc
glc
Glucose uptake by the brain
Properties of glucose transporters
Glycogen
glycogen is the storage body for glucose
main stores are in skeletal muscle and liver
provides a reserve of glucose that can be mobilised between feeding or during exercise
structure: a branched chain polymer
synthesis occurs when glucose is plentiful in the fed state and is stimulated by insulin
Glycogen biosynthesis
straight chain glucose polymers are synthesised by glycogen synthase
glycogen synthase can’t join together free glucose units
requires a primer to initiate synthesis
glycogenin is a protein, on which this primer is synthesised
glucose is added to glycogenin in the form of UDP-glucose
UDPG synthesis
glycogenin
tyr
Synthesis of glycogen primer on glycogenin
Glycogen synthase extends this primer
Activation of glucose
Glycogen has a branched structure
branching enzyme(amylo-(1,4 1,6)-transglycosylase)
Glycogen Storage Diseases
Glycogen Synthase Deficiency (Liver) glycogen synthesis slower; poor glycogen reserve symptoms:fasted state - hypoglycemia
fed state - hyperglycemia glucose intolerance
treatment: avoid long periods of fasting; diet
Branching enzyme deficiency: abnormal glycogen structure...cell damage consequences: liver cirrhosis, neuromuscular defects, death within 3 years
The take home message
glucose metabolism in the fed state is characterised by glucose uptake and storage
insulin is a key mediator of glucose metabolism in the fed state
a variety of glucose transporters mediate glucose uptake depending on tissue requirements
glycogen is the storage body for glucose
the highly branched structure of glycogen improves the efficiency of glucose mobilisation
defects in glycogen synthesis can cause disease