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