Transcript Gluconeogenesis

Neural - Endocrine Control
• Brooks ch 9 p181-191;197-201
– Some small sections already covered
• Outline
• Maintenance of Blood Glucose during exercise
– Feed forward Control - SNS
– Feed back Control - ratio of insulin / glucagon
– Control of Gluconeogenesis - Ca++, cAMP
Neural - Endocrine Control
• During exercise, the maintenance of homeostatic
levels is important, particularly blood glucose
• Blood glucose is maintained at 4-5.5 mM (90100mg/dl)
• Fig 5.5
Neural - Endocrine Control
• During exercise glucose uptake into muscle is
stimulated in order to maintain ATP homeostasis
• Blood glucose is maintained through release from
the liver and kidneys and the mobilization of
alternate fuels
• Response to maintain blood glucose is governed by
the endocrine system and the Sympathetic NS
– Via feed-forward and feed-back control mechanisms
• Glucose homeostasis is important for CNS
metabolism and the anaplerotic effect of
carbohydrates on fat metabolism
Glucose Appearance
• Several ways to increase blood glucose
– Release from gut (prior meal)
– Release from glycogen stores
– Gluconeogenesis - production of glucose from precursors
in kidney and liver - lactate, pyruvate, glycerol, alanine
• Body also raises levels of alternative substrates and
delivers them to active tissue
– fatty acids, TG, lactate, leucine
– Which serve to spare glucose use and postpone
hypoglycemia and fatigue
• Growth Hormone and Catecholamines mobilize FFA
and TG
Fasting State fig 5-3b
Feed forward Control
• During exercise the rise in
glucose uptake is primarily in
the active tissue beds
• Fig 9-2
• the addition of arm exercise,
further increases whole body
uptake but blood glucose rises
due to high Hepatic Glucose
Production (HGP)
• stimulated by increased
catecholamines and
decreased insulin (fig 9-3)
• This is a feed forward
response, as blood glucose
did not drop
Role of the Liver
• Liver is essential to the regulation of blood glucose
– Uptake and storage when levels are high
– Release when levels are low
• Uptake and Release are driven by [ ] gradients
– In and Out through high Km GLUT 2 (20mM)
• Insulin stimulates glucokinase synthesis which
phophorylates glucose preventing its efflux and
keeping the [ ] gradient high - glucose then stored
or metabolized
• When there is a fall in [glucose] in liver
– Activity of GK (also known as high Km HK) falls
– Activity of G6Pase inc, forming glucose for release
Energy Storage
• Storage of glycogen is limited to 5-6% of liver by
weight (5g/100g)
• As G6P builds up in the liver during the fed state, it
stimulates glycolysis and formation of acetyl-Co-A,
then FFA and the synthesis of TG
– TG packaged into VLDL and circulated to adipose
• Low insulin and blood glucose in fasting state
stimulates FFA release and a decrease in glycolysis
through glucose-fatty acid cycle (discussed earlier)
– Acetyl co A inhibits PDH
– Citrate inhibits PFK
– G6P inhibits HK and glucose uptake (skeletal ms)
Insulin and exercise
• Insulin falls during
exercise - likely due to rise
in epinephrine (both
changes result in
increased HGP)
• With aerobic training
– Decreased release of
glucagon and
catecholamines and an
reduction in the fall in
insulin at a given relative
intensity
– Fig 9-7
Glucagon
• Glucagon enhances glycogenolysis (glycogen
breakdown) and gluconeogenesis through
adenylate cyclase
• Alanine released from muscle after prolonged
exercise also stimulates glucagon
– Increases amino acid uptake for gluconeogenesis
• Glucagon response to exercise is also dampened
with training - Fig 9-8
Gluconeogenesis in Liver
• Glucose produced from lactate, pyruvate or alanine
through the use of bypass steps for the irreversible
steps of Glycolysis
• Pyruvate carboxylase (PC) and
Phophoenolpyruvate carboxylase (PEPCK) reverse
PK through Malate shuttle - Fig 9-15
• Fructose-1,6-Bisphosphatase reverses PFK
• Glucose 6 Phosphatase reverses HK (GK)
• These enzymes are mainly found only in liver and
kidneys
Control of Gluconeogenesis
• cAMP and Calcium thought to play important roles
in stimulation of gluconeogenesis
• PK-L liver type PK can be phosphorylated and
inhibited by Ca++ and cAMP dependant protein
kinases
– This will inhibit glycolysis and favour glucose release
• Fructose 2,6 Bisphosphate (present after eating)
will activate glycolysis and inhibit gluconeogenesis
– Activates PFK- and inhibits F 1,6 BPase
• PFK-2 in liver can act as either kinase or
phosphatase (reverse)
– cAMP dependant protein kinase will inhibit PFK-2 kinase
function and activate PFK-2 phoshorylase function