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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