The establishment of our comprehension of metabolic physiology is based on revelations in basic, however detached model

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The establishment of our comprehension of metabolic physiology is based on disclosures in basic, yet secluded model frameworks. Comes about because of qualities to organelles and cells may give a false representation of the physiognome. A component is just as vital as its practical effect in the entire life form.

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Well-Controlled Animal Models Bridge Cell Biology to the Physiology of Exercise

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The Study of Glucoregulation

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Provocative or Sensitizing Tests Physical Exercise Hormone and Metabolic Challenges (e.g. hyperinsulinemic, euglycemic glucose clips) Etcetera

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Four Grams of Glucose

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Maintaining 4 Grams of Glucose in the Blood Sedentary, Postabsorptive Brain Fat Glucose ~4 grams Liver Blood Liver Muscle

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Maintaining 4 Grams of Glucose in the Blood Feeding Suppression (Insulin) Brain Fat Glucose ~4 grams Liver Blood Liver GI Tract Stimulus (Insulin) Muscle

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Maintaining 4 Grams of Glucose in the Blood Exercise Stimulus Brain Fat Glucose ~4 grams Liver Blood Liver Muscle Stimulus

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Why don't we get hypoglycemic when we work out? On the off chance that the liver does not discharge more glucose amid practice . . . Hypoglycemia quickly results Exercise 6 Glucose Utilization mg・kg - 1 ・min - 1 0 6 Hepatic Glucose Production mg・kg - 1 ・min - 1 0 100 Arterial Plasma Glucose mg·dl - 1 0 - 30 0 60 Time (minutes)

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Five Guiding Principles to Study of Metabolism in vivo Glucose digestion system is about flux control. Glucose flux control is disseminated among particular frameworks that require an in vivo model to be completely caught on. Glucose fluxes are most delicately controlled and consequently best concentrated on in the cognizant state . Novel creature models can be utilized to extension essential and clinical research. Provocative tests are frequently important to accelerate phenotypes and uncover useful confinements.

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Endocrine and Sympathetic Nerve Response to Exercise 16 120 Glucagon Arterial Insulin 80 Arterial 12 Glucagon pg·ml - 1 µU ·ml - 1 40 8 Insulin 0 300 Norepinephrine Arterial Catecholamines 200 pg·ml - 1 100 Epinephrine 0 - 60 - 30 0 30 60 90 120 150 Time (min)

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Investigator sees… Liver sees… head and furthest points pancreas liver gut heart and lungs A Minimal Overview of the Circulation blood vessel trunk and lower limits gateway vein venous

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Chronically-Catheterized Conscious Dog Model

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Investigator sees… Liver sees… blood vessel trunk and Basal Exercise head and furthest points pancreas bring down Basal liver limits Exercise gut 300 entry vein Portal Vein Hepatic Vein venous 200 Arterial Plasma Glucagon (pg·ml - 1 ) Plasma Epinephrine (pg·ml - 1 ) Portal Vein 100 Artery Hepatic Vein heart and lungs 0 - 50 0 50 100 150 - 50 0 50 100 150 Time (min) Time (min)

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Protocols: Role of Glucagon 150 - 120 min 0 - 40 Basal Equilibration Moderate Treadmill Exercise Somatostatin + [3-3 H]glucose + [U-14 C]alanine Exercise-Simulated Intraportal Insulin Basal Intraportal Insulin Saline Variable Glucose Protocol A Basal Intraportal Glucagon Protocol B Exercise-Simulated Intraportal Glucagon Basal Intraportal Glucagon

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Exercise as a model to study glucagon activity Exercise 150 Simulated Glucagon 100 Arterial Glucagon pg/ml 50 Basal Glucagon 0 15 Basal Glucagon Arterial Insulin 10 µU/ml 5 Simulated Glucagon 0 - 60 - 30 0 30 60 90 120 150 Time (min)

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Exercise-instigated Increment in Glucagon Stimulates Hepatic Glucose Production Exercise 120 Simulated Glucagon Arterial Plasma Glucose mg·dl - 1 80 Basal Glucagon 40 0 Simulated Glucagon 10 Hepatic Glucose Production mg·kg - 1 ·min - 1 8 6 4 Basal Glucagon 2 0 - 40 0 30 60 90 120 150

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Exercise-actuated Increment in Glucagon Stimulates Gluconeogenesis from Alanine 400 300 200 100 0 400 300 200 100 0 Exercise Simulated Glucagon Gluconeogenesis from Alanine (% Basal) Basal Glucagon Simulated Glucagon Intrahepatic Gluconeogenic Efficiency from Alanine (% Basal) Basal Glucagon - 60 - 30 0 30 60 90 120 150 Time (min)

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Comparison of the Effects of Similar Increases in Glucagon at Rest and amid Exercise 6 5 Increase in Endogenous Glucose Production (mg·kg - 1 ·min - 1 ) 4 3 2 1 0 Rest Exercise

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Why is Glucagon so Effective amid Exercise? Mind Autonomic Nerve Activity Adrenal Working Muscle  Epi Intestine ? Fat Glycerol NEFA Pancreas Amino Acids  IL6 Lactate Amino Acids  RBP4 Glucose 4 grams Substrates GNG  Glucagon Signals  Insulin Gly Liver

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Why is Glucagon so Effective amid Exercise? Cerebrum Autonomic Nerve Activity Adrenal Working Muscle Body is in a 'Gluconeogenic Mode'  Epi Intestine ? Fat Glycerol NEFA Pancreas Amino Acids  IL6 Lactate Amino Acids  RBP4 Glucose 4 grams Substrates GNG  Glucagon Signals  Insulin Gly Liver

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Why is Glucagon so Effective amid Exercise? Mind Autonomic Nerve Activity Adrenal Working Muscle Body is in a 'Gluconeogenic Mode'  Epi Intestine ? Fat Glycerol NEFA Pancreas Amino Acids  IL6 Lactate Amino Acids  RBP4 Glucose 4 grams Substrates GNG  Glucagon Signals  Insulin Gly Effects are Potentiated by the Fall in Insulin Liver

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Why is Glucagon so Effective amid Exercise? Mind Autonomic Nerve Activity Adrenal Working Muscle Body is in a 'Gluconeogenic Mode'  Epi Intestine ? Fat Glycerol NEFA Pancreas Amino Acids  IL6 Lactate Amino Acids  Glucose Uptake Prevents Hyperglycemia  RBP4 Glucose 4 grams Substrates GNG  Glucagon Signals  Insulin Gly Effects are Potentiated by the Fall in Insulin Liver

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Protocol: Study of Splanchnic Amino Acid Metabolism amid Exercise - 120 min - 30 0 150 Equilibration Basal Treadmill Exercise 15 13 [5-N]Glutamine + [1-C]Leucine

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The Exercise-incited Glucagon Response is Essential to the Increment in Hepatic Glutamine Extraction Simulated Glucagon Basal Glucagon 0.60 * Hepatic * Fractional 0.40 * Glutamine ��  Extraction 0.20 ��  0.00 Basal 25-50 75-100 125-150 Basal 25-50 75-100 125-150 Exercise Duration Exercise Duration (min) (min)

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The Exercise-actuated Glucagon Response Drives Urea Formation in the Liver Simulated Glucagon Basal Glucagon 20 * Net Hepatic * 15 * Urea Output 10 - 1 - 1 (  mol · kg ・min ) 5 0 Basal 25-50 75-100 125-150 Basal 25-50 75-100 125-150 Exercise Duration (min) Exercise Duration (min)

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The Exercise-initiated Glucagon Response is Required for the Accelerated exchange of Glutamine Amide Nitrogen to Urea in the Liver 3.0 Formation of Urea from 2.0 Glutamine Amide Nitrogen amid Exercise 1.0 - 1 - 1 (  mol · kg ・min ) 0.0 Basal Simulated Glucagon

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Energy State and the Liver

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Energy State in the Liver is Controlled by Glucagon

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Studies utilizing the Phloridzin-Euglycemic Clamp encourage Illustrate the Role of Glucagon in Liver Energy Balance *

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Blood is Regulated like a Homeostat Liver is the Battery (rechargeable)

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Substrates and Signals Implicated in Control of Glucose Fluxes to Working Muscle amid Exercise Brain Sensors Carotid Sinus Liver/Portal Vein Working Muscle Autonomic Nerve Activity Feedback Chemical Mechanical Feedforward Adrenal  Epi Intestine  IL6 Adipose Working Muscle Glycerol NEFA Pancreas Amino Acids  IL6 Lactate Amino Acids  RBP4 Glucose 4 grams  Glucagon GNG Substrates  Insulin Signals Gly Liver

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What about the Famous Catecholamine Response to Exercise? Epinephrine assumes next to zero part in control of glucose creation amid work out. Moates et al Am J Physiol 255: E428-E436, 1988. Hepatic nerves are a bit much for the work out initiated ascend in glucose generation. Wasserman et al Am J Physiol 259: E195-E203, 1990. Liver particular bar of both -and -adrenergic receptors don't constrict the expansion in glucose generation amid work out. Coker et al Am J Physiol 273: E831-E838, 1997. Coker et al Am J Physiol 278: 444-451, 2000.

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Catecholamines Essential, in relationship with the fall in insulin, for extrahepatic substrate activation amid exercise. Muscle glycogenolysis Adipose tissue lipolysis

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NEFA Flux is Accelerated amid Moderate Exercise by Increased Lipolysis and Decreased Re-esterification ATP TG FFA G3P Glucose FFA TG N E TG Glycerol T G Glycerol G l y c e r o l

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NEFA Flux is Accelerated amid Moderate Exercise by Increased Lipolysis and Decreased Re-esterification ATP TG FFA G3P Glucose FFA TG N E TG Glycerol T G Glycerol G l y c e r o l

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Four Grams of Glucose Controlling Rate of Removal Extracellular Intracellular glucose 6-phosphate glucose • hexokinase # • hexokinase compartmentation • spatial hindrances • blood stream • slim enrollment • spatial boundaries Membrane • transporter # • transporter action

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Strategy Selectively evacuate locales of imperviousness to MGU in cognizant mice by utilizing transgenic mice or pharmacological strategies.

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Ohm's Law Applied to Glucose Influx Current (I) V 1 V 2 V 3 V 4 Resistor 3 Resistor 1 Resistor 2  V 1 = I · Resistor 1  V 2 = I · Resistor 2  V 3 = I · Resistor 3 Glucose Influx (I g ) G a G e G i 0 R Extracell R Transport R Phosp  G extracell = I g · R extracell  G transport = I g · R transport  G phos = I g · R Phosp

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Ohm's Law to Determine Sites of Resistance to Muscle Glucose Uptake G a G e G i 0 GLUT4 Tg HK Tg GLUT4 Tg HK Tg Glucose Influx WT Transgenics

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Artery Chronically Catheterized, Conscious Unstressed Mouse Sample [3-3 H]Glc Blood Insulin Glucose [2-14 C]DG Vein From: Glucose Clamping the Conscious Mouse by Vanderbilt MMPC 2005 ptf 2002/jea 2005 .:tslidesep

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