Glucose. Glucose. Insulin Action. Introduction to Hormonal Regulation of Fuel Metabolism

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1 Glucose Introduction to Hormonal Regulation of Fuel Metabolism Fasting level mmol (1 mmol = 18 mg/dl) Postprandial 6-10 mmol Amount of glucose in circulation is dependent on: Absorption from the intestine Uptake & release from liver Uptake by peripheral tissues (i.e. skeletal muscle & adipose tissue) Glucose After a meal serum [glucose] rises rapidly & blood glucose reaches a peak generally minutes after a meal Glucose is converted into glycogen in liver & muscle & may be converted to FFA in adipose tissue & liver Insulin Action Anabolic hormone Promotes insulin sensitive tissues, i.e. skeletal muscle & adipose tissue to take up glucose from the circulation, lowering blood glucose level Promotes the synthesis of: Protein Fat Also inhibits degradation of these Antilipolytic Vasodilator Decreases during exercise 1

2 Insulin Signaling X: Skeletal Muscle, Adipose Tissue, Heart IRS-1~P MITOGNIC MTABOLIC PI3-K Hexokinase (HK) xpression GLUT-4 Translocation Synthase (GS) G-6-P Formation Glucose Uptake Storage Insulin ffects on Adipose Tissue Insulin ffects on Fat Storage & Lipolysis LPL Insulin GLUT-4 Translocation/ Glucose Uptake HSL Insulin GLUT 4 LPL Adipocyte FFA HSL Glycerol - FFA MG 2 FFA storage FA synthesis Lipolysis Vessel LPL Glycerol FFA Fat Storage MG 2 FFA VLDL/Chylomicrons Remnant Insulin ffects on HSL receptor Adenylate Cyclase ATP camp PK I PKA P~HSL active HSL inactive Insulin IRS-1 PI3-K AKT Phosphatase Glucagon: Insulin Antagonist Protein hormone Single chain 3.5 kd, 29 amino acids Produced in alpha-cells blood glucose at onset of exercise protein & fat breakdown glycogenolysis & gluconeogenesis Fasting: 25pg/mL Half-life 3-6 min Removed by liver & kidney Adipose Cell 2

3 Glucagon Secretion Stimulation Low Glucose Amino acids Alanine Arginine (also stimulates insulin) Catecholamines Glucagon Glucose Liver Catecholamines: pinephrine () & Norepinephrine (N) Secreted from adrenal medulla Also released as neurotransmitters by the SNS heart rate & heart muscle contractile force skeletal muscle blood flow Stimulates glycogen breakdown in muscle & liver & lipolysis in adipose tissue ANS & Adrenal Medulla Catecholamine Biosynthesis 3

4 pinephrine ffects Lehninger 4th pinephrine ffects in Liver, Muscle & Adipose Tissue pinephrine Liver Muscle Adipose Regulation of Carbohydrate Utilization olysis olysis Lipolysis Fuel Availability Central role of glucose-6-phosphate in determining direction of carbon flow in glycolysis Glycolysis is predominantly controlled by feed-forward & feedback controls Feed-forward factors that G-6-P levels to stimulate glycolysis include: Stimulation of glycogenolysis (by epi contractions) Glucose uptake (by contractions & insulin) Moderate to high exercise causes a rise in blood glucose leading to glucose transport ATP Glucose Central Role of Glucose 6-phosphate Phosphorylase Hexokinase (all cells) Glucokinase (liver & kidney) Glucose-6-phosphatase (liver & kidney) ADP (Stored in Muscle & Liver) Glucose 1-phosphate Glucose 6-phosphate Glycolytic Pathway Synthase Pyruvate Lactate 4

5 The Cell-Cell Lactate Shuttle The Cell-Cell Lactate Shuttle Lactate is actively oxidized in working muscle beds & may be a preferred fuel in heart & red fibers Thus, glycogenolysis in one cell can supply a fuel for oxidation to another cell using the lactate shuttle Skeletal muscle is therefore a major site of lactate production & removal The Cori Cycle The Cori Cycle Muscle indirectly participates in gluconeogenesis through the Cori cycle Gluconeogenesis is an efficient way to reutilize the products of glycolysis, which maintains blood glucose and prolongs muscle glycolysis Regulation of Fat Use Regulation of Fat Utilization Availability/Mobilization AT Transport Intracellular Metabolism Other Factors 5

6 Lipid Metabolism 1. Mobilization - breakdown of adipose & intramuscular Lipolysis N N FA Mobilization = Lipolysis Re-esterification β-adrenergic receptor β 1 G S 1 α 2 G I Adenylate Cyclase ATP PK I - camp HSL inactive PK A PD 5 adenylate P~HSLactive 3 FFA Glycerol FABP Albumin FFA FAT Muscle Lipolysis: Rest: inhibited by α 2 (blocker is phentolamine) & insulin ( HSL) xercise: catecholamines ( HSL), stimulated by ß 1 (blocker is propanolol) The epinephrine:insulin will dictate fat metabolism when want lipolysis to elevated: high catecholamines, low insulin Adipose Cell Lipid Metabolism 2. Circulation - the transport of FFA from adipose to muscle 3. Uptake - entry of FFAs into muscles from blood N β-adrenergic receptor β 1 G S α 2 N G I Adenylate Cyclase ATP PK I - camp HSL inactive PK A PD 5 adenylate P~HSLactive 3 FFA Glycerol FABP 2 Albumin FFA FAT Muscle 3 Fatty Acid Regulation 4. Transport: FABP PM chronic FAT/CD36 in plasma membrane during exercise 5. β-oxidation - production of acetyl-coa from activated FAs; production of reducing equivalents (NADH & FADH) 4 5 Novel Regulators of Metabolism Major Fuel Substrates Adiponectin - adipokine secreted from adipose tissue; receptors present on skeletal muscle IL-6 - myokine secreted from skeletal muscle; also adipokine secreted from inflammatory cells in adipose tissue Muscle Carbohydrate Lipid 6

7 nergy Balance Traditional View: nergy Balance Stored nergy = nergy in nergy out TF Components of Daily nergy xpenditure 8% 17% nergy expenditure of physical activity 8% RMR 32% Food BMR Fat Alcohol Thermic effect of food Body Proteins Activity (X and NAT) 75% 60% Sedentary Person (1800 kcal/d) Physically Active Person (2200 kcal/d) Segal KR et al. Am J Clin Nutr. 40: , 1984 Typical nergy xpenditure with xercise (175 lb person) Activity nergy expended per hour (kcal/h) Walking (3.5 mph) 336 Bicycling (13mph) 672 Jogging (5 mph) 672 Swimming 504 CHO Fat Protein Body Weight BMR X NAT TF Aging & nergy xpenditure Fuel Sources nergy (kj in 1000 s) Tissue Store AT- Liverglycogen Muscleglycogen Glucose Total (g) Reserve (kcal) Starvation (days) (4.9 hr).78 (18.6) 15 kcal/min (min) 5400 (90hr) Age (years) 7

8 ffect of 12wks of RT on Body Composition ffect of 12wks of RT on Oral Glucose Tolerance Croymans et al. ACSM 2010 Croymans et al. ACSM 2010 ffect of 12wks of RT on Oral Glucose Tolerance Croymans et al. ACSM