Learning Objectives 1) Describe the structure/function of glycogen as an E and glucose storage molecule. 2) Outline the metabolic pathways that leads to glycogen synthesis and degradation. 3) Identify the signaling pathways that control glycogenesis and glycogenolysis. 4) Define the roles of insulin and glucagon in maintaining glucose homeostasis. 1) Describe the structure/function of glycogen as an E and glucose storage molecule. - Store carbs as glycogen= a polymer of glucose!- limited usefulness as long-term E source: finite capacity to accumulate it (1-2% of total body stores), req. more water to store (2.7x weight), kcal/g (E density) < triglys!- fats= a better long term E storage source!- BUT: fats can't be released as rapidly from trigly stores as glucose from glycogen, can't be used anaerobically (w/o O2) for E, fatty acids CAN'T be converted to gluocse for maintaining blood glucose levels in tissues that depend on glucose metabolism for needs (brain, RBCs)!- Structure of glycogen: 10-12 alpha-1,4 glycosidic linkages: alpha-1,6 glycosidic linkage (branch points)!- Glycogen polymers= spherical particles, contain 10,000-60,000 glucose residues!- Each particle built around glycogenin (core protein molecule) --> stimulates syn. of 1st few glucose residues!- Particles contain: enzymes inv. in glycogen synthesis (glycogenesis) and glycogen degradation (glycogenolysis)!- Glycogen particles found in pretty much every cell, abundant in liver (to reg. blood glucose levels) and skeletal m. (rapidly available E source)!- liver glycogen stores vary a lot during the day! 2) Outline the metabolic pathways that leads to glycogen synthesis and degradation. - Synthesis of Glycogen!- Catalyzed by glycogen synthase!- Precursor for adding glucose residues= UDP-glucose from UTP (aka E) + glucose-1-phosphate!- Tightly reg: POSITIVELY by insulin and substrate availibilty, NEGATIVELY by glucagon (liver), epinephrine or exercise!- Activation of glucose for glycogen synthesis: req 3 high E bonds, 2 are from UTP, 1 from ATP --> to make UDP-glucose - Glycogenolysis= breakdown of glycogen in times of E need!- key enzyme= glycogen phosphorylase --> removes glucose units 1 at time, release them as glucose-1-phoshate!- glycogen + Pi (not using ATP/E) --> glucose-1-phosphate (putting a phosphate on a sugar)!- this is not the reverse of the hexokinase rxn!- can only break down to 4 glucose chain!- gluc-1-phosphate --> glucose-6-phosphate for more metabolism!- liver: converted to glucose by glucose-6-phosphatase (G6Pase) --> exported to maintain blood gluc levels and supply tissues highly dep. on glycolysis !- skeletal m: no G6Pase, so is used directly for glycolysis (anaerobic or aerobic)!- concerted action of glycogen phosphorylase and debranching enzyme is req. !- debranching enzyme moves the 4 gluc chain to another end so glyc phosphory can start again from that end, deb enzy also breaks the 1-6 bond!- Glycogen storage disease!- accumulation of glycogen due to deficiency in an enzyme of glycogen metabolism!- many: hypoglycemia (low blood glucose) because liver can't provide glucose to maintain!- type I: muts in liver glucose-6-phosphatase --> accum. of glycogen in liver and hypoglycemia!- type III: muts in the debranching enzyme --> sim. conseq. to type I, milder!- type V: muts in muscle glycogen phosphorylase--> high m. glycogen content, reduced blood lactate after exercise 3) Identify the signaling pathways that control glycogenesis and glycogenolysis. - Control of glycogen metabolism= to prevent futile cycling!- differs between liver and muscle!- Control of liver glycogen metabolism= based on role of liver in maintaining blood glucose homeostasis!- blood glucose levels are maintained by actions of insulin and glucagon !- normal blood glucose: 70-105 mg/dl (4-5.8 mM)!- islet cells in the endocrine pancreas syn., store, and release the polypeptide hormones: insulin and glucagon!- B cells make insulin and release in resp. to hyperglycemia (high blood glucose)!- Insulin: primary anabolic/E storing hormone!- Insulin: promotes gluc uptake and utilization in liver, skeletal m., adipose!- Alpha cells made glucagon and release in resp. to hypoglycemia (low blood glucose)!- primary systemic hormone affecting fuel utilization!- promotes glucose formation and export by glycogenolysis (breaking down glycogen) and gluconeogenesis (making glucose) in liver!- Glucagon stimulates glycogenolysis - acts on liver --> binds to membrane receptor --> activate signaling pathway --> formation of second messenger cyclic AMP (cAMP) --> binds to/activates protein kinsase A --> phosphorylates specific serine or threonines on target protein to activate of inhibit their enzymatic activity --> one target= phosphorylase kinase --> phosphorylates glycogen phosphorylase (to activate it) --> glucose production!- Regulation of muscle glycogenolysis!- fasting state hormone = epinephrine --> binds toreceptor --> cAMP --> activates PKA --> activates phosphorylase kinase --> phosphorylates/activates glycogen phosphorylase --> glucose!- Protein kinases and protein phosphatase work in combination to control the level of phosphorylation and hence the activites of enzymes and proteins 4) Define the roles of insulin and glucagon in maintaining glucose homeostasis. - Actions of insulin stimulate glycogen deposition - Insulin promotes: !- glucose transport into skeletal m. and adipose!- glucose storage as glycogen in liver and m.!- storage of fatty acids as triglys in adipose!- conversion of glucose --> triglys in liver and adipose!- aa uptake and protein syn. in m.!- DNA syn in some cells!- Insulin inhibits:!- glycogenolysis!- gluconeogenesis (conversion of aa's and lactate --> glucose)!- lipolysis!- apoptosis (programmed cell death)!!S60: Adaptations to Fasting: Gluconeogenesis and Ketone Bodies Learning Objectives 1) Define metabolic fuels that are used durign short-term and prolonged fasting or starvation to maintain glucose homeostasis and E production. 2) Appreciate the critical steps in gluconeogenesis and how they are regulated in fed and fasting states. 3) Understand the origin of ketone bodies and their role as a metabolic fuel during prolonged fasting. 1) Define metabolic fuels that are used durign short-term and prolonged fasting or starvation to maintain glucose homeostasis and E production. - Fasting and starvation!- depend on E stores from glycogen, triglys and protein to provide the fuel needed to keep our
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