08 Pancreas - PSL302Y: Lecture 08, by Prof. Lam! Wed.,...

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Unformatted text preview: PSL302Y: Lecture 08, by Prof. Lam! Wed., Sept. 29, 2010 Pancreas (Endocrine) Which pancreatic hormone is anabolic; which is catabolic, which is negative? - Anabolic = insulin: favours glucose absorption into fat & muscle cells - Catabolic = glucagon: favours glucose release from storage as glycogen - Negative = somatostatin: inhibits release of insulin & glucagon via -ve feedback Metabolism = sum of all chemical rxns in the body Metabolic pathways are complex, stepwise, balanced; tightly regulated at multiple steps Endocrine Pancreas September 29, 2010 and intersections; redundant mechs -> maintain homeostasis - Energy: extracted from nutrients, stored and used for work Metabolic states: (1) Fed, absorptive, anabolic: glucose is key source of fuel (2) Fasted, post-absorptive, catabolic: glucose & fat used as key nutrient supplies Basal metabolic rate (BMR) = individual's energy expenditure when resting at comfortable temperature, fasted (post-absorptive); also called metabolic rate - Energy balance: control by caloric intake & energy expenditure (i.e. exercise) Nutrient pools closely regulated of the three nutrient pools - Plasma glucose concentration is the most closely regulated of the 3 nutrient pools b/c because glucose is the only fuel starvation. glucose is the only fuel that the brain can metabolize, except in times ofthat the brain can metabolize, except in times of starvation." - Storage: Storage - Carbs: glucose -> Carbohydrates Fat Protein glycogen (liver, muscle) Triglyceride Glycogen (muscle) - Fat: fatty acid+glycerol -> (adipose tissue) (liver, muscle) fat triglyceride (adipose tissue) Endocrine Pancreas September 29, 2010 - Protein: amino acids (muscle) glucose fatty acid, glycerol amino acids - Nutrient pools: Glycogenolysis, glycogenesis, glycolysis, gluconeogenesis, - Glycogenolysis & glycogenesisLipolysis, lipogenesis - Glycolysis (in liver & muscle) & gluconeogenesis (in liver) - Lipolysis & lipogenesis: insulin is anti-lipolytic & favours lipogenesis Endocrine pancreas, regulator of metabolism Nutrient Pools "Plasma glucose concentration is the most Endocrine pancreas: regulator of metabolism At organs: liver, stomach, pancreas, intestines Secretion from pancreas (beside duodenum) On pancreas: islet of Langerhans w/i exocrine tissue -> exocrine (acinar) cells separated into capsules by capillaries Diff pancreatic cells secrete diff hormones: -Beta cells: proinsulin -> insulin + c-peptide -Alpha cells secrete glucagon -Delta cells secrete somatostatin 1 of 4 3 PSL302Y: Lecture 08, by Prof. Lam! Endocrine Pancreas Wed., Sept. 29, 2010 September 29, 2010 Insulin & glucagon signal cells to change gears btwn feeding & fasting metabolism Insulin binds to receptor-enzyme on plasma membrane Glucagon binds to G protein-coupled receptor (like epinephrine) => 2nd messenger system -> proteins-P -> cellular response Insulin & glucagon signal target cells to change gears between feeding and fasting metabolism insulin glucagon Outside cell ReceptorR enzyme G Protein ProteinCoupled receptor Inside cell Second messenger system Insulin (anabolic) is the dominant hormone of theproteins state Phosphorylate fed Insulin (anabolic) is the dominant hormone of Preproinsulin Proinsulin Insulin "fed" state A-chain - Synthesized as a typical peptide B-chain B h i - Binds to a receptor tyrosine kinase - Effect: reduces blood glucose (inhibits glucose Endocrine Pancreas September 29, Signal peptide C-peptide synthesis in cells) & stores carbohydrate, fat 2010 and protein (absorb from blood into body cells) - Precursor: preproinsulin -> remove signal peptide = proinsulin -> remove A- and Bchains = insulin + C-peptide Glucose, primary stimulus of insulin secretion (+ other regulators): after a meal... Synthesized as a typical peptide Cellular response Binds to a receptor tyrosine kinase Reduces blood glucose Stores carbohydrate, fat and protein carbohydrate fat, 5 Glucose, Glucose, primary stimulus primary stimulus off insulin of insulin i li secretion secretion + other regulators. 6 1)Signal: [blood glucose] -> glucose enters beta cells via GLUT transporter Endocrine Pancreas September 29, 2010 -cell 2) Metabolic activity: Glycoysis & citric acid cycle 3) in ATP = shuts KATP channel 4)Cell depolarizes: K+ leaves cell = +ve charge w/i cell 5)Ca2+ channel opens: influx of extracellular Ca2+ 6)Intracellular signal: Ca2+ entry triggers exocytosis Micromanaging insulin secretion: = insulin is secreted Micromanaging insulin secretion - A microRNA in beta cells target myotrophin = inhibits insulin exocytosis - miRNA attracts RISC to mRNA -> RISC silences mRNA - myotrophin insulin exocytosis = myotrophin destroyed to inhibit insulin secretion a microRNA in beta cells targets myotrophin, myotrophin inhibiting insulin exocytosis 7 Mello & Czech 2004 Nat. Med. 10, p.1297 2 of 4 In the fed state, insulin, the most potent PSL302Y: Lecture 08, by Prof. Lam! September 29, 2010 ancreas Wed., Sept. 29, 2010 anabolic hormone known, increases the synthesis and storage of carbohydrates carbohydrates, lipids and protein while inhibiting their degradation and release in the blood. Effects of Insulin - In the fed state, insulin (the most potent anabolic hormone known) increases the synthesis & storage of carbohydrates, lipids and protein WHILE inhibiting their degradation and release in the blood. In liver: insulin indirectly increases glucose uptake. -Insulin also favours hexokinase-mediated conversion of intracellular glucose into G-6-P to keep [intracellular glucose] low -Thus glucose gradient maintained btwn cell & blood = glucose continues to pass into cells via GLUT transporters In fat & muscle cells: insulin directly increases glucose transport by stimulating the translocation of the glucose transporter, GLUT4), from intracellular sites to the plasma membrane. -Insulin adds more GLUT transporters (residing w/i cell) to cell membranes September - If signaling cascade impaired 29, 2010 = insulin resistance -> hyperglycemia = diabetes n liver, insulin ndirectly ncreases lucose uptake 9 Endocrine Pancreas Insulin-to-glucagon ratio controls glucose homeostasis [Blood glucose] kept steady via competing insulin & glucagon - Glucose spikes after meals: insulin spikes in response but quickly drop due to antagonism by glucagon 10 Insulin-toglucagon [glucagon]bl ratio controls [glucose] bl glucose Endocrine Pancreas homeostasis [insulin]bl September 29, 2010 Time Time Glucagon (secreted by alpha-cells), antagonizes insulins effects on metabolism - Precursor: proglucagon...but glucagon also synthesized elsewhere Glucagon, secreted by the pancreatic - ll Proglucagon allows lifor alternative splicing = glucagon or GLP-1 or GLP-2 -cells, antagonizes i t i insulin's effects ' ff t - GLP-1 (glucagon-like peptide 1): secreted by endocrine cells in small intestine, on metabolism 12 responding to nutrient influx = stimulates insulin release + inhibits glucagon release Proglucagon N Glucagon GLP-1 GLP-2 C GLP-I, glucagon-like peptide I ,g g p p secreted by endocrine cells in small intestine stimulates insulin release, inhibits glucagon release 3 of 4 PSL302Y: Lecture 08, by Prof. Lam! Wed., Sept. 29, 2010 Glucagon's goal is to prevent Glucagon's goal = prevent hypoglycemia hypoglycemia yp g y -In response to fasting, glucagon triggers the activation of a cascade of proteins inside the hepatocytes, each transmitting and amplifying the fasting signal the the next thru phosphorylation (-Pion). 1)Glucagon binds2010 G protein-coupled receptor September 29, to 2)Adenyl cyclase converts ATP -> cAMP activates PKA 3)PKA: phosphorylase b kinase (inactive) + ATP -> Pb kinase (active) 4)Pbk: phosphorylase b + ATP -> phosphorylase a 5)Pa: glycogen -> G-1-P -> glucose se to fasting, triggers ation of a cascade ns inside the tes, each ng and Endocrine Pancreas ng the fasting the next phosphorylation. h h l i glucagon glucose liver Somatostatins, a negative hormone Somatostatins, (insulin, glucagon, growth - Inhibits endocrinea negative hormone thathormone, etc.) and exocrine (gastic acid, inhibit endocrine etc.) secretions (insulin, glucagon, growth o o e ) and exocrine (gastric acid...) hormone...) a d e oc e (gast c ac d ) - Precursor: preprosomatostatin -> signal peptide cleavage + proteolytic cleavage -> secretions prosomatostatin -> somatostatin-28+ somatostatin-14 Signal peptide cleavage Proteolytic cleavage 14 preprosomatostatin prosomatostatin somatostatin-28 somatostatin-14 Somatostatins, cyclopeptides Weckbecker 2003 Nat Rev Drug Discovery 2, p.999 15 4 of 4 ...
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