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34 Cards in this Set
- Front
- Back
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Generation of ATP
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Cells derive energy from ATP, oxidized from dietary:
-Glucose (glycolysis and mitochondria) -Nonesterified Free Fatty Acids (FFAs) (mitochondria) -Amino acids (AAs) (mitochondria) (Ketone bodies made by liver) Daily, we generate ATP by alternating between: -Anabolic States (fed): nutrient availability for immediate use and storage -Catabolic States (fasted) states: limited nutrient intake, requiring mobilization and use of stored energy supplies. |
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Brain: Energy Use
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Obligate glucose user
-BBB limits FFA uptake -AA used to make neurotransmitters, not energy Consequences of hypoglycemia (fasting <60mg/100mls) -Acutely impaired CNS function: vision, cognition, muscle coordination, lethargy, weakness -Leads to coma and death Consequences of chronic hyperglycemia (fasting >110 mg/100mls) -Increased oxidative stress, osmotic burden, cellular lipotoxicity -Leads to diseased vasculature, nerves, kidneys, other organs |
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Sites of modulation of nutrient intake, absorption, transport, storage and metabolism
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Nutrient intake
Limbic forebrain: -Motivation for palatable food Hypothalamus -Huner and satiety Transport and absorption -Gastric emptying -GI motility -Ghrelin, CCK Storage and metabolism (liver, bone, adipocytes) -Glycogen and FFAs -Glucose uptake -Glucose, lipid oxidation -Lipolysis and lipogenesis |
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Glucose transporters
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GLUT1
-Ubiquitous -High-affinity, basal levels GLUT2 -Pancreatic β cell, liver -Low-affinity, during fasting-to-fed transition GLUT3 -Ubiquitous -High-affinity, primary transporter in neurons GLUT4 -Skel Muscle, adipose -Insulin-dependent translocation GLUT5 -Small intestine, sperm -Fructose transporter |
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Glucose trapping
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Hexokinases 6C-sugar + ATP => sugar-6-phosphate
Glucokinase (Pancreatic β cell, liver) low-affinity, Glucose +ATP => G-6-P Make glucose charged so it can't leave cell |
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Glycolysis
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Glycolysis to 3-C pyruvate (aerobic) or lactate (anaerobic)
Yields 2 ATP/glucose and pyruvate G-6-P <-> F-6-P => F-1,6-bisP <->2X Glyceraldehyde-3P <-> 2X Phosphoenolpyruvate (PEP) + 2X ADP => 2X ATP PEP => Pyruvate |
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Tricarboxylic acid cycle: glucose, FFAs, AA
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Tricarboxylic Acid Cycle (TCA) inner mitochondria matrix
Electron transport chain for oxidative phosphorylation Pyruvate from glycolysis enters mitochondria Pyruvate => Acetyl Co-A => TCA cycle {>Citrate + CO2 >>oxaloacetate>>} Electron transport chain utilizes O2, -regenerates NAD+, FAD as ATP is generated (up to 17) -contributes to generation of reactive oxygen species (ROS) FFAs transported into inner mitochondria via CPT-I and CPT-II -carnitine palmitoyl transferases β-oxidation cycles 2C units, generating 1 acetyl-CoA => TCA cycle AAs transaminated to pyruvate (Ala), acetyl CoA, α-ketoglutarate (Glt), succinyl CoA, fumarate, and oxaloacetate. |
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Ketone bodies
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Liver generates Ketone Bodies:
- acetoacetate & β-hydroxybutyrate from Acetyl Co-A => acetoacetyl CoA Peripheral tissues convert Ketone Bodies to Acetyl-CoA - via enzyme Thiophorase: Succinyl CoA + acetoacetate =>acetoacetyl CoA from which, 2 acetyl CoAs enter TCA cycle {>Citrate + CO2 >>oxaloacetate>>} Ketone bodies do not come from diet. Liver can generate ketone bodies, but does not express thiophorase, so cannot use ketone bodies as energy source. |
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Generation and storage of glycogen (short term)
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INSULIN: Glycogen synthesis: G-6-P => G-1-P => glycogen chains using Glycogen Synthase, highly-regulated by hormones
GLUCAGON, EPINEPHRINE: Glycogenolysis: G-1-P cleavage from Glycogen branches using Glycogen Phosphorylase, highly regulated by hormones Liver: G-1-P => G-6-P => (glucokinase) glucose transported out via GLUT2 Muscle: G-1-P => G-6-P => glycolysis => lactate diffuses out Glycogen stored: Liver 100g Skeletal muscle 400g |
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Long periods of fasting: energy use
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Over long periods of fasting, stored supplies of high-energy Free Fatty Acids (FFAs) support energy.
Storage of FFAs as triglycerides in adipose tissue provides a high-energy source of FFAs for entrance into the TCA cycle for ATP production. |
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Formation and storage of FFA
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After high-caloric intake, glucose metabolism to citrate in TCA cycle is stymied because of high ATP and NADH.
This diverts glucose from immediate use to storage as FFAs. -When glucose is plentiful, glucose is available for the Pentose phosphate shunt. This pathway makes NADPH (when there is high fructose) required for fatty acid synthesis. Mitochondrial Citrate is transported to cytoplasm, & converted to acetyl-CoA & oxaloacetate for FA synthesis. FA-CoAs & Glycerol-3-P form MGs, DGs, & TGs. TGs are packaged by liver into VLDLs with ApoB100, and secreted into blood. VLDLs can be acted on by capillary lipoprotein lipase in adipose tissue, for FFAs to be taken up for storage as TGs, |
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Triglycerides: energy storage in anabolic state
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Dietary Triglycerides digested to FFAs and 2-monoglycerides
Reassembled as Triglycerides by enterocytes and transported via lymphatics to blood as chylomicron lipoprotein particles -ApoB48 (primary apoprotein secreted with chylomicrons) surrounding TG & cholesterol ester core, with some superficial phospholipid. ApoCII, acquired from HDLs, activates lipoprotein lipase (LPL) Adipose tissue secretes LPL, which attaches to apical surface of capillary endothelial cells (bound via heparin-sulfate proteoglycans), digesting lipoprotein and releasing FFA and glycerol. FFAs and glucose are transported into adipocytes to be esterified into Triglycerides. FFA transported into tissues are converted to acyl-CoAs for energy use |
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Release of triglycerides from adipose cells
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Liver convert FFAs into Ketone bodies
Hormone-sensitive Lipase initiates TG catabolism to FFAs -Stimulated by glucagon, epinephrine, glucocorticoids, GH Peripheral tissues use FFAs for β-oxidation |
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AA as energy source
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After 6 weeks of starvation
Transaminase -Glutamine + pyruvic acid to a-ketoglutarate and alanine |
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Pancreatic hormones and cells
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Insulin
-Beta -~60% islet cells Glucagon -Alpha -25% Somatostatin -Delta -10% Pancreatic polypeptide -F -80% in head Blood flows from β cells passing across α and δ cells. |
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Insulin/glucagon balance and anabolic/catabolic state
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Anabolic
-Increased insulin and decreased glucagon -Diet as fuel source -Processes: glycogen synthesis, TG synthesis, protein synthesis Catabolic -Decreased insulin and increased glucagon -Storage pools as fuel source -Processes: Glycolysis, Glycogenolysis, Lipolysis, Proteolysis, Ketogenesis |
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Insulin: overview, synthesis, storage, release
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Insulin: anabolic hormone secreted upon ingestion of a meal to facilitate storage of carbohydrates and fats.
Synthesized from proinsulin in pancreatic islet β-cell granules by converting enzymes PC2 and PC3. Stored as zinc-crystals. C-peptide is released with insulin (used as diagnostic measure of release. |
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Insulin: pharmacokinetics
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Serum insulin rises within 10 min of a meal, and peaks after 30-45 min.
Insulin secreted into portal vein is significantly (approx 50%) degraded by insulinase in liver (and kidney) before accessing other tissues. Serum t1/2 = 5-8 min If continuous stimulus (e.g., glucose infusion), insulin secretion falls within 10 min (release of pre-formed stored insulin), and then rises over about 1 hr (newly synthesized insulin). |
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Insulin: secretion regulation
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Glucose is primary regulator of insulin release
Stimulated by glucose binding to Glut-2 transporter increasing signal transduction in the beta cell Increased generation of ATP blocks an ATP sensitive potassium channel (sulfonyurea drugs also block this channel and enhance insulin release) Membrane depolarization increases intracellular Ca+2, secretory granules move to membrane, extrude insulin (Ca+2 dependent) Insulin moves through islet inhibiting glucagon secretion (autocrine/paracrine activity) Liver is exposed to high levels of insulin - extracts insulin which binds to insulin receptor C-peptide is secreted in equimolar amounts with insulin and is used to assess beta cell activity since it is not extracted by the insulin receptor – …..beneficial for assessment of beta cell activity when insulin antibodies present or patient is taking insulin (exogenous insulin does not have C peptide) Potentiated by vagal stimulation (ACh) after a meal via M1/5 receptors and FFA via GPR40 which signal Gq and activate IP3 pathway and Ca release Potentiated by GLP-1 through Gs which makes cAMP and PKA Blocked by a2 adrenergic receptors (Epi, NE) via Gi which inhibit cAMP-PKA and close voltage gated calcium channels |
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Insulin, glucagon, somatostatin paracrine effects
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As Insulin exits the islet, it passes over the cells that release glucagon and somatostatin, and blocks their release
-Blocks own negative regulation so that it can continue to be released Somatostatin blocks release of insulin when glucagon is released -However, glucagon also has a small positive effect on insulin |
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Insulin's first pass action
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Liver
Insulin receptor internalization leads to degradation of insulin. This reduces the amount of insulin exiting the liver to access other tissues. Carbohydrate Metabolism: Glucose Buffer Function -Conversion of galactose and fructose to glucose -Storage of Glycogen -Gluconeogenesis Fat Metabolism -Oxidation of fatty acids -Synthesis of Cholesterol -Synthesis of fat from carbs Protein Metabolism -Deamination of amino acids -Removal of NH3 as urea -Synthesis of Plasma Proteins -Interconversion of amino acids |
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Insulin receptor and signalling pathways
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Receptor Tyrosine Kinase that initiates multiple signaling pathways
-Autophosphorylases Insulin triggers transport of glucose transporters to the plasma membranes in target tissues like liver, skeletal muscle, and adipocytes Insulin receptor triggers changes in enzymes that increase glucose storage as glycogen in liver and skeletal muscle, and lipid triglyceride storage of fatty acids in fat cells Insulin increases gene expression for enzymes involved in storage of energy sources (carbohydrates and fats) |
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Insulin's anabolic actions on liver (8)
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↑ Glucose uptake (in proportion to extracellular glucose)
↑ Glycolysis ↑ Fatty acid synthesis and VLDL ↑ Glucose storage as glycogen ↓ Gluconeogenesis ↓ Glycogenolysis ↓ Ketogenesis ↓ Urea cycle (AAs to glucose) |
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Insulin's anabolic actions on skeletal muscle (8)
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↑ Glucose uptake: increased GLUT4 at plasma membrane
↑ Glycolysis ↑ Protein synthesis ↑ Glucose storage as glycogen ↑ Amino acid uptake ↓ Gluconeogenesis ↓ Glycogenolysis ↓ Proteolysis |
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Insulin's anabolic actions on adipose (5)
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↑ Glucose uptake via GLUT4 at plasma membrane
↑ Glycolysis ↑ α-glycero-phosphate (αGP) ↑ Fatty acid esterification of αGP ↓ Lipolysis |
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Effects of insulindeficiency on FFA, glucose, and ketoacids
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Blood glucose rises
FFA rises Liver begins to make excess ketone bodies |
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Glucagon: release, pharmacokinetics, target
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α-cell of the pancreatic islets
Glucagon is of the “secretin” gene family, and is highly species-conserved. Secreted in response to decreased blood glucose (removal of suppression by insulin). Also, released upon stress, exercise, sympathetic activity (β2-AR); increased amino acids (arg, ala) in a protein meal (with insulin). Circulates unbound in serum. Acts at GPCR-Gs via cAMP and PKA. t1/2 = 6 min;predominantly degraded in the liver on first-pass metabolism. Liver is primary target tissue, with few effects on other tissues. |
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Glucagon-like peptide effects
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produced in Intestine
Glucagon-like peptide-1 (GLP-1) increases glucose-stimulated insulin release, GLP-1 increases beta cell hypertrophy and growth – can normalize glucose in NIDDM (GLP-1 is inactivated during nutrient ingestion) GLP-2 is an intestinal growth factor |
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Glucagon: effects
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Catabolic Usage of Glycogen
Glycogenolysis: G-1-P cleavage from Glycogen branches using Glycogen Phosphorylase, highly regulated by hormones Liver: G-1-P => G-6-P => glucose transported out via GLUT2 Muscle: G-1-P => G-6-P => glycolysis => lactate diffuses out (doesn't contribute to glucose in bloodstream, doesn't have glucokinase) |
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Sensitivity to insulin
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Sensitivity to Insulin is decreased by stress hormones, FFAs and disease states
Hormones: cortisol, growth hormone, catecholamines Free fatty acids Cytokines: TNF alpha |
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Brain-gut hormones that control feeding
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Empty stomach (hours) releases Ghrelin, which stimulates feeding.
A meal triggers stretch receptors that signal via the vagus, to inhibit feeding. As digestion progresses, CCK, insulin, and PYY reduce feeding. These are referred to as satiety signals. |
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Leptin
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Adipose hormone that regulates hunger and metabolic activity
Increase in total adipose tissue mass increases plasma leptin and decreases food intake, increases metabolic activity, etc. Hypothalamic effects -Increased energy -Increased activity -Decreased food intake (decreased NPY) Peripheral effects -Increase Temperature -Reproduction -Growth -O2 consumption -Decrease Insulin sensitivity |
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Reward pathway and obesity
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VTA Ventral Tegmental Area in the brain-stem senses signals that are of benefit to survival of the individual or the species.
Projections to the N. accumbens release Dopamine and to the Prefrontal Cortex release Dopamine as the neurotransmitter. The Prefrontal Cortex assists with goal setting, suppressing urges, judgement and other executive functions. |
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Orixigenic and anorexigenic mediators
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Orexigenic:
Ghrelin Orexin A and B AGRP NPY Galanin MCH Anorexigenic: Insulin Leptin PYY CCK α-MSH CRH CART Urocortin GLP-1 Oxytocin Neurotensin Enterostatin Somatostatin Bombesin |
