The Endocrine Pancreas: Regulation of Carbohydrate Metabolism

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The Endocrine PancreasRegulation of
Carbohydrate Metabolism

• Metabolism Food Utilization
• Major Metabolic Pathways for Carbohydrates,
  Lipids Proteins
• The Endocrine Pancreas
• Insulin and Carbohydrate Metabolism
• Glucagon and Carbohydrate Metabolism
• Other Factors Influencing Metabolism

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What is Metabolism?

• Metabolism is the sum of all chemical reactions
  in the body.
• Chemical reactions can either create larger
  molecules (requires energy) or break down large
  molecules into smaller molecules (releases
  energy).
• The process of breaking down large molecules is
  called catabolism.
• The process of building larger molecules is
  called anabolism.

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Catabolism

• Occurs in an orderly manner (not just random
  degradation).
• Breaks down large molecules into smaller
  molecules.
• In the process, energy is released.

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Anabolism

• Occurs in an orderly manner.
• Smaller molecules are used to build larger
  molecules.
• This process requires energy.
• The smaller molecules and energy are obtained
  from the catabolism of larger molecules (ie,
  food).

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Carbohydrates

• Composed of carbon, hydrogen, and oxygen
• General chemical formula (CH2O)n
• Used for energy production, energy storage, and
  signaling interactions
• Carbohydrates are polar, so theyre soluble in
  water
• They exist as monosaccharides, disaccharides, and
  polysaccharides

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Structures of Common Hexoses
The chemical composition of glucose, fructose,
and galactose is identical. What differs is
location of the hydrogen, hydroxyl, and oxygen
groups.
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Dissaccharides

• Dissaccharides are composed of two
  monosaccharides bonded together.
• For example
• sucrose glucose fructose
• lactose glucose galactose
• maltose glucose glucose

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Polysaccharides

• Many simple sugars join together to form long
  chains.
• Chains may be straight or branched.
• The most common form is glycogen, the storage
  form of glucose.
• Glycogen can be broken down to release glucose

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Proteins

• Proteins are made up of amino acids (the basic
  building block of proteins).
• - each consists of a carbon attached to a
  carboxyl group, an amino group, and an R group.
• - the R group differs between amino acids (and
  thus determines their unique qualities).

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Building Proteins from Amino Acids

• Amino acids attach to each other by joining the
  carboxyl group of one with the amino group of the
  next, forming a peptide bond.
• Similarly, peptide bonds can be broken, resulting
  in release of amino acids.

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Lipids

• Lipids are large chains or rings of carbon and
  hydrogen with some oxygen (less than that in
  carbohydrates).
• Lipids may also contain nitrogen, phosphorus, and
  sulfur.
• Lipids contribute to structure of cells, and are
  important in energy storage.

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Fatty acids

• Composed of long chains of carbon with hydrogen
  atoms attached, and a carboxyl group group at the
  end.
• If all carbon-carbon bonds are single bonds, the
  fatty acid is referred to as being saturated.
• If there are double bonds between carbons, its an
  unsaturated fatty acid.

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Triacylglycerol

• Fatty acids are usually attached to glycerol,
  with a -COOH group at the end.
• glycerol 3 fatty acids triacylglycerol
• Triacylglycerol can be broken down into fatty
  acids and glycerol.
• Represent 95 of stored fat in the body

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How do we use food components in catabolic and
anabolic pathways?

• Involves specific chemical reactions
• - Each reaction is catalyzed by a specific
  enzyme.
• - Other compounds, besides those being directly
  metabolized, are required as intermediates or
  catalysts in metabolic reactions
• - adenosine triphosphate (ATP)
• - nicotinamide adenine dinucleotide (NAD)
• - flavin adenine dinucleotide (FAD)
• - Coenzyme A

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ATP

• ATP is the energy currency of the cell
• The structure of ATP is similar to that of
  nucleic acids
• The energy in ATP is carried in the phosphate
  groups
• - to convert ADP into ATP requires energy
• - the energy is stored as potential energy in
  the phosphate group bond
• - removal of the third phosphate releases that
  energy

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NADH, FADH2

• NAD can accept a hydrogen ion and become reduced
  to NADH
• NAD 2H 2e- ? NADH H
• The added hydrogen ion (and electrons) can be
  carried to and used in other reactions in the
  body.
• FAD is similarly reduced to FADH2.
• NADH and FADH carry hydrogen ions and electrons
  to the enzymes in the electron transport chain of
  the mitochondria, allowing ATP production there.

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Coenzyme A

• The enzyme coenzyme A converts acetyl groups
  (2-carbon structures) into acetyl CoA, which can
  then be used in metabolic reactions
• During the course of acetyl CoA production,
  energy is released and is used to convert NAD to
  NADH

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Cellular Respiration

• Generating ATP from food requires glycolysis, the
  Krebs Cycle, and the electron transport chain.
• Overall reaction
• C6H12O6 6 O2----gt 6 CO2 6 H2O 38 ATP
  heat
• The Main point the break down of glucose
  releases LOTS of energy
• - about 40 in usable form (ATP)
• - about 60 as heat

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Glycolysis

• Glycolysis is the breakdown of glucose into
  pyruvic acid
• Two main steps are involved, occurring in the
  cytoplasm of cells (no organelles involved).

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The two main steps of glycolysis
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What happens to pyruvic acid?

• In aerobic respiration (oxygen present)
• - pyruvic acid moves from cytoplasm to
  mitochondria
• - pyruvic acid (3 carbons) is converted to
  acetyl group (2 carbons), producing CO2 in the
  process
• - acetyl group is converted to acetyl CoA by
  coenzyme A
• - acetyl CoA is used in the Krebs cycle.

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Krebs Cycle

• Acetyl CoA combines with oxaloacetic acid,
  forming citric acid
• A series of reactions then occurs resulting in
• - one ATP produced
• - three NADH and one FADH2 produced (go to
  electron transport chain)
• - two CO2 molecules produced

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Electron-transport Chain

• The main point NADH and FADH2 carry H ions to
  the electron-transport chain, resulting in
  production of ATP
• To do this, the H ions are moved along the
  transport chain, eventually accumulating in the
  outer mitochondrial compartment
• The H ions move back into the inner
  mitochondrial compartment via hydrogen channels,
  which are coupled to ATP production.
• At the end of the transport chain, four hydrogen
  ions join with two oxygen molecules to form
  water
• 4 H O2 ----gt 2 H2O
• In the absence of oxygen, the transport chain
  stalls (no ATP production)

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Net Result of Glycolysis, Citric Acid Cycle, and
Electron Transport Chain

• Production of ATP (stored, potential energy for
  chemical reactions in the body 40 of energy
  released).
• Production of heat (maintains body temperature
  60 of energy released).
• Also, production of CO2 and H2O.

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Storage Utilization of Glycogen

• Excess glucose can be stored as glycogen.

• Stored glycogen can be utilized, by
  glycogenolysis.
• Glycogenolysis
• -glycogen is broken down into glucose
  6- phosphate
• - liver transforms glucose 6-phosphate to
  glucose, maintaining blood glucose levels

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Lipid Metabolism

• Over 95 of stored energy in the body is in the
  form of triacylglycerol
• During lipid catabolism (lipolysis),
  triacylglycerol is broken down into free fatty
  acids and glycerol
• Free fatty acids are metabolized by
  beta-oxidation
• 1) fatty acid (18 C) coenzyme A
• 2) fatty acid (18 C)-coA
• 3) fatty acid (16 C) and acetyl-coA
• Acetyl-CoA used in citric acid cycle
• This reaction also yields NADH gt electron
  transport chain
• Excess acetyl-CoA forms ketone bodies

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Lipid Metabolism (cont.)

• The glycerol is converted into glyceraldehyde
  3-phosphate, which is converted to pyruvic acid
• Pyruvic acid is metabolized under aerobic
  conditions into acetyl-coA
• While lipids are major storage form of energy,
  accessing lipids for metabolism takes time
• - water insoluble
• - less efficient energy source
• - potential for keto-acidosis

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Protein Metabolism

• Amino acids are NOT stored for energy
• However, protein can be broken down, and amino
  acids can be modified and utilized to create
  glucose or for metabolism
• Modification of amino acids to produce substrate
  for energy involves oxidative deamination

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Oxidative Deamination

• Oxidative deamination removes the amino group
  from the amino acid, forming ammonia, NADH, and a
  keto acid
• NADH gt electron transport chain
• ammonia gt liver, converted to urea
• keto acid gt acetyl-coA gt citric acid cycle

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Proteins and Energy

• Utilization of proteins for quick energy is not
  very efficient
• - more difficult to break apart (multiple
  proteases)
• - toxic byproduct (ammonia)
• - can get accumulation of keto acids
• - proteins are important structural and
  functional components of cells

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Interconversion of Nutrients

• Lipogenesis once glycogen stores are filled,
  glucose and amino acids are converted to lipids
• Rate limiting enzyme acetyl CoA carboxylase

acetyl CoA carboxylase
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Interconversion of Nutrients (cont.)

• Gluconeogenesis amino acids and glycerol can be
  used to produce glucose (liver)
• More glucose is produced via gluconeogenesis than
  glycogenolysis
• Rate-limiting enzyme phosphoenolpyruvate
  carboxykinase

PEPCK
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Importance of Blood Glucose Homeostasis

• Blood glucose levels must be maintained as a
  nutrient source for nervous tissue (no glucose
  stores)
• What mechanisms regulate blood nutrient levels in
  tissues and blood glucose levels?

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The Endocrine Pancreas Regulation of Nutrient
Metabolism

• Located on the posterior abdominal wall,
  retroperitoneal.
• Exocrine portion secretes digestive enzymes via
  pancreatic duct, to small intestine.
• Endocrine portion pancreatic islets (of
  Langerhans), involved in regulation of blood
  glucose levels.

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Production of Pancreatic Hormones by Three Cell
Types

• Alpha cells produce glucagon.
• Beta cells produce insulin.
• Delta cells produce somatostatin.

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Structure of Insulin

• Insulin is a polypeptide hormone, composed of two
  chains (A and B)
• BOTH chains are derived from proinsulin, a
  prohormone.
• The two chains are joined by disulfide bonds.

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Roles of Insulin

• Acts on tissues (especially liver, skeletal
  muscle, adipose) to increase uptake of glucose
  and amino acids.
• - without insulin, most tissues do not take in
  glucose and amino acids well (except brain).
• Increases glycogen production (glucose storage)
  in the liver and muscle.
• Stimulates lipid synthesis from free fatty acids
  and triglycerides in adipose tissue.
• Also stimulates potassium uptake by cells (role
  in potassium homeostasis).

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The Insulin Receptor

• As we previously saw, the insulin receptor is
  composed of two subunits, and has intrinsic
  tyrosine kinase activity.
• Activation of the receptor results in a cascade
  of phosphorylation events

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Specific Targets of Insulin Action Carbohydrates

• Increased activity of glucose transporters.
  Moves glucose into cells.

• Activation of glycogen synthetase. Converts
  glucose to glycogen.
• Inhibition of phosphoenolpyruvate carboxykinase.
  Inhibits gluconeogenesis.

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Specific Targets of Insulin Action Lipids

• Activation of acetyl CoA carboxylase. Stimulates
  production of free fatty acids from acetyl CoA.
• Activation of lipoprotein lipase (increases
  breakdown of triacylglycerol in the circulation).
  Fatty acids are then taken up by adipocytes, and
  triacylglycerol is made and stored in the cell.

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Regulation of Insulin Release

• Major stimulus increased blood glucose levels
• - after a meal, blood glucose increases
• - in response to increased glucose, insulin
  is released
• - insulin causes uptake of glucose into
  tissues, so blood glucose levels decrease.
• - insulin levels decline as blood glucose
  declines

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Effect of Glucose on Insulin Release

• Glucose enters beta cell through a glucose
  transporter.
• Glucose is utilized to generate ATP.
• ATP closes a potassium channel, depolarizing the
  beta cell membrane (normally, K leaks out of
  cell).
• Depolarization activates a voltage-dependent
  calcium channel, increasing intracellular calcium
  levels.
• Increased calcium triggers insulin release.

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Other Factors Regulating Insulin Release

• Amino acids stimulate insulin release (increased
  uptake into cells, increased protein synthesis).
• Keto acids stimulate insulin release (increased
  glucose uptake to prevent lipid and protein
  utilization).
• Insulin release is inhibited by stress-induced
  increase in adrenal epinephrine
• - epinephrine binds to alpha adrenergic
  receptors on beta cells
• - maintains blood glucose levels
• Glucagon stimulates insulin secretion (glucagon
  has opposite actions).

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Structure and Actions of Glucagon

• Peptide hormone, 29 amino acids
• Acts on the liver to cause breakdown of glycogen
  (glycogenolysis), releasing glucose into the
  bloodstream.
• Inhibits glycolysis
• Increases production of glucose from amino acids
  (gluconeogenesis).
• Also increases lipolysis, to free fatty acids for
  metabolism.
• Result maintenance of blood glucose levels
  during fasting.

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Mechanism of Action of Glucagon

• Main target tissues liver, muscle, and adipose
  tissue
• Binds to a Gs-coupled receptor, resulting in
  increased cyclic AMP and increased PKA activity.
• Also activates IP3 pathway (increasing Ca)

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Targets of Glucagon Action

• Activates a phosphorylase, which cleaves off a
  glucose 1-phosphate molecule off of glycogen.
• Inactivates glycogen synthase by phosphorylation
  (less glycogen synthesis).
• Increases phosphoenolpyruvate carboxykinase,
  stimulating gluconeogenesis
• Activates lipases, breaking down triglycerides.
• Inhibits acetyl CoA carboxylase, decreasing free
  fatty acid formation from acetyl CoA
• Result more production of glucose and substrates
  for metabolism

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Regulation of Glucagon Release

• Increased blood glucose levels inhibit glucagon
  release.
• Amino acids stimulate glucagon release (high
  protein, low carbohydrate meal).
• Stress epinephrine acts on beta-adrenergic
  receptors on alpha cells, increasing glucagon
  release (increases availability of glucose for
  energy).
• Insulin inhibits glucagon secretion.

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Raises blood sugar
High blood sugar
Glucagon
Promotes insulin release
Stim glycogen breakdown
Glycogen Glucose
Pancreas
Liver
Insulin
Stim glycogen formation
Stim glc uptake from blood
Promotes glycogen release
Tissue cells
Lowers blood sugar
Low blood sugar
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Other Factors Regulating Glucose Homeostasis

• Glucocorticoids (cortisol) stimulate
  gluconeogenesis and lipolysis, and increase
  breakdown of proteins.
• Epinephrine/norepinephrine stimulates
  glycogenolysis and lipolysis.
• Growth hormone stimulates glycogenolysis and
  lipolysis.
• Note that these factors would complement the
  effects of glucagon, increasing blood glucose
  levels.

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Hormonal Regulation of Nutrients

• Right after a meal (resting)
• - blood glucose elevated
• - glucagon, cortisol, GH, epinephrine low
• - insulin increases (due to increased glucose)
• - Cells uptake glucose, amino acids.
• - Glucose converted to glycogen, amino acids
  into protein, lipids stored as triacylglycerol.
• - Blood glucose maintained at moderate levels.

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Hormonal Regulation of Nutrients

• A few hours after a meal (active)
• - blood glucose levels decrease
• - insulin secretion decreases
• - increased secretion of glucagon, cortisol, GH,
  epinephrine
• - glucose is released from glycogen stores
  (glycogenolysis)
• - increased lipolysis (beta oxidation)
• - glucose production from amino acids increases
  (oxidative deamination gluconeogenesis)
• - decreased uptake of glucose by tissues
• - blood glucose levels maintained

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Hypoglycemia

• Abnormally low blood glucose levels.
• If sustained, CNS does not get enough glucose
• - disorientation
• - convulsions
• - unconsciousness
• - death

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Diabetes lack of insulin (or insulin action)

• Glucose is not taken into cells for use.
• Increased use of lipids, amino acids for energy
  can lead to ketoacidosis (decline in blood pH).
• Get deposition of lipid on arterial walls
  (atherosclerosis)
• Damage to blood vessels in the kidney, eye, limbs
  (especially feet)

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Next Lecture

• Adrenal Steroids