Exam

Glucose Metabolism

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Glucose Metabolism, Glycolysis, Embden-Meyerhoff Pathway, Gluconeogenesis, Blood Sugar Regulation, Citric Acid Cycle, Krebs Cycle, Kreb Cycle, Tricarboxylic Acid Cycle, TCA Cycle, Carbohydrate Metabolism, Energy Metabolism, Incretin, Acetyl Coenzyme A

  • See Also
  1. Carbohydrate Metabolism
  2. High Energy Molecule (e.g. Adenosine Triphosphate, ATP)
  • Definitions
  1. Glycolysis (Embden-Meyerhoff Pathway)
    1. glycolysis.png
    2. glycolyticPathMolecules.png
    3. Catabolic pathway to breakdown carbohydrates (Glucose, fructose) into pyruvate, without need for oxygen
    4. Represents only a small part of the overall energy generation from carbohydrates (2 net ATP and 1 NADH)
    5. Pyruvate may then be converted to acetyl-CoA (or, when oxygen is unavailable to Lactic Acid)
      1. Acetyl CoA enters TCA Cycle for energy generation (or is used to form Triglycerides)
    6. Triggered by Insulin, which lowers Glucose via both Glycolysis as well as increasing glycogen stores
  2. Acetyl Coenzyme A (Acetyl CoA)
    1. Synthesized from Coenzyme A and acetic acid
    2. Acetyl CoA is substrate in the biosynthesis of Fatty Acids, sterols and amino acids
    3. Serves as entry point of Citric Acid Cycle
      1. Feeds it substrate from Glucose (and other carbohydrate), amino acid and Fatty Acid catabolism
  3. Citric Acid Cycle (Krebs Cycle, Tricarboxylic Acid Cycle, TCA Cycle)
    1. glycolysis.png
    2. krebCycle.png
    3. Universal pathway seen across multicellular organisms, taking place in mitochondria in humans
    4. Generates energy from Acetyl CoA (3 NADH, 1 FADH, 1 GTP) derived primarily from Glucose
    5. Intermediate steps include oxaloacetate, isocitrate, a-Ketoglutarate, succinyl-CoA, Succinate, fumarate, malate
      1. Kreb Cycle intermediates also lead to other pathways (e.g. succinyl-CoA to heme synthesis pathways)
    6. With decreased Energy Intake or increased Energy Expenditure, Glucose reserves (e.g. glycogen) are exhausted
      1. In early starvation, Fatty Acids are catabolized to acetyl CoA (and glycerol), fueling the Krebs Cycle
      2. With longer starvation, amino acids are catabolized to enter the Krebs Cycle
  4. Gluconeogenesis
    1. gluconeogenesis.png
    2. Pathway forms Glucose from 3- or 4-carbon noncarbohydrate precursors (e.g. pyruvate, amino acids and glycerol)
    3. Process takes place in the Kidneys and liver and is triggered when Insulin levels are low and in starvation states
    4. The same triggers for Gluconeogenesis also trigger Lipolysis and Ketogenesis
  • Physiology
  1. See Gastrointestinal Metabolism
  2. Images
    1. carbohydrateMetabolism.png
    2. gluconeogenesis.png
    3. glycolysis.png
    4. glycolyticPathMolecules.png
    5. krebCycle.png
  3. Blood Glucose
    1. Released from hepatic stores between meals
    2. Derived from ingested carbohydrates
      1. Postprandial Glucose >20 fold over hepatic release
  4. Insulin
    1. See Insulin
    2. General
      1. Insulin produced by pancreatic beta cells
      2. Insulin release stimulated by Blood Glucose
      3. Insulin response to Glucose is linear
        1. Insulin response is based on Glucose sensitivity
        2. Glucose sensitivity depends on Ambient Glucose
          1. Normal: Rapid Insulin release with a meal
          2. Fasting: Steeper rate of Insulin release
          3. Prolonged Hyperglycemia: Flattened response
      4. Overall Insulin effects
        1. Promotes Glucose uptake by liver and Muscle and for storage as glycogen
          1. Does not effect brain Glucose uptake (Glucose freely crosses blood brain barrier)
        2. Promotes cellular uptake of amino acids and protein synthesis
        3. Promotes hepatic synthesis of Fatty Acids, VLDL transport to adipose for Triglyceride storage
        4. Promotes Glycolysis for energy utilization
        5. Suppresses Gluconeogenesis
    3. Phase 1 Insulin Release
      1. Duration: 10 minutes
      2. Suppresses hepatic Glucose release
    4. Phase 2 Insulin Release
      1. Duration: 2 hours
      2. Controls mealtime carbohydrates
    5. Basal Insulin Release
      1. Low continuous Insulin level
      2. Covers metabolic needs between meals
  5. Glucagon
    1. See Glucagon
    2. Endogenous polypeptide Hormone secreted by pancreatic alpha cells
    3. Opposite effect of Insulin
      1. While Insulin lowers Serum Glucose (glycogen storage, Glycolysis), Glucagon increases Serum Glucose
      2. However, both Insulin and Glucagon increase amino acid uptake from the liver
    4. Hypoglycemia effect (primary)
      1. Hypoglycemia Increases pancreatic secretion of Glucagon
      2. Glucagon stimulates Glucose release from glycogen (glycogenolysis)
      3. Glucagon also stimulates Glucose synthesis (Gluconeogenesis)
    5. Inhibitors of Glucagon release
      1. Hyperglycemia
        1. Inhibits pancreatic secretion of Glucagon
      2. GLP1 (Incretin)
        1. Secreted by Small Bowel
        2. Stimulates pancreatic beta cells and inhibits Glucagon
        3. See Incretin Mimetics (used in Type 2 Diabetes Mellitus)
    6. Amino Acid Excess Effect
      1. Increases pancreatic secretion of Glucagon
      2. Glucagon stimulates liver uptake of amino acids
        1. Both Insulin and Glucagon increase liver uptake of amino acids
    7. Acts at Catecholamine-independent receptors on cardiac cells
      1. Increases intracellular Calcium in cardiac cells
      2. Increases myocardial contractions
  6. Growth Hormone
    1. See Growth Hormone
    2. Polypeptide produced in the acidophil cells of the anterior pituitary
    3. Hypothalamus controls release when triggered by Hypoglycemia, decreased amino acids
      1. Growth Hormone Releasing Hormone (GHRH) stimulates release
      2. Somatostatin inhibits release
    4. Biochemistry
      1. Liver converts Growth Hormone to Insulin-like growth factor (IGF-1) and stimulates other growth factors
      2. Growth Hormone is a precursor to Testosterone
    5. Positive Function (stimulates or promotes the following activities)
      1. Bone and cartilage growth
      2. Protein synthesis
      3. Promotes Fatty Acid use as fuel instead of Glucose
        1. Lipid catabolism to Fatty Acids (for energy source)
        2. Hyperglycemia (from decreased cell utilization of Glucose) resulting in an increase of glycogen stores
  7. Cortisol
    1. See Cortisol
    2. Cortisol is synthesized in the Adrenal Cortex, derived from Cholesterol (See Cortisol Synthesis_
    3. Cortisol secretion is stimulated by Adrenocorticotropic Hormone (ACTH) in response to stress (See Pituitary Gland)
    4. Cortisol functionality
      1. Mobilizes available energy sources (Glucose, fats, amino acids)
        1. Increases Serum Glucose by stimulating liver Gluconeogenesis and glycogenolysis
        2. Increases serum Fatty Acids by promoting lipolysis of adipose Triglyceride stores
        3. Increases blood amino acids by breaking down proteins (outside liver)
          1. Within liver, Cortisol induces protein synthesis
      2. Antiinflammatory activity
        1. Inhibit histamine release
        2. Inhibit Lymphocyte production
        3. Stabilize MacrophageLysosomes
      3. Increases gastric acid production
  8. Epinephrine
    1. See Epinephrine
    2. Epinephrine has alpha-adrenergic effects (esp. alpha-2) specific to metabolism
      1. Increases Serum Glucose (Gluconeogenesis, Glycogenolysis)
      2. Increases Fatty Acids (Fat cell lipolysis of Triglycerides)
    3. Most of Epinephrine's primary effects are cardiopulmonary
      1. Alpha Adrenergic Agonist Effects
        1. Vasoconstriction (increased Systemic Vascular Resistance and Blood Pressure)
        2. Increases Vital Organ Perfusion (myocardial and cerebral perfusion)
        3. Decreases Non-Vital Organ Perfusion
          1. Decreases splanchnic and intestinal perfusion
          2. Decreases renal and skin perfusion
      2. Beta Adrenergic Agonist effects (Under 0.3 ug/kg/min)
        1. Increases myocardial contractility and Heart Rate
        2. Relaxes Bronchial Smooth Muscle (bronchodilation)
  9. Incretin
    1. Group of peptides
      1. Glucagon-Like Peptide-1 (GLP-1)
      2. Glucose Dependent Insulinotropic Peptide (GIP) or Gastric inhibitory peptide
    2. Functions
      1. Triggers Insulin synthesis
      2. Inhibit Glucagon secretion
      3. Decreases gastric emptying
  • Pathophysiology
  1. Lactic Acid
    1. Generated when oxygen is unavailable to allow for Krebs Cycle related Oxidative Phosphorylation
    2. Glycolysis generates 7 net ATP/Glucose (compared with 25 for Kreb Cycle) and does not require oxygen
    3. However, Glycolysis does use NAD+ (for glyceraldehyde 3-P to 1,3P2-glycerate)
      1. NAD+ is typically replenished in the Krebs Cycle related Oxidative Phosphorylation
      2. When oxygen is unavailable, pyruvate is metabolized to Lactic Acid, regenerating NAD+
  1. Insulin excess
    1. See Hypoglcemia
    2. See Insulin Shock (Insulin Overdose, Insulin Reaction)
  2. Insulin at low levels or deficiency
    1. Causes
      1. Low Insulin due to Diabetes Mellitus
        1. In Type I Diabetes, Insulin deficiency is key
        2. In Type II Diabetes, Insulin Resistance is key initially, but later Insulin deficiency results
      2. Low Insulin as a normal physiologic response to Hypoglycemia
    2. Low Insulin effects
      1. Gluconeogenesis and Glycogenolysis results in Hyperglycemia
      2. Lipolysis (Triglyceride breakdown to Fatty Acids)
        1. Further lysed into acetyl coA to be utilized in the Kreb Cycle (TCA Cycle, Citric Acid Cycle)
        2. Other Fatty Acids are diverted to Ketogenesis (Ketone formation)
          1. Occurs in Diabetic Ketoacidosis, Starvation Ketosis, Alcoholic Ketoacidosis
        3. Fatty Acids also form excess Cholesterol, Triglycerides within VLDL with increasing atherosclerosis
  1. See Type I Diabetes Mellitus
  2. See Maturity Onset Diabetes of the Young
  3. Deficiency of Insulin, with multiple underlying mechanisms
  4. Type 1A
    1. Environmental and genetic factors
    2. HLA-DR4 association
    3. Cell mediated pancreatic beta cell destruction
  5. Type 1B (uncommon)
    1. Primary Autoimmune Condition
    2. Associated with other Autoimmune Conditions
      1. Hashimoto's Thyroiditis
      2. Grave's Disease
      3. Myasthenia Gravis
    3. HLA-DR3 association
    4. Incidence highest in 30-50 year olds
  6. Secondary Diabetes Mellitus
    1. Cystic Fibrosis
  1. See Type II Diabetes Mellitus
  2. Loss of Glucose sensitivity (see above)
    1. Loss of phase 1 Insulin response
    2. Insufficient phase 2 Insulin response
  3. Insulin production by beta cell
    1. First: Insulin increases to overcome Glucose toxicity
    2. Results in beta-cell exhaustion (Glucose Toxicity)
      1. Initially reversible beta cell exhaustion
      2. Permanent later as amyloid replaces beta cells
    3. Insulin levels decrease as beta cells fail
      1. Beta-cell function reduced to <50% by DM diagnosis
  4. Impaired Incretin action
    1. Incretins manage postprandial Glucose levels
      1. Incretin released from GI Tract following meals
    2. Endogenous Incretin effects
      1. Increases Glucose dependent Insulin secretion
      2. Delays gastric emptying
      3. Decreases food intake (improves satiety)
    3. Progressive Incretin reduced activity
      1. Glucagon-Like Peptide 1 (GLP-1) activity decreases
  5. Medications
    1. Increase Insulin sensitivity
      1. Metformin
      2. Thiazolidinediones
    2. Stimulate Insulin release from beta cells
      1. Meglitinides (act on phase 1 release)
      2. Sulfonylureas (act on phase 2 release)
    3. Replace Insulin
      1. See Insulin
    4. Increase Incretin levels (GLP-1)
      1. Exenatide (Byetta)
      2. Sitagliptin (Januvia)
  • References
  1. Goldberg (2014) Clinical Physiology, Medmasters, Miami, p. 120-46