Hormonal Reg of Fuel Metabolism

Nota:

• Insulin and glucagon/epinephrine are the major hormones regulating metabolic changes between fasting and the fed state.
• Glucagon and epinephrine activate PKA and thus promote enzyme phosphorylation.
• Insulin activates protein phosphatases which reverse the effects of glucagon.
• Some enzymes are activated by phosphorylation, while others are inactive when phosphorylated.
• insulin and glucagon/epinephrine activate signal transduction cascades which have opposite effects on key metabolic enzymes.

1. Insulin

   Nota:

   • Insulin is peptide hormone with chains A and B linked by disulfide bonds
   • Production of mature insulin: synthesis, cleavage in RER lumen, transport proinsulin to Golgi and storage vesicles cleavage --> insulin + C-peptie coprecipitation with Zn++ in storage vesicles
   • Insulin promotes glucose storage as glycogen and conversion of glucose to fat.
   1. B- cells of pancreas
      1. High [blood glucose]
         1. Secrete Insulin
   2. Action
      1. Stimulates
         1. Glucose
            1. Uptake
               1. From blood
               2. In muscle cells
                  1. + GLUT-4
                     1. Major glucose transporter
               3. In brain cells
                  1. Insulin independent
            2. Utilization
               1. In Liver

                  Nota:

                  • Insulin stimulates the utilization of glucose in the liver, but not glucose uptake
            3. Storage
         2. Fat
            1. Synthesis
            2. Storage
         3. Protein
            1. Synthesis
      2. Inhibits
         1. Glycogen
            1. Breakdown
         2. Fat
            1. Mobilization
   3. Response
      1. Biphasic
         1. Initial
            1. Release from vesicles
         2. Sustained
            1. De novo synthesis
      2. [Blood glucose] increase

         Nota:

         • For increases in plasma glucose concentrations up to 300 mg/dL, the normal increase in insulin release is proportional to the glucose level
         • Sugars stimulate a more rapid increase in blood sugar than complex carbs Fiber decreases glycemic index of foods (area under 2 hr glucose curve after feeding 50 g CHO portion)
         1. 2-3x normal range
   4. Reverse PKA Effects
      1. + protein serine/threonine phosphatase
         1. Reverses phosphorylation from PKA
         2. Inhibits mobilization of glucose from glycogen
         3. + glycogen synthase
2. Glucagon

   Nota:

   • 29 AA polypeptide hormone released by a-cells of pancreas Initial synthesis of proglucagon Plasma glucagon has half-life of 3-5 mins
   1. Fasted State
      1. Liver
         1. Releases glucose
            1. Maintains plasma levels
            2. Mobilizes glycogen
         2. Gluconeogenesis
            1. AAs
               1. Muscle Catabolism
      2. Major Energy Source
         1. Fatty Acids
            1. TAGs
   2. Secretion
      1. Stimulated
         1. Epinephrine
         2. Cortisol
         3. Exhaustive Exercise
         4. Amino Acids

            Nota:

            • in normal, "mixed" meals, amino acids, especially lysine and arginine, increase (or potentiate) the insulin response to glucose.
            1. Protein meal, no CHO
      2. Inhibited
         1. High [plasma glucose]
         2. Insulin
   3. Action
      1. Targets
         1. Liver
         2. Adipocytes
         3. NOT muscle
      2. Stimulates
         1. Glycogen breakdown
         2. Gluconeogenesis
         3. Glucose release
         4. TAG hydrolysis
         5. FA release
      3. Inhibits
         1. Glycogen synthesis
         2. Fat storage
      4. Increase cAMP
         1. Activate PKA
3. Epinephrine
   1. Synthesis
      1. Response to stress
         1. Adrenal Medulla
   2. Action
      1. Glycogen Mobilization
         1. Liver
            1. Blood Glucose
         2. Muscle
            1. glucose-P
               1. ATP generation
      2. Increase cAMP
         1. Activate PKA
            2. + phosphorylase kinase
               1. + phosphorylase
                  1. Release glucose -P from glycogen
            3. + lipase
               1. Hydrolysis of stored fat
            4. - glycogen synthase

               Nota:

               • First step in FA synthesis
               1. inhibits glycogen synthesis
            5. Insulin reverses effects
4. Glucocorticoids
   1. Action
      1. Stimulate fuel mobilization
         1. Regulate gene transcription
         2. Glycogen synthesis

            Nota:

            • Cortisol stimulates glycogen synthesis, then glucagon and epinephrine stimulate glycogen mobilization
      2. Bind intracellular receptors
      3. Mediate changes over long periods
         1. Starvation
         2. Sepsis
         3. Stress