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Glycogen Metabolism Storage and Mobilization of Glucose
Glycogen Functions
Liver– Buffer for regulating blood glucose levels
Muscle– Store of glucose as a fuel for exercise • high intensity exercise dependent on anaerobic
glycolysis
Glycogen SynthesisFigure 12-2
Regulation of Glycogen SynthaseFigure 12-4
Active/Inactive Forms– Active
• dephosphorylated
– Inactive • phosphorylated
Regulation of Glycogen Synthase
FastingFigure 12-4
Glucagon or epinephrine – G-protein
linked receptors
– increased [cAMP]
Regulation of Glycogen Synthase Fasting
Figure 12-4
cAMP activates Protein Kinase A
Protein kinase A phosphorylates and inactivates glycogen synthase
Little glycogen synthesis during fasting
Regulation of Glycogen Synthase Feeding
Figure 12-4
Insulin– Reduces [cAMP]
• Stimulates phosphodiesterase
– Induces and activates protein phosphatase-1•Activates GS
Feeding results in glycogen synthesis
Glycogen Degradation
Glycogen Phosphorylase– Hydrolyzes glucose units from glycogen– Produces glucose-1-P
Removal of branch points– Debranching enzyme complex•Glucan transferase•Alpha-1,6-glucosidase
Regulation of Glycogen Phosphorylase Fasting
Figure 12-7
Glucagon or epinephrine– Increase [cAMP]– Activates Protein
Kinase A– Phosphorylates and
activates glycogen phosphorylase
Fasting results in increased glycogenolysis
Regulation of Glycogen Phosphorylase Feeding
Figure 12-7
Insulin– Reduces [cAMP]– Induces and activates
Protein Phosphatase-1– Inactivates Glycogen
PhosphorylaseFeeding results in
decreased glycogenolysis
Allosteric Regulation of Glycogen PhosphorylaseTable 12-1
Regulation of Glycogen Degradation during ExerciseFigure 12-8
Coordinated Regulation of Glycogen Metabolism (Table 12-2)
Application:Pharmacological Agents for Diabetics
Insulin– Mandatory for Type 1 diabetics– Used in Type 2 diabetics as oral medications
become less effectiveOral medications– Mechanisms• Increase insulin production• Improve insulin receptor sensitivity• Inhibit gluconeogenesis• Inhibit carbohydrate absorption
Sulfonylureas
First widely used diabetic drugStimulates endogenous release of insulin from
pancreas– Direct action on ATP-K channel protein on beta-cells
Short and longer acting forms– Glipizide (Glucotrol), glyburide (Diabeta), tolazamide
(Tolinase)Side Effects– Hypoglycemia– Weight gain
Meglitinides
Like sulfonylureas, stimulate pancreatic secretion of insulin– Short-acting: taken with meals
Replaglinide (Prandin)Side Effects– Hypoglycemia– Weight gain
Biguanides
Mechanism of action– Reduces gluconeogenesis (stimulates (?) Protein kinase A)– Decrease absorption of dietary CHO– Increase insulin sensitivity
Metformin (Glucophage) (most widely used anti-diabetic drug)
Side effects (not hypoglycemia)– Lactic acidosis
•Contraindicated in heart failure, liver and kidney disorders– Diarrhea
Other facts– Only drug shown to reduced risk diabetes related heart disease– Derived from French lilac (known as useful for treating symptoms of
diabetes)
Thiazolidinediones (TZDs)
Mechanism of action– Binds to nuclear receptors that increase transcription of
certain genes•Decreased insulin resistance•Leptin levels decreased (increased appetite)
Rosiglitazone (Avandia)Side effects: edema, risk of hepatitis, increased
heart disease risk (5/07 – FDA safety alert)
Incretin mimetic
Incretins are GI hormones that increase insulin production
Exenatide (39aa peptide from saliva of gila monster (lizard spit), synthesized)– 50% homology with Glugacon-Like Peptide (GLP), an
incretin that stimulates insulin production and inhibits glucagon production
– Self-regulating: active only when during hyperglycemia– Appetite suppresent effect: gradual weight loss
Side effects: – may increase hypoglycemic risk with sulfonylureas– must be injected 2x per day