Download Glycogen Metabolism

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 Synthesis
Figure 12-2
Regulation of Glycogen Synthase
Figure 12-4
Active/Inactive
Forms
– Active
• dephosphorylated
– Inactive
• phosphorylated
Regulation of Glycogen Synthase
Fasting
Figure 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
Phosphorylase
Feeding results in
decreased
glycogenolysis
Allosteric Regulation of Glycogen Phosphorylase
Table 12-1
Regulation of Glycogen Degradation during
Exercise
Figure 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 effective
Oral medications
– Mechanisms
•
•
•
•
Increase insulin production
Improve insulin receptor sensitivity
Inhibit gluconeogenesis
Inhibit carbohydrate absorption
Sulfonylureas
First widely used diabetic drug
Stimulates 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