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