Glycogen Metabolism Storage and Mobilization of Glucose NUTR 543 – Advanced Nutritional Biochemistry David L. Gee, PhD Professor of Food Science and Nutrition Department of Health, Human Performance, and Nutrition Central Washington University

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