Glucagon

1. Glucagon What: 29 amino acid peptide Where: a cells of pancreas When: low blood glucose in response to adrenalin (stress)

2. Glucagon receptor What: 7 transmembrane, G protein coupled Where: liver, adipocytes, and elsewhere (brain, pancreas a cells) Effect: increased production of cAMP liver: increased glyogenolysis and gluconeogenesis adipocytes: increased lipolysis

3. Glucagon receptor (Gs) cAMP Liver Phos I-1 PP1 PKA GS PP1 PFK2 F 2,6 bisP Phosphorylase kinase Glycogen synthase FBPase PK Phosphorylase Glycolysis Glucose export Glycogenolysis Gluconeogenesis

4. Epinephrine/Adrenalin Epinephrine: R = CH3 Nor-epinephrine: R = H Where: adrenal medula When: stress – release of AcCholine by neurons stimulates chromaffin cells of adrenal medula to release adrenalin Receptors: a liver b liver and muscle (cAMP) Effect: liver increased glycogenolysis, gluconeogenesis muscle inclreased glycogenolysis, glycolysis

5. Adrenalin: a1-receptor (Gq) liver Ca2+ Insulin receptor PKC Glycogen synthase Phosphorylase kinase Glycogenesis Phosphorylase Glycogenolysis Epinephrine: R = CH3 Nor-epinephrine: R = H

6. Adrenalin: b-receptor (Gs) Muscle cAMP Phos I-1 PP1 PKA GS PP1 FBPase F 2,6 bisP Phosphorylase kinase Glycogen synthase Heart muscle Glycolysis Phosphorylase Note: muscle isoform of PK is not phosphorylated by PKA Glycogenolysis

7. Insulin What: dimeric polypeptide 21 and 31 amino acids linked by S-S Where: b cells of pancreas (note: b cells contain GluT2) When: post absorptive state

8. Insulin receptor What: tetrameric (2a, 2b), transmembrane tyrosine kinase Where: liver, muscle, adipocytes Effect: muscle – translocation of GluT4 increased glycogenesis liver: increased glycogenesis, increased glycolysis See figures 9-45 and 9-46 Horton

9. Insulin Liver IRTK Several steps Phos Several steps ISPK Phosphatase GS PK Glycogen synthase kinase PFK2 F 2,6 bisP PDH Glycogen synthase AcCoA (for biosynthetic purposes Glycolysis Glycogenesis

10. Insulin Muscle IRTK Several steps Phos Several steps ISPK Phosphatase GS Translocation of GluT4 Glycogenesis G6P Glucose uptake

11. Summary of regulation of carbohydrate metabolism • Regulation by energy charge or metabolic intermediates • Hexokinase G6P • Glucokinase F6P (with regulatory protein) • PFK1 ATP, citrate; AMP, F2,6 bisP • PK ATP, F1,6 bisP • PDH AcCoA, NADH • F-1,6 bis Pase citrate, AMP, F2,6,bisP • Pyruvate carboxylase AcCoA • Isocitrate dehydrogenase NADH • Phosphorylase bAMP (muscle), G6P, ATP • Glycogen synthase bG6P • 2. Regulation by phosphorylation • PFK2: inhibitedin liver, activated in heart muscle • F-2,6-bis Pase: activated in liver • Pyruvate kinase: inhibited • Pyruvate dehydrogenase: inhibited (liver, PDH kinase and PDH phosphatase) • Phosphorylase activated by phosphorylase kinase • Glycogen synthaseinhibited PKA and glycogen synthase kinase

12. 3. Regulation by calcium - muscle • PDH phosphatase activated • Phosphoryae kinase activated • Isocitrate dehydrogenase activated • a-ketoglutarate dehydrogenase activated • 4. Glucose “sensors” • GluT 2 liver, pancreas • Glucokinase liver • Phosphorylase a/PP1