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Hormonal regulation of metabolism © Michael Palmer 2016 1 Hormones that affect energy metabolism © Michael Palmer 2016 Hormone Message insulin glucose and amino acids available, more substrates on the way glucagon glucose and amino acids in short supply, need to mobilize internal reserves epinephrine prepare for imminent sharp rise in substrate demand glucocorticoids prepare for extended period of high demand thyroid hormones increase basal metabolic rate 2 Langerhans’ islets in the pancreas produce insulin and glucagon © Michael Palmer 2016 3 A little bit of history: The purification of insulin—the problem © Michael Palmer 2016 4 The purification of insulin—Banting’s solution © Michael Palmer 2016 5 Historical side note: Norman Bethune, Banting’s famous classmate © Michael Palmer 2016 6 Structure of insulin and its precursors (1) © Michael Palmer 2016 7 Structure of insulin and its precursors (2) © Michael Palmer 2016 8 Sequences of human, swine, and bovine insulins © Michael Palmer 2016 9 Insulin secretion in the β-cell is controlled by glucose and triggered by membrane depolarization © Michael Palmer 2016 10 The sulfonylurea receptor controls an associated potassium channel © Michael Palmer 2016 11 KATP channels also regulate the tone of smooth muscle cells © Michael Palmer 2016 12 Tolbutamide promotes closing of the KATP channel © Michael Palmer 2016 13 The insulin receptor is a receptor tyrosine kinase © Michael Palmer 2016 14 Insulin receptor first phosphorylates itself and then a number of insulin receptor substrate proteins © Michael Palmer 2016 15 Insulin effects on glycogen synthesis © Michael Palmer 2016 16 The role of insulin in glucose transport © Michael Palmer 2016 Active transport Facilitated transport insulin-independent small intestine, kidney tubules brain, β-cells, red blood cells, cornea and lens of the eye insulin-dependent never muscle, fat, most other tissues 17 Insulin promotes glucose uptake by increasing the surface exposure of GLUT 4 transporters © Michael Palmer 2016 18 Transcriptional regulation by insulin © Michael Palmer 2016 19 Other hormones © Michael Palmer 2016 20 Glucagon and epinephrine act via G-protein-coupled receptors © Michael Palmer 2016 21 The glucagon and epinephrine receptors activate adenylate cyclase and protein kinase A © Michael Palmer 2016 22 Metabolic effects of protein kinase A Target Metabolic consequence glycogen synthase ↓ glucose is not locked up in glycogen, remains available phosphorylase kinase ↑ phosphorylase is activated, glucose is released from glycogen storage PFK-2 / Fructose-2,6bisphosphatase ↓/↑ Fructose-2,6-bisphosphate drops; glycolysis is inhibited, gluconeogenesis is activated hormone-sensitive lipase © Michael Palmer 2016 Effect ↑ fatty acids are mobilized for β-oxidation and ketogenesis 23 Glucocorticoids and thyroid hormones act on nuclear hormone receptors to activate transcription © Michael Palmer 2016 24 DNA binding by thyroid hormone receptors © Michael Palmer 2016 25 Thyroid hormones induce respiratory chain uncoupling proteins © Michael Palmer 2016 26 Metabolic effects of glucocorticoid hormones • induction of enzymes for glycogen synthesis, glycogen breakdown, as well as gluconeogenesis • induction of enzymes for protein breakdown, which supplies substrates for gluconeogenesis • induction of adrenergic receptors …overall, glucocorticoids increase blood glucose © Michael Palmer 2016 27 Glucocorticoid receptor agonists and antagonists © Michael Palmer 2016 28 Control of food intake by leptin © Michael Palmer 2016 29
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