Hormonal regulation of metabolism

Hormones that affect energy metabolism 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

Langerhans’ islets in the pancreas produce insulin and glucagon

A little bit of history: The purification of insulin—the problem

The purification of insulin—Banting’s solution

Historical side note: Norman Bethune, Banting’s famous classmate

Structure of insulin and its precursors (1)

Structure of insulin and its precursors (2)

Sequences of human, swine, and bovine insulins

Insulin secretion in the β-cell is controlled by glucose and triggered by membrane depolarization

The sulfonylurea receptor controls an associated potassium channel

KATP channels also regulate the tone of smooth muscle cells

Tolbutamide promotes closing of the KATP channel

The insulin receptor is a receptor tyrosine kinase

Insulin receptor first phosphorylates itself and then a number of insulin receptor substrate proteins

Insulin effects on glycogen synthesis

The role of insulin in glucose transport 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

Insulin promotes glucose uptake by increasing the surface exposure of GLUT 4 transporters

Transcriptional regulation by insulin

Other hormones

Glucagon and epinephrine act via G-protein-coupled receptors

The glucagon and epinephrine receptors activate adenylate cyclase and protein kinase A

Metabolic effects of protein kinase A Target Effect 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-2,6-bisphosphatase ↓ / ↑ Fructose-2,6-bisphosphate drops; glycolysis is inhibited, gluconeogenesis is activated hormone-sensitive lipase fatty acids are mobilized for β-oxidation and ketogenesis

Glucocorticoids and thyroid hormones act on nuclear hormone receptors to activate transcription

DNA binding by thyroid hormone receptors

Thyroid hormones induce respiratory chain uncoupling proteins

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

Glucocorticoid receptor agonists and antagonists

Control of food intake by leptin