Physiological role of insulin
• Release of insulin by beta cells– Response to elevated blood glucose level– Effects of insulin
• Somewhat global• Major effects on muscle, adipose tissues, and
liver– Increased glucose uptake
• Glucose– Energy source
– Glycogen synthesis
• Increased hepatic glycogen synthesis– Increased glycogen synthase activity– Increased synthesis of glucose-6-P
• Prevention of glucose release
• Effects on adipocytes– Glycerol synthesis
• Increased glucose metabolism
– Increased lipoprotein metabolism• Lipoprotein lipase
– Increased free fatty acids release
– net results• Increased triglyceride synthesis
• Effects on adipocytes– Enzymes activated by insulin
• Citrate lipase• Acetyl-CoA carboxylase• Fatty acid synthase• Glycerol-3-phosphate dehydrogenase
• Effects on muscle– Increased transport of glucose and amino
acids• Increased synthesis of proteins
– Energy from glucose
• Maintenance of potassium homeostasis– Increased K uptake
• Extreme concentrations of insulin– Extracellular hypokalemia
Mechanism of insulin action• Insulin receptor
– Similar to type I IGF receptor• Two sets of subunits (alpha and beta)• Insulin binding
– Alpha
• Receptor tyrosine kinase– Beta
– Phosphorylation of intracellular domain• Docking sites for intracellular proteins
– Insulin receptor substrate-1 (IRS-1)
• Phosphorylation of IRS-1– Secondary messenger system
• Somewhat complicated– Ca ions– PKA– PKC
• Activation of glucose transport system
• Effects on glucose transport system– Glucose transport
• Facilitated diffusion• Diverse
– Types of proteins– Tissue-dependent distribution pattern– Evolved to accommodate specific energy needs
Physiological role of glycogen• Decreased blood glucose level
– Insulin-induced– Subsequent elevation of glucose
• Glycogen break-down• Gluconeogenesis
• Glycogen– Antagonistic to insulin
• Gluconeogenesis• Glycogen break-down
• Glycogen break-down– Short-term maintenance of glucose level
• Gluconeogenesis– Long-term
• Exercise• Fasting• Neonates
• Effects on amino acid and lipid metabolism– Used as precursor for gluconeogenesis
• Amino acids• Glycerol
– Lipolysis• Release of free fatty acids and glycerol
– Substrate for glucose synthesis
• Occurs when insulin concentrations are low– Potent inhibitor of lipolysis
• Undernutrition/fasting– Prevention of hypoglycemia
• Reduced insulin level• Elevated glucagon• Adrenal catecholamines
– Critical if glucagon is low
Mechanism of glucagon action
• Target organs– Liver– Adipose tissues
• Interaction of glucagon with its receptor– Increased cAMP production
• Activation of PKA system– Glycogen break-down– Gluconeogenesis– Lipolysis
• Inhibition of ketone formation from free fatty acid metabolism by liver
– Glucose sparing effects (use of fatty acids as energy source)
Control of pancreatic islet function
• Several factors– Hormones– Nervous system– Metabolic signals – Blood glucose level
• Most important• Hyperglycemia
– Stimulation of insulin secretion– Inhibition of glucagon synthesis
• Adrenal and neural catercholamines– Adrenal epinephrine
• Inhibition of insulin secretion– Alpha receptor-mediated– Glucose availability during stress
• Stimulation of glucagon secretion– Epinephrine and norepinephrine– Activation of beta receptors
• Amino acids and other metabolites (acetoacetic acid)– Increased insulin secretion
• Protein synthesis
• Fatty acid synthesis
– Increased glucagon secretion• Prevention of hypoglycemia
– Counteracts effects of insulin
• Abolished when CHO and proteins are ingested together
• Stimulation by GI tract (entero-insular axis)– Secretion of gastrointestinal inhibitory peptide
(GIP) and glucagonlike peptide 1 (GLP-1)• Response to orally ingested glucose• Stimulates secretion of insulin• GLP-1 stimulates cAMP production• Secretion of insulin above the level secreted in
response to glucose alone– Beta cells must be “competent” to respond to increased
glucose level
• Stimulation by GI tract (entero-insular axis)– Secretion of gastrointestinal inhibitory
peptide (GIP) and glucagonlike peptide 1 (GLP-1)
• Inhibition of glucagon secretion– Elevated glucose level– Elevated insulin level
• Neural control– Vagus nerves
• Stimulate insulin secretion
• Endocrine factors– Glucose homeostasis
• GH– Diabetogenic (stimulates insulin secretion but
reduces peripheral insulin sensitivity)
• Glucocorticoids
Glucose counterregulation
• Glucose– Primary energy source for brain
• No gluconeogenesis• No glycogen• No regulatory mechanisms for level of uptake
– Prevention of hypoglycemia• Decreased insulin secretion• Increased glucagon secretion• Release of epinephrine