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

–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