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Transcript
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