Transcript Physiological role of insulin

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
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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)
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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