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