{"id":4422475,"date":"2025-01-11T20:49:54","date_gmt":"2025-01-12T02:49:54","guid":{"rendered":"https:\/\/myendoconsult.com\/learn\/topics\/insulin-physiology\/"},"modified":"2025-01-12T13:15:33","modified_gmt":"2025-01-12T19:15:33","slug":"insulin-physiology","status":"publish","type":"oen_topic","link":"https:\/\/myendoconsult.com\/learn\/topics\/insulin-physiology\/","title":{"rendered":"Insulin Physiology"},"content":{"rendered":"\n<h2 class=\"wp-block-heading\">ACTIONS OF INSULIN<\/h2>\n\n\n\n<h3 class=\"wp-block-heading\">Molecular Structure and Clearance<\/h3>\n\n\n\n<ul class=\"wp-block-list\">\n<li><strong>Insulin<\/strong> = 56-amino acid polypeptide with two peptide chains (\u03b1 &amp; \u03b2) joined by two disulfide bridges.<\/li>\n\n\n\n<li>Secreted into <strong>portal vein<\/strong> \u2192 ~80% cleared by hepatocyte insulin receptors on first pass.<\/li>\n\n\n\n<li><strong>Overall Action<\/strong>: Anabolic \u2013 promotes synthesis of carbohydrates, fats, proteins.<\/li>\n<\/ul>\n\n\n\n<h3 class=\"wp-block-heading\">Insulin Receptor<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Structure<\/strong>\n<ul class=\"wp-block-list\">\n<li>Heterotetrameric glycoprotein (two \u03b1- and two \u03b2-subunits, joined by disulfide bonds).<\/li>\n\n\n\n<li><strong>\u03b1-subunits<\/strong>: extracellular, bind insulin.<\/li>\n\n\n\n<li><strong>\u03b2-subunits<\/strong>: transmembrane + intracellular, have intrinsic <strong>tyrosine kinase<\/strong> activity.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Signal Transduction<\/strong>\n<ul class=\"wp-block-list\">\n<li>Insulin binding \u2192 autophosphorylation of \u03b2-subunit tyrosine residues.<\/li>\n\n\n\n<li>Phosphorylation of <strong>insulin receptor substrates<\/strong> (IRS-1, 2, 3, 4) \u2192 activation of PI3K &amp; MAPK pathways.\n<ul class=\"wp-block-list\">\n<li><strong>PI3K pathway<\/strong> \u2192 metabolic (<a href=\"https:\/\/myendoconsult.com\/learn\/glucose-transporters\/\" data-wpil-monitor-id=\"226\">glucose transport<\/a>, glycogen\/protein synthesis, anti-apoptosis).<\/li>\n\n\n\n<li><strong>MAPK pathway<\/strong> \u2192 proliferative, differentiation effects.<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Receptor Modulation<\/strong>\n<ul class=\"wp-block-list\">\n<li>Downregulated by <strong>obesity<\/strong>, hyperinsulinemia.<\/li>\n\n\n\n<li>Upregulated by <strong>exercise<\/strong>, starvation.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<figure class=\"wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"3000\" height=\"2100\" src=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis.png\" alt=\"\" class=\"wp-image-4422757\" srcset=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis.png 3000w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis-300x210.png 300w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis-768x538.png 768w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis-1536x1075.png 1536w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/insulin-biosynthesis-2048x1434.png 2048w\" sizes=\"auto, (max-width: 3000px) 100vw, 3000px\" \/><figcaption class=\"wp-element-caption\">Insulin Biosynthesis Pathway<\/figcaption><\/figure>\n\n\n\n<h3 class=\"wp-block-heading\">Glucose Transport and Effects<\/h3>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Transporters<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>GLUT 1<\/strong>: all tissues, high-affinity; basal uptake.<\/li>\n\n\n\n<li><strong>GLUT 2<\/strong>: low-affinity, in liver\/pancreatic \u03b2-cells (handles postprandial hyperglycemia).<\/li>\n\n\n\n<li><strong>GLUT 3<\/strong>: high-affinity for neurons.<\/li>\n\n\n\n<li><strong>GLUT 4<\/strong>: <strong>muscle &amp; adipose<\/strong>; insulin-responsive.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Muscle<\/strong>\n<ul class=\"wp-block-list\">\n<li>Insulin \u2192 PI3K \u2192 <strong>GLUT 4<\/strong> translocation to plasma membrane \u2192 \u2191 glucose uptake.<\/li>\n\n\n\n<li>Promotes <strong>glycogen synthesis<\/strong> (\u2191 glycogen synthase, \u2193 glycogen phosphorylase).<\/li>\n\n\n\n<li>Enhances <strong>protein synthesis<\/strong> (\u2191 AA transport, kinase-mediated anabolic signals).<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Adipose Tissue<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Inhibits lipolysis<\/strong> (dephosphorylation of hormone-sensitive lipase).<\/li>\n\n\n\n<li>\u2193 breakdown of triglycerides \u2192 less FFA\/glycerol \u2192 less substrate for ketogenesis.<\/li>\n\n\n\n<li><strong>Induces lipoprotein lipase<\/strong> \u2192 frees FFA from chylomicrons\/VLDL \u2192 FFA uptake \u2192 re-esterification into TGs.<\/li>\n\n\n\n<li><strong>Stimulates lipogenesis<\/strong>: activates acetyl-CoA carboxylase, \u2191 \u03b1-glycerol phosphate (from \u2191 glucose uptake) \u2192 TG synthesis.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Liver<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Increases<\/strong> enzymes for glucose utilization (pyruvate kinase, glucokinase).<\/li>\n\n\n\n<li><strong>Decreases<\/strong> gluconeogenic enzymes (glucose-6-phosphatase, PEP carboxykinase).<\/li>\n\n\n\n<li><strong>Enhances glycogen<\/strong> storage (dephosphorylation of glycogen synthase &amp; phosphorylase).<\/li>\n\n\n\n<li><strong>Promotes<\/strong> triglyceride, VLDL, and protein synthesis.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">GLYCOLYSIS<\/h2>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Definition<\/strong>\n<ul class=\"wp-block-list\">\n<li>Main pathway for glucose metabolism in <strong>cytosol<\/strong> of all cells.<\/li>\n\n\n\n<li>Converts glucose (6C) \u2192 pyruvate (3C), can be <strong>aerobic<\/strong> or <strong>anaerobic<\/strong>.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Overall Reaction<\/strong>mathematica <code>Glucose + 2 ADP + 2 NAD+ + 2 Pi \u2192 2 Pyruvate + 2 ATP + 2 NADH + 2 H+ + 2 H2O<\/code><\/li>\n\n\n\n<li><strong>Key Steps<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Hexokinase\/Glucokinase<\/strong> phosphorylates glucose to glucose-6-phosphate.<\/li>\n\n\n\n<li><strong>Phosphofructokinase<\/strong> forms fructose-1,6-bisphosphate.<\/li>\n\n\n\n<li><strong>Aldolase<\/strong> cleaves to glyceraldehyde 3-phosphate + dihydroxyacetone phosphate (DHAP).<\/li>\n\n\n\n<li>Glyceraldehyde 3-phosphate \u2192 1,3-bisphosphoglycerate (NAD+ \u2192 NADH).<\/li>\n\n\n\n<li><strong>Substrate-level phosphorylation<\/strong> \u2192 2 ATP net from the 1,3-bisphosphoglycerate and phosphoenolpyruvate (PEP) steps.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Fate of Pyruvate<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Aerobic<\/strong>: enters mitochondria, converted to acetyl-CoA, <a href=\"https:\/\/myendoconsult.com\/learn\/tca-cycle\/\" data-wpil-monitor-id=\"227\">TCA cycle<\/a>.<\/li>\n\n\n\n<li><strong>Anaerobic<\/strong>: reduced to <strong>lactate<\/strong> (LDH) for regenerating NAD+ (2 ATP net per glucose).<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Regulation<\/strong>\n<ul class=\"wp-block-list\">\n<li>Major regulated enzymes = hexokinase, phosphofructokinase, pyruvate kinase.<\/li>\n\n\n\n<li>Aerobic <a href=\"https:\/\/myendoconsult.com\/learn\/glycolysis\/\" data-wpil-monitor-id=\"228\">glycolysis<\/a> yields ~30 ATP\/glucose; anaerobic yields 2 ATP\/glucose.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<figure class=\"wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"3000\" height=\"2100\" src=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met.png\" alt=\"\" class=\"wp-image-4422759\" srcset=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met.png 3000w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met-300x210.png 300w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met-768x538.png 768w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met-1536x1075.png 1536w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/fed-state-glucose-met-2048x1434.png 2048w\" sizes=\"auto, (max-width: 3000px) 100vw, 3000px\" \/><figcaption class=\"wp-element-caption\">Glucose Metabolism in the Fed State<\/figcaption><\/figure>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">TRICARBOXYLIC ACID (TCA) CYCLE<\/h2>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Overview<\/strong>\n<ul class=\"wp-block-list\">\n<li>Also called <strong>citric acid<\/strong> or <a href=\"https:\/\/myendoconsult.com\/learn\/krebs-cycle-mnemonic\/\" data-wpil-monitor-id=\"229\">Krebs cycle<\/a>.<\/li>\n\n\n\n<li>Final common pathway for oxidation of carbs, fats, proteins \u2192 <strong>Acetyl-CoA<\/strong> enters TCA.<\/li>\n\n\n\n<li>Produces intermediates for <a href=\"https:\/\/myendoconsult.com\/learn\/gluconeogenesis\/\" data-wpil-monitor-id=\"230\">gluconeogenesis<\/a>, fatty acid synthesis, protein catabolism.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Steps<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Pyruvate dehydrogenase<\/strong>: pyruvate \u2192 Acetyl-CoA + CO2 + NADH.<\/li>\n\n\n\n<li><strong>Citrate synthase<\/strong>: Acetyl-CoA + oxaloacetate \u2192 citrate.<\/li>\n\n\n\n<li><strong>Aconitase<\/strong>: citrate \u2192 isocitrate.<\/li>\n\n\n\n<li><strong>Isocitrate dehydrogenase<\/strong>: isocitrate \u2192 \u03b1-ketoglutarate + CO2 + NADH.<\/li>\n\n\n\n<li><strong>\u03b1-Ketoglutarate dehydrogenase<\/strong>: \u03b1-ketoglutarate \u2192 succinyl-CoA + CO2 + NADH.<\/li>\n\n\n\n<li><strong>Succinyl-CoA synthetase<\/strong>: succinyl-CoA \u2192 succinate + GTP\/ATP.<\/li>\n\n\n\n<li><strong>Succinate dehydrogenase<\/strong>: succinate \u2192 fumarate + FADH2.<\/li>\n\n\n\n<li><strong>Fumarase<\/strong>: fumarate + H2O \u2192 malate.<\/li>\n\n\n\n<li><strong>Malate dehydrogenase<\/strong>: malate \u2192 oxaloacetate + NADH.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Energy Yield<\/strong>\n<ul class=\"wp-block-list\">\n<li>From 1 turn (Acetyl-CoA): 3 NADH, 1 FADH2, 1 ATP (via GTP).<\/li>\n\n\n\n<li>Plus PDH step: 1 extra NADH.<\/li>\n\n\n\n<li>Each NADH ~2.5 ATP, FADH2 ~1.5 ATP \u2192 total ~12.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Vitamin Cofactors<\/strong>\n<ul class=\"wp-block-list\">\n<li>Riboflavin (B2, FAD), Niacin (B3, NAD), Pantothenic acid (B5, CoA), Thiamine (B1, decarboxylation).<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Regulation<\/strong>\n<ul class=\"wp-block-list\">\n<li>Intermediates modulate enzymes, e.g. citrate, succinyl-CoA, NADH, ATP.<\/li>\n\n\n\n<li>Links to HIF regulation, paraganglioma, pheochromocytoma in SDH or VHL gene mutations.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">GLYCOGEN METABOLISM<\/h2>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Glycogen Structure<\/strong>\n<ul class=\"wp-block-list\">\n<li>Branched \u03b1-D-glucose polymer. Storage form in liver, muscle.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Glycogenesis<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Hexokinase\/Glucokinase<\/strong>: Glc \u2192 Glc-6-P.<\/li>\n\n\n\n<li><strong>Phosphoglucomutase<\/strong>: Glc-6-P \u2192 Glc-1-P.<\/li>\n\n\n\n<li><strong>UDPGlc pyrophosphorylase<\/strong>: Glc-1-P + UTP \u2192 UDP-Glc.<\/li>\n\n\n\n<li><strong>Glycogen synthase<\/strong>: extends \u03b1(1\u21924) chain.<\/li>\n\n\n\n<li><strong>Branching enzyme<\/strong>: creates \u03b1(1\u21926) branch points.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Glycogenolysis<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>Glycogen phosphorylase<\/strong>: cleaves \u03b1(1\u21924) \u2192 Glc-1-P until 4 residues from branch.<\/li>\n\n\n\n<li><strong>Debranching enzyme<\/strong>: moves trisaccharide + hydrolyzes \u03b1(1\u21926) link.<\/li>\n\n\n\n<li>Glc-6-P can go to:\n<ul class=\"wp-block-list\">\n<li><strong>Glycolysis<\/strong><\/li>\n\n\n\n<li><strong>Pentose phosphate pathway<\/strong><\/li>\n\n\n\n<li><strong>Glycogenesis<\/strong> (recycle)<\/li>\n\n\n\n<li><strong>Glucose<\/strong> (in liver\/kidney via Glc-6-phosphatase).<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Regulation<\/strong>\n<ul class=\"wp-block-list\">\n<li>Key enzymes: glycogen synthase (anabolic) + glycogen phosphorylase (catabolic).<\/li>\n\n\n\n<li><strong>Insulin<\/strong> \u2192 promotes glycogen synthesis.<\/li>\n\n\n\n<li><strong>Glucagon, epinephrine<\/strong> \u2192 promote glycogenolysis.<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n\n\n\n<hr class=\"wp-block-separator has-alpha-channel-opacity\"\/>\n\n\n\n<h2 class=\"wp-block-heading\">CONSEQUENCES OF INSULIN DEPRIVATION<\/h2>\n\n\n\n<figure class=\"wp-block-image size-full\"><img loading=\"lazy\" decoding=\"async\" width=\"3000\" height=\"2100\" src=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting.png\" alt=\"\" class=\"wp-image-4422762\" srcset=\"https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting.png 3000w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting-300x210.png 300w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting-768x538.png 768w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting-1536x1075.png 1536w, https:\/\/myendoconsult.com\/learn\/wp-content\/uploads\/Glucose-Metabolism-Fasting-2048x1434.png 2048w\" sizes=\"auto, (max-width: 3000px) 100vw, 3000px\" \/><figcaption class=\"wp-element-caption\">Glucose Metabolism Fasting State<\/figcaption><\/figure>\n\n\n\n<ol class=\"wp-block-list\">\n<li><strong>Causes<\/strong>:\n<ul class=\"wp-block-list\">\n<li>Pancreatectomy, autoimmune \u03b2-cell destruction (type 1 <a href=\"https:\/\/myendoconsult.com\/learn\/diabetes-mellitus\/\" data-wpil-monitor-id=\"225\">diabetes mellitus<\/a>), etc.<\/li>\n\n\n\n<li>Lack of insulin \u2192 insulin-sensitive tissues deprived of glucose uptake + anabolic regulation.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Impaired Glucose Utilization<\/strong>\n<ul class=\"wp-block-list\">\n<li>\u2193 GLUT4-mediated uptake in muscle\/adipose.<\/li>\n\n\n\n<li><strong>Glycogenesis<\/strong> slowed; hepatic glucose production \u2191 (gluconeogenesis, glycogenolysis).<\/li>\n\n\n\n<li>Blood glucose rises, exceeding renal threshold \u2192 <strong>glucosuria<\/strong> &amp; osmotic diuresis \u2192 polyuria, polydipsia, dehydration.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Protein Catabolism<\/strong>\n<ul class=\"wp-block-list\">\n<li>Muscle breakdown \u2192 \u2191 amino acid release \u2192 negative nitrogen balance, weight loss, possible cachexia.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Enhanced Lipolysis<\/strong>\n<ul class=\"wp-block-list\">\n<li>\u2191 free fatty acids to liver \u2192 <strong>ketone bodies<\/strong> (acetoacetate, \u03b2-hydroxybutyrate) \u2192 <strong>ketoacidosis<\/strong>.<\/li>\n\n\n\n<li>Sodium lost with ketones \u2192 bicarbonate buffering leads to metabolic acidosis.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Electrolyte Depletion<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong>K+ deficit<\/strong> from osmotic diuresis &amp; excretion with ketones.<\/li>\n\n\n\n<li><strong>Phosphate deficit<\/strong> from diuresis + lack of insulin.<\/li>\n<\/ul>\n<\/li>\n\n\n\n<li><strong>Severe Metabolic Consequences<\/strong>\n<ul class=\"wp-block-list\">\n<li><strong><a href=\"https:\/\/myendoconsult.com\/learn\/diabetic-ketoacidosis-dka-protocol\/\" data-wpil-monitor-id=\"231\">Diabetic ketoacidosis<\/a><\/strong> (DKA) \u2192 acidosis, dehydration, hypotension, shock, coma, death (if untreated).<\/li>\n<\/ul>\n<\/li>\n<\/ol>\n","protected":false},"excerpt":{"rendered":"<p>ACTIONS OF INSULIN Molecular Structure and Clearance Insulin Receptor Glucose Transport and Effects GLYCOLYSIS TRICARBOXYLIC ACID (TCA) CYCLE GLYCOGEN METABOLISM CONSEQUENCES OF INSULIN DEPRIVATION<\/p>\n","protected":false},"featured_media":0,"template":"","oen_topic_chapter":[686],"class_list":["post-4422475","oen_topic","type-oen_topic","status-publish","hentry","oen_topic_chapter-the-pancreas","post-wrapper","thrv_wrapper"],"_links":{"self":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422475","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic"}],"about":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/types\/oen_topic"}],"version-history":[{"count":7,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422475\/revisions"}],"predecessor-version":[{"id":4422764,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic\/4422475\/revisions\/4422764"}],"wp:attachment":[{"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/media?parent=4422475"}],"wp:term":[{"taxonomy":"oen_topic_chapter","embeddable":true,"href":"https:\/\/myendoconsult.com\/learn\/wp-json\/wp\/v2\/oen_topic_chapter?post=4422475"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}