Fuel Use: Insulin Action PDF

Fuel Use: Insulin action on liver and adipose tissues Diabetes photo museum Prof Graham Rena  Learning objectives for this topic Name the hormones involved in regulating blood glucose Describe what these hormones do to the body (their physiological actions) Detail...

Fuel Use: Insulin action on liver and adipose tissues Diabetes photo museum Prof Graham Rena  Learning objectives for this topic Name the hormones involved in regulating blood glucose Describe what these hormones do to the body (their physiological actions) Detail how these hormones work (the molecular mechanisms of their action) including – Actions on the liver and adipose Homeostasis: Normal blood glucose level 3.9-5.9 mmols/l GR  églucose uptake into cells Insulin s crea glucose pan glycogen [glucose]blood falls to normal églycogen range Stimulus synthesis in é [glucose]blood liver Imbalanc e GR  s crea pan Homeostasis: Normal blood glucose level 3.9-5.9 mmols/l GR  Physiological actions of insulin ã glucose uptake into cells ã glycogenesis (formation of glycogen for storage) in skeletal muscle and liver ä glycogenolysis (breakdown of glycogen to glucose) ä gluconeogenesis (formation of glucose from non- carbohydrate precursors) Net effect is a ê of blood glucose INSULIN-only hormone that ê blood glucose levels  Glucose Insulin The insulin signalling pathway uptake PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor mTORC2 Insulin PH P P GSK3 P Akt glycogen inhibition synthesis P p70S6K GLUT4 (adipose/muscle) gluconeogenic gene FOXO P Protein translocation7 expression to cell membrane translation  Glucose Insulin Insulin signal transduction is mediated by a uptake protein kinase cascade to Akt PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH P P glycogen Akt synthesis gluconeogenic gene Protein expression 8 translation  Glucose Insulin Akt mediates many of the pleiotropic responses to uptake insulin by regulation of many targets PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P glycogen Akt synthesis gluconeogenic gene Protein expression 9 translation  Glucose Insulin GSK3 regulates hepatic glycogen synthesis uptake PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P GSK3 glycogen inhibition Akt synthesis gluconeogenic gene Protein expression 10 translation  Glucose Insulin GSK3 regulates hepatic glycogen synthesis uptake PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P GSK3 P glycogen inhibition Akt synthesis gluconeogenic gene Protein expression 11 translation  Glucose Insulin FOXO regulates hepatic gluconeogenesis uptake PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P GSK3 P glycogen inhibition Akt synthesis gluconeogenic gene FOXO P Protein expression 12 translation How FOXOs are inactivated (IGF-1 + serum) How FOXOs are inactivated (IGF-1 + serum)  Glucose Insulin GLUT4 translocation mediates insulin-stimulated uptake glucose uptake (muscle/adipocyte) PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P GSK3 P glycogen inhibition Akt synthesis FOXO P GLUT4 gluconeogenic gene Protein translocation expression 15 translation to cell membrane  Glucose Insulin Some aspects of insulin action impact on fuel use more uptake broadly than glucose regulation PtdIns PI3K (3,4,5)P3 PDK1 P IRS p110 PH P p85 receptor Insulin mTORC2 PH PH P P GSK3 P glycogen inhibition Akt synthesis P p70S6K FOXO P GLUT4 gluconeogenic gene Protein translocation expression 16 translation to cell membrane  KEY: Post-translational modification Insulin action on the hepatocyte Allosteric regulation Glucose Gene expression GLUT2 Glucose Gluco Glycogen G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Free fatty acids Gluconeogenesis Glycogen Fructose-6-phosphate Glycolysis synthesis Fatty acid synthesis Fatty acid Fructose-1,6- PFK+ synthase + phosphatase- Fructose-1,6-bisphosphate Malonyl CoA PEPCK - Acetyl CoA PEP Carboxylase + Pyruvate Oxaloacetate kinase+ Acetyl CoA Pyruvate citrate Acetyl CoA Mitochondria  KEY: Post-translational modification Glycogen synthesis is stimulated Allosteric regulation Glucose Gene expression GLUT2 Glucose Gluco Glycogen Kinase+ synthase+ Glucose-6-phosphate Glycogen synthesis  KEY: Post-translational modification Glycolysis is stimulated Allosteric regulation Glucose Gene expression GLUT2 Glucose Gluco Glycogen Kinase+ synthase+ Glucose-6-phosphate Glycogen Fructose-6-phosphate Glycolysis synthesis PFK+ Fructose-1,6-bisphosphate PEP Pyruvate kinase+ Pyruvate Acetyl CoA Mitochondria  KEY: Post-translational modification Gluconeogenesis is suppressed Allosteric regulation Glucose Gene expression GLUT2 Glucose Gluco Glycogen G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Gluconeogenesis Glycogen Fructose-6-phosphate Gluco=glucose, Glycolysis synthesis Fructose-1,6- PFK+ phosphatase- neo=new, Fructose-1,6-bisphosphate genesis=production. PEPCK - PEP Pyruvate Oxaloacetate kinase+ Pyruvate citrate Acetyl CoA Mitochondria  KEY: Post-translational modification Futile cycling suppressed allosterically Allosteric regulation Glucose Gene expression GLUT2 Prevention of futile Glucose Gluco Glycogen cycling by PFK2/FBPase-2 G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Gluconeogenesis Glycogen Fructose-6-phosphate Glycolysis synthesis Fructose-1,6- PFK+ phosphatase- Liver PFK2 Fructose-1,6-bisphosphate F6P F2,6P PEPCK - PEP Pyruvate Liver FBPase-2 Oxaloacetate kinase+ Pyruvate citrate Acetyl CoA Mitochondria  KEY: Post-translational modification Futile cycling suppressed allosterically Allosteric regulation Glucose Gene expression GLUT2 Prevention of futile Glucose Gluco Glycogen cycling by PFK2/FBPase-2 G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Insulin promotes dephosphorylation Gluconeogenesis Glycogen of PFK2/FBPase-2 Fructose-6-phosphate Glycolysis synthesis Fructose-1,6- PFK+ phosphatase- Liver PFK2 Fructose-1,6-bisphosphate (dephospho) F6P F2,6P PEPCK - PEP Pyruvate Liver FBPase-2 Oxaloacetate kinase+ (dephospho) Pyruvate citrate Acetyl CoA Mitochondria  KEY: Post-translational modification Futile cycling suppressed allosterically Allosteric regulation Glucose Gene expression GLUT2 Prevention of futile Glucose Gluco Glycogen cycling by PFK2/FBPase-2 G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Glucagon induces phosphorylation Gluconeogenesis Glycogen of PFK2/FBPase-2 Fructose-6-phosphate Glycolysis synthesis Fructose-1,6- PFK+ phosphatase- Liver PFK2 Fructose-1,6-bisphosphate (phospho) F6P F2,6P PEPCK - PEP Pyruvate Liver FBPase-2 Oxaloacetate kinase+ (phospho) Pyruvate citrate Acetyl CoA Mitochondria  KEY: Post-translational modification Fatty acid synthesis is promoted Allosteric regulation Glucose Gene expression GLUT2 Glucose Gluco Glycogen G-6-Pase - Kinase+ synthase+ Glucose-6-phosphate Fatty acids Gluconeogenesis Glycogen Fructose-6-phosphate Glycolysis synthesis Fatty acid synthesis Fatty acid Fructose-1,6- PFK+ synthase + phosphatase- Fructose-1,6-bisphosphate Malonyl CoA PEPCK - Acetyl CoA PEP Carboxylase + Pyruvate Oxaloacetate kinase+ Acetyl CoA Pyruvate citrate Acetyl CoA Mitochondria  Production and transport of very low-density lipoprotein (VLDL) and fatty acid (FA) between liver and adipose tissue VLDL Lipoprotein lipase+ Fatty acids LIVER VLDL FA+glycerol TG Fatty acids + ADIPOSE glycerol TG FA+glycerol HSL- Free fatty acids KEY: Post-translational modification Dysregulation of these transport mechanisms in diabetes Allosteric regulation causes hyperlipidaemia Gene expression  Overview of Insulin Action Insulin: – Promotes glucose uptake into liver – Promotes glucose storage as glycogen – Promotes glucose use in glycolysis/TCA cycle AND suppresses gluconeogenesis – Promotes glucose conversion into fatty acids which are shipped to the adipose tissue – Suppresses triglyceride breakdown in the adipose tissue – Insulin treatment in diabetes tends to result in weight gain Fuel Use: 1. Counterregulation & 2. Diabetes  Counterregulation Homeostasis: Normal blood glucose level 3.9-5.9 mmols/l GR  églucose uptake into cells Insulin s crea glucose pan glycogen [glucose]blood falls to normal églycogen range Stimulus synthesis in é [glucose]blood liver Imbalanc e GR  s crea pan Homeostasis: Normal blood glucose level 3.9-5.9 mmols/l GR  Imbalanc e [glucose]blood Stimulus rises to normal ê [glucose]blood range glucose glycogen c reas pan églycogen breakdown to glucagon glucose in liver GR Homeostasis: Normal blood glucose level 3.9-5.9 mmols/l c reas pan GR  églucose uptake into cells Insulin s crea glucose pan glycogen [glucose]blood falls to normal églycogen range Stimulus synthesis in é [glucose]blood liver Imbalanc e [glucose]blood Stimulus rises to normal ê [glucose]blood range glucose glycogen c reas pan églycogen breakdown to glucagon glucose in liver GR  Overview of Glucagon Action Glucagon opposes many of the regulatory effects of insulin through its own second messenger cAMP – Increases glycogenolysis – Increases gluconeogenesis – Suppresses glycolysis – Increases FA oxidation – In adipose tissues stimulates HSL  Glucagon is first-line in a battery of counter-regulatory responses! International textbook on Diabetes Mellitus (Wiley) Eds: DeFronzo, Ferrannini, Keen, Zimmet 35  Diabetes mellitus Most common of all endocrine disorders Major feature = hyperglycaemia ã blood glucose (>200mg/100ml; > 16mmol/l) Glucosuria = glucose in urine with large osmotic diuresis – dehydration – circulatory failure, brain damage & renal failure Following a meal, many cells cannot take up glucose properly – Extracellular glucose high – Intracellular glucose deficiency  Diabetes mellitus Before insulin there were a variety of dietary treatments including starvation diets. “Children hovered miserably between death from diabetes and death from starvation. One 12-year- old boy, already blind from diabetes, was reduced to eating toothpaste mixed with birdseed stolen from his pet canary. ‘These facts were obtained by confession after long and plausible denials’, remarked the pitiless Allen [the child’s physician]. Eli Lilly and The unfortunate child died of starvation.” Diabetologia 52: 1-7) ( Sawyer and Gale (2009) company archives  Diabetes mellitus Before insulin there were a variety of dietary treatments including starvation diets. “Children hovered miserably between death from diabetes and death from starvation. One 12-year- old boy, already blind from diabetes, was reduced to eating toothpaste mixed with birdseed stolen from his pet canary. ‘These facts were obtained by confession after long and plausible denials’, remarked the pitiless Allen [the child’s physician]. Eli Lilly and The unfortunate child died of starvation.” Diabetologia 52: 1-7) ( Sawyer and Gale (2009) company archives  Criteria for Diabetes WHO Criteria for Diabetes: FPG ≥ 7.0mmol/l OGTT (2hrs) ≥ 11.1mmol/l after 75g glucose load IGT = (FPG 8.5 mmol/L (2-hour OGTT)  HbA1C ADA: Diabetes Diagnosis: HbA1C >6.5% Pre-diabetes: 5.7-6.4% WHO “The HbA1c result is influenced by several factors including anaemia, abnormalities of haemoglobin, pregnancy and uraemia. Some of these factors may be a bigger problem in under-resourced countries due to a higher prevalence of anaemia and of haemoglobinopathies”  WHO Diabetes Criteria — What is the definition for type 1 diabetes? — What is the definition for type 2 diabetes? — Is there anything else?  WHO Types of Diabetes T1DM- pancreatic beta cell destruction/ insulin is required for survival - usually characterised by the presence of anti-GAD/ anti-islet cell antibodies T2DM- ‘a person is normally thought to have type 2 diabetes if he or she doesn’t have type 1 diabetes, monogenic diabetes or other medical condition or treatment suggestive of secondary diabetes’ i.e. a diagnosis of exclusion MODY (monogenic) Secondary Causes: e.g. drugs, pancreatic pathology, endocrine cause  Diabetes-type 1 vs type 2 Type 1 Type 2 Insulin status No insulin Normal or increased Age of onset Childhood Adulthood Defect Loss of b cells â Sensitivity of cells to insulin INSULIN RESISTANCE Obesity? No Yes Speed of development Fast Slow Dyslipidaemia No Plasma TG á HDL cholesterolâ Small dense LDL cholesterol á  Production and transport of very low-density lipoprotein (VLDL) and fatty acid (FA) between liver and adipose tissue VLDL Lipoprotein lipase+ Fatty acids LIVER VLDL FA+glycerol TG Fatty acids + ADIPOSE glycerol TG FA+glycerol HSL- Free fatty acids KEY: Post-translational modification Dysregulation of these transport mechanisms in diabetes causes Allosteric regulation hyperlipidaemia Gene expression  Learning Outcomes We found out what insulin does. (We found out that insulin has a variety of physiological actions which lower blood glucose) We learned how insulin secretion after a meal acts on: Fatty acid synthesis, glycogen synthesis and gluconeogenesis in the liver and triglyceride storage in adipose tissue through-insulin signal transduction Glucagon and other counterregulatory hormones oppose many of these effects We defined the main types of diabetes