NUTR3360 Module 7 Part 2 - Role of Liver in Metabolic Disease PDF

The role of the Liver in the development of metabolic complications Dietary Fats, Bile Acids & Hepatic Glucose Production PART II  Case Study Case Study: An 88-yr old man lived in a retirement community. His general health was considered...

The role of the Liver in the development of metabolic complications Dietary Fats, Bile Acids & Hepatic Glucose Production PART II  Case Study Case Study: An 88-yr old man lived in a retirement community. His general health was considered excellent, with no history of heart disease or stroke, and no history of gallstones or symptoms of biliary tract disease. The individual didn’t smoke or drink excessively. Blood cholesterol levels ranged from 3.88-5.18 mmol (less than 5.17 mmol is considered normal). The individual’s physician confirmed a daily consumption of 20-30 eggs for at least 15 years. What mechanisms could explain these normal blood cholesterol levels?  Different stages T2D development insulin a , ↑ resi Healthy IR Type 2 (early) Type 2 (late) > - hyper- -normal glucose -normal glucose -high glucose glycemic -high glucose -normal insulin -high insulin -high insulin -low insulin need more insulin to insulin no longer ↓ due to maintaing normal glucose workingas itd Pancreas Fatigues Can be managed by lifestyle or pharmaceutical interventions Pharmaceutical intervention is essential Glucose and insulin patterns (in fasted conditions) during the development of type 2 diabetes.  Assessing Insulin Sensitivity have a life Span fof 3mon. ↑ Problem : more stable HbA1c sensitive to Oral glucose change test easy To falsify V V V You do not need to memorize these numbers. This is purely a reference page for you as we move forward with the course. It will help you better interpret data. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care. 2012;35(Supp 1):S12, table 2  Assessing Insulin Sensitivity, Cont. Mathematically using the homeostatic model assessment (HOMA) > - notethnicity super accurate on other Uses fasting glucose and fasting insulin values Estimates 1. HOMA-IR (estimates a person’s insulin sensitivity) 2. HOMA-β (estimates a person’s insulin secretion) expensive > - very Experimentally using “clamps” – the gold standard most accurate until hypergly Glucose clamp (hyperglycemic clamp) I > - glucose clamp then – Plasma glucose concentrations are “clamped” at a high level by balancing endogenous and infused glucose. – Assesses insulin secretion by β-cells – The more glucose infused, the greater the insulin secretion level Insulin clamp (hyperinsulinemic-euglycemic clamp) normal glucose – Plasma insulin levels are “clamped” at a high level – Looking to maintain a steady state between blood glucose levels and glucose infusion caras – Assesses peripheral insulin sensitivity howperson > - – The more glucose infused, the greater the insulin sensitivity  Understanding Clamps Hyperglycemic Clamp Hyperinsulinemic-Euglycemic Clamp - > - stays high steady level o - > held steady of norm levels - · addmovthere glucose in response < Y go up to glucose going up Steady = & norm PMID: 382871  Assessing Insulin Sensitivity, Cont. Oral Glucose Tolerance of 2 types Type 2 Diabetic Obese, insulin sensitive Test (OGTT) ground middle Pre-diabetic Normal – (also know as glucose tolerance test) 240 Blood glucose (mg/dl) – Used to diagnose diabetes 220 - blood glucose or pre-diabetes (and GDM) 200 dosen't down come – Better than using fasting 180 values, but not as good as 160 > - shape changes clamps 140 not & as effective clearing 120 glucose – Patient fasts overnight and 100 ↑ respose is then consumes 75g of 80 same as normal glucose and blood is drawn 60 ↑ insulin over 2 hours. 40 workS nor m – Determines how quickly glucose is cleared from the 0 1/2 1 2 3 blood (glucose tolerance) Hours Rapid clearance = tolerant Slow clearance = intolerant  Liver is key tissue Hepatic Glucose Production (HGP) Blood glucose levels maintained through a balance of: – Intestinal absorption (from dietary carbohydrates) – Uptake by peripheral tissues (skeletal muscle, adipose, etc) – Uptake, storage and production by liver Liver plays a major role in blood glucose homeostasis in mammals: – Uptake and storage of glucose (glycogenesis) – Release of glucose (glycogenolysis; gluconeogenesis) uptake ↑ – HGP and glucose release are sensitive to hormones (e.g., insulin, glucagon, etc.) - release – Responsible for 90% of blood glucose in the fasting state  Hormonal Regulation of HGP afterea fasted - > - Pancreatic β-cell Pancreatic α-cell inhibit > - Inactiv im can PROINSULIN PROGLUCAGON PC1 PC2 INSULIN + C-Peptide GLUCAGON C-peptide Image From: Cartailler: Beta Cell Biology Consortium Insulin release will suppress HGP and, at the same time, inhibit the release of glucagon from pancreatic α-cells. Glucagon stimulates HGP.  Insulin Release from Beta Cells 1. Glucose enters pancreatic 1 β-cell via GLUT2. 2. Glucose undergoes glycolysis, increasing 3 cellular ATP levels. 3. High ATP levels shut down ATP-sensitive channels, causing a depolarization. 2 4. Depolarization results in calcium flooding inside the β-cell. 5. Insulin released from Grapidcase 4 granules into blood. 5 Image From: Cartailler: Beta Cell Biology Consortium  Phases of Insulin Release Obese, insulin sensitive Impaired glucose tolerance Type-2 Diabetes -RRP & RP have normal -RRP lost or problem with -RRP depleted with IGT (red) kinetics for obese (red) insulin exocytosis in T2D, and compared to NGT (black) compared to NGT (black) when RP depleted too (red) - RP has normal kinetics insulin sensitive -Pancreatic fatigue in T2D - ↑ β-cell mass with obesity Phase 1  rapid release of insulin from granules [RRP = readily releasable pool] Phase 2  production of a new insulin-containing granules [RP = reserve pool] PMID: 21633180 Insulin and Glucagon - Normal High Carb Meal Glucose 120 mg/dl 100 80 Insulin 120 uU/ml 80 40 0 120 Glucagon pg/ml 110 100 90 60 0 60 120 180 240 Minutes PMID: 11557965  Insulin and Glucagon – T2D Why? Because insulin is injected into the periphery, and not the portal vein where it can suppress glucagon release. After a CHO meal, blood glucose in T2D is very high, while insulin is low. Glucagon also remains high. After insulin injection, glucose is reduced, but glucagon still high. Aronoff & Berkowitz. Diabetes Spectrum 2004: 17: 183-190 Hormonal Regulation of Blood Glucose Fasting state (non-T2D): insulin is low, glucagon is high. HGP responsible for maintaining blood glucose levels. Basal insulin sufficient to clear blood glucose. Aronoff & Berkowitz. Diabetes Spectrum 2004: 17: 183-190  Hormonal Regulation of Blood Glucose Fed state (non-T2D): insulin is high, glucagon is low. Dietary glucose maintains blood glucose levels. Insulin ensures glucose clearance from the blood. Aronoff & Berkowitz. Diabetes Spectrum 2004: 17: 183-190  Hormonal Regulation of Blood Glucose Fasting state (T2D): insulin is low, glucagon is high. HGP responsible for maintaining blood glucose levels. Insulin injection sufficient to clear blood glucose. Aronoff & Berkowitz. Diabetes Spectrum 2004: 17: 183-190  Hormonal Regulation of Blood Glucose Fed state (T2D): insulin injected, glucagon is high. Dietary glucose and HGP cause blood glucose levels to be high. Insulin insufficient to clear blood glucose. Aronoff & Berkowitz. Diabetes Spectrum 2004: 17: 183-190  Insulin regulation of HGP We will GLUCOSE complete this slide Glut2 together GLUCOSE Glucose-6 Glucokinase Phosphatase GLUCOSE 6-P Phosphofructokinase Fructose-6 Phosphatase Pyruvate kinase PEPCK PYRUVATE Insulin also increases De Novo Lipogenesis, which causes glycerol to be used to make TAGs (and consequently prevents gluconeogenesis). IRS – insulin receptor substrate; PP1 – protein phosphatase 1 Chapter 10: Advances in Molecular and Cellular Endocrinology; Volume 5, 2006, Pages 187–210, 316–317  Glucagon regulation of HGP We will GLUCOSE complete this slide Glut2 together GLUCOSE Glucose-6 Glucokinase Phosphatase GLUCOSE 6-P Phosphofructokinase Fructose-2,6 Bisphosphatase Pyruvate kinase PEPCK PYRUVATE Chapter 10: Advances in Molecular and Cellular Endocrinology; Volume 5, 2006, Pages 187–210, 316–317  Direct vs. Indirect Regulation of HGP DIRECT: Insulin released by the pancreas is secreted into the portal vein to “directly” regulate HGP. – As shown in previous slides, insulin promotes hepatic glucose uptake (via GLUT2) and the production of glycogen, while at the same time inhibiting gluconeogenic enzymes. INDIRECT Insulin also regulates HGP “indirectly” by: – Inhibiting glucagon secretion from α-cells in pancreas – Inhibiting free fatty acid release from adipose tissue – Altering adipokine secretion (adiponectin inhibits HGP) – Regulating the hypothalamus-liver axis (communication between the brain and the liver regulate HGP) PMID: 16453016 Is there such a thing as monogenic diabetes?  Maturity onset diabetes of the young Maturity onset diabetes of the young (MODY) = Monogenic diabetes – Clinically the same as T2D except that diabetes develops early in life and stems from genetic mutations. – Autosominal dominant mode of inheritance. Nonsense mutation found in glucokinase (premature stop codon) in a French family Genetic mutations that prevent glucose uptake and storage as glycogen associated with severe, early onset diabetes characterized by severe hyperglycemia. PMID: 1570017 What is the impact of hepatic insulin signalling on whole- body glucose homeostasis?  Hepatic Insulin Receptor and HGP Liver-specific insulin receptor (IR)-knockout (LIRKO) controls mor every 1 ↑ Animals in fed state: LIRKO mice have high > - only gap blood glucose and very high insulin compared to control mice. Likko - Animals after OGTT: LIRKO mice have high **The IR is only absent in blood glucose the liver of LIRKO animals compared to control mice. Loss of insulin signalling in the liver causes significant increases in blood glucose levels. PMID: 10949030  Hepatic Insulin Receptor and HGP INS ↓ I V - GNG glycolysis In control animals, insulin reduces When examining liver expression HGP, as expected. However, in of key genes involved in glucose LIRKO mice, insulin is unable to handling, LIRKO animals have high suppress HGP. levels of gluconeogenic genes and low levels of glycolytic genes. GNG - HGP and expression of genes involved in gluconeogenesis are not suppressed by insulin in LIRKO mice. The livers of LIRKO animals “think” they are in a fasted state. PMID: 10949030  Does increasing hepatic glucose metabolism improve metabolic disorders seen with insulin receptor KO mice?  gluege-6-phosphate glucose > - Over-expressing Hepatic Glucokinase The goal was to see if over-expressing glucokinase (L-GK) would improve the metabolic disorders seen in mice with an insulin receptor mutation (therefore mice were severely diabetic). > - more pink = less lipids > White: - lipid ↳ - GK L-GK wt (1R0K L-GK mice had L-GK mice had increased L-GK mice had improved glucose reduced steatosis glucokinase activity in livers clearance following an OGTT compared to wild-type compared to wild-type mice. compared to wild-type mice. mice. Over-expression of hepatic glucokinase increases glucose metabolism in the liver and can compensate, in part, for the metabolic disorders seen in IR-/- mice. PMID: 12242462  Take-home messages Numerous methods exist to assess glucose tolerance and insulin sensitivity – Fasting glucose/insulin, HOMA-IR, OGTT, and clamps Insulin release from pancreatic β-cells is a coordinated process consisting of two phases, – Also suppresses glucagon secretion from pancreatic α-cells Regulation of HGP by insulin & glucagon is a coordinated process involving the regulation of glycogenesis, glycolysis, and gluconeogenesis. Insulin regulation of HGP is both direct and indirect.