Glucose Homeostasis_Powerpoint Slides.pdf

GLUCOSE HOMEOSTASIS Hans Strijdom Division of Medical Physiology 1 GLUCOSE HOMEOSTASIS: DIGESTION AND ABSORPTION ORAL CAVITY: Mechanical digestion of carbohydrates by chewing; saliva contains amylase for partia...

GLUCOSE HOMEOSTASIS Hans Strijdom Division of Medical Physiology 1 GLUCOSE HOMEOSTASIS: DIGESTION AND ABSORPTION ORAL CAVITY: Mechanical digestion of carbohydrates by chewing; saliva contains amylase for partial chemical digestion of carbohidrates to disaccharides. SMALL INTESTINE: Chemical digestion by pancreatic juice (contains amylase); intestinal secretions (contain maltase, sucrase en lactase). Absorption of monosaccharides (eg. glucose) via secondary active (symport) transport mechanisms. Glucose reaches the blood for further metabolism. 2 GLUCOSE HOMEOSTASIS: DIGESTION AND ABSORPTION GLUCOSE IS THE BODY’S PRIMARY ENERGY SUBSTRATE; ESPECIALLY ESSENTIAL FOR THE BRAIN AND NERVOUS SYSTEM The glucose pool (plasma glucose) is under meticulous regulation in order to maintain energy metabolism in most body tissues (ESPECIALLY THE BRAIN!!) 3 GLUCOSE HOMEOSTASIS: GLUCOSE POOL AND STORES Maintenance and regulation of the glucose pool and stores are essential for life, as the brain is almost exclusively dependent on glucose as its primary energy substrate, and red blood cells can only use glucose for their energy requirements. The daily glucose requirement of the brain in a typical adult human being is about 120 g, which accounts for most of the 160 g of glucose needed daily by the whole body. The amount of glucose present in body fluids is about 20 g, and that readily available from glycogen, a storage form of glucose is approximately 190 g. Thus, the direct glucose reserves are sufficient to meet glucose needs for about a day. However, things get complicated during longer periods of fasting. GLUCOSE HOMEOSTASIS: SHORTLY AFTER A MEAL Plasma glucose levels under STRICT control!! 5 GLUCOSE HOMEOSTASIS: FASTING SITUATION Plasma glucose levels under STRICT control!! 6 GLUCOSE HOMEOSTASIS: CELLULAR METABOLISM NB: ALTHOUGH GLUCOSE YIELDS LESS ATP / UNIT SUBSTRATE THAN LIPIDS, THE PROCESS BY WHICH GLUCOSE IS CONVERTED TO ATP IS MORE EFFICIENT (less cumbersome; quicker)... 7 REIN CONTROL OF PLASMA GLUCOSE: INSULIN AND GLUCAGON Insulin and Glucagon: (i) Are secreted under opposite conditions; (ii) Effects are therefore opposite to each other. FED STATE: FASTING STATE: INSULIN GLUCAGON DOMINATES DOMINATES REMOVAL OF GLUCOSE FROM BLOOD TO BE NEED ENERGY!! GLYCOGEN METABOLIZED IN CELLS FOR ENERGY SUPPLY… (STORAGE FORM OF GLUCOSE) IS BROKEN DOWN (GLYCOGENOLYSIS); PREPARATION FOR THE “LEAN YEARS”: NEW GLUCOSE IS MADE FROM GLUCOSE GLYGOCEN (GLYCOGENESIS); OTHER SOURCES: PROTEIN SYNTHESIS; LIPOGENESIS GLUCONEOGENESIS 8 REIN CONTROL OF PLASMA GLUCOSE: INSULIN AND GLUCAGON “INSULA” = Latin for “island” 9 INSULIN AND GLUCAGON: PANCREAS HORMONES ISLET OF LANGERHANS 0.2mm Only 1-2% of the pancreas mass consists of endocrine tissue - mostly in the tail of the pancreas 70-90% of all the endocrine cells in the Islets of Langerhans 10 ENDOCRINE RESPONSE TO CARBOHYDRATE-CONTAINING MEAL: Increase in plasma glucose has direct effect on ß-cells: most important insulin-releasing mechanism Glucose ingestion results in the release of incretins (GLP-1 and GIP) from the gut Possible: stimulatory effect on ß-cells via autonomic nervous system: exact mechanism unknown Target cells of insulin have insulin-receptors 11  ENDOCRINE RESPONSE TO CARBOHYDRATE-CONTAINING MEAL: THE INCRETINS Plasma glucose GLP-1: Glucagon-like peptide-1; GIP: glucose-dependent insulin-releasing polypeptide; DPP-4: dipeptidyl peptidase-4 GLUCOSE, GLP-1 AND GIP SIGNALLING IN THE PANCREATIC ß-CELL: Glucokinase Insulin Release INSULIN SYNTHESIS AND RELEASE: 14 CELLULAR ACTIONS OF INSULIN: THE INSULIN RECEPTOR: Tetramer protein 2 -subunits on the cell membrane surface with binding- sites for insulin 2 ß-subunits (transmembrane) connected with tyrosine-kinases The insulin-receptor is thus a “tyrosine-kinase-receptor” (belongs to the receptor-enzyme receptor class) Many of its signal transduction effects are via the PI3-kinase - protein kinase B/Akt pathway The kinase enzyme of the insulin- Liver-, Muscle- and Adipocytes receptor phosphorylates certain contain insulin receptors, and it is intracellular proteins that switch on therefore these cell types that are a signal transduction cascade sensitive for insulin actions. 15  CELLULAR UPTAKE OF GLUCOSE: ↑ [Glucose] ↑ Insulin secretion ↑ Glucose uptake Insulin Receptor cell membrane P inactive PI3-K P-Tyr IRS-1 IRS-1 Translocation active inactive to cell active PI3-K membrane PKB/ GLUT Akt vesicles IRS‐1: Insulin receptor substrate‐1 PI3‐K: Phosphatidylinositol 3‐kinase Cytoplasm PKB: Protein kinase B GSK-3 GSK‐3: Glycogen synthase kinase‐3 GLUT: Glucose transporter 16 CELLULAR UPTAKE OF GLUCOSE: GLUCOSE TRANSPORTERS: “GLUTS” : GLUT-1 to 6 GLUTS are carrier proteins residing in the cytoplasm GLUT-2 in pancreas- and liver cells and GLUT-4 in fat- and muscle cells Glucose cannot enter the cell on its own, needs a glucose transporter (GLUT) Inactivated GLUT is stored in intracellular vesicles; when insulin binds to the insulin-receptor, a signal transduction pathway is switched on that translocates the GLUT-vesicle to the membrane. The vesicle undergoes exocytosis and GLUT is exposed for glucose-binding and intracellular secretion. 17 FACTORS AFFECTING INSULIN-RELEASE: BIOLOGICAL EFFECTS OF INSULIN: “ANABOLIC HORMONE” Translocation of GLUT-4 in fat and muscle cells to the cell membrane, which leads to glucose-uptake in these cell types. Receptor-binding activates complex signal transduction pathways that eventually dephosphorylate several enzymes, which leads to the SYNTHESIS of: (i) Glycogen (liver and muscle), (ii) Triglycerides (in adipocytes), (iii) VLDL (liver), and (iv) Cholesterol Receptor-binding also leads to the activation of transcription factors that causes the SYNTHESIS of several proteins. Insulin is also an important promotor of GROWTH AND DEVELOPMENT 18 GLUCAGON: THE REIN CONTROL PARTNER OF INSULIN In contrast to insulin, described as “anabolic”, glucagon has opposite effects on plasma glucose levels. Glucagon is viewed as a “catabolic” hormone. SYNTHESIS AND SECRETION OF GLUCAGON… Glucagon is, like insulin, a peptide hormone (belongs to the secretin family). Glucagon is therefore also stored in intracellular vesicles and released via exocytosis. The most important stimulus for glucagon is a drop in plasma glucose (but not the only stimulus!). 19 GLUCAGON: LEADS TO GLYCOGENOLYSIS Hepatocyte Increased plasma glucose levels: DIABETOGENIC EFFECTS GSK: Inactivates Glycogen Synthase Glycogenolysis = breakdown of glycogen to glucose. Happens especially in the liver. Glycogenolysis supplies glucose as energy-substrate during fasting (lack of external glucose sources). Glucagon-binding to its receptor leads to the activation of the cyclic AMP (cAMP) - protein kinase A (PKA) signal transduction pathway resulting in increased glycogen-breakdown. 20 GLUCAGON: LEADS TO KETOGENESIS KETONES: Are breakdown products of + + fatty acids and used as alternative energy substrate + + during fasting. The brain especially uses ketones when there is an absolute shortage of glucose. + Ketones reduce the pH and + can lead to ACIDOSIS (low plasma pH), which is dangerous for the body. 21 FACTORS THAT INFLUENCE GLUCAGON-RELEASE: BIOLOGICAL EFFECTS OF GLUCAGON: “CATABOLIC HORMONE” cAMP-mediated phosphorylation of several enzymes leads to: (i) the BREAKDOWN of glycogen (liver) and triglycerides (fat cells); and (ii) the STIMULATION of gluconeogenesis (liver) and ketogenesis (liver). The net result of the abovementioned actions are thus: (i)  plasma glucose levels; (ii)  plasma free fatty acid levels, and (iii)  plasma ketone concentration. 22 CONCEPTS IN GLUCOSE METABOLISM: “ -GENESIS ” : To synthesize (“Genesis”: Beginning…) “ -NEOGENESIS ” : To synthesize new “ -LYSIS” : To break down “ LIPO-” : Fat 1. GLYCOGENOLYSIS: Breakdown of glycogen to glucose 2. LIPOLYSIS: Breakdown of triglycerides to fatty acids and glycerol 3. GLYCOLYSIS: Breakdown of glucose to pyruvate 4. GLUCONEOGENESIS: Synthesis of new glucose from non- carbohydrate precursors 5. KETOGENESIS: Synthesis of ketones 23 GLUCONEOGENESIS: In situations where glycogen stores are depleted, and glucose intake is insufficient (eg fasting), the body has to use alternative sources of glucose. The body has the ability to synthesize glucose from non-glucose precursor molecules. This is called GLUCONEOGENESIS (“birth of new glucose”). Three types of precursor molecules can be used: (i) Glycerol; (ii) Lactate, and (iii) Amino acids. NB: The final conversion to glucose can only happen in the liver and kidney!! Glucagon is one of the important hormones that activate gluconeogenesis, but there is also cortisol. 24  THE DIABETOGENIC HORMONES: A. INSULIN  B. GLUCAGON  C. ADRENALINE  D. CORTISOL  “Diabetogenic Effects” 25 FASTING: Fasting, or the unfed state, leads to a whole series of compensatory metabolic reactions, whereby the body attempts to draw energy from existing sources. This implies that food stores have to be broken down into basic nutrients – a state of CATABOLISM develops. Fasting and Diabetes Mellitus Type 1 share many commonalities with regards the metabolic reactions they elicit. 26 DIABETES MELLITUS: PATHOPHYSIOLOGY DIABETES MELLITUS CAN DEVELOP IF INSULIN LOOSES ITS ABILITY TO REGULATE PLASMA GLUCOSE LEVELS… BASIC PROBLEM:  insulin concentration in plasma, or  insulin-action, despite normal or even elevated insulin-levels [“insulin-resistance”] LEADS TO:  glucose-uptake in muscle, fat and liver cells  glucose-concentration in plasma with serious results if present over a long period of time. 27 GLUCOSE TOLERANCE TEST: 28 INSULIN RESISTANCE: Obesity ↑ FFA ↓ Glucose uptake cell membrane PKC Diacylglycerol P-Ser Translocation IRS-1 inactive = INSULIN RESISTANCE to cell membrane IRS-1 PI3-K PKB\ ↓GLUT Akt vesicles inactive FFA: Free fatty acids PKC: Protein kinase C Cytoplasm 3 GSK-3 29