Glucose in blood. Diabetes mellitus Seminar No. 4 What is glucose? • the most common monosaccharide / aldohexose [• ] C[6]H[12]O[6] (M[r] 180) • synonyms: grape sugar, blood sugar, dextrose • the most important sugar in the human body • the source of chemical energy (17 kJ/g) • metabolic nutrient for most tissues • prominent fuel for the brain and RBC Q. 1 A.1a) Free glucose in food is rare A.1 b) Glucose chemically bound • Starch (polysaccharide from glucose: amylose + amylopectin) cereals, bread, rolls, pastry, cakes, biscuits, dumplings, rice, pasta, semolina, legumes, potatoes, banana ... • Sugar (table sugar, sucrose, disaccharide: glucose + fructose) commercially available in 100% purity • Lactose (disaccharide: galactose + glucose) – milk Q. 2 A. 2 Symport (co-transport) with Na^+ ions • transporter binds together Glc and Na^+ (secondary active transport) – see also Harper (27^th ed., p. 436) • Na^+ ions move from high conc. space to low conc. space • Glc is expelled from enterocyte via GLUT2 (facilitated diffusion) • Na^+ ions are expelled from cell via Na^+,K^+-ATPase pump Symport of Glucose with Na^+ Q. 4 + 5 A. 4, 5 Lactate (60 %) Alanine + other glucogenic AA (30 %) Glycerol (10 %) Q. 7 A. 7 Cori cycle Q. 8 A. 8 • Liver glycogen is degraded by phosphate (phosphorolysis) • Phosphorylase – phosphoglucomutase – glc-6-phosphatase Q. 9 + 10 A. 9 + 10 (Harper, p. 173) • Glucose is highly polar compound, does not pass freely across hydrophobic cell membranes • Requires specific protein transporters • GLUT = glucose transporter Insulin-independent transporters • In most tissues (liver, CNS, Ery) • Passive transport – facilitated diffusion • Transporter – integral protein • After binding Glc it changes conformation and releases glucose into ICF Insulin-dependent transporters • In muscles, adipose tissue • After binding Glc it changes conformation and releases glucose into ICF • Free transporters are then transferred inside the cell by endocytosis • Insulin stimulates their incorporation into cell membrane when necessary Q. 12 A. 12 • night fasting – liver glycogen • one-day fasting - liver glycogen + gluconeogenesis • three-day fasting - gluconeogenesis Five stages of glucose homeostasis Five stages of glucose homeostasis • Stage I – glucose comes from food (mainly starch) • Stage II – glycogenolysis in liver • Stage III – gluconeogenesis in liver starts to work • Stage IV – in addition to liver, kidney starts to make Glc • Stage V – liver and kidney gluconeogenesis diminishes, energy needs of most tissues are met by FA + KB Hormonal regulation of Glc metabolism • insulin, glucagon • stress hormones: adrenalin, cortisol Q. 16 Harper, 27^th ed., Ch. 20, p. 170 Q. 17 A.17 • glucose - • FFA  Q. 18 Glucagon (fasting) • Low blood glucose level is the signal for glucagon secretion • Glucagon stimulates: • breakdown of glycogen in liver (not in muscles) • gluconeogenesis in liver (from lactate and AA) • lipolysis in adip. tissues Q. 19 Insulin (after meal) stimulates • in liver: glycolysis + synthesis of glycogen • in adip. tissue: synthesis of TAG • in muscles: synthesis of proteins Q. 20 A. 20 • Glc phosphorylation (hexokinase, glucokinase) • Glc-1-P isomeration • Fru-6-P isomeration Q. 21 A. 21 Glycogenolysis liver • cca 4-6 % of liver mass • Glycogenolysis affords free glucose - for other tissues • After about 18 h of fasting exhausted muscle • cca 1 % of muscle mass • Glycogenolysis affords Glc-6-P for muscle only • Storage lasts longer Q. 22 A. 22 • Liver: glucagon, adrenalin • Muscle: adrenalin Q.23 A. 23 Q. 24 A. 24 Q. 25 A. 25 glucose-6-phosphatase Glc-6-P + H[2]O ® Glc + P[i ] occurs in liver, kidney, intestine but not in muscles ^ Q. 26 A. 26 • Glc is the source of energy (aerobic glycolysis) • Glc is the source of NADPH +H^+ for FA synthesis (pentose cycle) • Glc is the source of glycerol-3-P for TAG synthesis glycerol-3-P ® 1-acylglycerol-3-P  1,2-diacylglycerol-3-P  1,2-diacylglycerol  TAG Adrenaline – acute stress • Signal that energy is needed immediately • Very quick action • Stimulates the breakdown of glycogen (in liver and muscles) and TAG (In adipos. tissue) Adrenaline action in fight-or-flight situation Metabolic Features of Diabetes (Type I) metabolic processes occur under influence of glucagon A. 30 Q. 31 Elevated: glucose FFA TG KB A. 31 – elevated Glc • The lack of insulin TH few GLUT4  Glc cannot enter adipose and muscle cells  elevated blood Glc • The lack of insulin TH decreased glycolysis in liver • The excess of glucagon  glycogenolysis  elevated blood glucose • The excess of glucagon  increased liver gluconeogenesis A. 31 – elevated FFA The excess of glucagon  lipolysis  elevated blood FFA (bound to albumin) A. 31 – elevated TG • The lack of insulin TH not enough LPL (insulin is the inducer of its synthesis)  elevated blood TG (CM + VLDL) A. 31 – elevated KB • The excess of FA from lipolysis  excess of acetyl-CoA (over CAC capacity)  synthesis of KB  elevated blood KB • Limited glycolysis in liver  not enough pyruvate  not enough oxaloacetate to run CAC  excess of acetyl-CoA (over CAC capacity)  synthesis of KB  elevated blood KB Q. 32 A. 32 Q. 33 A. 33 • The lack of insulin TH decreased glycolysis TH the shortage of pyruvate  the shortage of oxaloacetate • The excess of glucagon  increased utilization of oxaloacetate for gluconeogenesis Q. 34 A. 34 Complications of diabetes Acute • ketoacidosis (pH of blood < 7.36) • hyperosmolarity of blood plasma (> 310 mmol/l) Long-term • non-enzymatic glycation of proteins • AGE production (advanced glycation endproducts) • activation of sorbitol (glucitol) production Q. 35 A. 35 • Increased lipolysis, elevated FFA-albumin in blood • Shortage of LPL because of the lack of insulin TH elevated plasma TG (CM and VLDL) • Increased production of KB and VLDL Glycated hemoglobin HbA[1c ]• glycation is non-enzymatic and irrevesible • reaction of globin NH[2]-groups with aldehyde group of glucose • the concentration of HbA[1c] depends on: concentration of glucose in blood duration of hyperglycemia concentration of hemoglobin (less important factor) • normal values: 2.8 – 4.0 % • the value of HBA[1c] gives cumulative information on glucose level in recent 4-8 weeks Glycation of proteins Glycation of proteins