IAS13: Glucose metabolism

• common dietary carbohydrates

• outline basic digestion and absorptions of common sugars

• compare and contrast between anaerobic glycolysis and aerobic cellular respiration

• recognize the networks of glucose metabolism

• relate metabolic concepts to clinical connections

Dietary carbohydrates

• empirical formular: (CH2O)n, n >= 3

• α-glucose: starch (amylose, amylopectin), glycogen

• β-glucose: cellulose

→ affects angle of bonds formed, 3D molecular structure

• starch: major carbohydrate in diet

• glycogen: one of the fuel molecules in body stores

• glucose: common monomer

• lactose (β-1,4 between galactose, glucose)

• sucrose (α-1,2 between glucose, fructose)

Glucose metabolism degradation by α-amylases

• amylose (linked by α-1,4 glycosidic bonds) → maltotriose + maltose + glucose

• amylopectin (branched chain of glucose subunits linked by α-1,6, glycosidic bonds) → α-limit dextrin (α-1,6 + α-1,4)/isomaltose (disaccharide linked by α-1,6) (spatially branching enables more efficient packaging of polymers) glycosidase activities in glycoproteins:

• glucoamylase (oligosaccharides): release glucose from α-1,4 linked glucosyl residues

• sucrase-isomaltose complex: cleave sucrose, α-1,4, α-1,6 linked glucosyl residues

• trehalose: cleave trehalose (α-1,1 glucose-glucose, found in insects, algae, mushrooms)

• lactase-glucosylceramidase (β glycosidase complex): cleave β-1,4 between galactose and glucose in lactose → small intestinal disaccharidases

Processing from exogenous supply

→ salivary α-amylase cleave some α-1,4 bonds in amylose chain → hydrolase enzymes absorbed on mucosal cells to convert dietary carbohydrates into free monosaccharides → undigested carbohydrates in ileum (fermented by bacteria) enters colon, egested

Intestinal villi

• α-1,4 bonds in amylose cleaved by pancreatic α-amylase to release glucose

• glycosidases (small intestinal disaccharidases) attached to membrane in brush border of enterocytes

• monosaccharides transporters in intestinal absorptive cells

  • SGLT (sodium-glucose linked transporters): (brush border) active transport, co-transports glucose or galactose with Na ion down Na concentration gradient generated by Na-K ATPase pump in basolateral membrane

  • GLUT (glucose transporters):

    • GLUT5--fructose (brush border + basolateral)

    • GLUT2--fructose, galactose, glucose (basolateral)

Cellular uptake of glucose

• liver: GLUT2 (bidirectional glucose transporter), store glucose as glycogen/fatty acid & cholesterol in triacylglycerol TG

• muscles: GLUT4 (insulin-sensitive), glucose as major fuel, majorly use fatty acids & ketone bodies, store glucose as glycogen

• erythrocytes: GLUT1 depend on glucose

• brain: GLUT3, GLUT1 (endothelial cells lining blood-brain barrier), depend on glucose, can use ketone bodies in starvation

• adipocytes: GLUT4--increase in insulin → facilitate uptake of glucose → converted to acetyl-CoA for de novo fatty acid biosynthesis → converted to glycerol-3-phosphate (backbone for TG)

• galactose: converted to glucose then glycogen in liver

• fructose: converted to glucose then glycogen then lactate in liver/fatty acid (low blood fructose concentration)

Cellular fate of glucose

Glucose phosphorylation upon entry, glucose is converted to glucose-6-phosphate (irreversible) to trap glucose in the cell

Glycolysis energy investment phase: glucose -ATP + hexokinase→ glucose 6-P ←→ fructose 6-P -ATP + phosphofructonkinase-1 energy generation phase: fructose-1,6-bis P → 2 NADH + 4 ATP → 2 pyruvate (pyruvic acid) overall: 2 NADH, 2 ATP, 2 pyruvate anaerobic glycolysis:

• pyruvate converted by LDH-A to lactate

• lactate is exported by MTC (monocarboxylate transporter)

• no net generation of NADH Lactate:

• in heart muscles, resting skeletal muscles, converted to pyruvate for entering TCA cycle

• return to liver to reconvert to glucose by gluconeogenesis via pyruvate (Cori cycle)

Aerobic cellular respiration

• oxidation of pyruvate (release CO2) → acetyl-CoA

• TCA cycle: CO2, NAD+ → NADH (electron carrier)

• oxygen as final electron acceptor in electron transport chain to form water → glucose: CO2: H2O = 1:6:6, 30-32 ATP generated

Pentose phosphate pathway (PPP): provides cellular NADPH (biochemical reductants), ribose-5-phosphate for nucleotide biosynthesis UDP-glucose:

• intermediate in formation of glycogen

• channelled for addition of sugar to proteins in post-translational modification

Summary & clinical connections

Uptakes

• GLUT1: blood cell, blood-brain barrier, baby (fetus cells)

• GLUT2: liver, kidney, pancreas, intestine

• GLUT3: neurons, placenta

• GLUT4: muscle, fat cells

glucose can be synthesized from amino acids in dietary protein, triacylglycerol glucose can be synthesized into galactose, xylulose, and sugars for metabolic processes

Lactose intolerance condition of pain, nausea, flatulence after ingestion of foods containing lactose (dairy products) caused by low levels of lactase/intestinal injury

Malabsorption of fruit juice fructose absorption is less efficient in large amounts → enter colon alongside potential diarrhea inducing ingredients (e.g. sorbitol) → actively fermented by bacteria producing excess gases, excess water drawn in → diarrhea

PET (positron emission tomography) scan

• uses glucose analog as radioactive tracer (fluorine-18 fluorodeoxyglucose $^{18}F-FDG$)

• OH group on C2 position of glucose substituted by fluorine-18 (radioactive isotope) → taken up by glucose-using cells, phosphorylated by hexokinase (trapped in cell until decay)

• allows intense radiolabelling of tissues with high glucose uptake, characteristic to cancers