Carbohydrate Metabolism: Glycolysis and Gluconeogenesis

Salivary Amylase
- Cleaves α-(1,4)- glycosidic bonds of ingested carbohydrates.
- Inactivated by stomach acid.
Pancreatic Secretions
- Neutralize stomach acid.
- Convert oligosaccharides into smaller saccharides and disaccharides further broken down into monosaccharides.
Absorption
- Sugars taken up in portal circulation.
- Glucose is either stored in the liver as glycogen or released into the bloodstream.

Defines as a hexose monosaccharide and a primary carbohydrate form presented to cells.
Critical for brain function, which constitutes about 2% of body weight but consumes 20% of total body oxygen and 25% of glucose.
Acts as fuel, 'burned' to release energy via biochemical pathways.
Uptake into cells occurs through transporter mechanisms, specifically GLUT transporters.

Mechanism: Na+-independent facilitated diffusion (GLUT transporters) and Na+-dependent co-transporter systems (SGLT).
Facilitated Diffusion: Glucose moves from high concentration to low concentration.
Sodium Dependent Transport: Transports glucose against concentration gradient using energy.
GLUT Transporters: Can transport glucose in two manners:
- From extracellular to intracellular (with gradient).
- From intracellular to extracellular (against gradient).

GLUT1: Found in most tissues, erythrocytes, and brain; basal glucose uptake.
GLUT2: Located in liver, kidneys, and pancreas (β-cells); insensitive to insulin, removes excess glucose from blood.
GLUT3: Found in the brain; ensures glucose uptake under low concentration.
GLUT4: Present in muscle and adipose tissue; translocates to cell surface in the presence of insulin.
GLUT5: Primarily in small intestine; transports fructose, does not transport glucose.
GLUT6 & GLUT7: Present in brain/spleen and intestines; transport glucose and fructose.

Defined as the primary metabolic pathway for glucose breakdown.
Occurs in the cytosol of all cells and involves the chemical breakdown of one molecule of glucose (6 carbons) into two molecules of pyruvic acid (3 carbons).
Results in energy release in the form of ATP; glycolysis is categorized as a catabolic process.

Aerobic Glycolysis: Occurs in the presence of oxygen; results in the conversion of pyruvate to Acetyl CoA in the Krebs cycle.
- Important steps include the oxidation of NADH and conversion of glyceraldehyde-3-phosphate.
Anaerobic Glycolysis: Occurs in absence of oxygen; results in the conversion of pyruvate to lactate.
- Important for energy production in cells lacking mitochondria or in hypoxic conditions (e.g. erythrocytes, muscles during intense exercise).
- Involves the Cori cycle (aka fermentation).

Glycolytic pathway involves a series of 10 reactions converting glucose to pyruvate while providing energy (ATP) and intermediates for other metabolic pathways.
Glycolysis serves as a hub for carbohydrate metabolism; all sugars can be converted to glucose.

Preparatory Phase
- Includes phosphorylation of glucose and conversion to glyceraldehyde 3-phosphate using ATP.
- Key reactions include:
- Hexokinase converts D-glucose to glucose 6-phosphate (irreversible reaction).
- Phosphohexose isomerase converts glucose 6-phosphate to fructose 6-phosphate (reversible reaction).
- Phosphofructokinase-1 (PFK-1) phosphorylates fructose 6-phosphate to fructose 1,6-bisphosphate (committed, irreversible step).
- Aldolase cleaves fructose 1,6-bisphosphate into glyceraldehyde 3-phosphate (G3P) and dihydroxyacetone phosphate (DHAP).

Yields 2 ATP, 2 NADH, and 2 pyruvate.
ATP generation occurs through substrate-level phosphorylation:
- Phosphorylation of ADP using high energy phosphate groups from 1,3-bisphosphoglycerate and phosphoenolpyruvate.

Fructose 1,6-bisphosphate splits into G3P and DHAP, and DHAP is isomerized to G3P for continued processing.

Degradation of glucose carbon skeleton to yield pyruvate.
Phosphorylation of ADP to ATP using high phosphoryl transfer potential compounds formed during glycolysis.
Formation of NADH from reduction of NAD+.

Hormonal Regulation: Insulin increases during the well-fed state and activates regulatory enzymes like hexokinase, PFK-1, and pyruvate kinase, while glucagon has the opposite effect during starvation.
PFK-1 is regulated by AMP and fructose 2,6-bisphosphate, which activate glycolysis, and by ATP and citrate, which inhibit it.

Pyruvate is reduced to lactate by lactate dehydrogenase in anaerobic conditions.
Key for cells lacking mitochondria or undergoing intense exercise.

Pyruvate can undergo different pathways:
- Oxidative decarboxylation to acetyl CoA.
- Carboxylation to oxaloacetate.
- Reduction to ethanol.

Defined as the synthesis of glucose from non-carbohydrate precursors primarily in the liver.
Important for tissues like the brain and erythrocytes which constantly require glucose.

Conversion of Pyruvate to Oxaloacetate (OAA): Via pyruvate carboxylase.
- OAA converted to phosphoenolpyruvate (PEP) via PEP carboxykinase.
Reversal of Glycolytic Steps: Including the conversion of PEP to fructose 1,6-bisphosphate.
Final Steps: Conversion of fructose 1,6-bisphosphate to glucose.

An anabolic process requiring energy, summarizing the consumption of 4 ATP, 2 GTP, and 2 NADH, which is higher than energy produced in glycolysis.

Key enzymes such as pyruvate carboxylase and fructose 1,6-bisphosphatase regulate gluconeogenesis and are activated/inhibited by various metabolites enhancing reciprocal regulation with glycolytic enzymes.

The process involving the conversion of glucose to lactate in muscles during anaerobic conditions followed by the conversion of lactate back to glucose in the liver helps maintain glucose levels during fasting states.