Week 2

Entry of glucose into cells is mediated by carrier proteins called glucose transporters (GLUTs).
Integral membranes with glucose transporters help move glucose down its concentration gradient.

Sodium-Dependent Glucose Transporters (SGLTs): 2 identified isoforms.
- SGLT1 and SGLT2 are found in the luminal (apical) membranes of proximal renal tubular epithelial cells.
- SGLT1 also found in luminal membranes of mucosal cells in the small intestine.
- Function: Involvement in secondary active transport (symport) of glucose and galactose against their concentration gradients.
- Mechanism: Both transporters are insulin-independent and require sodium ions for glucose transport:
- SGLT1: Requires 2 Na+/glucose molecule.
- SGLT2: Requires only 1 Na+/glucose molecule.
GLUT Transporters: Five isoforms identified.
- GLUT1: Responsible for glucose reabsorption across the basolateral membrane of proximal renal tubular epithelial cells (S-3 segment); found in erythrocytes, colon, placenta, and blood-brain barrier.
- GLUT2: Functions as a pancreatic insulin-secreting beta-cell sensor; transports glucose into and out of the liver and proximal renal tubular epithelial cells (S-2 segment).
- GLUT3: Responsible for basal glucose uptake in neurons, placenta, and other organs.
- GLUT4: The only insulin-dependent transporter; translocated from the Golgi apparatus to the plasma membrane upon insulin binding and dislocation.
- GLUT5: Involved in the transport of fructose and minor glucose in duodenal and jejunal mucosal cells via facilitated diffusion.

Transport activity of GLUT4 increases through activation of protein kinase C (PKC).
Upon insulin binding, GLUT4 transporters translocate from an inactive pool in the Golgi apparatus to active sites on the plasma membrane.
When insulin is removed, GLUT4 transporters return to the Golgi apparatus; this process is energy and temperature dependent.

Glucose is phosphorylated to glucose-6-phosphate (Glc-6-P) when inside the cell, which "traps" it due to its charged phosphate group that prevents diffusion back out of the cell.
Phosphorylation Reaction: This critical step allows glucose to serve as a substrate for various pathways, including:
- Embden-Meyerhoff pathway (EMP)
- Glycogen synthesis in hepatocytes and muscle cells.
- Hexose monophosphate shunt (HMS)
- Uronic acid pathway in hepatocytes.
Enzymes responsible for glucose phosphorylation: glucokinase and hexokinase, which require ATP for energy input along with potassium (K+) and magnesium (Mg++) as cofactors.

Glucokinase:
- High Km (180 mg%): requires high glucose concentrations for maximal activity.
- Inducible: synthesis and activity can be increased by insulin.
- Located primarily in the liver and pancreatic beta-cells.
- Not inhibited by Glc-6-P.
Hexokinase:
- Low Km (0.9 mg%): works at maximal velocity at very low glucose concentrations.
- Inhibited by Glc-6-P significantly.
- Present in most tissues, not as inducible as glucokinase.

Muscle Contribution: Muscle cannot directly contribute glucose to the blood glucose pool as it lacks Glc-6-Pase.
Liver Functionality in Different Animals:
- Strict carnivores and ruminants have low hepatic glycogen reserves and produce glucose continuously through gluconeogenesis.
- Omnivores’ livers buffer large changes in blood glucose levels through both glucose production and storage.
Glucose-6-Phosphatase (Glc-6-Pase):
- Catalyzes breakdown of Glc-6-P to free glucose and inorganic phosphate (Pi).
- Present only in liver, kidneys, and gut, not in muscle/adipose tissue, allowing only these tissues to export glucose to circulation.
- Stimulated by diabetogenic hormones (epinephrine, glucagon, cortisol, growth hormone) but inhibited by insulin.

Identify the integral membrane glucose transporters (GLUTs & SGLTs) and their locations.
Explain glucose trapping and regulation mechanisms in liver and other sites.
Contrast glucose phosphorylating enzymes (glucokinase vs. hexokinase).
Discuss the significance of glucose metabolic processes in muscle, liver, and tissue types.

Glucose phosphorylation "traps" this monosaccharide inside cells because its charged phosphate group reduces its lipophilicity.
Erythrocytic senility declines with the activity of hexokinase.
The only insulin-dependent glucose transporter is GLUT 4.
Hexokinase responds to Glc-6-P negative feedback, while glucokinase does not.
Hepatocytes can export glucose to the circulation, unlike skeletal muscle, adipocytes, or neurons.
GLUT 4 activity is enhanced by PKC activation.
The liver of strict carnivores and ruminants primarily functions as a continuous glucose producer.
The liver of the rat typically has the greatest glucokinase activity per gram of tissue.
Glucokinase and hexokinase require Mg++ and ATP, but not NAD+.
GLUT 2 transporters are found in hepatocytes and pancreatic beta-cells.