04. Module 4.pdf

Module 4 Module 4: Glucose Transport Glucose Transport – Overview Most cells use facilitated transport via uniporters (GLUTs), because [glucose] is usually higher in extracellular fluids; however, in some cells (e.g., intestinal epithelial cells), glucose is transported against its concentration...

Module 4 Module 4: Glucose Transport Glucose Transport – Overview Most cells use facilitated transport via uniporters (GLUTs), because [glucose] is usually higher in extracellular fluids; however, in some cells (e.g., intestinal epithelial cells), glucose is transported against its concentration gradient via active transport. The family of glucose transporters (GLUTs) includes ~14 members. GLUTs transport glucose in both directions across membranes. GLUT 1, GLUT 2, GLUT 3, and GLUT 5 are insulin-independent; most cells express these. GLUT 4, insulin-dependent, is abundant in skeletal muscle and adipose cells. Facilitated Transport of Glucose by GLUT2 GLUT2 is in the liver and kidney (main sites of gluconeogenesis); it transports glucose into cells when [blood glucose] is higher, and out of cells into the blood, when [blood glucose] < [intracellular glucose]. GLUT2 is also in pancreatic β cells that sense a higher [blood glucose] and release insulin when needed. GLUT2 transporters are low affinity; they transport glucose when [blood glucose] > 5.5 mM (i.e., the normal concentration of glucose in the blood). Insulin and Glucose Transport Insulin: a hormone secreted by β pancreatic cells in response to glucose, other carbohydrates, proteins, and amino acids. Insulin circulates throughout the blood and binds to its receptors. Insulin-sensitive glucose transport: in skeletal muscle and adipocytes, via GLUT4 that usually resides in intracellular vesicles. After insulin-receptor binding, GLUT4 moves to the cell surface and transports glucose until the glucose concentration gradient exists. GLUT4 is removed from the plasma membrane by endocytosis and recycled back to its intracellular storage compartment. Active Glucose Transport: SGLT [Intracellular glucose] is > [extracellular glucose] at a few locations in the body, including the epithelial cell brush border of the small intestine. In the small intestines, dietary glucose is absorbed by epithelial cells and eventually enters the blood. The apical membranes of the intestinal cells contain sodium-glucose transporters (SGLT) that move glucose against its concentration gradient (in); the glucose is then transported out by GLUT2 in the basolateral membrane. SGLTs: secondary symport active transport, powered by the electrochemical gradient of sodium (maintained by the Na+/K+ ATPase, a primary active transport system). Module 4 GLUT2 in Food-facing Enterocytes (Only with the intake of sugar-rich foods) Typically, glucose uptake from the intestinal lumen is by SGLT1, and glucose release into the blood is by GLUT2. A pool of GLUT2 is stored in intracellular vesicles. Stored GLUT2 could be translocated to the apical membrane only when a sugar-rich meal is taken. Eventually, insulin triggers the internalization of GLUT2 and reduces sugar uptake. Glucose Transport in Diabetes Mellitus Type 1 diabetes: the pancreatic β cells are destroyed, and no insulin is produced; the individuals must receive exogenous insulin. Type 2 diabetes: insulin resistance (failure of cells to respond to insulin); insulin therapy may or may not be required; therapies include agents that decrease blood glucose (metformin), and weight loss. More than 100 million American adults have diabetes or prediabetes (prediabetes: a condition that, if not treated, often leads to type 2 diabetes within five years). The kidneys play a major role in the regulation of [plasma glucose]; oral administration of an SGLT inhibitor lowers [blood glucose] via excretion of glucose in the urine, due to suppression of renal SGLT function. Putting It Together Most cells use facilitated transport of glucose mediated by GLUT proteins. In most cases, glucose is moved from a higher concentration outside the cell toward a lower concentration inside the cell. Most cells have insulin-independent glucose transport. Skeletal muscle and adipose cells require insulin to stimulate the movement of GLUT4 proteins from intracellular vesicles to the plasma membrane, where they take up glucose. If insulin is absent (type 1 diabetes) or does not signal properly (type 2 diabetes), then insulin-dependent glucose transport will cease or be impaired. Secondary active transport of glucose occurs via symport with sodium, using SGLT proteins.