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Glucose uptake in skeletal muscle occurs by facilitated diffusion via glucose transporter (GLUT) 4.  In the fed state, insulin induces muscular glucose uptake by stimulating translocation of GLUT4 from intracellular depots to the plasma membrane and T tubules.  As circulating glucose and insulin levels fall in the fasting state, GLUT4 is resequestered, and muscle becomes increasingly dependent on internal stores of glucose and glycogen and, subsequently, on fatty acids released by lipolysis in the liver.

However, translocation of GLUT4 is also induced by muscle contraction, allowing insulin-independent glucose uptake during exercise.  Over time, regular exercise also causes increased expression of GLUT4 and greater insulin-dependent GLUT4 translocation, leading to increased skeletal muscle glucose uptake at any given insulin level (ie, increased insulin sensitivity) and therefore lower blood glucose.

This patient has been engaging in a regular exercise program and is likely experiencing rapid uptake of glucose while exercising.  As blood glucose levels fall, counterregulatory factors (eg, glucagon, epinephrine) are activated, leading to his symptoms (eg, palpitations, sweating), which are then relieved by the intake of sugar.  Exercise-induced hypoglycemia is common in patients with diabetes mellitus due to the lack of physiologic insulin regulation along with insufficient carbohydrate supplementation.

(Choice A)  As blood glucose levels fall during fasting or exercise, glucagon and epinephrine stimulate hepatic glycogenolysis and gluconeogenesis, leading to increased (not decreased) glucose production.

(Choice B)  Glucokinase phosphorylates glucose to glucose-6-phosphate, primarily for glycogen synthesis.  It is expressed mainly in the liver and is stimulated by rising, not falling, glucose levels.

(Choice C)  Glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate to glucose during gluconeogenesis, thereby helping to maintain glucose levels in the fasting state; increased activity would improve hypoglycemic symptoms by increasing circulating glucose levels.

(Choice D)  GLUT2 is found primarily in the liver and pancreatic beta cells, where it facilitates insulin-independent glucose uptake.  It is not expressed significantly in muscle or translocated in response to muscle contraction.

Educational objective:
Glucose uptake in skeletal muscle occurs primarily via glucose transporter (GLUT) 4.  Muscle contraction and insulin induce translocation of GLUT4 to the cell surface, increasing glucose uptake during exercise and the fed state, respectively.  Over time, regular exercise causes increased expression of GLUT4, leading to increased skeletal muscle glucose uptake at any given insulin level and therefore lower blood glucose levels.