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Glucose Uptake Pathways
How does physical activity signal skeletal muscle to take glucose from blood by a mechanism that does not use insulin? The insulin signaling pathway for glucose uptake by skeletal muscles in type 2 diabetes remains essentially dysfunctional both at rest and during physical activity.
Therefore, the contracting muscle takes up blood glucose by a pathway that is independent of insulin signaling. At least one other pathway signals skeletal muscle to take up glucose, independent of insulin signaling, and this explains the clinical observation made 50 years earlier that the dose of insulin has to be reduced when the diabetic patient exercises.
Clearance of glucose from the blood to skeletal muscle in healthy individuals:
• An individual without type 2 diabetes can use two signaling pathways to remove glucose from the blood into the muscle – via insulin receptor-mediated and physical activity-mediated translocation of the glucose carrier (GLUT4) to the muscle membrane.
• The importance of dual signaling is that blood insulin levels decline with physical activity. Thus, insulin will not signal non-contracting skeletal muscles to take up blood glucose, hence conserving the blood glucose for those muscles that are contracting.
• A localized exercise signal in the contracting skeletal muscles selectively signals GLUT4 to the contracting muscle’s plasma membrane so that blood glucose is only taken up by contracting muscles.
Clearance of glucose from the blood to skeletal muscle in patients with type 2 diabetes:
– Sedentary diabetic – The insulin signaling pathway is essentially inoperative in the diabetic skeletal muscle, and an inactive skeletal muscle has no exercise signal to stimulate the uptake of glucose from the blood.
– Physically active diabetic – Contracting skeletal muscles of the physically active individual with type 2 diabetes send a localized signal to move GLUT4 specifically to the contracting muscle membrane, thereby allowing the transport of glucose into the muscle cell even though the insulin signaling pathway is defective. The ability of localized muscle contraction to use a second signaling pathway to remove blood sugar explains why clinicians advise lowering the insulin dosage on days when patients with diabetes exercise.
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