Sending the signal: molecular mechanisms regulating glucose uptake.
The molecular signaling mechanisms by which insulin leads to increased glucose transport and metabolism and gene expression are not completely elucidated. We have characterized the nature of insulin signaling defects in skeletal muscle from Type 2 diabetic patients. Insulin receptor substrate (IRS-1) phosphorylation, phosphatidylinositol (PI) 3-kinase activity, and glucose transport activity are impaired as a consequence of functional defects, whereas insulin receptor tyrosine phosphorylation, mitogen-activated protein kinase (MAPK) phosphorylation, and glycogen synthase activity are normal. Using biotinylated photoaffinity labeling, we have shown that reduced cell surface GLUT4 levels can explain glucose transport defects in skeletal muscle from Type 2 diabetic patients under insulin-stimulated conditions. Current work is focused on mechanisms behind insulin-dependent and insulin-independent regulation of glucose uptake. We have recently determined the independent effects of insulin and hypoxia/AICAR exposure on glucose transport and cell surface GLUT4 content in skeletal muscle from nondiabetic and Type 2 diabetic subjects. Hypoxia and AICAR increase glucose transport via an insulin-independent mechanism involving activation of 5'-AMP-activated kinase (AMPK). AMPK signaling is intact, because 5-aminoimidazole-4-carboxamide 1-beta-D-ribonucleoside (AICAR) increased AMPK and acetyl-CoA carboxylase (ACC) phosphorylation to a similar extent in Type 2 diabetic and nondiabetic subjects. However, AICAR responses on glucose uptake were impaired. Our studies highlight important AMPK-dependent and independent pathways in the regulation of GLUT4 and glucose transport activity in insulin resistant skeletal muscle. Understanding signaling mechanisms to downstream metabolic responses may provide valuable clues to a future therapy for Type 2 diabetes.
Krook
Anna
A
Department of Physiology and Pharmacology and Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Hospital, Karolinska Institutet, Stockholm, Sweden.
Wallberg-Henriksson
Harriet
H
Zierath
Juleen R
JR
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D015444:Exercise / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction
D007328:Insulin; D005947:Glucose