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Insulin stimulation of pyruvate dehydrogenase in adipocytes involves two distinct signalling pathways
Sam A Johnson1, Richard M Denton
1Department of Biochemistry, University of Bristol, University Walk, Clifton, Bristol BS8 1TD, U.K.
The Biochemical Journal
|October 11, 2002
Summary
Insulin activates pyruvate dehydrogenase in rat fat cells via two pathways, one sensitive to wortmannin and the other to U0126. A synthetic molecule, PIG41, activates only one pathway.
Area of Science:
- Biochemistry
- Cell Biology
- Metabolic Signaling
Background:
- Insulin is a key metabolic hormone regulating glucose utilization.
- Pyruvate dehydrogenase (PDH) is a critical enzyme in glucose metabolism.
- Signaling pathways like PI3K and MAPK are involved in insulin action.
Purpose of the Study:
- To elucidate the distinct signaling pathways mediating insulin's effect on pyruvate dehydrogenase (PDH) in rat adipocytes.
- To investigate the role of phosphoinositolglycan PIG41 in PDH activation.
Main Methods:
- Isolated rat adipocytes were used to study enzyme activity.
- Inhibition of phosphoinositide 3-kinase (PI3K) with wortmannin and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK1/2) with U0126 were employed.
- Enzyme activity assays were performed to measure PDH stimulation.
Main Results:
- Insulin-stimulated PDH activity was partially inhibited by PI3K and MEK1/2 inhibitors.
- Combined inhibition of PI3K (wortmannin) and MEK1/2 (U0126) completely blocked insulin's effect on PDH.
- The synthetic phosphoinositolglycan PIG41 activated PDH but only to 30% of insulin's maximal effect.
- PIG41-induced activation was fully blocked by wortmannin alone.
Conclusions:
- Insulin activates PDH in rat adipocytes through two distinct signaling pathways: one wortmannin-sensitive and one U0126-sensitive.
- PIG41 appears to act through the wortmannin-sensitive pathway, suggesting it engages only one of the two insulin-mediated routes to PDH activation.