Cross-talk mechanisms in the development of insulin resistance of skeletalmuscle cells - Palmitate rather than tumour necrosis factor inhibits insulin-dependent protein kinase B (PKB)/Akt stimulation and glucose uptake

Insulin resistance in skeletal muscle is one of the earliest symptoms assoc iated with non-insulin-dependent diabetes mellitus (NTDDM). Tumour necrosis factor (TNF) and nonesterified fatty acids have been proposed to be crucia l factors in the development of the insulin-resistant state. We here show t hat, although TNF downregulated insulin-induced insulin receptor (IR) and I R substrate (IRS)-1 phosphorylation as well as phosphoinositide 3-kinase (P I3-kinase) activity in pmi28 myotubes, this was, unlike in adipocytes, not sufficient to affect insulin-induced glucose transport. Rather, TNF increas ed membrane expression of GLUT1 and glucose transport in these muscle cells . In contrast, the nonesterified fatty acid palmitate inhibited insulin-ind uced signalling cascades not only at the level of IR and IRS-1 phosphorylat ion, but also at the level protein kinase B (PKB/Akt), which is thought to be directly involved in the insulin-induced translocation of GLUT4, and inh ibited insulin-induced glucose uptake. Palmitate also abrogated TNF-depende nt enhancement of basal glucose uptake, suggesting that palmitate has the c apacity to render muscle cells resistant not only to insulin but also to TN F with respect to glucose transport by GLUT4 and GLUT1, respectively. Our d ata illustrate the complexity of the mechanisms governing insulin resistanc e of skeletal muscle, questioning the role of TNF as a direct inhibitor of glucose homoeostasis in this tissue and shedding new light on an as yet unr ecognized multifunctional role for the predominant nonesterified fatty acid palmitate in this process.