The role of TNF alpha and TNF receptors in obesity and insulin resistance

Insulin resistance, a smaller than expected response to a given dose of ins ulin, is associated with many common diseases including, ageing, polycystic ovarian disease, syndrome X, cancer, infections, trauma and, most signific antly, obesity and type 2 diabetes mellitus, The biochemical basis of insul in resistance in type 2 diabetes has been the subject of many studies. Earl ier studies have indicated that quantitative regulation of the insulin sens itive glucose transporters (Glut-4) and insulin receptors themselves may co ntribute to this disorder, however, these two factors are probably inadequa te to explain the extent of insulin resistance. This point also became appa rent by the development of only mild hyperinsulinaemia in mice with a targe ted mutation in the Glut-4 gene. Studies on postreceptor defects in type 2 diabetes has recently focused on the intrinsic catalytic activity of the in sulin receptor and downstream signalling events. A reduction in tyrosine ph osphorylation of both the insulin receptor (IR) and the insulin receptor su bstrate-1 (IRS-1) has been noted in both animal and human type 2 diabetes. Importantly, this appears to occur in all of the major insulin-sensitive ti ssues, namely the muscle, fat and liver, It is now clear that decreased sig nalling capacity of the insulin receptor is an important component of this disease. I will review some of the potential mechanisms underlying this def iciency.