TUMOR-NECROSIS-FACTOR-ALPHA - A KEY COMPONENT OF THE OBESITY-DIABETESLINK

Recent data have suggested a key role for tumor necrosis factor (TNF)- alpha in the insulin resistance of obesity and non-insulin-dependent d iabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adip ose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by in creasing the activity of the insulin receptor tyrosine kinase, specifi cally in muscle and fat tissues. On a cellular level, TNF-alpha is a p otent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate -1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resis tance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to ins ulin.