PEROXOVANADATE AND INSULIN ACTION IN ADIPOCYTES FROM NIDDM PATIENTS -EVIDENCE AGAINST A PRIMARY DEFECT IN TYROSINE PHOSPHORYLATION

We studied the effects of insulin and the stable peroxovanadate compou nd potassium bisperoxopicolinatooxovanadate (bpV(pic)), a potent inhib itor of phosphotyrosine phosphatases, on lipolysis and glucose uptake in subcutaneous adipocytes from 10 male patients with non-insulin-depe ndent diabetes mellitus (NIDDM) and 10 matched non-diabetic control su bjects. Lipolysis stimulated by isoprenaline or the cAMP analogue, 8-b romo-cyclic AMP (8-br-cAMP), was reduced by approximately 40% in NIDDM compared to control subjects. In both groups bpV(pic) exerted an anti lipolytic effect that was similar to insulin (similar to 50 % inhibiti on). C-14-U-glucose uptake was dose-dependently increased by bpV(pic) treatment, but this effect and also that of insulin were impaired in N IDDM compared to control (bpV(pic) 1.6-fold vs 2.4-fold and insulin 2. 2-fold vs 3.4-fold). Furthermore, low concentrations of bpV(pic) did n ot affect insulin-stimulated glucose uptake, although tyrosine phospho rylation of the insulin receptor beta-subunit was clearly increased by bpV(pic). In conclusion, 1) beta-adrenergic stimulation of lipolysis in vitro is attenuated in NIDDM adipocytes due to post-receptor mechan isms. 2) Both insulin and bpV(pic) decrease lipolysis and enhance gluc ose uptake in control as well as NIDDM adipocytes. The effect on gluco se uptake, but not that on lipolysis, is impaired in NIDDM cells. 3) P eroxovanadate does not improve sensitivity and responsiveness to insul in in NIDDM adipocytes, showing that insulin-resistant glucose uptake in NIDDM is not overcome by phosphotyrosine-phosphatase inhibition and , thus, probably is not caused by impaired tyrosine phosphorylation ev ents alone.