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 compound potassium bisperoxopicolinatooxovanadate (bpV(pic)), a potent inhibitor of phosphotyrosine phosphatases, on lipolysis and glucose uptake in subcutaneous adipocytes from 10 male patients with non-insulin-dependent diabetes mellitus (NIDDM) and 10 matched non-diabetic control subjects. Lipolysis stimulated by isoprenaline or the cAMP analogue, 8-bromo-cyclic AMP (8-br-cAMP), was reduced by approximately 40% in NIDDM compared to control subjects. In both groups bpV(pic) exerted an antilipolytic effect that was similar to insulin (approximately 50 % inhibition). 14C-U-glucose uptake was dose-dependently increased by bpV(pic) treatment, but this effect and also that of insulin were impaired in NIDDM 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 not affect insulin-stimulated glucose uptake, although tyrosine phosphorylation 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 mechanisms. 2) Both insulin and bpV(pic) decrease lipolysis and enhance glucose uptake in control as well as NIDDM adipocytes. The effect on glucose uptake, but not that on lipolysis, is impaired in NIDDM cells. 3) Peroxovanadate does not improve sensitivity and responsiveness to insulin 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 events alone.
Yu
Z W
ZW
Department of Medicine, University of Göteborg, Sahlgrenska University Hospital, Sweden.
Jansson
P A
PA
Posner
B I
BI
Smith
U
U
Eriksson
J W
JW
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000328:Adult; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D008066:Lipolysis / Q000187:drug effects*; D008297:Male; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation / Q000187:drug effects; D011972:Receptor, Insulin / Q000187:drug effects* / Q000378:metabolism; D014443:Tyrosine / Q000187:drug effects / Q000378:metabolism; D014638:Vanadates / Q000494:pharmacology*
D000318:Adrenergic beta-Agonists; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; C069276:peroxovanadate; D015124:8-Bromo Cyclic Adenosine Monophosphate; D014638:Vanadates; D014443:Tyrosine; D011972:Receptor, Insulin; D007545:Isoproterenol