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Peroxovanadate and insulin action in adipocytes from NIDDM patients. Evidence against a primary defect in tyrosine
Z W Yu1, P A Jansson, B I Posner
1Department of Medicine, University of Göteborg, Sahlgrenska University Hospital, Sweden.
Abstract:
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.
Insights
Peroxovanadate compound (bpV(pic)) inhibits lipolysis and enhances glucose uptake in adipocytes. However, these effects are impaired in non-insulin-dependent diabetes mellitus (NIDDM) cells, suggesting insulin resistance is not solely due to impaired tyrosine phosphorylation.
Area of Science:
- Metabolic research
- Cellular biology
- Diabetes mellitus
Background:
- Non-insulin-dependent diabetes mellitus (NIDDM) is characterized by insulin resistance.
- Lipolysis and glucose uptake are key metabolic processes affected in NIDDM.
- Phosphotyrosine phosphatases play a role in insulin signaling.
Purpose of the Study:
- To investigate the effects of insulin and a peroxovanadate compound (bpV(pic)) on lipolysis and glucose uptake in adipocytes from NIDDM patients.
- To compare the efficacy of bpV(pic) with insulin in modulating these processes.
- To explore the role of phosphotyrosine phosphatase inhibition in NIDDM-related insulin resistance.
Main Methods:
- Subcutaneous adipocytes were isolated from male NIDDM patients and matched non-diabetic controls.
- Lipolysis was stimulated using isoprenaline or 8-bromo-cyclic AMP (8-br-cAMP).
- Glucose uptake was measured using 14C-U-glucose.
- Effects of insulin and bpV(pic) on lipolysis, glucose uptake, and insulin receptor tyrosine phosphorylation were assessed.
Main Results:
- Beta-adrenergic stimulated lipolysis was reduced in NIDDM adipocytes compared to controls.
- Both insulin and bpV(pic) inhibited lipolysis and enhanced glucose uptake in both groups.
- The enhancement of glucose uptake by bpV(pic) and insulin was impaired in NIDDM adipocytes.
- bpV(pic) increased tyrosine phosphorylation of the insulin receptor but did not improve insulin-stimulated glucose uptake in NIDDM cells.
Conclusions:
- In vitro lipolysis stimulated by beta-adrenergic agents is reduced in NIDDM adipocytes via post-receptor mechanisms.
- Insulin and bpV(pic) affect lipolysis and glucose uptake in both control and NIDDM adipocytes, with impaired glucose uptake response in NIDDM.
- Peroxovanadate inhibition of phosphotyrosine phosphatases does not overcome insulin resistance in NIDDM glucose uptake, indicating it's not solely due to impaired tyrosine phosphorylation.