Impaired tyrosine-kinase activity of muscle insulin receptors from hypomagnesaemic rats

Abstract

The effect of magnesium deficiency on glucose disposal, glucose-stimulated insulin secretion and insulin action on skeletal muscle was investigated in rats which were fed a low magnesium-containing diet for 4 days. Control rats were fed a standard diet. Compared to the control rats, the rats fed with low magnesium diet presented: 1) lower serum magnesium levels (0.45±0.02 vs 0.78±0.01 mmol/l, p<0.001), 2) higher basal serum glucose (6.8±0.2 vs 5.5±0.2 mmol/l, p<0.05) and similar basal serum insulin, 3) 40% reduction (p<0.001) in the glucose disappearance rate after its i.v. administration, and 4) 45% reduction (p<0.05) in the glucose-stimulated insulin secretion. The insulin action upon the glucose uptake by skeletal muscle was determined by means of hindquarter perfusions. Compared with control rats, magnesium-deficient rats presented: 1) normal basal glucose uptake, 2) lower stimulatory effect on the glucose uptake by insulin at the concentrations of 5×10-10 mol/l (3.0±0.9 vs 5.4±0.6, p<0.05) and 5×10-9mol/l (6.3±0.5 vs 8.0±0.5, p<0.05), 3) normal glucose uptake at a maximal insulin concentration of 1×10-7 mol/l, and 4) 50% reduction in the insulin sensitivity (ED50: 1.3±0.3 vs 0.55±0.1 mol/l, p<0.05). In partially purified insulin receptors prepared from gastrocnemius muscle, 125I-insulin binding was similar in both groups of rats. However, the autophosphorylation of the Β-subunit of the insulin receptor was significantly reduced by 50% in magnesium-deficient rats and the tyrosine kinase activity of insulin receptors toward the exogenous substrate Poly Glu4: Tyr 1 was also reduced (p<0.05) by hypomagnesaemia. The abundance of the insulin-sensitive glucose transporter protein (muscle/fat GLUT4), measured by Western blot analysis using polyclonal antisera, was similar in muscles of control and hypomagnesaemic rats. These findings indicate that hypomagnesaemia has a deleterious effect on glucose metabolism due to an impairment of both insulin secretion and action. The insulin resistance observed in skeletal muscle of magnesium-deficient rats may be attributed, at least in part, to a defective tyrosine kinase activity of insulin receptors. © 1995 Springer-Verlag.