Insulin influences both glucose metabolism and magnesium homeostasis in humans. The present studies sought to determine whether insulin-induced stimulation of magnesium uptake is impaired in noninsulin-dependent diabetes mellitus (NIDDM) and enhanced by acute hyperglycemia. To do so, we measured plasma magnesium concentrations in diabetic and nondiabetic subjects on two occasions: once when glucose concentrations were maintained constant and once when glucose concentrations were varied to mimic a postprandial pattern. The same amount of insulin was infused on both occasions in a manner that reproduced the systemic insulin concentrations normally observed after glucose ingestion. During the prandial insulin infusion, the decrement in the plasma magnesium concentration was lower (P < 0.05) in the diabetic patients than that in the nondiabetic subjects during both the euglycemic (4.1 +/- 0.9 vs. 7.8 +/- 1.3 mmol/L.4 h) and hyperglycemic (1.7 +/- 1.1 vs. 6.6 +/- 1.4 mmol/L.4 h) studies. Glucose disappearance also was lower (P < 0.05) in the diabetic patients than that in the nondiabetic subjects, and the insulin-induced decrement in plasma magnesium was correlated (P < 0.01) with glucose disappearance. On the other hand, despite higher (P < 0.05) rates of disappearance in the hyperglycemic than euglycemic experiments, the decrement in plasma magnesium did not differ in either group on either occasion. We conclude that insulin resistance in subjects with NIDDM impairs the ability of insulin to stimulate magnesium as well as glucose uptake.