Insulinomimetic properties of trace elements and characterization of their in vivo mode of action

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Abstract
Lithium and vanadate have insulinomimetic actions in vitro. In this study, we examined the in vivo effects of lithium and vanadate on glucose metabolism in diabetic (90% partial pancreatectomy) rats. Four groups of chronically catheterized rats were studied: control, diabetic, diabetic treated with lithium (plasma concn 1.0 ± 0.1 meq/L) and vanadate (0.05 mg/ml in drinking water), and diabetic treated with lithium, vanadate, zinc, and magnesium. Postmeal plasma glucose was increased in diabetic versus control rats (18.7 vs. 7.7 mM, P < 0.01) and was normalized by addition of lithium and vanadate (8 mM) or lithium, vanadate, zinc, and magnesium (7.4 mM). Euglycemic insulin-clamp studies were performed 2 wk posttreatment; insulin-mediated glucose uptake was reduced in diabetic compared with control rats (142 ± 4 vs. 200 ± 5 μmol · kg−1 · min−1 P < 0.01), returned to normal with lithium and vanadate (206 ± 6 μmol · kg−1 · min−1), or increased to supranormal levels with lithium, vanadate, zinc, and magnesium (238 ± 6 μmol · kg−1 · min−1). During the insulin clamp, muscle glycogenic rate was severely impaired in diabetic versus control rats (18 vs. 70 μmol · kg−1 · min−1) and was normalized by lithium and vanadate (91 μmol · kg−1 · min−1) or lithium, vanadate, zinc, and magnesium (93 μmol · kg−1 · min−1). Whole-body glycolytic rate (conversion of [3H]glucose to 3H2O) accounted for 55% of glucose disposal in control (106 ± 5 μmol · kg−1 · min−1), 72% in diabetic (103 ± 3 μmol · kg−1 · min−1), 49% in lithium- and vanadatetreated diabetic (98 ± 4 μmol · kg−1 · min−1), and 56% in lithium-, vanadate-, zinc-, and magnesium-treated diabetic (132 ± 4 μmol · kg−1 ± min−1) rats. We conclude that, in diabetic rats, 1 ) insulin-mediated glucose disposal is markedly impaired, and this primarily reflects a defect in muscle glycogen synthesis, whereas glycolytic flux is not decreased; 2 ) combined lithium and vanadate treatment normalizes insulin sensitivity and muscle glycogen synthesis; 3 ) the addition of zinc and magnesium further improves glucose disposal, primarily by stimulating glycolysis. These results suggest that trace-element therapy, either alone or in combination, may prove effective in the treatment of non-insulin-dependent diabetes in humans.