Insulinomimetic Properties of Trace Elements and Characterization of Their In Vivo Mode of Action

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.