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 less than 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 mumol.kg-1.min-1, P less than 0.01), returned to normal with lithium and vanadate (206 +/- 6 mumol.kg-1.min-1), or increased to supranormal levels with lithium, vanadate, zinc, and magnesium (238 +/- 6 mumol.kg-1.min-1). During the insulin clamp, muscle glycogenic rate was severely impaired in diabetic versus control rats (18 vs. 70 mumol.kg-1.min-1) and was normalized by lithium and vanadate (91 mumol.kg-1.min-1) or lithium, vanadate, zinc, and magnesium (93 mumol.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)