Vanadate restores glucose 6-phosphate in diabetic rats: a mechanism to enhance glucose metabolism

Vanadate mimics the metabolic actions of insulin. In diabetic rodents, vana date also sensitizes peripheral tissues to insulin. We have analyzed whethe r this latter effect is brought about by a mechanism other than the known i nsulinomimetic actions of vanadium in vitro. We report that the levels of g lucose 6-phosphate (G-6-P) in adipose, liver, and muscle of streptozotocin- treated (STZ)-hyperglycemic rats are 77, 50, and 58% of those in healthy co ntrol rats, respectively. Normoglycemia was induced by vanadium or insulin therapy or by phlorizin. Vanadate fully restored G-6-P in all three insulin -responsive peripheral tissues. Insulin did not restore G-6-P in muscle, an d phlorizin was ineffective in adipose and muscle. Incubation of diabetic a dipose explants with glucose and vanadate in vitro increased lipogenic capa city three- to fourfold (half-maximally effective dose = 11 +/- 1 mM vanada te). Lipogenic capacity was elevated when a threshold level of similar to 7 .5 +/- 0.3 nmol G-6-P/g tissue was reached. In summary, 1) chronic hypergly cemia largely reduces intracellular G-6-P in all three insulin-responsive t issues; 2) vanadate therapy restores this deficiency, but insulin therapy d oes not restore G-6-P in muscle tissue; 3) induction of normoglycemia per s e (i.e., by phlorizin) restores G-6-P in liver only; and 4) glucose and van adate together elevate G-6-P in adipose explants in vitro and significantly restore lipogenic capacity above the threshold of G-6-P level. We propose that hyperglycemia-associated decrease in peripheral G-6-P is a major facto r responsible for peripheral resistance to insulin. The mechanism by which vanadate increases peripheral tissue capacity to metabolize glucose and to respond to the hormone involves elevation of this hexose phosphate metaboli te and the cellular consequences of this elevated level of G-6-P.