Improvement of glucose homeostasis and hepatic insulin resistance in ob/ob mice given oral molybdate.

Molybdate (Mo) exerts insulinomimetic effects in vitro. In this study, we evaluated whether Mo can improve glucose homeostasis in genetically obese, insulin-resistant ob/ob mice. Oral administration of Mo (174 mg/kg molybdenum element) for 7 weeks did not affect body weight, but decreased the hyperglycaemia (approximately 20 mM) of obese mice to the levels of lean (L) (+/+) mice, and reduced the hyperinsulinaemia to one-sixth of pretreatment levels. Tolerance to oral glucose was improved: total glucose area was 30% lower in Mo-treated mice than in untreated ob/ob mice (O), while the total insulin area was halved. Hepatic glucokinase (GK) mRNA level and activity were unchanged in O mice compared with L mice, but the mRNA level and activity of L-type pyruvate kinase (L-PK) were increased in O mice by 3.5- and 1.7-fold respectively. Mo treatment increased GK mRNA levels and activity (by approximately 2.2-fold and 61% compared with O values), and had no, or only a mild, effect on the already increased L-PK variables. mRNA levels and activity of the gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK) were augmented in O liver (sixfold and by 57% respectively), and these were reduced by Mo treatment. Insulin binding to partially purified receptors from liver was reduced in O mice and restored by Mo treatment. Despite this correction, overall receptor tyrosine kinase activity was not improved in Mo mice. Moreover, the overexpression (by two- to fourfold) of the cytokine tumour necrosis factor alpha (TNF alpha) in white adipose tissue, which may have a determinant role in the insulin resistance of the O mice, was unaffected by Mo. Likewise, overexpression of the ob gene in white adipose tissue was unchanged by Mo. In conclusion, Mo markedly improved glucose homeostasis in the ob/ob mice by an insulin-like action which appeared to be exerted distal to the insulin receptor tyrosine kinase step. The blood glucose-lowering effect of Mo was unrelated to over-expression of the TNF alpha and ob genes in O mice, but resulted at least in part from attenuation of liver insulin resistance by the reversal of pre-translational regulatory defects in these mice.