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.
Reul
B A
BA
Endocrinology and Metabolism Unit, University of Louvain, Faculty of Medicine, Brussels, Belgium.
Becker
D J
DJ
Ongemba
L N
LN
Bailey
C J
CJ
Henquin
J C
JC
Brichard
S M
SM
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D020738:Leptin; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008982:Molybdenum / Q000494:pharmacology*; D009765:Obesity / Q000378:metabolism*; D011506:Proteins / Q000235:genetics; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D011506:Proteins; D014409:Tumor Necrosis Factor-alpha; C044659:molybdate; D008982:Molybdenum; D005941:Glucokinase; D011770:Pyruvate Kinase