Gluconeogenesis in non-obese diabetic (NOD) mice: in vivo effects of vandadate treatment on hepatic glucose-6-phoshatase and phosphoenolpyruvate carboxykinase.
The contribution of gluconeogenesis to hyperglycemia in non-obese diabetic (NOD) mice has been investigated using oral vanadate administration. Vanadate compounds have been shown to mimic many actions of insulin; however, the exact mechanism is poorly understood. The aims of the present study were (1) to elucidate vanadate's action in vivo, and to assess the possibility that its glucose-reducing effect is dependent on the presence of a minimal concentration of insulin; and (2) to evaluate the effects of vanadate administration on the key hepatic gluconeogenesis enzymes, glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK), as well as glucose-6-phosphate dehydrogenase (G-6-PDH). Vanadate caused a significant reduction in blood glucose but failed to normalize it, despite effective serum vanadate concentrations (26.2 +/- 1.6 micromol/L). Two weeks after initiation of treatment, blood glucose levels were 26.0 +/- 1.8, 21.7 +/- 3.0, 16.0 +/- 1.6, and 14.3 +/- 2.3 mmol/L in the control (C), insulin (I), vanadate (V), and combined vanadate and insulin (V + I) groups, respectively (P < .001). G-6-Pase activity was significantly reduced by vanadate (622 +/- 134 v365 +/- 83 nmol/min/mg protein in C vV, P < .05). PEPCK activity was also significantly reduced (844 +/- 370, 623 +/- 36, 337 +/- 43, and 317 +/- 75 nmol/min/mg in the C, I, V, and V + I groups, respectively, P < .001). No significant differences in the hepatic glycogen stores and G-6-PDH activity were noted between treatment groups. Our study suggests that the inhibition of hepatic G-6-Pase and PEPCK activity by vanadate plays an important role in reducing blood glucose levels in NOD mice.
Mosseri
R
R
Department of Pediatrics, Schneider Children's Medical Center, Ragin Campus, Petah Tikva, Israel.
Waner
T
T
Shefi
M
M
Shafrir
E
E
Meyerovitch
J
J
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D005260:Female; D005943:Gluconeogenesis / Q000187:drug effects; D005952:Glucose-6-Phosphatase / Q000187:drug effects / Q000378:metabolism*; D008099:Liver / Q000201:enzymology*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000187:drug effects / Q000378:metabolism*; D012044:Regression Analysis; D013997:Time Factors; D014638:Vanadates / Q000097:blood / Q000494:pharmacology*
D001786:Blood Glucose; D008112:Liver Glycogen; D014638:Vanadates; D005952:Glucose-6-Phosphatase; D010729:Phosphoenolpyruvate Carboxykinase (GTP)