Hepatic insulin resistance in KKA(y) mice and its amelioration by pioglitazone do not involve alterations in phospholipase C activity.
It has been proposed that an abnormality in the regulation of cytosolic-free Ca2+ may be the cause of some forms of insulin resistance. In support of this proposition, it was reported that phospholipase C-catalyzed hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by liver plasma membranes from obese patients with non-insulin-dependent diabetes mellitus (NIDDM) was abnormally augmented (Thakker et al., J. Biol. Chem. 264, 7169-7175). The objective of this investigation was to determine if a novel antidiabetic agent, pioglitazone, ameliorated hepatic insulin resistance in KKA(y) mice and to identify any alterations in PIP2-phospholipase C activity of liver plasma membranes that may accompany changes in insulin sensitivity. Treatment of KKA(y) mice for 4 days with pioglitazone (20 mg/kg per day) decreased blood glucose and insulin and improved a variety of indices of hepatic insulin resistance, but did not alter the rate of PIP2 hydrolysis by liver plasma membranes. Acute treatment of isolated liver plasma membranes with pioglitazone (1-100 microM) also failed to alter PIP2-phospholipase C activity. Furthermore, the specific activity, Ca(2+)-requirement, pH-dependence and sensitivity to guanosine 5'-thiotriphosphate of the PIP2-phospholipase C in KKA(y) liver membranes were indistinguishable from those of C57BL/6J (normal) mice. Among C57BL/6J and KKA(y) mice fed either a control or pioglitazone-supplemented diet, there was no correlation between PIP2-phospholipase C activity in isolated liver membranes and either glucose or insulin concentrations in the circulation. These data indicate that an alteration in PIP2-phospholipase C activity of liver plasma membranes is neither a cause nor an obligatory consequence of insulin resistance in KKAy mice or its amelioration by pioglitazone. Alterations of liver membrane phospholipase C activity in NIDDM, therefore, may reflect diabetic pathology other than the insulin resistance associated with this disease.
Metabolic Diseases Research, Upjohn Company, Kalamazoo, MI.
J E
JE
Bleasdale
M L
ML
Swanson
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000201:enzymology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D054801:Phosphoinositide Phospholipase C; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D000077205:Pioglitazone; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones
D007004:Hypoglycemic Agents; D013844:Thiazoles; D045162:Thiazolidinediones; D010727:Phosphoric Diester Hydrolases; D054801:Phosphoinositide Phospholipase C; D000077205:Pioglitazone