Role of the liver in glucose homeostasis in PI 3-kinase p85α-deficient mice

Aoki K, Matsui J, Kubota N, Nakajima H, Iwamoto K, Takamoto I, Tsuji Y, Ohno A, Mori S, Tokuyama K, Murakami K, Asano T, Aizawa S, Tobe K, Kadowaki T, Terauchi Y. Role of the liver in glucose homeostasis in PI 3-kinase p85 alpha-deficient mice. Am J Physiol Endocrinol Metab 296: E842-E853, 2009. First published January 27, 2009; doi:10.1152/ajpendo.90528.2008.-Phosphoinositide 3-kinase (PI3K) p85 alpha-deficient mice exhibit hypoglycemia as a result of increased insulin sensitivity and glucose uptake in peripheral tissues. Although PI3K is central to the metabolic actions of insulin, its mechanism of action in liver is not well understood. In the present study, we investigated hepatic insulin signaling and glucose homeostasis in p85 alpha-deficient and wild-type mice. In the livers of p85 alpha-deficient mice, p50 alpha played a compensatory role in insulin-stimulated PI3K activation by binding to insulin receptor substrate (IRS)-1/2. In p85 alpha-deficient mice, the ratio of p50 alpha over p110 catalytic subunit of PI3K in the liver was higher than in the muscles. PI3K activity associated with IRS-1/2 was not affected by the lack of p85 alpha in the liver. Insulin-stimulated Akt and phosphatase and tensin homologue deleted on chromosome 10 ( PTEN) activities in the liver were similar in p85 alpha-deficient and wild-type mice. A hyperinsuline-mic-euglycemic clamp study revealed that the glucose infusion rate and the rate of disappearance were higher in p85 alpha-deficient mice than in wild-type mice but that endogenous glucose production tended to be higher in p85 alpha-deficient mice than in wild-type mice. Consistent with this finding, the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase in livers after fasting was higher in p85 alpha-deficient mice than in wild-type mice. After mice were fasted, the intrahepatic glucose-6-phosphate level was almost completely depleted in p85 alpha-deficient mice. The glycogen content fell to nearly zero as a result of glycogenolysis shortly after the initiation of fasting in p85 alpha-deficient mice. The absence of an increase in insulin-stimulated PI3K activation in the liver of p85 alpha-deficient mice, unlike the muscles, may be associated with the molecular balance between the regulatory subunit and the catalytic subunit of PI3K. Gluconeogenesis was rather elevated in p85 alpha-deficient mice, compared with in wildtype mice, and the liver seemed to partially compensate for the increase in glucose uptake in peripheral tissues.