Specific Inhibition of PTEN Expression Reverses Hyperglycemia in Diabetic Mice

Abstract

Signaling through the phosphatidylinositol 3-kinase (PI3K) pathway is crucial for metabolic responses to insulin, and defects in PI3K signaling have been demonstrated in type 2 diabetes. PTEN (MMAC1) is a lipid/ protein phosphatase that can negatively regulate the PI3K pathway by dephosphorylating phosphatidylinositol (3,4,5)-triphosphate, but it is unclear whether PTEN is physiologically relevant to insulin signaling in vivo. We employed an antisense oligonucleotide (ASO) strategy in an effort to specifically inhibit the expression of PTEN. Transfection of cells in culture with ASO targeting PTEN reduced PTEN mRNA and protein levels and increased insulin-stimulated Akt phosphorylation in ␣-mouse liver-12 (AML12) cells. Systemic administration of PTEN ASO once a week in mice suppressed PTEN mRNA and protein expression in liver and fat by up to 90 and 75%, respectively, and normalized blood glucose concentrations in db/db and ob/ob mice. Inhibition of PTEN expression also dramatically reduced insulin concentrations in ob/ob mice, improved the performance of db/db mice during insulin tolerance tests, and increased Akt phosphorylation in liver in response to insulin. These results suggest that PTEN plays a significant role in regulating glucose metabolism in vivo by negatively regulating insulin signaling.

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

“…Unfortunately, Pten-deficient mice die at early stage of embryonic development (17)(18)(19)(20), which precludes study of the role of PTEN in the mammalian insulin signaling pathway in a wholeanimal setting. Injection of antisense oligonucleotide has demonstrated that inhibiting Pten may improve the glycemic control in ob͞ob and db͞db mice (21). In this study, we have generated an animal model by disrupting the Pten gene in mouse liver to assess the biological functions of PTEN in insulin signaling and the development of insulin resistance.…”

Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse

“…To inhibit expression of SOCS-1 and -3 in vivo, db͞db mice were treated by i.p. injection with 25 mg͞kg of AS1, AS3, C1, C3, or PBS once per week for 2 weeks as described (23).…”

Physiological Functions of Pten in Mouse Tissues.

“…However, no gross abnormalities, changes in cell size, or alterations to serum glucose levels were observed. Butler et al reported that specific inhibition of Pten by in vivo administration of antisense oligonucleotide improves the hyperglycemia in diabetic mice (Butler et al, 2002). The generation of mutant mice specifically lacking Pten in hepatocytes or adipocytes will be required to clarify the function of Pten in glucose metabolism.…”