Pten (phosphatase and tensin homologue gene) haploinsufficiency promotes insulin hypersensitivity.

Abstract

AIMS/HYPOTHESIS:

Insulin controls glucose metabolism via multiple signalling pathways, including the phosphatidylinositol 3-kinase (PI3K) pathway in muscle and adipose tissue. The protein/lipid phosphatase Pten (phosphatase and tensin homologue deleted on chromosome 10) attenuates PI3K signalling by dephosphorylating the phosphatidylinositol 3,4,5-trisphosphate generated by PI3K. The current study was aimed at investigating the effect of haploinsufficiency for Pten on insulin-stimulated glucose uptake.

MATERIALS AND METHODS:

Insulin sensitivity in Pten heterozygous (Pten(+/-)) mice was investigated in i.p. insulin challenge and glucose tolerance tests. Glucose uptake was monitored in vitro in primary cultures of myocytes from Pten(+/-) mice, and in vivo by positron emission tomography. The phosphorylation status of protein kinase B (PKB/Akt), a downstream signalling protein in the PI3K pathway, and glycogen synthase kinase 3beta (GSK3beta), a substrate of PKB/Akt, was determined by western immunoblotting.

RESULTS:

Following i.p. insulin challenge, blood glucose levels in Pten(+/-) mice remained depressed for up to 120 min, whereas glucose levels in wild-type mice began to recover after approximately 30 min. After glucose challenge, blood glucose returned to normal about twice as rapidly in Pten(+/-) mice. Enhanced glucose uptake was observed both in Pten(+/-) myocytes and in skeletal muscle of Pten(+/-) mice by PET. PKB and GSK3beta phosphorylation was enhanced and prolonged in Pten(+/-) myocytes.

CONCLUSIONS/INTERPRETATION:

Pten is a key negative regulator of insulin-stimulated glucose uptake in vitro and in vivo. The partial reduction of Pten due to Pten haploinsufficiency is enough to elicit enhanced insulin sensitivity and glucose tolerance in Pten(+/-) mice.

• Authors: J T Wong, P T W Kim, J W Peacock, T Y Yau, A L-F Mui, S W Chung, V Sossi, D Doudet, D Green, T J Ruth, R Parsons, C B Verchere, C J Ong
• Journal: Diabetologia (Diabetologia) Vol. 50 Issue 2 Pg. 395-403 (Feb 2007) ISSN: 0012-186X [Print] Germany
• PMID: 17195063 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Glucose Transporter Type 1
• Glucose Transporter Type 4
• Insulin
• Slc2a1 protein, mouse
• Slc2a4 protein, mouse
• Fluorodeoxyglucose F18
• Deoxyglucose
• Phosphatidylinositol 3-Kinases
• PTEN Phosphohydrolase
• Glucose

Topics

• Animals
• Blood Glucose (drug effects, metabolism)
• Crosses, Genetic
• Deoxyglucose (metabolism)
• Diabetes Mellitus, Type 2 (genetics)
• Fluorodeoxyglucose F18
• Genetic Carrier Screening
• Glucose (pharmacology)
• Glucose Tolerance Test
• Glucose Transporter Type 1 (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Insulin (blood, pharmacology)
• Insulin-Secreting Cells (metabolism)
• Islets of Langerhans (drug effects, metabolism)
• Mice
• PTEN Phosphohydrolase (deficiency, genetics, metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Positron-Emission Tomography