Scientific Background - Type II Diabetes
Phosphoinositide (PI) activity
The activity of PI second messengers is determined by their phosphorylation state, the enzymes that act to modify these lipids are central to the correct execution of these signaling events. Defects in PI3K response to insulin stimulation are associated with non-insulin dependent diabetes mellitus (NIDDM), or ?type II? diabetes. Inhibition of PI3K blocks insulin-stimulated glucose uptake as well as GLUT4 vesicle translocation. Altered activity of Akt has also been observed in muscle biopsies from NIDDM patients. PIP3 has been indicated as the major mediator of the PI3K dependent insulin response.
SHIP2 is closely related to SHIP1 and also hydrolyzes PIP3 to produce PI(3,4)P2. In contrast to SHIP1, SHIP2 is widely expressed in a variety of fibroblast and non-hematopoetic tumor cell lines and in particular is expressed in target tissues regulating glucose homeostasis. Tyrosine phosphorylation of SHIP2 occurs in response to treatment by a number of growth factors, including insulin, and is thought to act in the regulation of PI3K signaling through insulin.
SHIP2 has recently emerged as a potential therapeutic target for treating glucose metabolism in NIDDM and insulin resistance. By modulating the amount of PIP3 in insulin-responsive cells, SHIP2 acts as a negative regulator of insulin-induced glucose uptake and glycogen synthesis. Thus, SHIP2 appears to be an essential negative regulator of insulin signaling and sensitivity, and altered SHIP2 activity may be a contributing factor to the insulin resistance associated with NIDDM and obesity.
PTEN plays a role in controling insulin sensitivity as a negative regulator of PI3K dependent insulin signaling which may generate interest in PTEN as a potential therapeutic target for modulating glucose metabolism in NIDDM.