Control of glucose homeostasis in vertebrate organisms is achieved through tight regulation of glucose storage in the liver and usage in muscle and adipose tissues. The pancreatic hormone insulin is recognized as a pivotal regulator for processes such as glucose uptake and glycogen synthesis. A lack of insulin or the failure to compensate for diminished insulin response at various target tissues (insulin resistance), hallmark of type 1 and type 2 diabete mellitus (DM), leads to disregulated high levels of circulating glucose that underlie a set of long term debilitating heath consequences including retinopathy, nephropathy, neuropathy, and vascular disease in human. Insulin also acts as a mitogenic factor that controls basic cellular functions such as DNA and lipid synthesis, cell proliferation, differentiation and apoptosis. The pleckstrin domain interacting protein (Phip) was identified as adaptor protein that binds to the insulin receptor substrate 1 and 2 (Irs1 and Irs2). However the functional significance of the interaction between Phip and Irs proteins is not well understood.
To explore the functional significance of Phip/Irs interactions in insulin signaling, we inactivated the Phip gene in mice. We show that mice lacking Phip (Phip-/-) are growth-retarded, have aberrant glucose homeostasis at birth, develop insulin resistance and lack of pancreatic beta compensatory expansion. These impairments are reminiscent of the growth and metabolic defects observed in Irs1 and Irs2 knockout mice. Thus, these in vivo functional data are in line with the notion that Phip is a critical component of the Irs1 and Irs2 branch of the insulin signaling pathway.
The last two decades have seen an increased prodisposition of type 2 diabetes in the United States and around the world. A goal of diabetic research has been to identify molecular targets that can be used to design effective therapeutical treatments for this disease. This goal will likely be facilitated by a complete knowledge of pancreatic organogenesis and insulin signaling pathways. Most critical is an understanding of the molecules that direct: 1) development, growth and survival of panreatic islet cells; 2) glucose sensing and insulin secretion; and (3) insulin signaling. The insights generated in this project will not only help better understand the molecular mechanisms underlying the pathogenesis of type 2 diabetes, but will help design more effective therapies for diabetes.