News & Research

    Yale University, New Haven, Connecticut

Spatiotemporal regulation of phosphoinositides by SHIP2 in insulin signaling

General Research Subject: Type 2 Diabetes

Focus: Insulin Action\Signal Transduction

Type of Grant: Mentor Based Postdoctoral Fellowship

Project Start Date: July 1, 2008

Project End Date: June 30, 2012

Research Description

Type 2 Diabetes Mellitus (T2DM), previously referred to as adult-onset diabetes or non insulin-dependent Diabetes Mellitus (NIDDM), currently accounts for nearly 90% of diabetes cases nationwide. While it was once considered a disease of late adulthood, T2DM is now increasingly diagnosed in overweight children and young adults reaching near epidemic proportions. In spite of massive efforts, an effective cure for T2DM is still not available.

In a mouse model, it was shown that functional perturbations of an enzyme called SHIP2 prevents the development of T2DM and obesity. SHIP2 inactivates a signaling molecule (a phospholipid) that plays an important role in mediating the action of insulin in target cells, such as muscle and adipose tissue. Thus, SHIP2 is a potential therapeutic target for treatment of T2DM. However, a precise understanding of how SHIP2 functions within the cell has not yet been achieved. The goal of this proposal is to advance our understanding of how SHIP2 participates in the cellular signaling pathways required for insulin action within target tissues. We hope that these investigations will propel us forward in developing a cure for T2DM.

Reseacher Profile

Mentor: Pietro De Camilli, MD   Postdoctoral Fellow: Fubito Nakatsu, PhD

What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?

My project focuses on the mechanisms through which the signal of insulin in decoded in target cells and on the mechanisms that control the intensity and the duration of such signal. Binding of insulin to its receptors, for example on muscle and fat cells, generates a lipid molecule, a phospholipid called PIP3. This molecule, in turn, activates a series of molecular reactions that represent an important aspect of the physiological response to insulin. Eventually PIP3 is degraded, thus helping to terminate such response. Modulating the level and lifetime of PIP3 will have an impact on insulin action. Our project is focused on the intracellular localization, function and regulation of an enzyme, called SHIP2, which degrades PIP3. A main working hypothesis of the project is that inhibition of SHIP2 may potentiate and prolong the insulin signal. Thus, a further characterization of the properties of SHIP2 may validate this enzyme as a potential target for drugs aimed at enhancing the response to insulin.

If a person with diabetes were to ask you how your project will help them in the future, how would you respond?

Our work may help to develop a cure for some forms of diabetes. More specifically, we hope that our studies will provide information towards the development of drugs for the treatment of diabetes due to defective insulin levels and for some forms of diabetes resulting from an impaired cellular response to insulin.

Why is it important for you, personally, to become involved in diabetes research? What role will this award play in your research efforts?

For nearly 30 years my lab has been interested in research on mechanisms underlying cell communication in the nervous system and the endocrine system. I have already made major contributions to the field of diabetes. For example, my lab identified the enzyme GAD as the main autoantigen in type I diabetes. For many years I have directed (or co-directed) a cell biology core facility at Yale supported by an NIH DERC (Diabetes and Endocrinology Research Center) grant. I have an M.D. degree and I have carried out postgraduate studies in Medical Endocrinology. This training has motivated me to work at the interface between fundamental cell biology and medicine. This award will further motivate me and members of my lab to search for interfaces between our studies and the field of diabetes.

In what direction do you see the future of diabetes research going?

I see many promising directions including the following:1) Our understanding of the mechanism of insulin action will continue to advance. This progress will point to powerful new targets for therapeutic interventions for type II diabetes and early stages of type I diabetes. My current work relates to this area. 2) Progress in immunology will help to slow the course of type I diabetes, which is due to an autoimmune attack against insulin secreting pancreatic beta-cells. 3) Advances in the field of stem cell research may make possible replace missing beta-cells with new ones.