Current Projects:
1. Diabetic kidney disease:
Diabetes is the leading cause of end-stage renal disease (or ESRD), which underlies most of the morbidity and mortality among individuals with diabetes. Diabetic kidney disease shows strong familial aggregation and is highly heritable. The Diabetes Research Unit recently completed a genome scan to identify genes involved in the development and progression of renal failure attributed to diabetes. Using an unique pooling design, state-of-the-art technology, and innovative analytical tools, we identified major loci underlying susceptibility to kidney failure.

The Diabetes Research Unit is also completing whole genome scans to identify genes underlying ESRD attributed to type 1 diabetes. Although type 1, or insulin-dependent, diabetes, is etiologically distinct from type 2 diabetes, the development of kidney disease in both disorders follows a similar pathophysiological course. Incorporating a two-pronged case-control and family-based study design, combined with linkage and whole genome association analyses, linkage disequilibrium mapping, and candidate gene screening, we are identifying variants that substantially increase risk of developing kidney disease in individuals with both type 1 and type 2 diabetes and determining the functional consequences of these mutations. This research will pave the way toward more advanced diagnostic strategies and improved therapeutic options to slow the progress of or even prevent this complication of diabetes.

Using high-throughput genomics tools and cell biology methodology, we are actively delineating the molecular mechanisms underlying protein and mRNA changes that occur in mesangial cells in response to hyperglycemia. This work is providing both an enhanced understanding of genetic and molecular factors that contribute to disease progression in susceptible individuals and a basis upon which to build more advanced treatment strategies aimed at key target pathways.

2. Type 2 diabetes mellitus:
In collaboration with investigators from the Keck School of Medicine at the University of Southern California, we are examining genetic factors that determine how well an individual responds to anti-diabetic drug therapy. Approximately 30-45% of individuals treated with diabetes medication do not respond to treatment with the expected improvement in insulin sensitivity. Our research will unravel the genetic architecture underlying response to these therapeutics and allow individuals to receive the most effective drug for the treatment of their diabetes.

Post-transplantation diabetes mellitus (PTDM) is a common complication of renal replacement therapy and is associated with substantial morbidity and mortality among kidney transplant recipients. There is substantial variability in reported incidence rates for PTDM, which is likely attributable to the absence of standard diagnostic criteria for the disease and a lack of a classification system for PTDM patients. Further, although age, ethnic background, obesity, immunosuppressive agents, and genetic factors have been associated with increased susceptibility to PTDM, risk factors for disease development are not clearly established, and it is not currently possible to predict which patients will develop PTDM following kidney transplantation. In collaboration with clinicians at the Mayo Clinic, we are refining the ability to identify patients at highest risk for PTDM developing following kidney transplantation prior to surgery.

3. Other Projects:
Other projects in this unit include efforts to identify effects of lifestyle factors, such as dietary composition and physical activity levels, on underlying genetic susceptibility. It is clear that some individuals with a genetic predisposition, will not develop diabetes in the absence of mitigating environmental factors. Elucidation of these interactions will not only help identify who is at risk of developing diabetes, but will also allow managed control of dietary factors or other environmental stimuli, to prevent development of the disease.

Staff:
Johanna K. DiStefano, Ph.D., Unit Head
Mahtab Nourbakhsh, PD Ph.D., Adjunct Faculty
Chris Kingsley, Ph.D., Associate Investigator
Lucrecia Alvarez, Ph.D., Research Associate
Meredith P. Millis, B.S., Research Associate
Kimberly A. Yeatts, B.S., Research Associate

Related Links
American Diabetes Association