Mary Elizabeth Patti, M.D., is an Investigator and adult endocrinologist at the Joslin Diabetes Center and Assistant Professor of Medicine at Harvard Medical School. The primary long-term goal of our laboratory research is to define cellular mechanisms of insulin resistance and type 2 diabetes risk in humans, by evaluating patterns of dysregulation prior to diabetes onset. Our early genomic approaches using samples from metabolically characterized human subjects demonstrated that a key signature of type 2 diabetes in multiple insulin target tissues is altered transcriptional regulation of mitochondrial function. While this is likely to contribute to disordered metabolism in established type 2 diabetes, this pattern appears relatively late in diabetes progression. Thus, our current primary focus utilizes both genomic and metabolomic approaches to identify potentially pathogenic patterns of both transcriptional and metabolic dysregulation in tissue and plasma samples from normoglycemic humans at risk for diabetes. A second focus is identification of mechanisms by which the prenatal and early postnatal nutritional environment mediate risk for diabetes during adult life. Using mouse models developed in the lab, we have shown that fetal exposure to either undernutrition or maternal insulin resistance alters developmental patterns, contributing to increased adiposity and DM during adult life. Importantly, these phenotypes can be reversed by nutritional manipulation during early postnatal life and can be transmitted to subsequent generations. We are currently studying how early life nutrition alters adipose tissue transcription patterns, differentiation, and metabolic function We are hopeful that our approaches will ultimately lead to identification of both novel targets for treatment of DM as well as signatures of diabetes risk, in order to guide targeted prevention and therapy of DM2 in the clinical setting.