Type 2 diabetes is typically present for years before diagnosis, and individuals at risk for diabetes have insulin resistance and other metabolic abnormalities for years before that. The primary focus of the Patti Laboratory is to identify the molecular and metabolic pathways which are disrupted in individuals at risk for diabetes. We are particularly interested in mechanisms by which environmental or nutritional factors can mediate risk, potentially by altering transcriptional regulation and metabolism at a cellular level. By understanding these mechanisms, we are hopeful that we will be able to identify new approaches to diabetes prevention and treatment. To address these key questions, scientists in the Patti Lab utilize both cellular and animal models of diabetes risk, as well as tissue samples from human volunteers with insulin resistance or established type 2 diabetes. Current projects include analysis of metabolism and transcriptional regulation in (1)  iPS cells (skin-derived induced pluripotent stem cells) derived from patients with diabetes or insulin resistance, and (2) mouse models of diabetes risk created by disruption of candidate genes or in response to prenatal nutritional exposures. With these studies, we continue to identify and test new genes and pathways in the cell which are important for maintaining normal insulin response (insulin sensitivity) and blood glucose levels.   

Some of the recent findings include:

• Insulin resistance and nutrition during early life can profoundly influence disease risk in adult life and may also impact on health of subsequent generations. We recently demonstrated (Science 2014) that prenatal nutritional exposures of a pregnant mouse confer diabetes risk not only in offspring, but also in grandoffspring mice, potentially by altering germ cell epigenetic regulation of transcription. Current studies aim to understand whether epigenetic signals can be modified during postnatal life and to determine the mechanisms by which these signals can affect early-life development.
   
• Insulin resistance and nutrition during early life can affect the metabolic function of stem cells - cells which are critical for normal development. We are analyzing how diabetes risk affects metabolism, transcriptional regulation, and differentiation programs in iPS and other stem cell populations. 

We are hopeful that understanding how transcriptional, epigenetic, and metabolic regulation is altered prior to the onset of diabetes will provide us the opportunity to identify new methods to reduce diabetes risk and also to reduce risk for subsequent generations.

In Dr. Patti's role as an endocrinologist and director of the hypoglycemia clinic at Joslin, she cares for patients with severe hypoglycemia, a condition which sometimes occurs after bariatric or other forms of gastrointestinal surgery. Given the severity of this condition, she is working to identify mechanisms responsible for hypoglycemia and reductions in glucose levels after bariatric surgery, and is investigating new therapies to reduce its frequency and severity.