Metabolic stressors are known to induce heart arrhythmias such as atrial fibrillation. Inflammation has also been associated with both heart disease and metabolic diseases like diabetes. However, the cellular and molecular mechanisms for this link remains poorly understood.

Our lab uses multi-pronged unbiased approaches to take a fresh look at this problem. We incorporate novel preclinical modes of the disease as well as taking a translational approach with samples from humans with cardiovascular disease.

This has led to the discovery that specific metabolites, inflammatory cell types, and cytokines play an important pathogenic role in atrial fibrillation. These novel observations change our view of the disease and nominate specific molecular targets.

The adipose organ is complex and composed of many different cell types including adipocytes, endothelial cells, preadipocytes and immune cells (such as macrophages and lymphocytes). Aside from the well-known role of adipocytes to store energy, adipocytes secrete many adipocytokines that can modulate systemic energy homeostasis and diseases such as diabetes and obesity. Fat has often been cast as a “bad player” in diseases. However, we know that fat cells can also secrete many beneficial adipocytokines. The Lo lab is interested in understanding how the adipose organ strikes this delicate balance and harnessing the power of specific adipokines to prevent and treat cardiometabolic diseases.

We made the discovery that the adipokine adipsin can control blood sugar levels in a mouse model of type 2 diabetes. Adipsin acts via the pancreatic beta cell to induce insulin secretion and protect against beta cell failure. In support of our basic research studies, we found that human patients with low levels of adipsin are at higher risk of developing type 2 diabetes and beta cell failure. We are finding ways to leverage this novel adipose to pancreatic islet axis to combat diabetes mellitus.

The lab is actively exploring other new adipokines and adipocyte factors involved in metabolism, viral and inflammatory diseases.

The pancreatic islets are clusters of endocrine cells embedded within the exocrine part of the pancreas. Although these islets are relatively “small”, they have a large impact on whole body energy metabolism. The beta cell is responsible for secreting insulin, a hormone that is a central regulator of blood glucose levels. In type 2 diabetes or prediabetes (where blood glucose levels are too high), insulin may initially increase to help compensate for hyperglycemia. However, in advanced and chronic cases of type 2 diabetes there is a decline in beta cell secretion of insulin termed beta cell failure. There are no current treatments that can arrest or reverse beta cell failure. We discovered that blocking the DUSP26 phosphatase may prevent beta cell death and dedifferentiation. Studies are underway to see how leveraging this knowledge can treat or prevent diabetes.

We are using state of the art molecular techniques to investigate how beta cell failure develops. Our data suggest that beta cells transition into differing populations with some that become dysfunctional. We are working on identifying the molecular mechanisms that cause this shift in beta cell heterogeneity.