Research Description
Ceramides are a class of lipids that can accumulate in response to excess intake of saturated fat and inflammation. The class of lipids circulates in the serum, where it serves as a strong biomarker for the prediction of diabetes, heart disease, and cardiovascular mortality. We hypothesize that many patients have an enhanced genetic propensity to accumulate these toxic lipids, which can be identified and can serve to inform diabetes treatment options. From patients with Type 2 diabetes and end-stage renal disease, we have identified rare genetic variants which impair the cellular breakdown of ceramides and strongly enhance the abundance of circulating ceramides. Using genetically diverse mouse strains, we have identified dozens of novel genes which may contribute to elevated levels of circulating ceramides. Many of these genes have common genetic variants that strongly correlate with diabetes, obesity, kidney disease, or cardiovascular disease. Here we propose to: 1) validate these novel genes as drivers of ceramides in cultured cells; 2) determine if genetic variants of these genes correlate with altered plasma ceramides in patient samples from multiple cohorts; and 3) evaluate the effect of ceramide-lowering drugs on glucose and lipid metabolism from mouse models that recapitulate 2 severe models of ceramide accumulation. These studies will establish a framework for the genetic identification of individuals prone to diabetes and its complications as a result of ceramide accumulation, and determine if targeted therapies which block ceramide formation can prevent or reverse diabetes resulting from even the most severe genetic propensities.Research Profile
What area of diabetes research does your project cover? What role will this particular project play in preventing, treating and/or curing diabetes?Our research examines a class of lipids that contributes to type 1 diabetes, type 2 diabetes, and diabetes complications (most critically diabetic kidney disease). Our ADA-funded work evaluates novel therapeutic strategies for lowering glucose and lipid levels in mice which mimic newly identified genetic variants which were identified from family members who are genetically prone to diabetes and rapid-progressing diabetic kidney disease.
If a person with diabetes were to ask you how your project will help them in the future, how would you respond?Diabetes has been pervasive in my family for generations, and I hypothesize that hundreds of genes may contribute to the genetic predisposition for diabetes (or resistance to the disease). Using mouse and human cohorts, we believe we have identified dozens of genes which contribute to the excess accumulation of a toxic lipid --ceramide-- that predicts diabetes and contributes to the onset of the disease. In particular, we have identified two families with a strong genetic propensity to accumulate ceramide, develop diabetes, and rapidly progress to kidney failure. Using mice designed to mimic the disease-causing genetic variants in these patients, we will test novel therapeutic compounds which lower ceramides in mice, and may provide an ideal therapeutic option for these families (and millions of other diabetics) to improve glucose control and prevent diabetic complications.
Why important for you, personally, to become involved in diabetes research? What role will this award play?I have had a passionate disdain for diabetes since childhood, and have devoted my entire professional career to combatting the disease. I have witnessed the debilitating effects of diabetes, and its complications harm my mother, her siblings, her parents, and grandparents. With each generation, it is clear that improvements in diabetes care lead to a better quality of life. I have long been motivated to ensure that the next generation of diabetics (my kids and nieces) will have better therapeutic options to predict, prevent, detect, or treat diabetes.
In what direction do you see the future of diabetes research going?The ultimate goal of our work is to improve the quality of life for diabetics and patients at risk for diabetes. My sincere hope is that the burgeoning prognostic and therapeutic approaches, will enable precision interventions to fight diabetes. By directly combatting each of the many underlying causes of diabetes, we hope to equip at-risk patients with ideal treatments to prevent, delay, or reverse diabetes and its comorbidities.