UF Health Jacksonville
UF Health Jacksonville is recognized for its multidisciplinary efforts to improve diabetes tracking, prevention and care in the North Florida region. Physician scientists are working to enhance quality of patients through new research, education and participation in clinical trials. Learn about UF Health Jacksonville leaders at the forefront of these efforts.
Division of Endocrinology, Diabetes and Metabolism
Under the leadership of Kent Wehmeier, M.D., the division’s research team has set forth the following aims to help stem the tide of the epidemic rise in the pervasiveness of diabetes:
- Delineate factors augmenting expression of the apo AI gene, the most important protein in the high-density lipoprotein (HDL) particle.
- Evaluate the effects of oxidative stress and endoplasmic reticulum stress on endothelial cells and macrophages.
- Identify control mechanisms for cholesterol efflux in macrophages.
- Describe the control of fatty acid oxidation in hepatocytes.
The division is conducting several on-going clinical trials assessing the efficacy and safety of longer-acting insulin analogues, long-acting GLP-1 receptor agonists, concentrated insulin formulations and sodium-glucose transport protein (SGLT2) inhibitors. These trials include some long-term studies to evaluate the effect of these agents on atherosclerotic heart disease and are focused on type 2 diabetes management.
Claudia Gragnoli, M.D., Ph.D., associate professor, focuses on the contribution of mental and behavioral traits to type 2 diabetes and associated aging disorders and specifically in elucidating the basis for the clinical association of depression, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Dr. Gragnoli is intrigued by the complex hormonal pathways existing behind complex disorders and their clinical association, and loves combining her clinical interests with her genetic expertise to satisfy her driving clinical and research goal-oriented perceptions and intuitions. She is interested in studying the genetically shared predisposition to neuro-endocrine dysfunction and impaired stress response, which both contribute to the association of mental-behavioral traits and common disorders (i.e. type 2 diabetes, metabolic syndrome, depression).
Division of Cardiology
Major emphasis has been placed on studies of antithrombotic therapies in patients with cardiovascular disease manifestations. Headed by Dominick Angiolillo, M.D., studies range from ex vivo, in vitro and proof-concept studies to clinical trials. An area of key interest has been in patients with type 2 diabetes mellitus (T2DM) and cardiovascular disease. In particular, the Angiolillo research group has conducted seminal studies characterizing platelet function profiles and antiplatelet drug response to key antiplatelet medications, including aspirin and clopidogrel, defining different profiles in T2DM. Further, the group’s investigations have shown how these may be affected by the severity of diabetes. The prognostic implications of these findings have also been verified in clinical outcome studies, demonstrating an association between specific profiles of platelet reactivity and risk of adverse outcomes, such as recurrent myocardial infarction. The results of this translational research can contribute to the increased atherothrombotic burden observed in T2DM patients and also suggesting the need for more potent antithrombotic drug regimens in this high-risk setting.
The observations above have prompted the Angiolillo group to conduct further investigations to define the mechanisms of platelet dysfunction and impaired response to standard antiplatelet therapies among T2DM patients. These include defining the impact of concomitant risk factors, such as chronic kidney disease, or specific genetic determinants modulating insulin signaling (i.e. insulin receptor substrate-1 genetic polymorphisms) and assessing how these impact drug response profiles and cardiovascular outcomes. They also conducted several in vitro and ex vivo experiments in order to define how differences in drug absorption/metabolism may impact antiplatelet drug response in T2DM, which adds to findings of dysfunction of platelet signaling pathways.
Finally, they performed several proof of concept studies aimed to investigate how to optimize antiplatelet therapy in coronary artery disease patients with TD2M, assessing the effects of alternative antithrombotic medications, including clopidogrel, prasugrel, ticagrelor, cangrelor, cilostazol, thromboxane A2 receptor antagonists, pioglitazone, pentoxifylline, and dabigatran.
Angiolillo’s group has initiated a series of prospective randomized pilot investigations defined “OPTIMUS” (Optimizing Antiplatelet Therapy in Diabetes Mellitus) to provide insights on potential treatment strategies which may allow more effective antithrombotic protection. And has completed the OPTIMUS-1 (standard versus high dose clopidogrel), OPTIMUS-2 (standard dose clopidogrel vs adjunctive cilostazol), and OPTIMUS-3 (high dose clopidogrel vs standard dose prasugrel) studies.
The OPTIMUS-4 (prasugrel vs ticagrelor) is currently ongoing (NCT01852214) and the ongoing THEMIS (Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus Patients Intervention Study (NCT01991795) will assess long-term clinical outcomes of ticagrelor vs placebo in aspirin-treated diabetic patients.
Department of Ophthalmology
UF has come a long way in the fight to uphold a unifying vision for people with diabetes: a life without complications. It has been reported that ocular complications from diabetes remain the most common cause of blindness among American adults 20-74 years of age. In fact, a recent survey reported that loss of vision is the most feared of all diabetic complications.
Under the leadership of K. V. Chalam, M.D., Ph.D., M.B.A., F.A.C.S., UF researchers have hypothesized that it is possible that an educational intervention at the ophthalmology office may have additional impact beyond the current standard of diabetes education at the primary care or diabetologist/endocrinologist office alone. To test this hypothesis, the research team is presently conducting a study entitled, Effect of Diabetes Education during Retinal Ophthalmology Visits on Diabetes Control, (Protocol-M).
The UF COM Department of Ophthalmology in Jacksonville is a charter member of the Diabetic Retinopathy Clinical Research (DRCR) Network, a collaborative network funded by National Eye Institute (NEI) dedicated to facilitating multicenter clinical research of diabetic retinopathy, diabetic macular edema and associated conditions. Since 2007, Jax Opthamology has been been continuously recognized as a high-performing clinical site among the 200 certified sites in the DRCR network.
Division of Nephrology and Hypertension
Dr. Charles W. Heilig‘s labaoratory investigates the roles of glucose transporters in the development of disease. His focus has been primarily on the roles of glucose transporters in kidney disease, particularly diabetic kidney disease, however he also has investigated glucose transporter involvement in nondiabetic kidney disease, diabetic embryopathy, the glucose transporter deficiency syndrome, and cardiovascular disease.
Dr. Heilig has worked to demonstrate the protective effect of antisense-GLUT1 treatment against high glucose – induced matrix production in kidney mesangial cells. This treatment was highly effective and the first manuscript on this work was published in the Am. J. of Physiology. A 50% suppression ofGLUT1 in cultured mesangial cells also suppressed glucose uptake, reducing baseline matrix synthesisand preventing high glucose-induced stimulation of GLUT1 and matrix expression. Dr. Heilig patented his continuous lines of rat mesangial cells with altered GLUT1 expression as an in vitro model for thetesting of new drugs to prevent diabetic glomerulosclerosis (U.S. Pat. #5,939,275). This in vitro model has been used to identify a promising class of anthraquinone drugs to prevent diabetic kidney disease.
Dr. Heilig also developed transgenic mice with overexpression of GLUT1 in kidney mesangial cells to mimic the increased glomerular GLUT1 in diabetic animals. The transgenic GLUT1-overexpressing mice (GT1S mice) develop renal disease simulating diabetic nephropathy, withalbuminuria, glomerulosclerosis, and a progressive decline in renal function. A manuscript on this animal model was published by Dr. Heilig in the American Journal of Physiology, Renal Physiology (2010). Dr. Heilig has also identified how angiotensin-II stimulates glucose uptake into kidney mesangial cells leading to matrix production, which may be important in the development of diabetic glomerulosclerosis.
Dr. Heilig also developed antisense-GLUT1 transgenic mouse lines to mimic diabeticembryopathy, which exhibit severely impaired embryonic development leading to intrauterine demise and stillbirths in the homozygotes. A characteristic set of malformations was observed, which closely resembled diabetic embryopathy.
He is currently investigating mechanisms by which reduced GLUT1 in the embryonic kidney impairs renal development, and has discovered the combination of reduced GLUT1 and increased apoptosis indeveloping glomeruli from embryos exposed to maternal (Streptozotocin-induced) diabetes mellitus. Dr. Heilig’s GLUT1-deficient transgenic mice will allow him to test a mechanism by which maternal diabetes impairs glomerular formation in the developing embryos.
Dr. Heilig’s GLUT1 glucose transporter research in rats and mice led to numerous research studiesof GLUT1 and diabetic kidney disease in humans. These investigations have identified at least 2 important SNP sites in the GLUT1 gene, each associated with approximately 2-fold increased risk for the nephropathy in diabetic patients. Both Type 1 and Type 2 diabetic patients demonstrate associations of GLUT1 susceptibility alleles with increased risk for the nephropathy. Dr. Heilig and colleagues reported on GLUT1 susceptibility alleles in the largest study ever performed on this topic (BMC Med Genet, 1/2011).
Future research investigations for Dr. Heilig and his team include:
- Transgenic mouse model for Reversal of Diabetic Glomerulosclerosis: The DNA constructs have been completed to produce transgenic Tet-inducible Antisense-GLUT1 mice, which will be activated afterdiabetic glomerulosclerosis and albuminuria have been allowed to develop. The potential of such a maneuver to reverse diabetic glomerulosclerosis by reducing the glucose transport in mesangial cells in vivo in mice will be determined, along with an analysis of the induced changes in signaling pathwayactivation to extracellular matrix production, and metalloproteinase expression, in the glomeruli.
- Translational Research: Examination of GLUT1 susceptibility allele frequencies in patients with ESRD on dialysis or with a renal transplant; also in patients with CKD to determine prospectively whether the GLUT1 susceptibility genotypes correlate with progression of CKD going forward in diabetic and nondiabetic patients.
- Characterization of the role of MGF in both diabetic and nondiabetic glomerular diseases, where its stimulation of mesangial matrix production could facilitate development of progressive glomerulosclerosis