Research Theme 3
Complications of Diabetes Mellitus
Robert Abbott | Alaa Awad | Kline Bolton | Viktor Bovbjerg | Robert
Carey | William Clarke
Daniel Cox | Brian Duling | Jay Fox | Adrian Gear <| Linda Gonder-Frederick
Karen Johnston | Boris Kovatchev | Norbert Leitinger | Klaus Ley | Anthony McCall
Coleen McNamara | Mark Okusa | Gary Owens | Helmy Siragy | Thomas Skalak | Amy Tucker
Professor of Public Health Sciences
Through the Administrative Core, Dr. Abbott provides expertise on probability modeling, experimental design, and power analysis. He reviews pilot and feasibility projects for statistical design integrity. He has a longstanding and specific interest in Diabetes as he continues to have a lead role in the analysis the effects of diabetes and hyperglycemia in the Honolulu Heart Study.
Alaa S. Awad
Assistant Professor of Research
Research focus: Inflammation in diabetic nephropathy: podocyte microenvironment; podocyte/macrophage interaction.
Accumulating evidence indicates that diabetic nephropathy is a
disorder of the immune system. We are studying the critical role of
macrophages that play a pivotal role in the development and progression
of diabetic nephropathy through direct effects on podocytes or through
alterations of the podocyte niche (microenvironment). In diabetic
nephropathy, alterations in the podocyte niche are likely responsible
for abnormal podocyte function leading to progressive albuminuria and
progressive renal failure. Podocyte function is intimately linked to
its complex cytoskeletal structure. As a result of injury, cytoskeletal
rearrangement ensues leading to foot process effacement.
Demonstrating that macrophages or its effect on podocyte environment play a central role in DN will have important clinical relevance. A number of pharmacological agents targeted to macrophages secretory products could be considered in future trials.
Professor of Medicine - Chief, Division of Nephrology
Research focus: Mechanisms of autoimmune and diabetic glomerular disease
Areas of interest in this laboratory include experimental models of autoimmune glomerulonephritis and the role of angiotensin-converting enzyme inhibitors and inhibitors of advanced glycosylation end products in the prevention of the progression of glomerular disease in normotensive and hypertensive diabetic subjects. In the autoimmune nephritis model They are studying the nephritogenic (disease causing) T cell epitope and regulatory elements involved in initiation and progression of disease, including T regulatory cells. Clinically they are also interested in ghrelin and growth hormone secretagogues in the nutritional and immunological status of patients with chronic kidney disease and on dialysis. They have also been involved in clinical studies of the beneficial effects of monoclonal antibodies to connective tissue growth factor on diabetic nephropathy.
Diabetes control requires the widespread adoption of effective interventions, both for prevention and treatment. Our work focuses on translating efficacious lifestyle interventions into clinical and community settings, complementing both primary and specialist medical care. Ongoing projects include a multi-site clinical trial of individually tailored lifestyle intervention for obese patients with type 2 diabetes, targeting long term glycemic control, cardiovascular risk, body composition, diet and physical activity, and quality of life. Research underway and proposed examines the role of community organizations in diabetes control, the potential of parish nurses to promote diabetes prevention and control activities, and factors influencing physical activity in rural environments. Overall, the goal of our group is to promote the translation of effective medical and behavioral interventions to practice.
Hypertension is almost twofold more prevalent in diabetic patients and accelerates both cardiovascular and microvascular complications of diabetes. This laboratory studies the mechanism of pressure-natriuresis, which is disordered in virtually all forms of hypertension. The specific goals of their current studies are to understand the role of renal interstitial cyclic-GMP in mediating pressure-natriuresis. They are testing the hypothesis that pressure-natriuresis is mediated by extracellular cyclic GMP and whether the dampening of pressure-natriuresis in salt-sensitive hypertension is due to a defect in the renal interstitial cyclic GMP production.
Dr. Clarke is investigating methods for improving glucose control is persons with Type 1 Diabetes. His current research involves; 1) developing and testing algorithms for use in a "Closed loop" artificial pancreas; 2) developing and testing methods for describing the clinical accuracy of continuous glucose monitoring devices; 3)developing and testing the utility of Blood Glucose Awareness Training for parents of children with T1DM; 4)developing and testing a bio-behavioral intervention to reduce driving mishaps among persons with T1DM; and 5) understanding how external and internal physiologic and behavioral mechanisms affect glucose levels in T1DM and how this information can be used to better describe glucose variability. He is Co-investigator on 3 NIH RO1 grants and a grant from the JDRF.
This laboratory focuses on identifying risk factors associated with occurrence of hypoglycemia-related driving mishaps and subsequently modifying these risk related driving mishaps, and how best to reverse such risk factors, following their bio-psycho- behavioral model. Dr. Cox and collaborators have developed methods for assessment of hypoglycemic awareness, fear of hypoglycemia, impact of hypoglycemia on driving performance, and glucose utilization in Type I patients. They have also examined the impact of Blood Glucose Awareness Training on the prevention and detection of hypoglycemia and reduction of severe hypoglycemia, in collaboration with researchers from Europe and Japan. Their unique resources include use of hand held computers to collect patient data during patients' daily routine, use of driving simulation to quantify the effects of neuroglycopenia on driving performance, use of the internet to deliver psycho-educational intervention for patients with diabetes, and blood flow biofeedback to reverse vascular disease to prevent amputation. They have expertise in assessing a variety of psychological issues relevant to diabetes, such as quality of life, diabetes knowledge, fear of hypo and hyperglycemia, family interactions around diabetes management.
This lab studies the means by which the cells of the arteriolar wall (smooth muscle and endothelium) operate as a coordinated unit, and to determine how these cells communicate with the parenchymal cells of the organs in which they reside. We are particularly interested in the possible contribution of the gap junctinos to the pathophysiology of hypertension. They also study the chemical, mechanical, and electrical signaling processes, which establish cell-cell communication within and between smooth muscle and endothelial cell and the trigger mechanisms responsible for stretch and flow sensitivity of blood vessels. Using video microscopy of living cells combined with state-of-the-art imaging technologies and computer processing, and newly developed specific cell surface labels and detection indicators allows the visualization of the individual cells of the microvessel wall, as well as the formed elements of the blood in the living animal. With these tools the lab is also attempting to understand the role played by the endothelial cell glycocalyx in the control of erythrocyte and leukocyte distribution in the microvessels.
Professor of Microbiology
Assistant Dean for Research Support
Director DERC Quantitative Omics Facility
Research focus: Host-tumor cross-talk, metalloproteinases, extracellular matrix and omics technologies
Our laboratory is investigating the molecular mechanisms in host-tumor cross talk as involved in melanoma metastasis. In conjunction with tumor metastasis and other disease states we are interested in the role of extracellular matrix in disease and the proteolytic modulation of matrix to affect cellular signaling processes. In conjunction with diabetes we are very interested in perturbogens that affect cell-signaling processes associated with diabetes using genomic and proteomic read-outs to understand these effects. Finally, our laboratory is also heavily engaged in mapping the phosphoproteomic of focal adhesions during cellular migration.
This laboratory studies how oxidized LDL, in particular LDL oxidized by hypochlorous acid (HOCL-LDL), stimulates platelet aggregation under arterial and venous blood-flow conditions. Candidate lipids in HOCL-LDL include lysophosphatidic acids (LPAs) and sphingosine-1- phosphate (S1P). Inflammatory chemokines such as stromal-cell-derived factor-1 (SDF-1), macrophage-derived chemokine (MDC), RANTES, IL-8 and others are also being evaluated for their ability to enhance platelet function induced by low non-aggregatory levels of primary agonists (ADP and thrombin). A second research area targets how two toxins, endotoxin (lipopolysaccharide, LPS) and Shiga toxins (Stx1, 2) are able to enhance platelet function. New evidence suggests that LPS directly stimulates platelets, involving new synthesis of mitochondrial inner-membrane components. Shiga toxin and LPS can both work indirectly by targeting endothelial cells and leukocytes, promoting synthesis and release of inflammatory chemokines. The increased chemokines in the blood likely provides a significant stimulation of platelet function induced by ADP, thrombin or other agonists. New studies will test the hypothesis that direct platelet and leukocyte interactions with 'inflamed' endothelial cells will stimulate not just more platelet aggregation, but also rapid and major blood-clot formation. Control and chemokine rich 'diabetic' plasma environments will be contrasted their ability to stimulate platelet consumption and clot generation.
This program studies the cognitive effects of acute episodes of hypo- and hyperglycemia in children and adults with type 1 diabetes. They focus particularly on the emotional effects of severe hypoglycemia on people with diabetes and their families and develop patient education programs for continuous glucose monitoring technology and use PDA technology to deliver feedback concerning diabetes management and control. This has included translating Blood Glucose Awareness Training for parents of children with type 1 diabetes.
The Glucose Regulation in Acute Stroke Patients (GRASP) trial is an NINDS funded multicenter, randomized, controlled trial that is assessing the feasibility and safety of insulin infusion therapy in hyperglycemic acute ischemic stroke patients. Stroke patients may be randomized to tight control (glucose levels maintained 70-110 mg/dL), loose control (70-200 mg/dL) or usual care (70-300 mg/dL) for a 5 days in the acute stroke period.
Associate Professor of Psychiatry and Neurobehavioral Sciences
Head, Section Computational Neuroscience
Research focus: The application of engineering and technology to the assessment and treatment of diabetes
The Diabetes Technology group at the University of Virginia led by Dr. Kovatchev conducts both basic and translational research. Since 1996 Dr. Kovatchev has enjoyed continuous NIH funding for the development of mathematical theory and applied computational methods related to the control of diabetes, particularly T1DM. At a basic science level he investigates, from a computational point of view, two processes determining a person’s risk for hypoglycemia: (i) the process of insulin transfer from circulation to interstitium using a stochastic model of insulin-induced microvascular recruitment and subsequent insulin transport through the capillary endothelium, and (ii) the time course of development, and the dynamical characteristics of hypoglycemia-associated autonomic failure (HAAF). The translation components of their NIH-funded studies include the creation of an Integrated Biobehavioral Monitoring and Feedback system providing algorithm-based feedback about average glycemia, glucose variability, symptoms and self-treatment behaviors to patients with T1DM in their natural environment. The effectiveness of this is system in now prospectively tested in a field outcomes study.
Patients with diabetes suffer from increased incidence and severity of atherosclerotic cardiovascular diseases. To study the mechanisms through which diabetes accelerates vascular disease, we have identified mouse models of insulin resistance, i.e. C57BL/6 apoE-/- mice fed a fat-rich western diet(1) and insulin receptor and insulin receptor substrate-1 double heterozygous (IR+/-IRS1+/-) mice (2), which we have successfully crossed into the apolipoprotein E-deficient (apoE-/-) mouse on the C57BL/6 background. ApoE-/- mice, like humans who are at elevated risk for atherosclerotic cardiovascular disease, are hypercholesterolemic. We have recently shown that T cells, B cells, macrophages and dendritic cells even in the normal aortic wall of healthy C57BL/6 mice under baseline conditions(3). Most of these lymphocytes reside in the adventitia. The total number of leukocytes in the healthy mouse aorta is almost one million, which is equivalent to the contents of a small lymph node. We have also demonstrated homing of T and B cells into the aortic wall of normal C57BL/6 mice. These findings suggest that the aortic wall and, by inference, the walls of other large arteries, are constantly surveyed by the adaptive and innate immune systems. We now hypothesize that lymphocyte trafficking into and out of the walls of large arteries is altered in diabetes, and that this process contributes to accelerated atherosclerotic vascular disease. We have experiments under way that are designed to determine why and how atherosclerosis results in chronic inflammation of the vascular wall that does not resolve, and how insulin resistance and type 2 diabetes modify this process.
We try to understand how oxidative modification of lipids during tissue damage leads to monocyte-specific inflammation and phenotypic changes of macrophages in the vascular wall and in adipose tissue. Furthermore, we investigate the hypothesis that the induction of the potent anti-inflammatory gene heme oxygenase-1 (HO-1) by PPARs significantly contributes to their anti-inflammatory effects.
Professor of Medicine
Chair, DERC Pilot and Feasibility Committee
Research focus: Physiological regulation of hypoglycemia counterregulation in the pancreas and the effects of hypoglycemia on brain glucose transport and signal transduction in the brain.
Dr. McCall's lab examines the role of antecedent hypoglycemia upon glucose transport proteins and signal transduction and their influence upon hypoglycemia unawareness and defective hypoglycemic counterregulation, two of the most important predictors of severe hypoglycemia during therapy of Type 1 diabetes mellitus. The work examines the hypothesis that abnormal signal transduction in the hypothalamus and other brain areas may influence hypoglycemia recognition and defenses in part through regulation of glucose transport proteins. Separately he is also working with a mathematician, Dr. Leon Farhi, studying the effects and mathematically modeling intraislet signaling with hypoglycemia counter-regulation in insulin deficient diabetes focusing on glucagon counterregulation. By understanding mechanisms of intra-islet hypoglycemia induced glucagon pulsatile secretion and its defective responses in diabetes and understanding mechanisms through which the brain recognizes and organizes hormonal defenses against hypoglycemia, the ultimate goal of these two lines of work is to reduce the risks of severe hypoglycemia with insulin therapy.
This laboratory studies the cellular regulatory mechanisms involved in vascular smooth muscle cell proliferation. They have observed that in animal models of type 2 diabetes there are increases of smooth muscle cell proliferation in response to injury. This laboratory has demonstrated that 12 lipoxygenase regulates vascular smooth muscle cell growth and this is one potential mechanism for the accelerated response to vascular injury in diabetes. This laboratory has shown that a helix-Loop-helix transcription factor, Id3, is increased in multiple animal models of diabetes. The laboratory is currently involved in studying the cis and trans-acting elements that mediate 12 lipoxygenase-induced increases in Id 3 expression.
Dr. Okusa's laboratory examines mechanisms of renal injury associated with diabetic nephropathy and potential novel therapeutic interventions. Inflammation is regarded as an important pathogenic mechanism leading to podocyte dysfunction and progressive proteinuria and loss of kidney function. Current therapies delay the disease progression but does not stop or reverse the disease process. Selective agonists of the adenosine 2a receptor block inflammation and protect kidneys from acute injury. We now show that these receptors are expressed on podocytes and when activated by novel agonists can preserve podocyte morphology leading to preservation of kidney structure and function. A second area focuses on the role of sphingosine 1 phosphate receptors in diabetic nephropathy. Selective activation of sphingosine 1 phosphate receptors leads to marked reduction of proteinuria. We collaborate with clinical investigators who are currently planning to initiate human studies.
Dr. Owens' laboratory has been specifically addressing the role of growth factors in regulating both the hypertrophic and proliferative response of vascular smooth muscle. These studies have indicated a series of complex control mechanisms responsive to both endocrine and paracrine regulation. Defining these basic signaling processes will have long-term implications for addressing the role of insulin and hyperglycemia in the generation of hypertension associated with insulin-resistant states.
The overall objective of our studies is to test the hypothesis that the reduction in the angiotensin subtype-2 (AT2) receptor expression and activity contributes to development of renal histologic and functional abnormalities that are seen during the early stage diabetic nephropathy through enhancement of renal inflammation. Understanding the mechanisms involving the AT2 receptor in diabetic nephropathy may lead to the development of new therapeutic modalities that can help prevent or slow down the development of this disease. Our studies suggest that in early stage diabetic nephropathy AT2 receptor expression and function are decreased while angiotensin subtype-1 (AT1) receptor activity is increased leading to increased generation of inflammatory factors. AT2 may inhibit renal generation of growth factors, cytokines and pressor hormones that participate in early changes associated with diabetic nephropathy, directly or through its mediators NO and cGMP.
Professor and Chair of Biomedical Engineering
Research focus: Use of biomedical engineering technology to study microvascular flow and blood vessel remodeling in response to stress
Using several state-of-the-art engineering technologies including confocal microscopy, computer simulation of blood vessel network flow dynamics, and tissue mechanics, this laboratory studies blood flow in the microvasculature. There is special interest in the retinal microvasculature and how it is affected by diabetes and in the role of the microvasculature in wound healing. We showed that in a rat model of diabetes, leukocyte plugging of capillaries is increased, which may be a source of flow impairment early in diabetic neovascularization. Novel technical approaches include multicellular computer simulations that provide predictive capability for complex system pattern formation and remodeling in the cardiovascular system and in developmental morphogenesis. Dr. Skalak is the author of comprehensive reviews of the role of mechanical stresses in microvascular remodeling. Recent experimental work has focused on identification of the cell types and molecular signaling processes responsible for arteriolar assembly in adult tissues, including the role of bone marrow-derived stem cells. He has given more than 80 invited talks on these topics throughout the world to both industrial partners and academic groups, and has delivered short courses on blood rheology for R&D groups at corporate clients such as Abbott Laboratories.
This laboratory uses novel, subtype-selective ligans to adenosine receptors to identify the role of adenosine A1,A2A, A2B, and A3 receptors in the process of adenosine-stimulated angiogenesis. The laboratory uses three models of angiogenesis: 1) the chicken chorioallantoic membrane, rat drastic aortic rings, and rat mesenteric vasculature to assess in vivo modulation of angiogenesis by adenosine agonists, antagonists, and allosteric effectors. The ultimate goal of these studies is to develop pharmacologic agents which could be used in the therapeutic manipulation of angiogenesis.