Diabetes mellitus is the pandemic of the new millennium. Research into the causes and treatment of diabetes is a major strength and area of emphasis at Wake Forest University Medical Center.
Ongoing diabetes research projects cover the spectrum from focused laboratory studies aimed at understanding the molecular mechanisms that lead to diabetes to population-based studies with the purpose of developing better methods for treatment and prevention of diabetes mellitus.
In the current fiscal year, diabetes-related studies account for more than $38.2 million of research at the Medical Center. Thus, diabetes research was the number one ranked source of research funding for the Institution.
The medical school has special strengths in several areas of diabetes research. Of note are studies of the genetic contributors to diabetes and diabetic complications, such as cardiovascular disease and nephropathy. Genetic research in minority populations is also a special area of emphasis.
In addition, Wake Forest is a major participant in NIH-sponsored clinical trials targeting diabetes prevention and prevention of cardiovascular disease and other complications in people with diabetes. There are numerous researchers investigating the influence of lipids, hormones, and blood pressure on the metabolic components of diabetes such as insulin resistance. In addition, Wake Forest is a leader in stem cell research aimed at developing pancreatic ß-cells for the production of insulin.
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Highlights of diabetes research at the medical center are summarized below.
Cellular Mechanisms and Animal Models of Diabetes and Obesity
Central to understanding why people develop diabetes and obesity is the ability to identify the pathways in cells that lead to diabetes or those that are changed when a person develops diabetes. An essential element in diabetes and obesity research is the ability to change the way that specific genes function to understand how such a gene affects diabetes and obesity.
The Center for Diabetes Research is the home for researchers investigating cellular and physiological pathways that are involved in the functioning of the insulin secreting ß-cell of the pancreas, insulin sensitivity, and obesity. In particular, studies are underway investigating links with inflammation and neuroendocrine control of insulin sensitivity. These studies encompass both evaluations of cellular mechanisms at the cellular level and mouse knockout models. An important aspect of this research is using genetic discoveries to target specific genes for detailed mechanistic evaluation.
Genetics of Diabetes and Genetics of Diabetes Complications
Risk for developing diabetes is powerfully linked to the genes that we carry in our chromosomes. For almost 20 years, Wake Forest researchers have played an active and prominent role in research targeted at identifying genes that contribute to diabetes and complications of diabetes.
The search for genes that contribute to diabetes has taken many paths, with studies focused on large groups of patients with diabetes or diabetic complications such as kidney disease or heart disease. These studies are complemented by studies of metabolic measures related to diabetes such as insulin sensitivity, insulin secretion and obesity.
Multiple NIH funded studies support an active program of genetic studies that are now utilizing genome wide association approaches to carry out detailed fingerprinting of the genome to identify genes that affect diabetes risk, insulin sensitivity, ß-cell function, and measures of obesity. Among these studies, members of the Center for Diabetes Research Play a leading role in the Meta-analysis of Type 2 Diabetes in African Americans Consortium, or the MEDIA Consortium which includes the study of over 29,000 African Americans from 19 separate studies to better understand the genetic contributions to diabetes susceptibility in this population.
Diabetes in Minority Populations
Minority populations in the United States have significantly higher levels of diabetes. Researchers at Wake Forest are active in many research projects that focus on the reasons for this high prevalence. These studies encompass a wide range of approaches, but include studies of the genes that contribute to diabetes and complications of diabetes in African Americans and Hispanic Americans. Diabetes risk cannot, however, be viewed solely through the lens of physiology. Health and disease are the result of a complex interaction of socioeconomic factors, culture, genetics, and access to care. These factors may have an amplified affect in minority populations.
There are extensive outreach and active educational programs, many of which are sponsored by the Maya Angelou Center for Health Equity. These programs are targeted to the large African American, growing Hispanic, and Native American populations of our region. For example, North Carolina has the largest Native American population east of the Mississippi River, including 8 federal or state recognized tribes. Investigators at the Medical Center have conducted research among North Carolina’s American Indian populations and have documented high rates of diabetes and diabetes related risk factors and complications.
Clinical Studies of Diabetes
Multiple investigators in the clinical sciences play active roles in numerous aspects of diabetes research. Among these activities, participation in clinical trials of new drugs to find more effective ways of treating diabetes and participation in large national trials of diabetes care and treatment are active and continuous activities. Many of these studies are targeted directly at improving health care delivery in diabetes patients, such as using patient databases to follow efforts at achieving treatment goals and evaluating “process of care” measures among our patients to assess the effectiveness of those outcomes.
Other activities include studies in which new treatments are being tested to treat gastrointestinal disorders in people with diabetes and to develop new approaches for controlling diabetes and glucose metabolism in patients that are undergoing cardiothoracic surgery to prevent cerebrovascular complications. Complementary studies are assessing how and where fat is developed as people age and become overweight.
Clinical Pancreas Transplantation as a Treatment for Diabetes
Diabetes is a pandemic with a devastating affect on the public health of the United States.
Vascularized or whole organ pancreas transplantation was first developed as a means to re-establish endogenous insulin secretion that is responsive to normal feedback controls. Successful pancreas transplantation results in an insulin-free condition with improved quality of life, life expectancy, and the potential to prevent or ameliorate the secondary complications of diabetes.
The trade-offs for normal glucose homeostasis are the surgical risks of the transplant procedure and the medical risks from chronic immunosuppression. The Wake Forest University Abdominal Organ Transplant Program actively performs pancreas transplants in the 3 major categories (simultaneous kidney-pancreas, sequential pancreas after kidney, and pancreas alone transplants).
Areas of clinical research interest and focus are refining procurement and surgical techniques, improving pancreas preservation to minimize ischemia-reperfusion injury, advancing the science of immunosuppression with new drug regimens, minimizing early graft failure, investigating quality issues including economics/quality of life/long-term outcomes (including prevention of diabetic complications), liberalizing criteria for donor and recipient selection (including transplantation of type 2 diabetic patients), studying new methods for the early detection of allograft rejection, and analyzing novel protocols of infection prophylaxis.
An important complement to this program is research developing methods for encapsulating pancreatic beta cells to reintroduce into people to cure diabetes.
Diabetes and Aging
As people age, their risk of developing diabetes increases and diabetes has a dramatic impact on health and quality of life in the aging population. In addition to increasing risk for heart, kidney, nerve, and eye disease, diabetes has a powerful impact on cognition in aging individuals and contributes to accelerating disability in aging patients.
Diabetes has, in fact, been described as a model of aging due to its impact on the entire person. Understanding the relationship between cognitive decline, disability, and diabetes is an active area of research in the Sticht Center for Aging. Among studies that are underway are comprehensive assessments of brain anatomy, brain function, and their relationship with cognition in diabetes-affected patients. These studies include sophisticated magnetic resonance brain imaging evaluation of patients and detailed testing of cognitive abilities.
Nonhuman Primate Models of Diabetes and Related Disorders
Nonhuman primates are unique animal models for research relevant to understanding the origins and treatment of diabetes. Primates offer opportunities for researchers to carry out studies in species closely related to people in which diet, activity, and environment can be controlled in ways that are not possible with human subjects.
Researchers at the Wake Forest University Primate Center have numerous studies underway to investigate obesity, insulin resistance and inflammation, and their role in both progression of diabetes and exacerbation of cardiovascular disease. In addition, adipose tissue is an important source of circulating inflammatory cytokines that represents a possible link between obesity and subsequent disease risk.
Further studies are focused on changes in pancreatic function with the progression of insulin resistance to diabetes with a particular emphasis on islet-associated amyloid and its role in beta cell failure. In addition, studies that are best carried out in primates are relevant to women’s health and nutrition, specifically in the areas of cardiovascular disease and diabetes, through investigating the effects of hormones and dietary soy components on lipids, insulin, and atherosclerosis. Pedigreed nonhuman primates provide novel opportunities to explore the genetic and epigenetic contribution to obesity, diabetes and related comorbidities.
Childhood Obesity: Prevention of Diabetes and Heart Disease
The increase in prevalence of diabetes is strongly linked to increased obesity in our society. It is now clear that overweight young people become overweight adults with all the implications of increased risk for diabetes and heart disease. How to stem this tide is an important focus of Pediatrics researchers who believe that early, effective intervention with young people may reduce the subsequent risk of adult disease. To develop effective programs requires outreach research and the development of community intervention programs that can identify, involve, and help young people who are overweight. Among these activities is an ongoing project with the NC association of YMCAs to develop community-based family centered programs for childhood obesity prevention and treatment. At local YMCAs, families receive nutritional education by a registered dietitian and the children receive supervised physical activity.
It is recognized that childhood obesity is a family problem, not just an individual problem. Another part of this research involves the development of office-based motivational interviewing programs by pediatricians and dietitians in order to counsel parents on how to adopt healthier lifestyles for their families. In addition, the Division of Public Health Sciences is the Coordinating Center for the national, multicenter SEARCH for Diabetes in Youth study, which is following 9,000 young people with diabetes in an effort to gain a better understanding of diabetes in young people and the impact of the disorder on their lives.
Regenerative Medicine: Stem Cell Research
Regenerative medicine, the science of using stem cells and reprogramming other cells from the body to repair or replace damaged cells or tissues, has enormous promise and potential for contributing to diabetes research and treatment. Researchers in the Wake Forest Institute for Regenerative Medicine (WFIRM) are internationally recognized for their expertise in stem cell research and the new and novel field of “reprogramming” cells to carry out new tasks. Of particular note are research studies supported by a Quantum Grant from the National Institute of Biomedical Imaging and Bioengineering, the Juvenile Diabetes Research Foundation and other sources. This research is aimed at developing insulin secreting ß-cells for research with the ultimate goal of replacing the damaged or missing ß-cells in people with diabetes.
The group is currently assessing function by injecting the cells into a mouse model of diabetes. The numerous other activities within the center, such as developing replacements for vascular tissue, have direct applications to diabetic patients due to their high risk of having cardiovascular disease.
Models of Insulin Resistance: Lipid Sciences Program
There is growing interest in the relationship between lipid metabolism and diabetes. Increasing evidence suggests that insulin resistance, a key component of type 2 diabetes, is associated with chronic low-grade inflammation. In addition, there is mounting evidence that genetic variations in the human ABCA1 gene are associated with altered glucose metabolism, onset of obesity, and insulin resistance. Although polymorphisms in the human population likely affect ABCA1 function in all tissues, the loss of ABCA1 function in macrophages may lead to increased low-grade chronic inflammation in vivo, which may predispose to insulin resistance. Saturated fatty acids can stimulate inflammation in macrophages and studies are underway to test whether a high saturated-fat diet in animal models where the ABCA1 gene is specifically knocked out in macrophages results in increased obesity and insulin resistance due to chronic low-grade inflammation. If true, individuals with polymorphisms in ABCA1 that compromise function may be at increased risk for developing obesity and insulin resistance when dietary consumption of saturated fatty acids is high.
Hypertension & Vascular Disease Center
Many of the same hormonal and neural systems important to control of blood pressure are also involved in the regulation of glucose and body weight. Recent studies are focusing on the role of the brain and the renin-angiotensin system in the development of age-related declines in insulin and leptin sensitivity, which occur in parallel with the decline in cardiovascular control mechanisms.
Transgenic rats with alterations in brain levels of angiotensin peptides have provided insights into the potential brain signaling mechanisms responsible for the beneficial effects on blood pressure and metabolic function of long-term treatments that block the renin-angiotensin system. These treatments may become preferred therapies in patients that have the combination of high blood pressure, resistance to insulin and leptin, and obesity.
Population-Based Studies of Diabetes & Diabetes Complications
Wake Forest has a long and rich history of coordination and participation in major national trials sponsored by the National Institutes of Health. Of particular note, the Division of Public Health Sciences currently houses the coordinating centers for the Action to Control Cardiovascular Risk in Diabetes (ACCORD) and the Action for Health in Diabetes (Look AHEAD) trials.
- ACCORD is a trial evaluating different treatment strategies in an effort to identify better ways of preventing heart disease events in 10,251 people with established diabetes.
- Look AHEAD is a trial investigating an intensive lifestyle intervention designed to produce and maintain weight loss which can prevent heart disease in overweight and obese people with diabetes.
These are 2 among many similar studies that directly interact with patients in the community in an effort to identify better ways of treating or preventing diabetes, obesity, and their associated complications, such as heart disease, in the general population.
Social and Behavioral Sciences in Diabetes Care and Treatment
Diabetes is one of the few chronic diseases which require ongoing, vigilant action by the patient to control both short- and long-term outcomes. Although self-management behaviors in the domains of diet, physical activity, glucose monitoring, foot care, medications, and medical monitoring are prescribed, patients must interpret and carry out these behaviors within the context of their lives and resources.
Researchers in the Department of Family and Community Medicine and the Department of Epidemiology and Prevention are performing studies designed to identify the common-sense models for understanding of diabetes by patients of different ages and ethnic backgrounds. Identification of these models is the basis for investigating the affect of using these models targeted to different age groups and ethnicities in diabetes self-management strategies, and to measure the effects of these strategies on glycemic control and diabetes complications.