Diabetes is an epidemic with profound impacts on quality of life, productivity, and health care costs. Currently there are over 25.8 million Americans with diabetes or pre-diabetes, which works out to approximately 8.3 percent of the population. Statistics also show that the number of diabetes patients is increasing by 5 percent per year and that one in three Americans born in 2000 will likely develop diabetes in his or her lifetime. In just the 10-year period from 1997 to 2007, the annual cost of diabetes in medical expenditures and lost productivity climbed from $98 billion to $174 billion, and the direct medical costs of diabetes almost tripled in that time, from $44 billion to $116 billion (www.diabetes.org).
Diabetes comes in two forms: type 1, which usually begins in childhood and is the result of destruction of critical insulin-secreting cells in the pancreas, and type 2, the form that is rapidly increasing in prevalence as the American population becomes more obese. The destruction of insulin-secreting cells in the pancreas, and severe obesity and the dysregulation of metabolism, cause failure of the body’s glucose regulatory mechanisms. This results in persistent increased blood glucose. Persistent elevated blood glucose that is not properly regulated by insulin damages many tissues, and is associated with the development of debilitating complications that affect the eyes, kidneys, heart, and particularly, the nerves. Almost every person with diabetes will experience at least one of these complications during his or her lifetime.
Despite the high prevalence and the dire need for interventions to assist the growing diabetic population, there are no treatments for diabetic complications and little is known about how and why they occur.
The most common complication of diabetes is nerve damage in the feet, which is initially characterized by intense pain and abnormal sensations of heat, cold, or prickling. This pain is caused by the damaging effects of high blood glucose on peripheral nerves, and is followed over time with numbness and loss of sensation as peripheral nerves die. Pain sensations in the limbs serve to protect the body, and once patients’ nerves die and no longer send signals to the brain, patients become at high risk for undetected limb injuries. These injuries can lead to cutaneous ulcers, infections, tissue death, and lower-limb amputations.
The PNR&D is attacking this huge health problem in many ways. Our scientists are discovering how high blood sugar injures nerves, why this causes pain, and how over time diabetes destroys the nerves. By using animals with diabetes, simulating the insults that nerve cells undergo with diabetes in cultured cells, and studying neuronal changes in patients with diabetic neuropathy, we have discovered some of the key mechanistic pathways involved in neuronal injury during diabetes. These pathways have become the subjects for development of new, groundbreaking therapies.
CURRENT RESEARCH PROJECTS
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Diabetic neuropathy typically affects the sensory and motor neurons with longer axons first, or those that innervate the hands and feet. To track neuropathy progression in mouse models of diabetic neuropathy, scientists examine nerves in mouse footpads where the nerves with longer axons that are typically affected in diabetes are found. This provides a reliable approach to understand how neuropathy progresses in diabetic mouse models and to examine the effects of treatments. Similar approaches can also be used to track nerve function, evaluate neuropathy progression rates, and measure the effectiveness of clinical intervention trials in patients affected by diabetic neuropathy.
Investigators in the PNR&D have optimized a technique to reliably quantify nerve density in human skin punch samples. Essentially, a skin biopsy measuring only a few millimeters across is collected from the ankle or thigh and the number of healthy nerve fibers in the outer skin layer is determined using sensitive staining and imaging techniques in the laboratory. When these fibers are damaged and degenerate during diabetes, patients experience nerve pain and ultimately complete loss of sensation. Therefore, it is critical to understand why this happens and develop ways to examine the effectiveness of new treatments.
In the Cutaneous Innervation Center at the University of Michigan, skin samples are collected and analyzed for nerve fiber density in order to provide a qualitative assessment of nerve function and neuropathy progression for investigators within and outside of the university. This approach is currently being used for diagnostic purposes or as a clinical trial endpoint. For example, a clinical trial examining the effectiveness of a particular drug for diabetic neuropathy can utilize the services of the Cutaneous Innervation Center for nerve density analysis.
Diabetic neuropathy is a prevalent complication of type 2 diabetes and obesity-induced metabolic syndrome and has attributes of a chronic inflammatory disease driven by innate immunity. In the PNR&D, our goal is to identify specific cellular and cytokine targets that can be used to tailor stage-dependent therapeutic interventions for peripheral neuropathy. This is currently underway using animal models of type 2 diabetes. The results of this project will provide valuable insight into the role of the immune system in diabetic neuropathy onset and progression, and is likely to identify targets for novel drug treatments.
Diabetic cardiac autonomic neuropathy is a complication of diabetes that impacts heart function. Glucose fluctuations in diabetes cause dysfunction in cardiac muscle fibers that affect the efficiency and rhythm of heart beats. PNR&D investigators are using multiple approaches to understanding this defect in diabetic animal models and in patients.
One project in the laboratory uses animal models to understand the link between diabetic autonomic neuropathy and sudden cardiac death. Hearts from mouse diabetes models are being studied using advanced electrophysiology and pathological techniques to determine why hearts from diabetic animals are more susceptible to this devastating risk.
Projects in the clinic provide an alternative viewpoint on this complication in patients. With support from a clinical research award from the American Diabetes Association, investigators are working to understand the molecular mechanisms of cardiac autonomic dysfunction in patients with metabolic syndrome. This study is also evaluating the effects of lifestyle interventions in this patient population. Finally, MRI and diffusion tensor imaging techniques are being tested as a new non-invasive approach to diagnose neuropathy in diabetic patients.
The prevalence of diabetes in children and adolescents, especially type 2 diabetes, has increased dramatically in recent years. However, the incidence of diabetic complications like peripheral neuropathy and cardiac autonomic neuropathy in young patients is not well understood.
That is why Dr. Eva Feldman and Dr. Rodica Pop-Busui are working with the SEARCH study to better understand the prevalence and impact of cardiac complications and diabetic neuropathy among young people with type 1 and type 2 diabetes.
The SEARCH for Diabetes in Youth Study is a national multi-center effort focused on understanding the impact of diabetes on children and young adults. Funded by the Centers for Disease Control and Prevention and the NIH/NIDDK, this longitudinal study was initiated in 2000 to harness the efforts of six clinical centers across the country to recruit approximately 9,000 children and youth to participate. The goal of this study is to characterize the key risk factors for diabetic complications as they pertain to this population. Understanding the prevalence of cardiac complications and peripheral neuropathy in young people with type 1 and type 2 diabetes will provide important information for future screening and treatment needs.
Painful diabetic neuropathy is a major complication of diabetes. Diabetics with painful neuropathy report a significantly decreased quality of life, and experience lower extremity burning or shock-like sensations with increased sensitivity to both painful (hyperalgesia) and non-painful stimuli (allodynia). The mechanisms underlying the onset and progression of this complication are poorly understood.
Research by Dr. Thomas Cheng and investigators in the PNR&D on painful diabetic neuropathy is focused on identifying specific proteins that could serve as therapeutic targets for the treatment of diabetic neuropathic pain. Using molecular and biochemical techniques on a genetic model of type 2 diabetes, the db/db mouse, PNR&D investigators found that pain corresponds with upregulation of a protein called nerve growth factor, or NGF. Activation of the tropomysin-related kinase A receptor, subsequent p38 kinase activation, and increases in the expression of a protein called substance P were also observed in sensory neurons of diabetic mice. These findings suggest that NGF signaling in these neurons underlies the development of diabetes-induced pain behavior in type 2 diabetes. Based on these findings, current research is examining the efficacy of treatments that target NGF signaling as a new approach to treat diabetic neuropathic pain in type 2 diabetes animal models, and eventually, patients.
The latest advances in neuroimaging techniques can provide critical insight into the pathology and mechanisms underlying chronic pain, and offer a non-invasive and safe means to study the progression of disease in living patients. Using a combination of established and novel MRI techniques, PNR&D investigators were the first to report alterations in excitation-inhibition chemistry of the brain during neuropathic pain associated with diabetes. These encouraging results paved the way for more elaborate studies of brain changes caused by neuropathic pain, which are currently underway.
Using cutting-edge imaging techniques, PNR&D investigators are currently studying two aspects of neuropathic pain in patients. The first area is the balance of neurotransmitter levels in the brain. This study is based on evidence indicating that increases in excitatory neurotransmitter levels and decreases in inhibitory neurotransmitter levels are associated with nerve pain. The second area of research is investigating the role of brain inflammation in chronic pain. Using PET nuclear imaging technology, brain inflammation in patients with neuropathic pain can be compared to inflammatory responses in healthy controls. PNR&D scientists can also compare these patient findings to those from animal models of neuropathic pain. These comparisons will aid in the identification of similarities and differences between patients and animal models, and provide useful guidance for developing novel treatments for pain.
Ultimately, PNR&D scientists believe that studying how chronic pain causes changes in the brain will directly lead to breakthroughs in the discovery of effective treatments for patients suffering with pain.
Diabetic peripheral neuropathy is a common complication of diabetes, affecting nearly 60 percent of diabetes patients. It is associated with increased hospital admissions, lower-limb amputations, severe pain, suffering, and disability. Damage to nerves that are associated with the heart, or cardiac autonomic neuropathy, is another complication of diabetes and is associated with an increased risk of heart and blood vessel disease, and even death. Given the effect of diabetes on nerves, identifying treatments that improve or prevent nerve damage in diabetes is essential.
Previous studies have shown that GLP-1 hormone treatment plays a role in controlling blood sugar in diabetes and may also have positive effects in the nervous system. Therefore, PNR&D investigators are examining the effects of a drug called exenatide, which works like GLP-1, on neuropathic pain and cardiac autonomic neuropathy in patients with type 2 diabetes. The study will enroll up to 80 patients between 18-70 years of age with type 2 diabetes, blood glucose levels that are not at recommended levels, and evidence of nerve pain. Participants will be treated for up to 18 months with exenatide or insulin and the severity of peripheral neuropathy, peripheral nerve pain, and cardiac autonomic neuropathy will be monitored periodically. Nerve regrowth will also be assessed by measuring peripheral nerve fiber density in skin punches, as described in the Cutaneous Innervation Center for diabetic neuropathy section above. The goals of the study are to determine if drug treatment can improve peripheral and cardiac autonomic nerve function, if exenatide is capable of promoting nerve regrowth, and if this treatment could be potentially useful to treat or prevent nervous system complications in diabetic patients.
The most common complication of diabetes is neuropathy, occurring in approximately 60 percent of all diabetic patients. Recent findings in the PNR&D have supported the theory that glucose-mediated death in neurons contributes to the development of diabetic neuropathy. One way high glucose causes injury and death to cells is through a process known as oxidative stress.
In oxidative stress, substances formed by the cells exposed to high glucose cause an interruption in the normal functions of the cell. This can occur through altered function of a mitochondrial enzyme called NAPDH oxidase, or through the release or leakage of toxic oxygen radicals from mitochondria. Studies are currently underway to determine which mechanism contributes to the increased oxidative stress observed in diabetes. This understanding will shed light on potential therapeutic targets for the treatment of diabetic complications and aid in the development of much-needed therapies.
While diabetes studies often focus on the effects of high blood sugar levels on the body, recent studies in the PNR&D indicate that the amount of fat in the blood is also important. This conclusion is based on results analyzing data from over 400 patients with diabetes and neuropathy. The study revealed that patients with elevated triglycerides, a type of fat that is commonly measured in routine blood tests, were significantly more likely to experience a worsening of their neuropathy over a one-year period. This finding provides a reliable predictor for nerve damage that may be used to identify patients that require aggressive treatment along with diet and lifestyle modification at a point when treatments may still provide some benefit. It also indicates that striving to lower fat counts in diabetes patients might be just as important and achieving good glucose control.
Current studies in the PNR&D that have developed from this recent finding are now aimed at understanding how elevated triglycerides, in addition to high glucose, contribute to the development and progression of neuropathy. To study this, mice are fed diets with varying levels of fat to induce increased levels of fat in the blood with and without high blood glucose so that the effects of high triglycerides vs. high glucose on diabetic complication-prone tissues like nerves can be studied. These studies will shed light on the links between obesity, insulin resistance, oxidative stress, inflammation and the development of neuropathy so that effective treatments can be developed.
Diabetes often leads to the development of diabetic complications in tissues such as the nerves (neuropathy), eyes (retinopathy), and kidneys (nephropathy). Some 60-70 percent of people with type 1 diabetes have some form of neuropathy, and reports indicate that diabetes is the leading cause of kidney failure. While the exact mechanisms underlying the development of diabetic complications are unknown, one likely avenue involves long-term modification of genes when cells are chronically exposed to toxic stresses associated with diabetes.
PNR&D investigators are using advanced technologies to examine the effects of diabetes on genes in tissues from patients with diabetes and animal models. Comparing genetic changes that are similar between laboratory animal models and patients, as well as between the various complication prone tissues such as nerve, eye, and kidney, will provide tremendous insight into common pathways that underlie the development of multiple features of diabetes and its complications. These studies will also provide rationale to develop new genomic and proteomic approaches to identify complication-prone diabetic individuals. To read more about specific ongoing projects in the PNR&D utilizing these approaches, visit the Bioinformatics page.
Both high blood sugar and increased levels of fat associated with diabetes result in cellular stress responses that potentially play a role in the development of diabetic complications such as neuropathy. One important component in the cellular response to stress is an organelle called the endoplasmic reticulum, or ER. In addition to a normal role in protein biosynthesis, the ER can also sense and respond to various stress situations including oxidative stress, nutrient deprivation, and low oxygen. When these stress signals are perceived, the ER activates different mechanisms to alleviate stress, or when this is not possible cell death is initiated.
ER stress has been implicated in neurodegenerative diseases like Alzheimer’s and Parkinson’s disease, and more recently, in type 1 and type 2 diabetes. New evidence also suggests that ER stress contributes to the development of diabetic complications affecting the nerves, kidneys, and eyes. Little is known, however, about the mechanisms behind how ER stress contributes to disease progression.
Using both cellular and animal models of diabetes, investigators in the PNR&D are advancing the understanding of these molecular mechanisms behind how the diabetic environment activates the ER stress response. The goal is to unravel the signaling pathways by which high glucose and increased fat contribute to cellular stress and play a role in the development and progression of diabetic complications. This research will support future efforts developing therapeutic approaches that target specific aspects of the ER stress response so that the onset and progression of disease can be prevented.
With NIH funding support, the PNR&D is collaborating with other investigators at the University of Michigan to examine two of the most devastating complications of diabetes – neuropathy and kidney disease. As these complications are likely the result of multiple complex insults, initial efforts involved characterizing multiple rodent diabetes models to establish the best model for examining diabetic complications.
With excellent models in hand, investigators are now working together to identify the mechanisms and molecular responses that are present in both diabetic patients and in rodent models with diabetic complications. The approach combines analyses of genetic transcripts, proteins, and metabolites so that common features in complication-prone tissues between humans and rodent models can be identified. These studies will identify critical pathways and mechanisms that will aid in the understanding of how multiple complications develop and progress. Overall, the knowledge gained from this team approach will identify targets that are most amenable to conventional or novel therapies, determine biomarkers that reflect disease states and responsiveness to treatments, and enable development of new comprehensive treatment strategies that target common pathways in nerve and kidney that can be translated to patients.
Dr. Eva Feldman and multiple investigators across the University of Michigan Health System have recently received a Diabetes Impact Award from the NIH to support research investigating the metabolic responses of complication-prone tissues during diabetes. Diabetes impacts how tissues metabolize sugars, amino acids, and fats. While historical studies have examined this metabolic profile in insulin-sensitive tissues, evidence indicates that complication-prone tissues like nerve, kidney, and eye respond differently in diabetes. This is presumed to contribute to the development of neuropathy, nephropathy, and retinopathy. However, an understanding of how metabolism in these tissues is altered is still lacking.
PNR&D investigators, along with experts in other diabetes and its complications, are working to determine which energetic pathways are involved in the onset of complications in nerve, kidney, and eye. Using molecular phenotyping techniques in both animal models and in humans, this project aims to define the specific changes in cellular substrate metabolism that drive the development of diabetic complications. Interventions that modulate these specific metabolic pathways will also be examined as potential approaches to mitigate or prevent the development or progression of complications. This study will provide a better understanding of the changes in metabolite levels and flux in complication-prone tissues in animal models and patients with diabetes. This will also allow investigators to determine how metabolite changes reflect the altered levels or activities of specific proteins and lipids that contribute to diabetic complications, so that comprehensive therapies may be developed.