Current Research: Diabetes
- A New Cocktail Treatment for Diabetic Neuropathy
- Identification of New Biomarkers in Diabetes
- Gene Regulation in Diabetes
- Diabetes Injures the Nervous System
- Creation of Research Models of Diabetic Complications
A New Cocktail Treatment for Diabetic Neuropathy
Reactive Oxygen Species (ROS) are the products of oxidative stress and damage nerve cells during diabetes causing diabetic neuropathy.The Diabetes Control and Complications Trial (DCCT) has implicated high glucose as a major factor in the development of diabetic neuropathy. We are interested in the defects in metabolism produced by high glucose as a first step towards understanding why diabetic neuropathy develops. In our work, we simulate in culture and in animals the stressors that the peripheral nervous system is subjected to in the diabetic state. Our work has generated a new theory: that a specialized type of cell death within neurons contributes to the development of diabetic neuropathy. We see typical death-inducing changes in neurons after one month of diabetes in animal models with neuropathy. These same changes occur in cultured autonomic neurons (those important for normal organ function) with glucose levels similar to those of poorly controlled diabetics.
The PNR&D, in conjuction with the Juvenile Diabetes Research Foundation Center, continues to focus on the link between oxidative stress, caused by excess glucose, and cellular damage. Oxidative stress and its role in cellular dysfunction and death are now broad themes in the diabetes literature, especially that concerning complications. Experimental diabetes causes cell death in those tissues prone to diabetic complications.
The roles of protective agents, including antioxidants, are currently being examined alone and in combination in order to optimize their therapeutic effects. Data collected over the last four years demonstrates that these compounds decrease nerve and kidney damage in a rat model of diabetes and in newly developed mouse models. This work is now being tested in a clinical trial of heart function. A combination therapy of three antioxidants is currently under investigation (for a complete description, please see the clinical trials section).
This study, if positive, will provide rationale for examining the role of oxidative stress in the complications of diabetes, including retinopathy, nephropathy, autonomic neuropathy and wound healing. This work is funded by the Juvenile Diabetes Research Foundation grant entitled "Oxidative Stress and Apoptosis in Diabetic Complications."
Identification of New Biomarkers in Diabetes
The goal of this project is to discover new ways to detect complications of diabetes within blood vessels in type 1 diabetic patients. This project explores the idea that markers of cell stress and inflammation found within the blood can identify diabetic subjects at risk for the rapid development of chronic blood vessel complications such as nerve, eye and kidney disease. For the second goal of this project, we have partnered with the Michigan Proteome Consortium to look for potential markers in our type 1 diabetic patients. This partnership has enabled us to propose the analysis of biomarkers in type 1 patients without complications and in patients both treated and untreated for complications. This partnership will generate new information that may allow us to predict the early onset of specific complications and identify new treatments for the complications.
Gene Regulation in Diabetes
Type 1 diabetes is an autoimmune disease resulting in the destruction of pancreatic beta cells with a loss of insulin within the blood. Without the intricate regulation of glucose metabolism normally mediated by insulin, type 1 diabetics develop high blood glucose levels. High blood glucose results in diabetic complications to sensitive tissues such as the nerves (neuropathy) and kidneys (nephropathy), with 50 percent of type 1 diabetics experiencing neuropathy and 30 percent experiencing nephropathy.
It is now widely believed that the majority of effects of high glucose on the nerves and kidneys are due to stress that occurs in cells as a result of toxic substances produced by glucose-exposed cells. The majority of these toxic effects occur due to long term changes in genes. In this study, we are using new technology to examine effects of high glucose on genes in two cell types sensitive to diabetic stress, the podocytes of the kidney and dorsal root ganglion neurons of the spinal cord. We believe that similar genetic changes occur in both types of cells in response to high glucose levels. Once completed, these studies will result in a broad understanding of the changes in genes resulting from high glucose in two cell types critically important in the progression of diabetic complications.
This study, if positive, will provide rationale to develop new proteonomic approaches to identify complications-prone diabetic individuals.
A grant has been submitted to the American Diabetes Association, entitled "An Informatics Approach to Human Sural Nerve Biomarkers of Diabetic Neuropathy."
Diabetes Injures the Nervous System
The most common complication of diabetes is neuropathy, a decrease in sensation and normal organ function resulting from damage to neurons, occurring in approximately 60 percent of all diabetic patients. Our work has generated a new theory: that glucose-mediated death in neurons contributes to the development of diabetic neuropathy. Therefore, if we could disrupt the death pathway within neurons, we could potentially provide a new means of therapy. We have found that insulin-like growth factor I (IGF-I) rescues neurons from cell death, so we believe that IGF-I could be used to interrupt the death pathway. In this project we aim to learn more about how glucose kills neurons and conversely, how IGF-I saves them from death. We speculate that high glucose probably kills cells in a number of steps, and that IGF-I blocks one or more of these distinct steps.
Another way that 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. Treatment strategies that stop oxidative stress decrease cell injury and, in many cases, restore function in cell culture and animal models of diabetic complications. Substances produced during oxidative stress, therefore, are potential therapeutic targets in the treatment of diabetic complications. We are currently enrolling type 1 diabetic patients in a clinical trial of triple antioxidant therapy, which would prevent oxidative stress, for the treatment of diabetic autonomic neuropathy. Our goal in this project is to define new therapeutic targets, based on our increased understanding of how oxidative stress is caused by high glucose.
Creation of Research Models of Diabetic Complications
PNR&D investigators use rodent models for examining diabetic complications such as nerve and kidney disease. However, their efforts are limited because the rodent models do not completely develop the complications seen in humans. We believe this resistance to full-blown diabetic complications is because the mice lack genetic susceptibility and do not live long enough to develop these complications. To get around these problems, we developed a technique for altering the rodents’ genetic predisposition to the cellular injury involved in diabetic complications. If successful, these rodent models we are currently developing will show rapid progression of diabetic injury, will be easy and inexpensive to study due to this rapid and reproducible downhill course, and will provide excellent models for evaluation of potential therapeutic interventions in human cases.
This study, if positive, will provide rationale to develop mouse models of diabetic nephropathy and diabetic neuropathy in mice via state-of-the-art mouse engineering technology. This research is funded by the National Institutes of Health grant U01 DK60994 entitled "Mouse models of Diabetic Nephropathy and Neuropathy. "
