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September/October 2007 Issue
• Claudia Gragnoli: Diabetes |
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Claudia Gragnoli: Diabetes Pierpaolo Basso Claudia Gragnoli, MD, PhD is an Assistant Professor in Medicine and Cellular & Molecular Physiology at Penn State University in Hershey, Pennsylvania. Dr. Gragnoli's research aims to identify genes and/or gene variants responsible for type 2 diabetes in the Italian population and for complex disorders including polycystic ovary syndrome, hypertension, dyslipidemia, obesity, depression, anxiety, all of which are associated with type 2 diabetes. Earlier this year, researchers from the Columbia University Medical Center found that type 2 diabetes is consistently related to a higher risk of Alzheimer's disease. Any thoughts? Type 2 diabetes is a complex disorder related to aging and accompanied by factors associated with aging such as insulin resistance, hyperglycemia, microvascular disease, depression and cognitive impairment. Several theories have tried to explain the pathogenesis of the common link between type 2 diabetes and Alzheimer's; however, we cannot yet give a definite answer. The most probable link between Alzheimer's and type 2 diabetes is insulin resistance in the brain and the periphery, which leads to insulin dysregulation and promotes plaque formation contributing to Alzheimer's. This doesn't mean that all subjects with type 2 diabetes will have Alzheimer's disease or that all subjects with Alzheimer's will have type 2 diabetes, but that the risk of Alzheimer's is higher in type 2 diabetes patients compared to the general population. Researchers have also connected depression with diabetes. Depression often precedes type 2 diabetes. Several potential reasons may explain this link. The simplest explanation may be hyperactivity of the hypothalamic-pituitary-adrenal axis present in depressed patients, who have higher levels of the stress hormone cortisol than healthy subjects. Cortisol is a hormone responsible for increasing glucose levels in the blood as well as impairing the action of insulin in the periphery. High levels of this stress hormone in subjects genetically predisposed to type 2 diabetes, may precipitate or anticipate the onset of the disease. Another theory holds that the hormone resistin, which causes insulin resistance, is higher in depressed patients than normal subjects. It has also been shown that decreased levels of brain-derived neurotrophic factor are implicated in the pathogenesis of both Alzheimer's disease and depression. Animal models suggest that brain-derived neurotrophic factor contributes to insulin resistance and that low levels of brain-derived neurotrophic factor play a role in impaired glucose metabolism. Thus, decreased brain-derived neurotrophic factor may be a pathogenetic factor implicated in dementia, depression and type 2 diabetes. One area of your study involves the genetics of type 2 diabetes in Italian families. My work has focused on the genetics of MODY (maturity-onset-of-the-young), early-onset type 2 diabetes and late-onset type 2 diabetes in Italians. I was able to identify several unique mutations in different genes in MODY families, early-onset type 2 diabetes families, and late-onset type 2 diabetes patients. One mutation was the molecular link in vivo of the MODY1 gene with the MODY3 gene, as it affects the binding of the product of the MODY1 gene on the MODY3 gene and the regulation of one gene on the other in the beta cell -- whose regulation, if disrupted, causes type 2 diabetes at an early age. A link also exists between a mutation in the MODY4 gene and low birth weight, which is of relevance given the correlation between low birth weight and increased predictive risk for both type 2 diabetes and cardiovascular disease. Another gene of interest is NEUROG3, in which we have identified a haplotype which may contribute to type 2 diabetes in Italians. These gene variants may be responsible for reduced ability of the beta cell to replicate during aging. In Italian patients with type 2 diabetes we have also, for the first time, identified unique mutations in the PSMD9 gene, which are implicated in the transcription of insulin and can cause diabetes if disrupted in mice. These mutations highlight that few patients may have type 2 diabetes because of rare mutation in the PSMD9 gene, although the impact of the disease on the general population still needs to be clarified and understood. My next goal is to genetically tackle the complex phenotypes of type 2 diabetes as well as the other associated complex disorders, such as hypertension, obesity, and depression in Italians and in an U.S. population by relying on multiple genetic and statistical approaches and multidisciplinary studies. My strong belief is that only a complete overview of patients and healthy subjects will give an answer to the complicated and intricate network of gene and proteins causing age-related disorders. Are there any new treatments for this chronic disease? There are some new types of insulin which allow injection directly at eating times and a new inhaled insulin, which has proven to be as effective as the injected one, although it may cause some pulmonary problems in the long-term. There are also new oral agents, which target different mechanisms of the disease and provide better control of glucose metabolism. Obesity in young children has become a huge issue in the U.S. What's the diabetes connection? Type 2 diabetes is due to decreased insulin secretion in the beta cells of the pancreas as well as to impaired action of insulin in the periphery. Impaired action of insulin, known as insulin-resistance, is present in obesity. The more obese a subject, the more insulin-resistant he/she will be or become. With time, since insulin cannot be easily produced in the peripheral organs, the beta cell will be prompted to secrete more insulin in an attempt to compensate for the reduction. Eventually, this ability to compensate may diminish and then be lost and lead to overt type 2 diabetes. Overweight or obese children have a higher risk of developing insulin resistance and are more likely to develop type 2 diabetes in childhood, adolescence or in later life. Plus, reversing obesity and obesity related-insulin-resistance is harder for those who develop it while young. It's possible that the body memorizes the number of fat cells and with difficulty adjusts to a lower number, once the obesity is established. More information on future diabetes treatments: |
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September/October 2007 
Health Briefs: Ilene Raymond Improved Insulin-Cell Transplants A new process to track pancreatic beta cells inside the body may remove a stumbling block to developing insulin-cell transplants for people type 1 diabetes, according to researchers at Johns Hopkins University. Traditional transplant of the cells, accompanied by necessary Immune suppressing drugs, has had highly variable results, from well to poorly tolerated. The new technique encapsulates the insulin-producing cells in magnetic capsules, using an FDA-approved iron compound with an off-label use, which can be tracked by magnetic resonance imaging (MRI). The product, tested in swine and diabetic mice, also simultaneously avoids rejection by the immune system, likely a major reason for transplant failure. On the Web: Anger=Immune Disorders? Hostile men who experience frequent intense feelings of anger and depression could be harming their immune systems and putting themselves at risk for coronary heart disease , type 2 diabetes and high blood pressure. Researchers at the Duke University Medical Center studied 313 male Vietnam veterans who were part of a larger 20-year study on the effects of Agent Orange. The veterans, who underwent a standard psychological test used to assess hostility, depression and anger, had a series of blood levels taken on three occasions between 1992 and 2002. Researchers measured two immune system proteins known as C3 and C4. Both are markers of inflammation, which is the body's response to injury or infection. Changes in C3 and C4 are associated with a number of diseases, including some that negatively can affect the arteries around the heart, such as diabetes. The researchers factored in other risk factors for higher C3 levels such as smoking, age, race, alcohol use, and body mass index (a measure of obesity). They also could find no known influence of Agent Orange exposure on the increased C3 levels. Men whose psychological screening showed the highest level of hostility, depressive symptoms and anger had a 7.1 percent increase in their C3 levels, while men with low levels of these attributes showed no change over the 10-year study period. "Hostile, depressed and angry people see the world around them in a different way, and sometimes they see it as them against the world," said study co-author Edward Suarez, Ph.D. "That kind of lifestyle often leads to greater stress and possibly changes in the way the body functions that could lead to disease." Brain, Behavior and Immunity: |
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