7 July DRC Director's Report - July 2020 July 7, 2020 By The Fraternal Order of Eagles Diabetes Research Center Eagles, drc, diabetes, iowa, dr. abel, report 0 The greatest risks to long-term health in people with diabetes arise from diabetic complications, particularly cardiovascular disease. However, the mechanisms by which the metabolic changes associated with type 2 diabetes like insulin resistance increases the risk of heart failure are less understood. In a recent publication in JCI Insight, E. Dale Abel, MD, PhD, and other members of the Fraternal Order of Eagles Diabetes Research Center in collaboration with other institutions, have uncovered an important molecular link between diabetes and heart failure. In previous studies, Abel and his fellow researchers revealed that exposure of the heart to higher levels of insulin, which often occurs in people with Type 2 diabetes who are insulin resistant, may accelerate heart failure when heart damage occurs. This current study clarifies what signals within the cell trigger this event. Specifically, insulin receptor substrate-1 (IRS1) is a protein required for insulin to transduce its signals to the rest of the cell. Another protein, IRS2, is equally expressed in heart muscle, but it was unclear whether IRS1 or IRS2 equally contributed to accelerating heart failure in insulin resistant states. The Abel laboratory created genetically engineered mice lacking either IRS1 or IRS2 in cardiac muscle cells and subjected these mice to a stress that induces heart failure, namely pressure overload. The IRS1-deficient mice were completely protected from heart failure in the face of this injury, while IRS2-deficient mice were not. Calling the IRS1 protein the “bad cop,” Abel explained their next task was then to uncover why, which led to two discoveries. “Number one,” he said, “IRS1 seems to drive inflammation in the heart. Number two, IRS1 suppresses a protective pathway in the heart called ‘signaling via cyclic GMP,’ which provides additional protection.” Another pair of signaling molecules were also identified in this recently published project, AKT1 and AKT2. Similarly, to their work with IRS1 and IRS2, the researchers identified another “bad cop” in the pair. Deletions of the AKT1 gene in mice also lacking IRS2, which led to worse heart failure, were protected from heart failure, when AKT1 levels were genetically reduced. Finally, human heart samples obtained at the time of left ventricle assist device-implantation surgeries in patients with heart failure—performed at the University of Utah—were compared with normal donor hearts. The Abel team found their results confirmed. Just as in the mice, the heart failure samples revealed hyperactivation of AKT1 and IRS1. Implications of the study point toward treatments for people with diabetes that also take the cardiac risk into account. “Therapies to treat people with diabetes at risk of heart failure should ideally seek to do so in ways that lower insulin levels,” Abel said. SGLT2 inhibitors, he explained, are the only class of diabetes treatment proven to consistently reduce the risk of heart failure. These also cause the kidney to excrete glucose, which in turn would lower circulating concentrations of insulin. “More attention to agents that might lower insulin levels might actually help to reduce the risk of heart failure in diabetes.” Contributors to this work, which was funded by the National Institutes of Health and the American Heart Association, include researchers from the University of Iowa, the University of Utah, the University of Alabama Birmingham, Harvard Medical School, and the University of California Davis. Related Articles DRC Director's Report - October 2020 Please join us in welcoming Bhagirath Chaurasia, MS, PhD, to the University of Iowa and to the Fraternal Order of Eagles Diabetes Research Center. Dr. Chaurasia also joins the Division of Endocrinology from his previous position as Assistant Professor of Nutrition and Integrative Physiology at the University of Utah. He received his PhD from the University of Cologne in Germany before working as a Postdoctoral Research Fellow at Duke-NUS Medical School in Singapore. DRC Director's Report - May 2020 Diabetes is a disease of uncontrollable high blood glucose. Insulin, the hormone that reduces blood glucose, is secreted from beta cells embedded in the pancreas in structures called islets. Although overnutrition has been blamed for the inability of beta cells to secrete enough insulin in type 2 diabetes, it has remained unclear how overnutrition causes beta cells to fail. This is a critical question to solve in order to develop effective therapy to protect beta cells in conditions of overnutrition and to cure type 2 diabetes. DRC Director's Report - December 2020 Dr. Vitor Lira Associate Professor of Health and Human Physiology and member of the FOEDRC was recently awarded a new grant from the National Institutes of Health in the amount of $563,723. The grant entitled: “Molecular regulation of protein turnover in skeletal muscle” will study an important condition that afflicts many individuals as they age, particularly those with diabetes. Aging-related skeletal muscle atrophy and weakness, also referred to as sarcopenia, affects millions of people contributing to the development of several chronic conditions associated with poor health outcomes, such as diabetes, cardiovascular diseases and neurodegenerative diseases. Although sarcopenia remains poorly understood and lacks effective therapy, aged muscles manifest a problem of poor protein turnover or recycling which is called proteotoxicity. DRC Director's Report - August 2020 The prevalence of obesity continues to increase worldwide due to changes in dietary composition including the addition of sweetners to many food products and evolving patterns of eating behaviors. In particular, excessive consumption of sugars has been linked to metabolic diseases such as diabetes, insulin resistance and type 2 diabetes. Fibroblast growth factor 21 (FGF21) is a liver-derived hormone that signals to the brain to reduce sugar intake, but the mechanism for this effect was unknown. This new study by Ph.D. student Sharon Jensen-Cody and other colleagues in the laboratory of Matt Potthoff, Associate Professor in the Fraternal Order of Eagles Diabetes Center and Department of Pharmacology and Neuroscience discovered that FGF21 signals to specific nerve cells called glutamatergic neurons in the brain to lower sugar intake and sweet-taste preference. DRC Director's Report - September 2020 Renata Pereira, PhD, Research Assistant Professor of Internal Medicine, Endocrinology and Metabolism, and member of the FOEDRC, is the recipient of a new NIH R01 grant for $1.9M to support her work entitled The role of the integrated stress response in brown adipose tissue-mediated metabolic adaptations. “Obesity and related conditions, such as diabetes and heart disease, are some of the greatest health problems affecting today’s society. In an effort to better understand ways in which the body can increase its metabolism to burn fat and prevent the effects of those diseases, Dr. Pereira has focused her studies on special fat cells called brown (or beige) fat cells. DRC Director's Report - November 2020 FOE Diabetes Research Center scientists from the University of Iowa have discovered a safe new way to manage blood sugar non-invasively. Exposing diabetic mice to a combination of static electric and magnetic fields for a few hours per day normalizes two major hallmarks of type 2 diabetes, namely reducing blood glucose levels and preventing insulin resistance. These new findings were published Oct. 6 in Cell Metabolism. Showing 0 Comment Comments are closed.