1 August Targeting Mitochondrial Fission for Neuroprotection in Diabetic Neuropathy August 1, 2018 By The Fraternal Order of Eagles Diabetes Research Center 0 Drs. Stefan Strack and Yuriy Usachev Professors of Pharmacology and members of the FOEDRC recently received a new grant from the National Institutes of Health and the National Institutes of Diabetes Digestive and Kidney Disease (NIDDK) entitled “Targeting mitochondrial fission for neuroprotection in diabetic neuropathy” for a total award of $1,702,888 over four years. The grant will support studies that will examine a new approach for treating Diabetic Nerve damage, also known as diabetic neuropathy. Presenting with chronic pain or loss of sensation, peripheral diabetic neuropathy (PDN) is a debilitating comorbidity of diabetes that affects at least half the diabetic patient population. Since only palliative treatments are available, there is an urgent need for therapies that prevent or reverse the “dying back” degeneration of sensory fibers innervating the skin. Recent evidence suggests that diabetes compromises mitochondria, the cellular powerhouse, in sensory neurons. However, the underlying mechanisms are unknown. Mitochondrial shape is controlled by opposing fission and fusion events. Mutations in mitochondrial fusion proteins (mitofusin-2 or Opa1) cause neurological disorders that present similarly to neurological complications in diabetic patients. Specifically, mutations in the protein mitofusin-2 result in Charcot-Marie-Tooth disease type 2A, a peripheral neuropathy characterized by primary axon degeneration, while mutations in the protein Opa1 cause dominant optic atrophy, the most common form of hereditary blindness. The mitochondrial fission enzyme dynamin-related protein 1 (Drp1) is activated by removal of phosphates (dephosphorylation) from a highly conserved inhibitory phosphorylation site. Two phosphatases target this site to promote mitochondrial fission, a widely expressed the Ca2+-dependent phosphatase (PP2B or calcineurin) and a neuron-specific and mitochondria-localized protein phosphatase 2A isoform (PP2A/Bb2). Their team, which also included FOEDRC member Dr. Mark Yorek, generated a mouse knock-out (KO) of PP2A/Bb2 and found elongated mitochondria in neurons, consistent with reduced activity of Drp1. Predicated by preliminary evidence that Bb2 KO mice are resistant to peripheral neuropathy in both type-1 and type-2 diabetes models, the grant seeks proof-of-concept evidence that Bb2 (and other, as yet undiscovered, neuron-specific Drp1 activators) could be a drug target for the treatment of PDN. The research team further proposes to investigate how diabetes causes mitochondrial fragmentation in sensory neurons and how inhibiting mitochondrial fragmentation protects peripheral axons in diabetes. Using new mouse models and innovative in vivo imaging approaches, they will test the hypothesis that dysregulation of the mitochondrial fission/fusion equilibrium contributes to the pathogenesis of diabetic neuropathy, and that inhibition of Drp1-dependent mitochondrial fission provides neuroprotection via improvement of mitochondrial metabolism, reduction of oxidative stress, modulation of mitochondrial calcium transport and enhanced regeneration of sensory axons. We anticipate that these studies will shed light on PDN etiology, suggest new therapeutic strategies, and thus help improve quality of life for a rapidly growing diabetic population. The preliminary studies for this proposal were supported by a pilot and feasibility grant to Drs. Strack and Usachev from the Fraternal Order of Eagles Diabetes Research Center. Related Articles Technology Developed By DRC Enhances Detection of Eye Disease in Diabetics DRC Director's Report, February 2018 Diabetic retinopathy (DR), a complication of diabetes, is the leading cause of preventable blindness in the developed world, and it is one of the most feared complications for people with diabetes. In the US, at least 25,000 people with diabetes go blind every year from this almost entirely preventable disease, and there are 25 million Americans with diabetes at risk for the disease, projected to increase to 50 million over the next 10 years. There is extensive proof that an annual eye exam to detect the retinopathy early and treat it before the onset of symptoms can prevent almost all permanent visual loss, unfortunately the annual eye exam is expensive and access may be difficult. DRC Researchers Publish Major Breakthrough In Understanding How Diabetes Induces Eye Damage In the retina, diabetes damages nerves before it damages blood vessels. Diabetes is a major risk factor for severe vision loss and blindness. A condition known as retinal diabetic neuropathy causes visual impairment through the degeneration of small nerves (neurons) in light-sensitive tissue called the retina, which lines the back of the eye. Technology Developed By DRC Researcher Could Preserve Vision for Diabetes Patients University of Iowa Health Care patients are the first in the nation to have access to a new technology that uses artificial intelligence (AI) to diagnose diabetic retinopathy. The technology, known as IDx-DR, is the only medical device authorized by the Food and Drug Administration that uses AI for the autonomous detection of diabetic retinopathy. The device’s algorithm makes the diagnosis based on imaging of the patient’s retina without the need for an eye specialist to interpret the results. A Vitamin For Diabetes And Its Complications? Prediabetes, type 2 diabetes (T2D), and diabetes that is complicated by nerve damage (neuropathy) are increasingly common conditions worldwide. These conditions are the result of progressive problems in metabolism. Prediabetes and T2D are characterized by increasing levels of blood sugar and circulating fats (lipids) in conjunction with insulin resistance. Many prediabetics and half of T2D patients develop progressive damage to their nerves that can be painful or lead to a loss of sensation. Diabetic neuropathy can lead to loss of limbs and is severely debilitating. We know that weight management and keeping active are among the most important components for preventing these conditions and arresting their progression. However, scientists are always on the lookout for healthy ingredients that can help people control their weight, improve their blood glucose control, and help their nerves stay healthy. Recent research at the University of Iowa, supported by the Fraternal Order of Eagles Diabetes Research Center (FOEDRC), suggests that an over-the-counter vitamin supplement called nicotinamide riboside (NR) may do just that. DRC Researchers Describe A Novel Effect of A Heart Failure Medication to Reduce Diabetes Nerve Damage Peripheral neuropathy affects more than 50% of patients with diabetes and about 30% of subjects with pre-diabetes. There is no completely effective treatment for this complication of diabetes. The University of Iowa and FOE DRC Welcome Dr. Ethan Anderson I am pleased to announce the recruitment of Ethan Anderson, PhD to the FOEDRC. Dr. Anderson recently joined the Division of Pharmaceutics and Translational Therapeutics within the Department of Pharmaceutical Sciences and Experimental Therapeutics as an Associate Professor in the University of Iowa College of Pharmacy. Dr. Anderson received his B.S. from the University of Minnesota and PhD from Yale University. Dr. Anderson’s research is focused on cardiac complications of diabetes, cardiac inflammation and fibrosis, and towards development of novel therapeutics and biomarkers of heart disease risk. Showing 0 Comment Comments are closed.