Breaking News
March 21, 2019 - Mutations in noncoding genes could play big role in regulating cancer, study finds
March 21, 2019 - A medical student’s thoughts on Match Day
March 21, 2019 - Are eggs good or bad for you?
March 21, 2019 - New analysis reveals precision oncology insights for colorectal cancer
March 21, 2019 - Pollutants appear to weaken immune system and increase pathogen virulence
March 21, 2019 - Researchers develop and validate scale for rating severity of mononucleosis
March 21, 2019 - Scientists identify generation of key immune response in mice on introducing solid food
March 21, 2019 - New nanomaterial could restore internal structure of damaged bones
March 21, 2019 - Selective destruction of prostate tumor as effective as complete prostate removal
March 21, 2019 - 2011 to 2015 Saw Increase in Psychiatric ED Visits for Youth
March 21, 2019 - Tapeworm drug targets common vulnerability in tumor cells
March 21, 2019 - Off the beaten path for global health residency
March 21, 2019 - European Parliament’s report calls on EU to develop policies to regulate endocrine-disrupting chemicals
March 21, 2019 - Women with undiagnosed diabetes in pregnancy more likely to experience stillbirths
March 21, 2019 - Fish consumption can help prevent asthma, study reveals
March 21, 2019 - Royal Holloway professors to lead new to research into curing Neurofibromatosis type 1
March 21, 2019 - NSF offers grant to improve treatment approaches for pelvic organ prolapse
March 21, 2019 - Your Apple Watch Might Help Spot a Dangerous Irregular Heartbeat
March 21, 2019 - Research team uncovers critical new clues about what goes awry in autistic brains
March 21, 2019 - From March Madness to medicine with help from mentors
March 21, 2019 - Mental health disorders among young adults may be on the increase
March 21, 2019 - New study examines smarter automatic defibrillator
March 21, 2019 - UC Riverside research shows how natural selection favors cheaters
March 21, 2019 - Mother’s diet during pregnancy can impact lung-specific genes of her offspring
March 21, 2019 - AeroForm Tissue Expanders makes breast reconstruction after mastectomy more comfortable
March 21, 2019 - New project focuses on creating more responsive, intuitive prosthetics
March 21, 2019 - New case study describes adolescent patient with rapid-onset schizophrenia and Bartonella infection
March 21, 2019 - Umass Amherst food scientist honored with 2019 Young Scientist Research Award
March 21, 2019 - Smell of skin could lead to early diagnosis for Parkinson’s
March 21, 2019 - Difference in brain connectivity may explain autism spectrum disorder
March 21, 2019 - Untangling the microbiome — with statistics
March 21, 2019 - Human microbiome metabolites enhance colon injury by enterohemorrhagic E. coli, study shows
March 21, 2019 - Written media can improve citizens’ understanding of palliative care
March 21, 2019 - New research aims to find how asthma symptoms are aggravated
March 21, 2019 - New $9.7 million NIH grant project seeks to improve hearing restoration
March 21, 2019 - Researchers measure brain metabolite levels in people with mild memory problems
March 21, 2019 - FDA approves first drug for treatment of postpartum depression in adult women
March 20, 2019 - Gene editing and designer babies experiments face global moratorium
March 20, 2019 - Major scientific study of wound care dressings wins ‘Best Clinical or Preclinical Research Award’
March 20, 2019 - Biohaven Enrolls First Patient In Phase 3 Generalized Anxiety Disorder (GAD) Trial Of Troriluzole
March 20, 2019 - Big data study identifies drugs that increase risk of psychosis in youth with ADHD
March 20, 2019 - Mystery novel and dream spur key scientific insight into heart defect | News Center
March 20, 2019 - Study measures impact of policies designed to reduce air pollution in two mega-cities
March 20, 2019 - Mild sleep apnea during pregnancy changes sugar levels and may affect infant growth patterns
March 20, 2019 - SSB and Novasep collaborate to develop new membrane chromatography systems
March 20, 2019 - Leaky valve repair improves quality of life in heart failure patients
March 20, 2019 - Diattenuation Imaging offers structural information of difficult to access brain regions
March 20, 2019 - Early sports specialization linked to increased injury rates during athletic career
March 20, 2019 - Study brings clarity about milk intake for children with Duarte galactosemia
March 20, 2019 - Allergan Announces FDA Acceptance of New Drug Application for Ubrogepant for the Acute Treatment of Migraine
March 20, 2019 - Maternal smoking during pregnancy increases risk of ADHD among offspring up to three-fold
March 20, 2019 - Pioneering pediatric kidney transplant surgeon Oscar Salvatierra dies at 83 | News Center
March 20, 2019 - F.D.A. Approves First Drug for Postpartum Depression
March 20, 2019 - TB remains a major public health challenge in the European region
March 20, 2019 - Most pills contain common allergens, warn experts
March 20, 2019 - Researchers discover previously unknown mechanism by which cells can sense oxygen
March 20, 2019 - World’s leading source of data on diagnosis, treatments for aortic dissection
March 20, 2019 - Breast cancer relapse predictor may soon be a reality
March 20, 2019 - Researchers identify origin of chronic pain in humans
March 20, 2019 - Two-drug combinations containing calcium channel blocker significantly lowers BP
March 20, 2019 - King’s scientists to monitor air quality exposure of 250 children
March 20, 2019 - Active substance from plant could turn into a ray of hope against eye tumors
March 20, 2019 - Preventative cardioverter defibrillator implantation is of little benefit to kidney dialysis patients
March 20, 2019 - New method based on neurofeedback may reduce anxiety
March 20, 2019 - Study explores whether alcohol consumption can have an effect on arthritis
March 20, 2019 - Merck to collaborate with GenScript for plasmid and virus manufacturing in China
March 20, 2019 - FDA Approves Zulresso (brexanolone) for the Treatment of Postpartum Depression
March 20, 2019 - Study examines long-term opioid use in patients with severe osteoarthritis
March 20, 2019 - Retired Stanford professor Edward Rubenstein, pioneer in intensive care medicine, dies at 94 | News Center
March 20, 2019 - Aaron Diamond AIDS Research Center to Join Columbia University
March 20, 2019 - Call for halt to human gene editing and designer babies experiments
March 20, 2019 - Study illuminates how hot spots of genetic variation evolved in the human genome
March 20, 2019 - Roundworm study suggests alternatives for treatment of schizophrenia
March 20, 2019 - Sphingotec reports new applications of bio-ADM at 39th ISICEM
March 20, 2019 - Preventing falls through free community-based screenings for older adults
March 20, 2019 - AAOS: Supplement Use Low in Patients With Osteoporosis, Hip Fracture
March 20, 2019 - Does intensive blood pressure control reduce dementia?
March 20, 2019 - Nut consumption could be key to better cognitive health in older people
March 20, 2019 - Drinking hot tea associated with increased risk of esophageal cancer
March 20, 2019 - Androgen receptor plays vital role in regulating multiple mitochondrial processes
Newly published research provides new insight into how diabetes leads to retinopathy

Newly published research provides new insight into how diabetes leads to retinopathy

image_pdfDownload PDFimage_print
Diabetic retinopathy is the most common diabetic eye disease and a leading cause of adult blindness. Chronically high blood sugar from diabetes damages the tiny blood vessels in the retina, leading to diabetic retinopathy, according to the National Eye Institute of the National Institutes of Health. Credit: Kathy Keatley Garvey

An international team of scientists led by Professor Ingrid Fleming of Goethe University, Frankfurt, Germany, and including Professor Bruce Hammock of the University of California, Davis, provides new insight into the mechanism by which diabetes leads to retinopathy and often to blindness.

An inhibitor to the enzyme, soluble epoxide hydrolase (sEH), discovered in the Hammock lab, prevented the eye disease in diabetic mice, Fleming said.

The paper, “Inhibition of Soluble Epoxide Hydrolase Prevents Diabetic Retinopathy,” involving six years of research and 22 scientists, is published today (Dec. 6) in the journal Nature.

“This has been a long but exciting project where Dr. Fleming’s team used tools developed to study the biology of fatty acid epoxides to probe the fundamental mechanism of diabetic retinopathy,” said co-author Hammock, a distinguished professor of entomology who holds a joint appointment with the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center “This work has targeted many possible sites for intervention that could preserve vision, and one such target is using inhibitors of the soluble epoxide hydrolase which block diabetic retinopathy in mice.”

Fleming, who directs Goethe University’s Institute for Vascular Signaling, Centre for Molecular Medicine, said a major cause of blindness stems from diabetes “where there is a loss of vascular cells in the retina of the eye, loss of barrier function in vessels, edema, and a cascade of inflammatory events leading to blindness.”

The eye generates a dihydroxy metabolite from polyunsaturated fatty acids that initiates pericyte loss and breakdown of the endothelial barrier function in the eye, the scientists said. This leads to vascular edema and ultimately to a proliferation of new blood vessels and loss of vision.

The small molecule which initiates this process is a diol of a long chain poly unsaturated fatty acid produced by sEH, the researchers said. The enzyme converts an anti-inflammatory epoxy fatty acid into the pro inflammatory and in this case, toxic diol. The research team demonstrated this process and the cellular mechanism involved in diabetic mice and in transgenic mice that over-produce the sEH enzyme.

They were able to block the process by inhibiting the sEH enzyme. The expression of the sEH enzyme also increased with severity of diabetic retinopathy in human patients.

“The expression of the soluble epoxide hydrolase gene was shown to increase in the retinas of human patients with the severity of the disease with non-proliferative diabetic retinopathy,” Hammock said. “Thus, there appears a connection to human medicine.”

Newly published research provides new insight into how diabetes leads to retinopathy
Diabetic eye disease can affect many parts of the eye, including the retina, macula, lens and the optic nerve. Credit: National Eye Institute

Diabetic retinopathy is the most common diabetic eye disease and a leading cause of adult blindness. Chronically high blood sugar from diabetes damages the tiny blood vessels in the retina, leading to diabetic retinopathy, according to the National Eye Institute (NEI) of the National Institutes of Health. The blood vessels can leak fluid or hemorrhage, distorting vision. NEI officials predict that the number of Americans with diabetic retinopathy will nearly double from 7.7 million in 2010 to 14.5 million by 2050.

Fleming said the sEH enzyme generates a toxic metabolite, but when the enzyme is inhibited, eye disease is prevented.

Earlier work reported in the Proceedings of the National Academy of Sciences from the Kip Connor laboratory at Harvard University showed that inhibiting the soluble epoxide hydrolase preserves fatty acid epoxides which reduce the late or proliferative stages of diabetic retinopathy and macular degeneration. Now the Fleming team used the same soluble epoxide hydrolase inhibitors to block production of a pro inflammatory mediator that initiates the early stages of vascular permeability and inflammation of the retina.

Connor, an assistant professor of ophthalmology at Harvard Medical School, praised the work as bringing to light “a previously unknown mechanism of action.” Said Connor: “The identification by the laboratories of Drs. Fleming and Dr. Hammock that 19,20-dihydroxydocosapentaenoic acid, a product of soluble epoxide hydrolase (sEH) activity, as a key regulator of pericyte loss and endothelial barrier breakdown has brought to light a previously unknown mechanism of action in the induction of diabetic retinopathy. Moreover, the authors clearly show that inhibition of sEH blocks formation of this degenerative lipid metabolite thereby halting disease progression, which is of vital interest for the potential management of this blinding disease.

Mehran Moghaddam and David Grant, then with the Hammock lab, demonstrated that the diol of the fatty acid linoleate produced by the soluble epoxide hydrolase was highly toxic to cells leading to vascular permeability and sepsis. They published their work in 1997 in Nature Medicine.

“It is interesting how discoveries of years ago resurface as a critical lead in another disease indication,” commented Moghaddam. “It certainly seems hopeful we will be able to treat blindness resulting from severe diabetes.”

The Hammock laboratory has published almost 900 peer-reviewed papers on the sEH enzyme, discovered while Hammock and Sarjeet Gill (now of UC Riverside) were researching insect developmental biology and green insecticides at UC Berkeley. The work, begun in 1969, led to the discovery that many regulatory molecules are controlled as much by degradation as by biosynthesis, Hammock said. These epoxy fatty acid chemical mediators control blood pressure, fibrosis, immunity, tissue growth, pain and inflammation to name a few processes, and now Fleming’s team has shown the diols products from these epoxides can cause diabetic retinopathy.

For many years Gill and Hammock were alone in studying this enzyme but today its importance is well recognized in mammalian biology, with more than 17,000 peer-reviewed papers in the area. Hammock credits the National Institute of Environmental Health Sciences (NIEHS) for supporting research in this area since the 1970s.

A Davis-based company, EicOsis, has received a large grant from the U.S. National Institutes of Health to move inhibitors to the clinic to treat diabetic neuropathic pain. “We are developing a non opiate analgesic to treat the chronic pain often associated with diabetes,” said William Schmidt, vice president of clinical development at EicOsis. “It would be wonderful if the came drug also could be used to prevent the blindness driven by diabetes.”


Explore further:
Drug dramatically reduces diabetes symptoms in mice

More information:
Jiong Hu et al. Inhibition of soluble epoxide hydrolase prevents diabetic retinopathy, Nature (2017). DOI: 10.1038/nature25013

Journal reference:
Nature

Provided by:
UC Davis

Tagged with:

About author

Related Articles