February. 16, 2017

Dual-drug combination shows promising potential against diabetic eye disease in animal model.

 

A two-drug cocktail provided better protection against diabetes-related vision loss than a single drug during testing in rat models, a team of University of Florida Health and Dutch researchers has found. Researchers say the drug combination is a promising and unique potential treatment for patients with diabetic retinopathy, a major cause of vision loss in middle-age diabetes patients. Diabetic retinopathy damages blood vessels in the retina at the back of the eye, leading to distorted vision or blindness. There were 4.2 million cases of diabetic retinopathy among people ages 40 and over in the United States, according to a 2016 estimate by the American Academy of Ophthalmology. Now, researchers from UF and the Erasmus Medical Center in the Netherlands have shown that the two drugs were more effective than a single drug at reducing the symptoms of diabetic retinopathy within the animals' retinas. The findings were published recently in the journal Investigative Ophthalmology & Visual Science. During the 12-week study, the two-drug treatment reduced capillary loss by 68 percent compared with 43 percent with the single drug. Known as angiotensin receptor neprilysin inhibitor, or ARNI, the cocktail is a combination of irbesartin (an angiotensin receptor blocker) -- a medication already being used to treat high blood pressure -- and the anti-diarrhea compound thiorphan, a neprilysin inhibitor. In the laboratory, its effectiveness was compared with using irbesartin alone. The two drugs did not completely reverse the effects of diabetic retinopathy, but they slowed it in the animal models, said Tuhina Prasad, Ph.D., a postdoctoral associate in the UF College of Medicine's department of ophthalmology research and a co-author of the paper. Most significantly, Prasad said the two drugs were much more effective at decreasing inflammation, which is one of the main symptoms of diabetic retinopathy. "If you can decrease that inflammation, it protects the retinal cells and delays the progression of the disease," Prasad said. The two-drug combination was also more effective than the lone drug at reducing cell death in the retina after 12 weeks in the rat models. The two drugs produced a 51 percent reduction in cell death, while the single drug showed only a 25 percent reduction, according to the findings. That is potentially significant in the development of drugs to treat diabetic retinopathy because the disease is strongly associated with prolonged diabetes in patients, the researchers noted. Before a treatment can be brought to patients, researchers still have some work ahead: The possible chronic side effects of the neprilysin enzyme inhibitor on the eye have yet to be studied. Likewise, the long-term effects of giving that inhibitor are still unknown. Still, Prasad said, the newly discovered compound may someday be a promising option for the millions of people living with diabetic retinopathy.

 

 

Pancreatic islet cells in animals can 'flip' their fate to produce insulin

 

Alpha cells in the pancreas can be induced in living mice to quickly and efficiently become insulin-producing beta cells when the expression of just two genes is blocked, according to a study led by researchers at the Stanford University School of Medicine. "It is important to carefully evaluate any and all potential sources of new beta cells for people with diabetes," said Seung Kim, MD, PhD, professor of developmental biology and of medicine. "Now we've discovered what keeps an alpha cell as an alpha cell, and found a way to efficiently convert them in living animals into cells that are nearly indistinguishable from beta cells. It's very exciting." Chakravarthy and her colleagues have made an important step toward realizing the therapeutic potential of alpha cell transdifferentiation. Transdifferentiation of alpha cells into insulin-producing beta cells is a very attractive therapeutic approach for restoring beta cell function in established Type 1 diabetes. By identifying the pathways regulating alpha to beta cell conversion and showing that these same mechanisms are active in human islets from patients with Type 1 diabetes. Kim is the senior author of the study, which has published online Feb. 16 in Cell Metabolism. Postdoctoral scholar HariniChakravarthy, PhD, is the lead author.

February 15, 2017

Changes in the size of mitochondria play a crucial role in maintaining blood sugar levels.

 

Keeping blood sugar levels within a safe range is key to managing both type 1 and type 2 diabetes. In a new finding that could lead to fewer complications for diabetes patients, Yale School of Medicine researchers have found that changes in the size of mitochondria in a small subset of brain cells play a crucial role in safely maintaining blood sugar levels. The study is published in the Feb. 9 issue of the journal Cell Metabolism. "Low blood sugar can be as dangerous as high blood sugar," said senior author Sabrina Diano, professor in the Departments of Obstetrics, Gynecology & Reproductive Sciences, Neuroscience, and Comparative Medicine. "We've found that changes in the size of mitochondria -- small intracellular organelles responsible for energy production -- in certain cells in the brain, could be key to maintaining the blood sugar within a safe range." "This new finding adds to our understanding of how the body keeps blood sugar levels within a safe range when sugar levels drop, like during fasting, or when they spike after a meal," Diano added. Diano and her research team designed the study to help understand how neurons in the brain that regulate appetite affect systemic glucose levels. The team used mouse models in which a specific mitochondrial protein, dynamin-related protein 1 (DRP1), was either missing or present in varying amounts in the subset of brain cells that sense circulating sugar levels. The researchers found that depending on whether the mouse was hungry or not, mitochondria displayed dynamic changes in size and shape, driven by the DRP1 protein. "We found that when DRP1 activity in the neurons was missing, these neurons were more sensitive to changes in glucose levels," said Diano, who is also a member of the Program in Integrative Cell Signaling and Neurobiology of Metabolism and the director of the Reproductive Neuroscience Group at Yale University School of Medicine. "What surprised our research team was that these intracellular changes in this small subset of neurons were specifically important to increase blood sugar levels during a fasting period by activating the so-called counter-regulatory responses to hypoglycemia, in which the brain senses lower glucose levels and sends signals to peripheral organs such as the liver to increase glucose production." Diano said the findings suggest that alterations in this mechanism may be critical for the development of hypoglycemia-associated autonomic failure (HAAF), a complication of several diabetes treatments occurring most often in people with type 1 diabetes who must take insulin for survival. Diano's research team will now focus on assessing how mitochondrial morphological changes relate to mitochondrial function in this subset of neurons in the development of HAAF.