Investigators from Cedars-Sinai have provided new understanding of how diabetes delays wound healing in the eye, identifying for the first time two related disease-associated changes to the cornea.

The findings, published today in the peer-reviewed journal Diabetologia, also identified three therapeutic pathways that reversed these changes and partially restored wound-healing function to the cornea—a discovery that could ultimately inform new treatments for diabetes.

“We have found that diabetes induces more cellular changes than we were aware of previously,” said Alexander Ljubimov, PhD, director of the Eye Program at Cedars-Sinai’s Board of Governors Regenerative Medicine Institute and senior author of the paper. “The discovery does not affect gene sequence but entails specific DNA modifications altering gene expression—what are known as epigenetic alterations.”

More than 37 million people in the United States—11% of the population—have diabetes, a systemic disorder that can result in kidney disease, heart disease, amputation, stroke and nerve damage. Most diabetes drugs are designed to increase glucose tolerance or supply depleted insulin, but do not address molecular and cellular changes or their associated complications.

The new research also identifies for the first time an important role of Wnt-5a, a secreted signaling protein investigators found responsible for corneal wound healing and the function of stem cells—cells capable of differentiating into many cell types.

“Current treatments only address symptoms, so there is an urgent need to understand the molecular mechanisms of diabetes-related wound-healing problems,” said Ruchi Shah, PhD, a scientist in Ljubimov’s lab and the study’s first author. “Understanding of this novel epigenetically regulated wound-healing mechanism could lead to therapeutic treatments that could help patients avoid further long-term ocular health issues.”

Though much focus of diabetic eye disease is on the retina, up to 70% of diabetes patients suffer from problems of the cornea, the transparent, protective exterior surface of the eye. In advanced diabetes, corneal stem cells become dysfunctional, and the cornea heals more slowly and less completely following an injury or procedures such as cataract surgery and laser treatment for diabetic retinopathy.

To identify the epigenetic changes discovered in this study—changes not hard-wired into the genome from birth, but introduced later—Ljubimov and his team compared cells from the corneas from six diabetic patients with those of five healthy donors. They found that in diabetic corneas, the protein product of the WNT5A gene was repressed. Additionally, in diabetic samples, they found an increase in the microRNA that inhibits WNT5A.

The team of scientists then induced wounds to corneal cells in culture and corneal organ cultures, and tested three interventions designed to normalize Wnt-5a protein expression. They added the Wnt-5a protein directly; they introduced a DNA methylation inhibitor, originally approved to treat cancer; and they targeted microRNA levels with a novel gene therapy approach using a nanoscale compound. The team developed the compound, which uses synthetic molecules to block the microRNA, as a substitute for a viral gene therapy they found to be toxic to stem cells.

All three therapeutic methods, in the diabetic samples, stimulated stem cell marker production and improved tissue regeneration, accelerating wound healing.

“Novel therapies to reverse epigenetic effects could improve corneal function, and may also prove significant in other diabetic complications,” said Clive Svendsen, PhD, director of the Board of Governors Regenerative Medicine Institute and study co-author. “This work certainly helps move the field forward.”

“Our goal is to develop topical, sustained-release drugs for corneal wound healing,” said Ljubimov. “Drugs that are FDA [Food and Drug Administration] approved and could be easily applied may be one of the most promising approaches for effective future therapies.”

An extract from dahlia flower petals has been found to stabilise blood sugar levels of diabetes patients in University of Otago-led clinical trials.

A team led by neuroendocrinologist Associate Professor Alexander Tups, of the Centre for Neuroendocrinology, showed that the inhibition of brain inflammation – brought about by the excess consumption of a Western diet – markedly improves blood sugar regulation.

His team then went on to discover an anti-inflammatory plant molecule that acts in the brain and potently improves the ability of the body to process blood sugar.

“We then found that the dahlia plant is a cultivatable source of this molecule and that it contains two additional plant molecules that enhanced the effect of the original one. This specifically blocked brain inflammation and improved blood sugar regulation in preclinical trials,” Associate Professor Tups says.

About 25 per cent of the adult population in Aotearoa have prediabetes – a condition where blood glucose levels are slightly elevated, indicating that a person is at risk of progressing to type 2 diabetes. Without intervention about 70 per cent of people go on to develop type 2 diabetes later in life.

In a randomised controlled cross-over clinical trial on participants with prediabetes or type 2 diabetes, researchers were able to show that the dahlia extract considerably improved blood sugar regulation.

In preclinical animal studies researchers were able to reverse brain inflammation, improve sensitivity to the hormone insulin in the brain and improve blood sugar regulation.

The project started with a grant in 2015 in collaboration with Plant and Food Research and eight years on he considers it a career high, he says.

“As scientists, often our work finishes when we find the mechanism of how something works. So in this case finding three compounds that occur in a flower that in combination improved blood sugar regulation was a dream come true.

“Impaired blood sugar regulation is a debilitating condition affecting millions of people around the world.  I hope and I really believe that the outcome of our intensive research will benefit people suffering from this condition.”   

The technology has been patented and the research team has worked with Otago Innovation Limited (OIL) and external stakeholders to bring a natural dahlia-extract supplement to the market, aiming to support normal blood sugar and insulin levels.

OIL project lead Dr Graham Strong says the collaboration brings together diverse perspectives, knowledge, and expertise, leading to an innovative and science-based nutraceutical product.

“This diversity, along with our and other stakeholder investment, resulted in the launch of a product we are very proud to be associated with.

“The product provides a unique blend of nutritional compounds to support normal blood sugar and insulin levels. The trials showed that this will be useful for those diagnosed with prediabetes or type 2 diabetes to help stop the progression of the condition,” he says.

An analysis on the positive effects of exercise on blood sugar levels in people with Type 2 diabetes shows that while all exercise helps, certain activities – and their timing – are extremely good for people’s health.

The study, published in The American Journal of Medicine, provides a comprehensive but straightforward summary of the benefits of exercise on controlling blood glucose levels in people with Type 2 diabetes.

“The challenge with this is that most, if not all, people know exercise is good for them but they don’t know the best approach,” said Steven Malin, an associate professor in the Department of Kinesiology and Health at the Rutgers School of Arts and Sciences and an author of the study. “We targeted this issue by focusing on a few key parameters: the utility of aerobics versus weightlifting, the time of day that is optimal for exercise, whether to exercise before or after meals and whether we have to lose weight to get benefits or not.”

As part of the analysis, researchers sifted through dozens of studies and extracted common conclusions. Some of the key findings include:

• Habitual aerobic exercise: Physical activity, such as cycling, swimming and walking, that increases the heart rate and the body’s use of oxygen helps manage blood glucose.
• Resistance exercise: Working muscles using an opposing force such as dumbbells, resistance bands or a person’s own body weight benefits insulin sensitivity in those with Type 2 diabetes.
• Movement throughout the day by breaking up sitting time benefits blood glucose control and insulin levels.
• Performing exercise later in the day can result in better control of blood sugar levels as well as improve insulin sensitivity.

“In short, any movement is good and more is generally better,” Malin said. “The combination of aerobic exercise and weightlifting is likely better than either alone. Exercise in the afternoon might work better than exercise in the morning for glucose control, and exercise after a meal may help slightly more than before a meal. And, you don’t have to lose weight to see the benefits of exercise. That is because exercise can lower body fat and increase muscle mass.”

More than 37 million Americans have diabetes, and between 90 and 95 percent have Type 2 diabetes, according to the U.S. Centers for Disease Control and Prevention. People with Type 2 diabetes are insulin resistant, meaning that their cells don’t respond normally to insulin, a hormone that controls the level of sugar, or glucose, in the blood. High blood sugar is damaging to the body and can cause serious health issues.

While insulin resistance is harmful, scientists believe increased insulin sensitivity is beneficial. High insulin sensitivity allows the cells of the body to use blood glucose more effectively, reducing blood sugar.

Malin researches insulin sensitivity and teaches kinesiology, the study of human movement. He and several other faculty members at Rutgers support the concept of “exercise as medicine.” The idea, which is supported by the American College of Sports Medicine and is increasingly being borne out by research, is that exercise can be considered a first-line therapy.

“I’m one of those individuals who subscribes to that notion, and in that way, I think of exercise as a drug,” Malin said.

Malin and colleagues authored the study to offer the medical community up-to-date practical advice for their patients.

“Together, this idea of exercise timing and type is important because it helps medical professionals more accurately recommend exercise prescriptions to combat high blood glucose,” Malin said.

More than half a billion people are living with diabetes worldwide, affecting men, women, and children of all ages in every country, and that number is projected to more than double to 1.3 billion people in the next 30 years, with every country seeing an increase, as published today in The Lancet.

The latest and most comprehensive calculations show the current global prevalence rate is 6.1%, making diabetes one of the top 10 leading causes of death and disability. At the super-region level, the highest rate is 9.3% in North Africa and the Middle East, and that number is projected to jump to 16.8% by 2050. The rate in Latin America and the Caribbean is projected to increase to 11.3%.

Diabetes was especially evident in people 65 and older in every country and recorded a prevalence rate of more than 20% for that demographic worldwide. The highest rate was 24.4% for those between ages 75 and 79. Examining the data by super-region, North Africa and the Middle East had the highest rate at 39.4% in this age group, while Central Europe, Eastern Europe, and Central Asia had the lowest rate at 19.8%.

Almost all global cases (96%) are type 2 diabetes (T2D); all 16 risk factors studied were associated with T2D. High body mass index (BMI) was the primary risk for T2D – accounting for 52.2% of T2D disability and mortality – followed by dietary risks, environmental/occupational risks, tobacco use, low physical activity, and alcohol use.

“The rapid rate at which diabetes is growing is not only alarming but also challenging for every health system in the world, especially given how the disease also increases the risk for ischemic heart disease and stroke,” said Dr. Liane Ong, lead author and Lead Research Scientist at the Institute for Health Metrics and Evaluation (IHME) at the University of Washington’s School of Medicine. “While the general public might believe that T2D is simply associated with obesity, lack of exercise, and a poor diet, preventing and controlling diabetes is quite complex due to a number of factors. That includes someone’s genetics, as well as logistical, social, and financial barriers within a country’s structural system, especially in low- and middle-income countries.”

“Some people might be quick to focus on one or a few risk factors, but that approach doesn’t take into account the conditions in which people are born and live that create disparities worldwide,” said Lauryn Stafford, second author and Post-Bachelor Fellow at IHME. “Those inequities ultimately impact people’s access to screening and treatment and the availability of health services. That’s precisely why we need a more complete picture of how diabetes has been impacting populations at a granular level.”

Using the Global Burden of Disease (GBD) 2021 study, researchers examined the prevalence, morbidity, and mortality of diabetes for 204 countries and territories by age and sex between 1990 and 2021 and forecasted diabetes prevalence to 2050. They also provided estimates of type 1 diabetes (T1D) and type 2 diabetes (T2D) and quantified the proportion of T2D burden attributable to 16 risk factors. The study team included researchers from IHME and GBD 2021 collaborators from around the world.

Fewer than six hours or more than 10 hours of sleep, and poor quality of sleep are associated with a greater risk for diabetes, according to research being presented Thursday at ENDO 2023, the Endocrine Society’s annual meeting in Chicago, Ill.

Poor sleep quantity and quality, and its impact on the risk for diabetes or obesity has been previously studied. However, this study sought to explore the longitudinal effects.

“Most previous studies did not examine changes in various glycometabolic parameters, like over 14 years. The pattern of changes in various glycemic parameters may provide clues to the mechanism underlying the association between sleep duration and incident diabetes mellitus,” said Wonjin Kim,  M.D., Ph.D., of CHA Gangnam Medical Center and associate professor at CHA University School of Medicine in Seoul, South Korea.

Kim and colleagues collected data from 8,816 of 10,030 healthy participants of the ongoing Korean Genome and Epidemiology Study (KoGES)-Ansung and Ansan Cohort Study. They identified diabetes cases and sleep duration and quality. Sleep duration was categorized into four groups: <6, 6-7, 8-9, or 9 hours per day. Sleep quality was measured among those with a sleep duration of <10 hours per day.

During the 14-year follow-up period, 18% (1630/8816) were diagnosed with diabetes. The researchers observed a U-shaped relationship between sleep duration and incident diabetes, with the greatest risk when sleep duration was ≥10 hours per day. During the study, this group also showed decreased insulin glycogenic index, which is a marker of insulin secretory function. The risk for incident diabetes increased among study participants who slept <10 hours per day when their Epworth Sleepiness Scale (ESS) score was >10.

“Even if sleep duration is less than 10 hours, the likelihood of developing diabetes is greater when quality of sleep decreases,” Kim said.