Tag Archives: #diabetes

Major New Study Could Help Protect Millions of People With Type 2 Diabetes From Cardiovascular Disease (Medicine)

A new study led by the Nuffield Department of Population Health at the University of Oxford will research whether a daily tablet could help protect the millions of people worldwide with type 2 diabetes from developing cardiovascular disease.

Cardiovascular disease is the leading global killer, causing approximately 18 million deaths worldwide each year. Even when non-fatal, cardiovascular events (such as heart attacks and strokes) often result in reduced quality of life and disability. People with diabetes are especially vulnerable, since this condition roughly doubles the risk of developing cardiovascular disease. Given that approximately one in eleven adults worldwide has diabetes (with around 90% having type two diabetes), there is an urgent need for effective treatments that can protect this at-risk group. 

To date, most studies have focused on stopping the recurrence of cardiovascular events in those who already have type 2 diabetes and cardiovascular disease (secondary prevention) or are at high risk of developing cardiovascular disease because of other conditions. 

A major new investigator-initiated study, coordinated by the Nuffield Department of Population Health at the University of Oxford and funded by the Danish healthcare company, Novo Nordisk, will test whether taking a daily tablet that contains semaglutide can protect people with type 2 diabetes from suffering heart attacks, strokes and other cardiovascular events. The study, ASCEND PLUS, is the latest in the ASCEND (A Study of Cardiovascular Events iN Diabetes) series of clinical trials and aims to recruit 20,000 UK adults, aged 55 years and older, who have diabetes but have not suffered a heart attack or stroke in the past. 

Dr Marion Mafham, co-lead investigator for the study, said ‘Previous trials suggest that semaglutide, and similar drugs, reduce the risk of heart attacks, strokes and other cardiovascular events in people with type 2 diabetes. However, these trials studied people who already had cardiovascular disease or were at high risk of developing it. 

‘The exact mechanism for these protective effects is not fully understood, but semaglutide has been shown to lower blood pressure, reduce weight and lead to improved control of blood sugar. This means that taking semaglutide could also bring various long-term benefits, particularly in reducing complications caused by obesity, other health problems such as liver and kidney disease, and potentially dementia. However, we need to test the treatment in a large-scale study to find out whether it will help a wide range of people with type 2 diabetes.’ 

The study will draw on the Department’s established expertise in leading large, streamlined, ground-breaking trials. Rather than seeing participants in person, the treatment with oral semaglutide or a placebo will be sent to them by post. Information on side effects will be collected remotely every six months, using online questionnaires, telephone surveys and video chats. 

Associate Professor David Preiss, co-lead investigator, said ‘We know that needing to travel to trial sites can be a barrier to participating in clinical trials for some people. Using postal, phone and online services will allow people from across the UK to participate. It will enable us to include those living in remote areas and those who would find travel difficult, whilst making sure that participants have a variety of ways to keep in touch with us.’ 

People with type 2 diabetes who may be eligible for the study will be sent an invitation letter and information leaflet and will be asked to contact the coordinating centre if they are interested in taking part. The trial will begin enrolling participants in 2022. Participants will be asked to take the treatment with oral semaglutide or placebo for about five years. 

Dr Elizabeth Robertson, Director of Research at Diabetes UK, said ‘Cardiovascular disease is a serious complication of diabetes, and with over 590 heart attacks and over 770 strokes related to diabetes each week in the UK, it’s crucial we find new ways to help people reduce their risk of these complications.’ 

‘Lifestyle changes such as eating healthily, stopping smoking, and keeping active can help people with type 2 diabetes to reduce their risk of complications, but these can be difficult to achieve and what works for some people may not work for others. We hope this large-scale trial will uncover whether taking semaglutide could help reduce the risk of heart complications in a wide range of people living with type 2 diabetes, helping more people to live well with the condition.’

Featured image credit: Shutterstock

Provided by University of Oxford

Common Diabetes Drug Shows Promise as Treatment for COVID-19 Lung Inflammation (Medicine)

The blood sugar-lowering drug metformin prevented pulmonary inflammation, a major factor in COVID-19 severity and mortality, in studies of mice infected by the SARS-CoV-2 coronavirus

Metformin is a widely prescribed blood sugar-lowering drug. It is often used as an early therapy (in combination with diet and lifestyle changes) for type 2 diabetes, which afflicts more than 34 million Americans.

Metformin works by lowering glucose production in the liver, reducing blood sugar levels that, in turn, improve the body’s response to insulin. But scientists have also noted that metformin possesses anti-inflammatory properties, though the basis for this activity was not known.

In a study published online June 8, 2021 in the journal Immunity, a multi-institution team led by researchers at University of California San Diego School of Medicine identified the molecular mechanism for the anti-inflammatory activity of metformin and, in mouse studies, found that metformin prevents pulmonary or lung inflammation in animals infected with SARS-CoV-2, the virus that causes COVID-19.

Over the past year, several retrospective clinical studies had reported that metformin use by diabetic and obese patients prior to hospital admission for COVID-19 correlated to reduced severity and mortality. Both diabetes and obesity are recognized risk factors for COVID-19, and are linked to more severe outcomes. Notably, other drugs used to control blood sugar levels do not appear to produce a similar effect.

But while these clinical studies suggested metformin’s anti-inflammatory activity, rather than lowering of blood glucose, could be responsible for reduced COVID-19 severity and mortality, none of the studies offered an explanation or prompted large, randomized clinical trials needed for obtaining conclusive answers.

“The clinical studies were plagued by confounders that made conclusions hard to reach. There was some skepticism in their findings,” said corresponding study author Michael Karin, PhD, Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine. “And because metformin is an out-of-patent, low-cost drug, there is little impetus to conduct large-scale trials, which are quite expensive.”

Karin, with co-senior author Elsa Sanchez-Lopez, PhD, an assistant professor at the Department of Orthopedic Surgery, postdoctoral fellow Hongxu Xian, PhD, and others, turned their focus to a mouse model of acute respiratory distress syndrome (ARDS), a life-threatening condition in which fluids leak into the lungs, making breathing difficult and restricting oxygen supply to essential organs.

ARDS is triggered by trauma and by bacterial or viral infections. It is a frequent cause of death in patients hospitalized with COVID-19. The researchers found that metformin administered to mice prior to or after exposure to bacterial endotoxin, a surrogate for bacterial pneumonia, resulted in the inhibition of ARDS onset and lessening of its symptoms. Metformin also produced a marked reduction in mortality in endotoxin-challenged mice and inhibited IL-1β production and inflammasome assembly within alveolar macrophages — immune cells found in the lungs.

IL-1β, along with IL-6, are small proteins called cytokines that cause inflammation as an early immune response. Their amounts are often highly elevated in persons infected by SARS-CoV-2, creating “cytokine storms” in which the body starts attacking its own cells and tissues. They are signs of an acute immune response gone awry.

Production of IL-1β depends on a large protein complex called the inflammasome, whose presence in lung tissue is found to be highly increased in deceased COVID-19 patients, a discovery made by co-authors Moshe Arditi, MD, and Timothy R. Crother, PhD, at Cedars-Sinai Medical Center in Los Angeles.

Working with colleagues at The Scripps Research Institute, the UC San Diego researchers confirmed that metformin inhibited inflammasome activation and prevented SARS-CoV-2-induced pulmonary inflammation in mice.

Cell culture studies using macrophages revealed the underlying mechanism by which metformin exerts its anti-inflammatory activity: reduced production of ATP by mitochondria. ATP is the molecule that mitochondria use to store chemical energy for cells. It is essential to all cellular processes, but blunted ATP production in liver cells is responsible for the glucose lowering effect of metformin.

Lower amounts of ATP in macrophages led to inhibition of mitochondrial DNA synthesis, which had been previously identified by Karin’s lab as a critical step in NLRP3 inflammasome activation. Subsequent research found that clearing away damaged mitochondria reduced NLRP3 inflammasome activity and reduced inflammation.

UC San Diego researchers also confirmed that specific interference with mitochondrial DNA synthesis in macrophages caused by removal of the enzyme CMPK2 (cytidine monophosphate kinase 2) inhibited IL-1β (but not IL-6) production and prevented ARDS onset.

“These experiments strongly suggest that improved delivery of metformin or CMPK2 inhibitors into lung macrophages can provide new treatments for severe COVID-19 and other forms of ARDS,” said Sanchez Lopez.

The authors said the findings suggest metformin may have therapeutic potential for treating a variety of neurodegenerative and cardiovascular diseases in which NLRP3 inflammasome activation is a factor. “Inhibition of inflammasome activation may also account for the poorly explained anti-aging effect of metformin,” said Karin.

Co-authors include: Alexandra Rundberg Nilsson, Raphaella Gatchalian and Sarah Kang, UC San Diego; Warren G. Tourtellote and Yi Zhang, Cedars-Sinai; German R. Aleman-Muench, Gavin Lewis, Weixuan Chen and Pejman Soroosh, Janssen Research & Development; and Melissa Luevanos, Dorit Trudler, Stuart A. Lipton, John Teijaro, and Juan Carlos de la Torre, The Scripps Research Institute.

The study, “Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation”, published in Immunity, 2021. DOI:https://doi.org/10.1016/j.immuni.2021.05.004

Featured image: Michael Karin, PhD, is Distinguished Professor of Pharmacology and Pathology and Ben and Wanda Hildyard Chair for Mitochondrial and Metabolic Diseases at UC San Diego School of Medicine. © UC San Diego Health Sciences

Provided by UCSD

Blood Sugar Highs and Lows Linked to Greater Dementia Risk in Type 1 Diabetes (Medicine)

Risk May Be 6 Times Higher for Those Experiencing Both

Older people with type 1 diabetes who have been to the hospital at some point for both low and high blood sugar levels may be at six times greater risk for developing dementia years later. The research is published in the June 2, 2021, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study also found that people with type 1 diabetes who visit the hospital for just one of the blood sugar extremes may also be at greater risk for developing dementia.

Type 1 diabetes is a chronic condition in which the pancreas produces little or no insulin. Hypoglycemia is low blood glucose, or the main sugar in blood, that may result in loss of consciousness.

Hyperglycemia results from insulin deficiency or extremely high blood sugar and dehydration. This study looked at severe glycemic events, which were defined as episodes of high or low blood sugar that resulted in an emergency room visit or hospital stay.

“For people with diabetes, both severely high and low blood sugar levels are emergencies and both extremes can largely be avoided. However, when they do occur, they can lead to coma, increased hospitalization and even death,” said study author Rachel A. Whitmer, PhD, of the University of California Davis School of Medicine in Sacramento, Calif. “People with type 1 diabetes are living longer than before, which may place them at risk of conditions such as dementia. If we can potentially decrease their risk of dementia by controlling their blood sugar levels, that could have beneficial effects for individuals and public health overall.”

The study looked at 2,821 people with an average age of 56 who had type 1 diabetes. Of those, 398, or 14%, had a history of severe low blood sugar; 335, or 12%, had a history of severe high blood sugar and 87, or 3%, had both. Researchers followed up with the people for an average of seven years to determine who had been diagnosed with dementia.

Researchers found that 153 people, or about 5%, developed dementia. After adjusting for age, sex and ethnicity, the people with low blood sugar events had a 75% greater risk of developing dementia than those without one. People with high blood sugar events had more than twice the risk of developing dementia than those without one.

However, the people who experienced both types of events had more than six times the risk of developing dementia than people who had neither event.

Researchers also looked at dementia incidence rates. After adjusting for age, the incidence rate of dementia in people with low blood sugar events was 26.5 cases for every 1,000 person-years compared to 13.2 for people without. Person-years take into account the number of people in a study as well as the amount of time spent in the study. The incidence rate of dementia in people with high blood sugar events was 79.6 cases for every 1,000 person-years, compared to 13.4 for people without. For people who had both high and low blood sugar events at various times, the incidence rate of dementia was 98.5 for every 1,000 person-years, compared to 12.8 for those who had neither.

“Our findings suggest that exposure to severe glycemic events may have long-term consequences on brain health and should be considered additional motivation for people with diabetes to avoid severe glycemic events throughout their lifetime,” Whitmer said.

A limitation of the study is that people had to be diagnosed with dementia by a health care provider to be counted as having dementia. Since many dementia cases go undiagnosed, this may have resulted in underreporting the number of dementia cases. Whitmer noted that the study was not designed to determine whether high and low blood sugar events caused dementia. It only showed an association.

The study was supported by the National Institutes of Health.

Reference: Rachel A. Whitmer, Paola Gilsanz, Charles P. Quesenberry, Andrew J. Karter, Mary E. Lacy, “Association of Type 1 Diabetes and Hypoglycemic and Hyperglycemic Events and Risk of Dementia”, Neurology Jun 2021, 10.1212/WNL.0000000000012243

Provided by AAN

Covid-19 Can Trigger Diabetes (Medicine)

Some Covid-19 patients develop diabetes in the course of their infection. An international study with participation by the University of Basel has mapped how coronavirus attacks and destroys insulin-producing pancreatic cells. The researchers also identified a way to protect these cells.

Diabetes is considered a risk factor in contracting a severe bout of coronavirus SARS-CoV-2. That a severe Covid-19 infection can, conversely, lead to diabetes is less well known. Yet a number of studies have shown that roughly 15% of hospitalized Covid-19 patients are newly diagnosed with diabetes.

An international research team led by the Stanford University School of Medicine, including participation by researchers from the University of Basel and the University Hospital of Basel, has now been able to show that coronavirus can actually infect pancreatic beta cells. The scientists report their findings in the journal Cell Metabolism. Beta cells produce the hormone insulin, which stimulates tissue cells to absorb sugar from the blood, thus lowering blood sugar.

Alternative entry point

Unlike lung tissue, where coronavirus primarily uses a protein called ACE2 as a portal of entry into the cells, the beta cells of the pancreas have only low quantities of ACE2. For this reason, it has been unclear until now whether and how the virus enters these cells. To answer this question, the researchers analyzed tissue samples from seven deceased Covid-19 ‑patients in Basel.

The analysis found evidence of SARS-CoV-2 in the pancreatic beta cells of the victims. These cells also contained large quantities of a protein that the virus uses as an alternative entry point to ACE2: neuropilin-1 (NRP1). Laboratory tests on cultured beta cells further showed that infected cells produced less insulin and exhibited signs of die-off. When the researchers used an inhibitor to block neuropilin-1, the virus was much less successful at penetrating the cells.

Possible protection

The fact that infection of beta cells could be reduced in this way, at least in lab tests, shows that it might also be possible to protect these cells in patients with a severe case of Covid-19.

“Current research cannot say for sure whether sugar metabolism normalizes again in all Covid-19 patients after an infection, or whether and how often permanent diabetes may develop,” explains pathologist Dr. Matthias Matter of the University of Basel and the University Hospital Basel. Dr. Matter lead the parts of the study that were conducted in Basel. He says there is evidence that patients with “long Covid” – i.e. symptoms that persist after the infection has cleared – have signs of diabetes several weeks to months afterwards. It would therefore be extremely useful to develop a way to prevent lasting damage to the pancreas.

Further information

Featured image: Fluorescent microscopic image of cells: When SARS-CoV-2 (red) infects beta cells, they produce less insulin (green) and show signs of death. The cell nuclei are stained blue. (Fluorescent microscopic image: Chien-Ting Wu et al., Cell Metabolism)

Original publication: Chien-Ting Wu, Peter V. Lidsky, Yinghong Xiao, Ivan T. Lee, Ran Cheng, Tsuguhisa Nakayama, Sizun Jiang, Janos Demeter, Romina J. Bevacqua, Charles A. Chang, Robert L. Whitener, Anna K. Stalder, Bokai Zhu, Han Chen, Yury Goltsev, Alexandar Tzankov, Jayakar V. Nayak, Garry P. Nolan, Matthias S. Matter, Raul Andino, Peter K. Jackson, SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment, Cell Metabolism, 2021, , ISSN 1550-4131, https://doi.org/10.1016/j.cmet.2021.05.013. (https://www.sciencedirect.com/science/article/pii/S1550413121002308)

Provided by University of Basel

People Who Eat A Healthy Diet Including Whole Fruits May be Less Likely to Develop Diabetes (Food)

A new study finds people who consume two servings of fruit per day have 36 percent lower odds of developing type 2 diabetes than those who consume less than half a serving. The research was published in the Endocrine Society’s Journal of Clinical Endocrinology & Metabolism.

Diabetes is a disease where people have too much sugar in their bloodstream, and it is a huge public health burden. Approximately 463 million adults worldwide were living with diabetes in 2019, and by 2045 this number is expected to rise to 700 million. An estimated 374 million people are at increased risk of developing type 2 diabetes, the most common form of the disease. A healthy diet and lifestyle can play a major role in lowering a person’s diabetes risk.

“We found people who consumed around 2 servings of fruit per day had a 36 percent lower risk of developing type 2 diabetes over the next five years than those who consumed less than half a serving of fruit per day,” said study author Nicola Bondonno, Ph.D., of Edith Cowan University’s Institute for Nutrition Research in Perth, Australia. “We did not see the same patterns for fruit juice. These findings indicate that a healthy diet and lifestyle which includes the consumption of whole fruits is a great strategy to lower your diabetes risk.”

The researchers studied data from 7,675 participants from the Baker Heart and Diabetes Institute’s Australian Diabetes, Obesity and Lifestyle Study who provided information on their fruit and fruit juice intake through a food frequency questionnaire. They found participants who ate more whole fruits had 36 percent lower odds of having diabetes at five years. The researchers found an association between fruit intake and markers of insulin sensitivity, meaning that people who consumed more fruit had to produce less insulin to lower their blood glucose levels.

“This is important because high levels of circulating insulin (hyperinsulinemia) can damage blood vessels and are related not only to diabetes, but also to high blood pressure, obesity and heart disease,” Bondonno said.

Other authors of the study include: Raymond Davey of Curtin University in Perth, Australia; Kevin Murray of the University of Western Australia in Perth, Australia; Simone Radavelli-Bagatini of Edith Cowan University; Catherine Bondonno, Lauren Blekkenhorst, Marc Sim, Joshua Lewis, and Jonathan Hodgson of Edith Cowan University’s Institute for Nutrition Research and the Royal Perth Hospital Research Foundation in Perth, Australia; Dianna Magliano of the Baker Heart and Diabetes Institute in Melbourne, Australia; Robin Daly of Deakin University in Geelong, Australia; and Jonathan Shaw of the Baker Heart and Diabetes Institute and the Monash University in Melbourne, Australia.

The manuscript received funding from the National Heart Foundation of Australia and the National Health and Medical Research Council.

The manuscript“Associations Between Fruit Intake and Risk of Diabetes in the AusDiab Cohort,” was published online, ahead of print.

Provided by Endocrine Society

Diabetes Remission Diet Lowers Blood Pressure And Reduces Need For Medication (Medicine)

New research has shown that if people achieve and maintain substantial weight loss to manage their type 2 diabetes, many can also effectively control their high blood pressure and stop or cut down on their anti-hypertensive medication.

A weight management programme, developed by researchers at the Universities of Glasgow and Newcastle for the Diabetes UK-funded DIabetes REmission Clinical Trial (DIRECT), has proved effective at lowering blood pressure and reducing the need for anti-hypertensive medications, as well as bringing remission of type 2 diabetes.

The programme involves an initial 12 weeks on a nutritionally complete formula diet (low calorie soups and shakes) which will induce weight loss of over 15 kg (over 2 stones) if followed fully. Diabetes and blood pressure drugs were stopped at the start, and only re-started if blood sugar or blood pressure rose.

The weight loss phase is followed by support to choose foods and eat wisely for weight loss maintenance. Maintaining the 15 kg weight loss allowed 8 out of 10 people to become free from type 2 diabetes, without the need for diabetes medications for at least 2 years.

This study, published in the journal Diabetologia, looked at 143 people who started the diet programme, with more than half (78 people) on tablets for high blood pressure at the start (and 44 on two or more drugs). The researchers found that, overall, average blood pressure fell steadily as people lost weight. And blood pressure remained lower after the formula diet period finished, and then at 12 and at 24 months.

For those not previously treated for high blood pressure, blood pressures fell sharply from week one. For those who had stopped their blood pressure tablets, blood pressure still fell, although more slowly. Just over a quarter (28%) needed to reintroduce a blood pressure tablet during the formula diet period. However, researchers also found that the same proportion of participants (28%) were able to remain off their medications for at least two years.

Prof Mike Lean, from the University of Glasgow, said: “We wanted to evaluate the safety and efficacy of withdrawing blood pressure medication when beginning our specially-designed weight-loss programme for type 2 diabetes, and we are really pleased with the results.

“Our study shows that, in addition to possible remission from type 2 diabetes, there are other very important health benefits, as weight loss is a very effective treatment for hypertension and its associated serious health risks.

“Currently, over half of all the 4.5 million people with type 2 diabetes in UK also require tablets for hypertension, to reduce serious vascular complications. Being overweight is the main cause, and losing weight can bring a remission from hypertension for many, as well as a remission of diabetes. Withdrawing blood pressure medications is safe, provided people lost weight and blood pressure was checked regularly, in case tablets needed to be reintroduced.

“The DiRECT trial was done entirely in primary care. The evidence shows that GPs can safely offer an evidence-based intensive weight management intervention, aiming for substantial weight loss and remission of type 2 diabetes. The study further highlights the links between diet, weight, type 2 diabetes and hypertension, and how long-term support to maintain weight loss is vital.”

Professor Roy Taylor, from Newcastle University, said: “Guidelines encourage doctors to start tablets but there have been few demonstrations of how tablets can be stopped.

“My patients, like so many, do not like swallowing multiple tablets, and this study is important as we can now reassure them that stopping blood pressure tablets is not only safe but also good for their health. We’ve shown that when substantial weight loss is achieved and maintained, patients can effectively manage both their blood pressure and type 2 diabetes without drugs.”

Dr Wilma Leslie, University of Glasgow, said: “The potential to no longer need medications for blood pressure and diabetes is a big incentive for people. We hope our results will reassure health professionals that this is possible, and encourage the wider provision of diabetes remission services.”

Dr Elizabeth Robertson, Director of Research at Diabetes UK, said: “These important results show that the Diabetes UK-funded DiRECT low-calorie, weight management programme not only helps some people put their type 2 diabetes into remission, but can also lower blood pressure, allowing some people to safely stop taking their blood pressure medication.

“We’re delighted to see more evidence of the life-changing impact of the DiRECT programme on people’s health. This makes us even more determined to make sure as many people as possible have access to type 2 diabetes remission services.”

The study, ‘Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT),’ is published in Diabetologia.

The study was funded by Diabetes UK, with support in kind (Counterweight-Plus formula diet sachets) provided by Cambridge Weight Plan to Counterweight Ltd.

Reference: Leslie, W.S., Ali, E., Harris, L. et al. Antihypertensive medication needs and blood pressure control with weight loss in the Diabetes Remission Clinical Trial (DiRECT). Diabetologia (2021). https://doi.org/10.1007/s00125-021-05471-x

Provided by University of Glasgow

Genetic Tools Help Identify a Cellular Culprit for Type 1 Diabetes (Medicine)

By mapping its genetic underpinnings, researchers at University of California San Diego School of Medicine have identified a predictive causal role for specific cell types in type 1 diabetes, a condition that affects more than 1.6 million Americans.

The findings are published in the May 19, 2021 online issue of Nature.

Type 1 diabetes is a complex autoimmune disease characterized by the impairment and loss of insulin-producing pancreatic beta cells and subsequent hyperglycemia (high blood sugar), which is damaging to the body and can cause other serious health problems, such as heart disease and vision loss. Type 1 is less common than type 2 diabetes, but its prevalence is growing. The U.S. Centers for Disease Control and Prevention projects 5 million Americans will have type 1 diabetes by 2050. Currently, there is no cure, only disease management.

The mechanisms of type 1 diabetes, including how autoimmunity is triggered, are poorly understood. Because it has a strong genetic component, numerous genome-wide association studies (GWAS) have been conducted in recent years in which researchers compare whole genomes of persons with the same disease or condition, searching for differences in the genetic code that may be associated with that disease or condition.

In the case of type 1 diabetes, identified at-risk variants have largely been found in the non-coding regions of the genome. In the Nature study, senior author Kyle Gaulton, PhD, an assistant professor in the Department of Pediatrics at UC San Diego School of Medicine, and colleagues integrated GWAS data with epigenomic maps of cell types in peripheral blood and the pancreas. Epigenomic mapping details how and when genes are turned on and off in cells, thus determining the production of proteins vital to specific cellular functions.

Specifically, researchers performed the largest-to-date GWAS of type 1 diabetes, analyzing 520,580 genome samples to identify 69 novel association signals. They then mapped 448,142 cis-regulatory elements (non-coding DNA sequences in or near a gene) in pancreas and peripheral blood cell types.

“By combining these two methodologies, we were able to identify cell type-specific functions of disease variants and discover a predictive causal role for pancreatic exocrine cells in type 1 diabetes, which we were able to validate experimentally,” said Gaulton.

Pancreatic exocrine cells produce enzymes secreted into the small intestine, where they help digest food.

Co-author Maike Sander, MD, professor in the departments of Pediatrics and Cellular and Molecular Medicine at UC San Diego School of Medicine and director of the Pediatric Diabetes Research Center, said the findings represent a major leap in understanding the causes of type 1 diabetes. She described the work as “a landmark study.”

“The implication is that exocrine cell dysfunction might be a major contributor to disease. This study provides a genetic roadmap from which we can determine which exocrine genes may have a role in disease pathogenesis.”

First author Joshua Chiou, PhD, a recent graduate of the Biomedical Sciences graduate program at UC San Diego added: “Understanding how type 1 diabetes originates at the cellular level is a critical step in finding treatments for reversing its course and, ultimately, preventing the disease altogether.”

Co-authors include: Ryan J. Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Rebecca Melton, Elisha Beebe, Paola Benaglio, Serina Huang, Katha Korgaonkar, and Sebastian Preissl all at UC San Diego; David U. Gorkin, Emory University; and Sandra Heller and Alexander Kleger, Ulm University, Germany.

Funding for this research came, in part, from the National Institutes of Health (grants DK112155, DK120429, DK122607 AND T32 GM008666).

Reference: Chiou, J., Geusz, R.J., Okino, ML. et al. Interpreting type 1 diabetes risk with genetics and single-cell epigenomics. Nature (2021). https://doi.org/10.1038/s41586-021-03552-w

Provided by UC San Diego

Finerenone May Delay Onset Of AFib in Patients With Chronic Kidney Disease, Diabetes (Medicine)

Patients with chronic kidney disease and diabetes saw lower rates of heart rhythm disorder, other benefits

Patients with chronic kidney disease and Type 2 diabetes who took the experimental drug finerenone were about 30% less likely to develop the heart rhythm disorder atrial fibrillation (AFib) than those taking a placebo, according to data presented at the American College of Cardiology’s 70th Annual Scientific Session.

Last year, researchers reported that the trial, called FIDELIO-DKD, met its primary endpoint showing a significant benefit of finerenone, a nonsteroidal, selective mineralocorticoid receptor antagonist, in terms of a composite of sustained decrease in kidney function, kidney failure and renal death. The new analysis reveals that patients derived these benefits regardless of their history with AFib and suggests that taking finerenone also reduced the rate of new-onset AFib.

“Finerenone can lower the risk of development of atrial fibrillation in patients with chronic kidney disease and diabetes and can be used as a therapeutic strategy to delay its onset,” said Gerasimos Filippatos, MD, from the National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital in Athens, Greece, and the study’s lead author. “It can also protect the heart and the kidney from further damage caused by chronic kidney disease and diabetes in these patients with or without pre-existing atrial fibrillation.”

Chronic kidney disease, diabetes and AFib are major public health concerns worldwide. Patients with chronic kidney disease and diabetes face an increased risk of developing AFib because these conditions can cause changes in the heart’s structure and electric signaling, leading to fast and erratic heart rhythms. During preclinical studies, finerenone was reported to slow these structural changes.

FIDELIO-DKD randomly assigned 5,674 patients with chronic kidney disease and diabetes to take finerenone or a placebo and tracked outcomes for a median of 2.6 years. The primary endpoint was a composite of kidney failure, renal death or sustained decrease in estimated glomerular filtration rate (a measure of kidney function) of 40% or more from baseline. The key secondary outcome included death by loss of heart function, nonfatal heart attack, nonfatal stroke or hospitalization for heart failure.

As previously reported, finerenone significantly lowered the risk of kidney events by 18% and the risk of cardiovascular events by 14% compared with placebo. For the new analysis, researchers assessed outcomes among patients with and without a history of AFib or atrial flutter (about 8% of participants had AFib or atrial flutter at the start of the trial) and the risk of patients developing AFib or atrial flutter during the study.

The results found the primary and secondary endpoints were significantly lower in patients taking finerenone regardless of their AFib status at the start of the study.

“The previously-reported kidney and heart protection with finerenone applied equally to patients with and without pre-existing atrial fibrillation,” Filippatos said.

In addition, new-onset AFib or atrial flutter was reported in 3.2% of patients taking finerenone and 4.5% of those taking a placebo, a significant difference in favor of finerenone.

Researchers said that previous findings from preclinical studies have suggested that finerenone may help reduce scarring and thickening of the heart tissue, possibly through its action of blocking mineralocorticoid receptors, a type of protein molecule present on many cell types in the heart and kidney that has been shown to be especially abundant in patients with AFib.

“Preventing or delaying the onset of atrial fibrillation in patients with chronic kidney disease and diabetes is particularly important since having atrial fibrillation can worsen chronic kidney disease and having diabetes can worsen atrial fibrillation symptoms,” Filippatos said. “Treatment in these patients can also be challenging because they are prone to developing blood clots [which can lead to stroke] and bleeding. Finerenone has the potential to reduce the burden of atrial fibrillation in these patients.”

Filippatos said that larger studies focused specifically on new-onset AFib would be needed to confirm the findings. Because participants underwent heart rhythm tests only once per year in FIDELIO-DKD, Filippatos said it is possible that researchers missed asymptomatic AFib or cases that were not apparent from tests. A separate trial is currently underway to examine finerenone’s effects in patients with less severe chronic kidney disease and diabetes.

This study was simultaneously published online in the Journal of the American College of Cardiology at the time of presentation. The study was funded by Bayer AG. Filippatos will be available to the media in a virtual press conference on Monday, May 17, at 12:15 p.m. ET / 16:15 UTC.

Filippatos presented the study, “Finerenone Reduces Onset of Atrial Fibrillation in Patients with Chronic Kidney Disease and Type 2 Diabetes” in JACC.

Provided by American College of Cardiology

UC Cardiologist Finds Proteins in Diabetic Patients May Indicate Future Heart Disease (Medicine)

Donald Lynch Jr., MD, presents findings at the American College of Cardiology’s national meeting

Laura Riesenberg was visiting a local amusement park with three of her children when she suffered a massive heart attack.

“I was down for about 20 minutes and they defibrillated me twice on site, possibly three times,” she says. “Obviously, I was unaware of it. I know from reading the reports what happened.”

“I was extremely fortunate that someone found me within seconds of collapsing,” says Riesenberg. “Had it happened anywhere else I wouldn’t be talking to you right now. If I had been in the basement doing laundry, I would have been in trouble.”

The 51-year-old Loveland, Ohio, resident was transported to UC Health’s West Chester Hospital where she learned she was a Type 2 diabetic and had suffered previous damage to the heart that led to a big blockage of her left coronary artery while at the amusement park. That type of blockage is often referred to as the “widow maker.”

Laura and the Riesenberg family are shown. Front row(sitting): Emily, Tori, Sophia; Middle row (kneeling): Luke, Grant, Brett; Back row (standing):  Hannah, Jacob, Jay, Laura Cade and William.
Laura Riesenberg (back row center) surrounded by her family: Emily, Tori and Sophia (seated); Luke, Grant and Brett (kneeling); Hannah, Jacob, Jay, Laura, Cade and William (standing). Photo/provided.

Donald Lynch Jr., MD, assistant professor at the University of Cincinnati College of Medicine and UC Health cardiologist, says that the link between diabetes and heart disease often leads to adverse health outcomes for patients. Approximately 65% of deaths among patients with diabetes are due to cardiovascular disease.

Lynch, also Riesenberg’s current cardiologist, will be presenting preliminary research virtually at the American College of Cardiology on Saturday, May 15, that suggests plasma proteins discovered in the blood samples of diabetic patients who went on to develop obstructive coronary disease (OCAD) may serve as biomarkers of severe heart blockage. The findings might benefit patients like Riesenberg in the future.

Riesenberg says an internal defibrillator was implanted in her heart after her heart attack.

“There was no explanation why I survived the first heart attack or second heart attack. They also diagnosed me as diabetic that day. Mind you, I should have known. I had been a gestational diabetic, and I had been overweight, but I thought I was doing all the right things.

Donald Lynch, Jr., MD
Donald Lynch, Jr., MD, is shown in the UC College of Medicine. Photo by Colleen Kelley/UC Creative + Brand.

“I had lost a significant amount of weight, and I was active. I was eating well or at least I thought I was eating well. I had absolutely no idea,” she adds. “I wish someone had been able to tell me that there was a strong link between diabetes and heart disease.”

Riesenberg, a homemaker, and her husband, Jay, are both diabetic and they worry if their medical hereditary history might someday impact their family; in addition to the three children who joined their mom at the park the couple have another seven.

As part of his research Lynch, a researcher in the UC Division of Cardiovascular Health and Disease, looked at stored plasma samples from 70 diabetic patients: one group was found to have obstructive coronary disease while the second group did not. A total of 248 plasma proteins were identified; 15 were present in patients with obstructive coronary disease while only three were present in patients without OCAD.

“We took samples of plasma and used mass spectrometry to see if we could find biomarkers that were predictive of patients developing obstructive coronary disease,” says Lynch. “The significance of this is I see patients who have diabetes and unfortunately develop blockages but no symptoms.”

Lynch says Riesenberg was fortunate that she survived her heart attack and cardiac arrest. “For many patients that’s not the case,” he says. “We know patients with diabetes are much more likely to have blockages in the heart and unfortunately they are more likely to be asymptomatic which places them at significant risk. We don’t have good tools to figure out which patients will develop blockages.”

“What we found is that we can use a blood test and identify patients with diabetes who might develop obstructive coronary disease,” says Lynch. “It is a challenge to identify which patients with diabetes are at higher risk. This may be a good tool in our toolbox to help us in our fight against cardiovascular disease in patients with diabetes.”

“We can get them to a provider and have them assessed early for the possibility of developing obstructive coronary disease,” says Lynch.

The research is particularly important to Lynch, who disclosed he also battles diabetes. He has planned future studies to further evaluate the ability of these biomarkers to identify patients with coronary disease and improve cardiac outcomes for patients with diabetes. 

The preliminary research has definitely captured the interest of Riesenberg, who spoke with Lynch about his findings.

“It fascinates me that a simple blood test might be able to tell my children that this is on their horizon, and you don’t have to be dependent on a cardiac device for the rest of your life,” says Riesenberg.

Other research co-authors from UC include David Hui, PhD, professor of pathology and laboratory medicine along with Auriela Howze, a UC undergraduate majoring in chemistry. Additional co-authors include Koen Raedschelders, PhD, Jennifer Van Eyk, PhD, and Mitra Mastali, PhD, all of Cedars-Sinai Medical Center, Los Angeles and James Januzzi, MD, of Massachusetts General Hospital, Boston. 

Funding for the research is from Cedars-Sinai Advanced Clinical Biosystems Research Institute, University of Cincinnati College of Medicine Department of Internal Medicine Rehn Family Research Award. 

Featured image at top: Donald Lynch, Jr., MD. Photo/Colleen Kelley/UC Creative + Brand.

Provided by University of Cincinnati