Hypoglycaemia presents particular challenges for older people, yet is frequently misdiagnosed in this group. In his new module, launching today, Professor Brian Frier sheds new light on this important but often underestimated aspect of diabetes.  

Among our many current global health challenges, two of the most commonly cited are ageing populations and the rising tide of diabetes. Yet the two are rarely considered together – with the result, perhaps, that complex and significant aspects of diabetes care are sometimes neglected. Diabetes in older people presents particular challenges, not least among them being the issue of hypoglycaemia – the subject of the latest module from EASD e-Learning. 

Written and presented by Professor Brian Frier of the University of Edinburgh, UK, an international authority on diabetes and hypoglycaemia, ‘Hypoglycaemia in older people’ examines the particular experience of hypoglycaemia for older people. As Brian’s module clearly outlines, hypoglycaemia’s physiological effects change with age and for older people with diabetes the associated risks can be significantly more perilous. For example, he notes research showing that severe hypoglycaemia is associated with a more than twofold higher risk of falls – clearly a significant concern for older people.  

More controversial, perhaps, is the possible association between hypoglycaemia and cognitive impairment – again, potentially highly significant for older people. As Brian points out, research in this area is tricky. “Annual incidences of dementia and severe hypoglycaemia are relatively low in older populations with diabetes, so large cohort sizes and long follow-up are required to ensure adequate statistical power.” Nevertheless, large patient registries from healthcare providers provide valuable sources of data – and most show a positive association between severe hypoglycaemia and cognitive decline. 

For a deeper understanding of this major and underestimated problem, enroll on our Hypoglycaemia course to watch Professor Frier’s module, ‘Hypoglycaemia and older people’. 

About the author 
Professor Brian Frier’s research interests include the pathophysiology of insulin-induced hypoglycaemia in diabetes, including cognitive function, neuroimaging, symptom responses, physiological manifestations and clinical syndromes, such as impaired awareness of hypoglycaemia, insulin therapy and driving. He has published extensively on these research topics, with over 500 publications, and has co-edited two international major textbooks on hypoglycaemia and diabetes. 
Although Brian retired from clinical practice in 2012, he continues to collaborate with colleagues in the UK and abroad on hypoglycaemia research, including the effects on cognitive function and studies on symptomatology, morbidity and epidemiology. 

For more on cognitive dysfunction and hypoglycaemia, watch out for our forthcoming debate between Professors Stephanie Amiel and Rory McCrimmon – part of our series ‘The long and the short of it’. Launching in September. 

The pandemic has provided healthcare professionals with a unique opportunity to make the most of a digital approach to diabetes care.

The last year has seen dramatic changes in the way diabetes teams deliver care – with COVID-19 dictating a switch from traditional face-to-face appointments to remote care, backed up by the use of digital diabetes technology. This is something every diabetes healthcare professional has had to address. Therefore, when introducing a discussion on virtual and digital diabetes care at Advanced Technologies & Treatment for Diabetes, Satish Garg of the Barbara Davis Center, Colorado, argued that this was one of the most important sessions the online meeting had to offer.  He’s been publishing widely on diabetes telehealth and keeping a close eye on the data. As is well known, glucose control among people with diabetes has got worse in the USA over the past five years, as shown by data from the Type 1 Diabetes Exchange, possibly because more people with type 1 have overweight and obesity.

Maybe telemedicine, driven by the pandemic, offers an opportunity to address this?

Satish noted that all diabetes care at the UNC Diabetes Care Centre had to be transitioned to a virtual setting from March/April 2020 and this had been achieved within two weeks. “Data shows this can be managed with no adverse effects on time in range or rates of hypoglycaemia. Emergency use of continuous glucose monitoring (CGM) was authorised, which facilitated the transition.” At the Barbara Davis Diabetes Centre, CGM use is now up to 80% and he noted that time in range during the pandemic actually improved. “However, the improvement was directly related to socioeconomic status, which is unfortunate, but it was still seen in all groups.”

Newer CGM systems, like the Dexcom G7, and smart solutions like the InPen insulin pen- like pump are beginning to make an important contribution and Satish is working to standardise downloads from these systems and multiple daily injection (MDI) with connected pens. “I think CGM and MDI, with connected pens, might be the best way to manage diabetes globally – though in the USA and Europe, maybe insulin pumps are preferred – with data being shared through iCloud and apps. I do think that COVID-19 might have shown us that remote care through telehealth might be the way to reduce costs in diabetes care. Of course, I don’t know what the future is, but I hope diabetes telehealth is here to stay, as it will remove many barriers and patients can receive more equal care. We may even be able to use the digital and virtual approach to go beyond HbA1c and find new ways of managing diabetes.”

Telemedicine certainly seems to offer much in terms of paediatric type 1 diabetes care delivery, which can be taken into the post-pandemic world, according to Lori Laffel, of the Joslin Diabetes Centre. The gold standard would be to spend up to an hour with patient and family in an attempt to combat that suboptimal glucose control, which reaches its peak in adolescent years. Previous research has shown that more frequent follow-up visits may help in this respect. “Research at Joslin shows paediatric patients were offered six visits over two years on average, but 15% of these were ‘Did Not Attend’ or were cancelled – maybe because the face-to-face visit is inconvenient. But those who missed two visits did have worse HbA1c.” In this analysis, they looked at who attended the visit with the patient, and found lower HbA1c among those who had fathers in attendance. “Virtual care may encourage more contact and presence of one or more parents,” Lori said. “So telehealth is a potential way to improve care and outcomes.”

Telehealth can increase the pool of healthcare professionals involved in paediatric diabetes care and there is data from CGM and from insulin pumps – which converted very quickly, at the start of the pandemic, to remote data acquisition. With all this, there is now data showing that telehealth can increase frequency of care and this, in itself, may improve outcomes. “Virtual care itself isn’t new, because the intensive group in the Diabetes Control and Complications Trial had telephone calls. I think we need to look at the hybrid approach going forward, combining face-to-face with virtual or remote care.” Hybrid rather than 100% remote, because in paediatric diabetes care the remote approach has gaps. Personal interaction is needed to assess growth, inspect injection sites and carry out eye and foot examinations.

These limitations notwithstanding, the stats around remote care are impressive, with a big increase in mental health, educator and dietitian appointments. “We’ve done a study of over 600 patients before and after the pandemic and there was an increase from 2.7 to 3 visits per person per year. We saw an improvement in glycaemic control, with a doubling of those reaching target. Therefore, by potentially changing process of care through telehealth, we are able to change the outcomes.”

What are the hopes for post-pandemic paediatric care? “This increased frequency of visits works, so we are looking for a hybrid model with face-to-face visits twice a year, and remote [appointments] four times [a year]. But we will need to show non-inferiority and cost-effectiveness,” Lori concluded.

For more on the pandemic and diabetes care, see our series of short tutorials ‘Diabetes and COVID-19’.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.

At the American Diabetes Association (ADA) 81st Scientific Sessions, two fascinating presentations on the evolution of diabetes nutrition therapy revealed how we’ve got to where we are today.

We’ve known about the importance of nutrition in diabetes for more than a century. Melinda Maryniuk, a renowned dietitian who was previously Director of Care Programs at the Joslin Diabetes Center, looked back at diabetes diets of the past and the leading lights who played vital roles in our present-day understanding.

It was 1921 when the first doctor in the USA to specialise in diabetes, Elliott P Joslin, wrote about diabetes prevention and obesity, and Frances Stern (one of the USA’s first nutritionists) wrote presciently in 1927: ‘A consideration of the environment, racial habits and national customs is of more importance in the dietetic treatment of diabetes than in any other field of medicine.’

But the initial eating plans for people with diabetes were not what they are today. When we think of diets 50 to 100 years ago, said Melinda, weighing, measuring, precise, extremely low-carb and not individualised are some of the words that spring to mind.

They were created by nutrition leaders such as Frederick Allen, who wrote about the starvation diet. This involved one to four days alternating between coffee and whisky until the urine was free of sugar and then adding in thrice-boiled veg (to make them even lower carb) for two days and then gradually adding protein and fat.

There were also the Joslin diets – weighed diets with exact portions that were moderate in carbs at 40%. Over time, they became a little more adaptive and individualised.

Edward Tolstoi created ‘The Free Diet’. Food was neither weighed nor measured, but was self-chosen; patients were permitted to choose foods that didn’t differ from members of their family and desserts were allowed – but not over-indulgence.

Formal exchange lists to support the Exchange System came out in 1950 to address needs for standardisation, simplification and individualisation, but the term had been around for years before that.

Fascinatingly, in this centenary year of insulin’s momentous discovery, Melinda reflected on whether it was a setback to nutrition research. She highlighted a quote from a 2006 article written by obesity specialist, Dr Eric Westman: ‘The rapid adoption of insulin therapy and the hope that it would “cure” diabetes may have led to premature abandonment of earlier successful nutrition treatments.’

The 1980s to 2021

Dietitian and diabetes nutrition management specialist, Hope Warshaw, followed with a journey through the 1980s to the present day, first pointing out that diabetes nutrition therapy has been greatly impacted by factors such as changing eating style/patterns, the advent of glucose-lowering medications, diabetes technologies and growing pathophysiology knowledge.

The 1980s saw a study that led to the rethinking of how carbohydrates were viewed. It found that eating potatoes gave essentially the same response as oral glucose when they measured blood glucose and endogenous insulin; rice and corn gave much lower blood glucose responses, and bread came out between the two.

In the 1986 ADA Nutrition Position Statement, the recommendation for the percentage of calories as carbohydrates was set at the highest levels to date – at 55-60%. It also noted the importance of eating unrefined carbs containing fibre, after work that showed the beneficial effects of fibre intake on glycaemia.

In the 1990s, a glut of influential, long-term research was published, including the UK Prospective Diabetes Study (UKPDS) in 1998 and the Diabetes Control and Complications Trial (DCCT) in 1993. The DCCT Ancillary Study identified four key diet behaviours for improving glycaemic control: promptly treat hyperglycaemia, never overtreat hypoglycaemia, minimise extra snacking and adjust insulin for changes in food intake. 

She shared a 2021 quote from Linda Delahanty, one of the study’s authors: ‘In the DCCT, we learned that intensive insulin therapy alone was not sufficient to achieve glycaemic targets. We learned the role of the registered dietitian/registered dietitian nutritionist and that careful attention to diet was key to achieving glycaemic targets in intensive diabetes therapy without undue hypoglycaemia or weight gain.’

The next update to the ADA Nutrition Position statement came in 1997. A decrease in the consumption of saturated fat (less than 10%) was now included, along with the concept of considering medication to promote weight loss in tandem with nutrition management.

The advent of nutrition labelling also happened in the 1990s. Prior to 1990, information on the calorie, fat, carbohydrate and sugar content of foods was limited. When it became available on labelling, it was extremely useful for people living with diabetes. The addition of ‘added sugars’ on labels only came into effect in 2020.

In the 2000s, findings from the Diabetes Prevention Program showed that weight loss is a dominant predictor of reduced type 2 diabetes incidence and return to normoglycaemia, with a 16% reduction in risk per kilogram of weight loss. Physical activity was shown to be important in sustaining it. The 2004 ADA statement reflected this with an increased emphasis on insulin resistance and obesity, and the importance of weight loss.

The 2010s saw a leap in the continuous glucose monitoring (CGM) technology advances that have helped clinicians to assist patients in more closely understanding and managing their glycemic trends and food choices.

The updated ADA nutrition statement of 2013 added statements to the effect that there’s no ‘one-size-fits-all’ eating pattern, promoting instead a healthful eating pattern with a variety of nutrient-dense foods, maintaining pleasure of eating and limiting food choices only when indicated by scientific evidence. A far cry from the early days of diabetic diets.

Hope shared a succinct summary of where we are now from the session’s moderator, Alison Evert, manager of the Nutrition and Diabetes Education Programs at UW Medicine: ‘Evidence does not support a clear preference for any specific eating plan or macronutrient range for weight loss. A variety of eating plans are effective. Total energy intake versus macronutrient source of energy is of greatest importance. And what the person is willing to follow long-term.’

The ADA no longer publishes position statements but produced a nutrition therapy consensus report in 2019. Point two in particular takes us back to that first Frances Stern quote of 1927:

‘Address individual nutrition needs based on personal and cultural needs, literacy, numeracy, access to healthy foods, willingness and ability to make behaviour changes, and understanding a person’s barriers.’

It also included an extensive review of different eating patterns for people with diabetes, such as low fat, low carbohydrate, vegetarian/vegan, paleo, intermittent fasting, etc. However, there are four common denominators that hold without digging deeper into specific meal plans:

  1. Emphasise consumption of non-starchy vegetables
  2. Minimise consumption of added sugars and refined grains
  3. Choose whole foods over highly processed foods
  4. Replace sugar-sweetened beverages with water as often as possible

What’s on the menu for the future?
Crystal-ball predictions on which factors will impact nutrition therapy in the coming years from Hope and her colleagues include the role of the gut microbiome, the impact of mental health, epigenomics, metabolomics and nutrigenomics, and eating for a healthy planet.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.

Topline results from the EMPEROR-Preserved Phase 3 trial suggest potential for empagliflozin as a treatment for heart failure with preserved ejection fraction. The as-yet-unpublished findings are due to be presented at the European Society of Cardiology (ESC) Congress 2021 in August.

The EMPEROR-Preserved trial investigated the safety and efficacy of the SGLT-2 inhibitor Jardiance® (empagliflozin)in patients with chronic heart failure with preserved ejection fraction (HFpEF) and met its primary endpoint, establishing empagliflozin as ‘the first and only therapy to significantly reduce the risk of the composite of cardiovascular death or hospitalisation for heart failure in adults, with or without diabetes, who live with HFpEF’, according to the announcement from Boehringer Ingelheim and Eli Lilly and Company.

It follows the positive results from the EMPEROR-Reduced trial, which investigated the safety and efficacy of Jardiance in patients with chronic heart failure with reduced ejection fraction (HFrEF). It found that Jardiance significantly lowered the combined relative risk of cardiovascular death or hospitalisation for heart failure by 25% compared to placebo.

This Phase 3, randomised, parallel-group, double-blind, placebo-controlled trial involved 5988 symptomatic HFpEF patients left ventricular ejection fraction of >40%, who were given 10 mg Jardiance or placebo. The primary endpoint was time to first event of adjudicated cardiovascular death or adjudicated hospitalisation for heart failure. The safety profile was generally consistent with the known safety profile of Jardiance.

Jardiance is currently used alongside lifestyle changes to lower blood glucose in adults with type 2 diabetes and also to reduce the risk of cardiovascular death in adults with type 2 diabetes who have cardiovascular disease.

Diabetes and heart failure

Diabetes and heart failure are risk factors for one another and are often seen together. According to a 2020 paper in Diabetes Therapy (Williams DM, Evans M. Are SGLT-2 inhibitors the future of heart failure treatment? The EMPEROR-Preserved and EMPEROR-Reduced Trials. Diabetes Therapy. 2020. 11:1925-1034. https://doi.org/10/1007/s13300-020-00889-9), the worldwide prevalence of heart failure is substantial and increasing. Diabetes increases the risk of developing it by more than twofold in men and fivefold in women, with an estimated 25% of people with diabetes suffering chronic heart failure.

It also highlighted a study in which 45.5% of people with HFpEF and 41.8% with HFrEF were diagnosed with diabetes, respectively.

In people with diabetes, it stated that several mechanisms may explain the relatively high risk of HFpEF, including impaired cardiac metabolism and substrate utilisation, altered insulin signalling and cardiac deposition of advanced glycated end products.

There is currently no approved therapy that demonstrates an improvement in mortality for people with HFpEF.

For more on EMPEROR study results, enroll on our SGLT-2 inhibitors course.

The opinions expressed in this article are those of the author, Dr Eleanor D Kennedy.

People with type 1 diabetes have been pushing the boundaries of sporting excellence for the past 100 years. Now, thanks to technology like continuous glucose monitoring (CGM) and closed-loop, they are achieving more than ever before

Several athletes with type 1 diabetes are aiming for a medal at this summer’s Tokyo Olympics, while professional cyclists with Team Novo Nordisk continue to ride high. But how do they overcome the challenges to glycaemic control that sport and exercise pose in type 1? At this year’s Advanced Technologies and Treatment for Diabetes meeting, Dr Mike Riddell of the Muscle Health Research Centre, York University, Toronto, discussed how technology helps athletes with type 1 diabetes exercise safely and achieve sporting success.  

“Glycaemic control in sport is a major challenge, but CGM has taught us a lot and our research group is focused on how it can help support athletes. And there’ll be future advances in technology which will put more people on the podium,” he said.  

In 1926, the British physician RD Lawrence, who had type 1, discovered that aerobic exercise – tennis or rowing – made his insulin work much more effectively which, of course, can lead to hypoglycaemia. While this makes some fear exercise, and miss out on all its well-established benefits, others have taken on the challenge. Mike – who lives with type 1 himself and is a keen cyclist – cited examples including baseball player Bobby Clarke, who blazed the trail in the 1970s, long before CGM, and Olympic swimmer Gary Hall.

Technology makes it all possible

CGM, closed-loop, better insulins and glucagon have all helped make sport and exercise safer and pushed athletes to higher performance levels, by addressing the great glucose variability that exercise can bring. “We’re starting to understand the relationship between time in range and performance and we are now testing several closed-loop systems in exercise mode to see if we can protect athletes from hypo- or hyperglycaemia in sporting competition,” Mike explained. “We’re also starting to incorporate some other wearables, including heart rate and sleep monitors, to see if we can better understand the physiologic demands athletes placing on themselves. We have ambitious goals for athletes with type 1 diabetes.”     

Team Novo Nordisk cyclist Sam Scott then took to the stage to talk about the day-to-day reality of pursuing his sport. CGM and cycling monitors can be used remotely to investigate non-invasively some of the challenges during elite-level cycling and retrospectively analyse the data and highlight challenges with the team doctor. This approach was used in the team’s 2019 tour of California, where seven male athletes with type 1 diabetes raced for three to six hours per day, covering a distance of 126 to 218 km with a total elevation almost 21 km – all at a top speed 50 km/h. Then there’s the logistics. “When you come on one of these tours you realise it’s kind of like a moving circus. Finish your race, back to the van, get to the next hotel, recover and get ready for next race! It’s more difficult than waking up in your own bed and doing these races.”

Team Novo Nordisk has been very successful in competing against teams without diabetes. One rider was awarded the ‘most courageous rider’ jersey, and there were Top 20 and Top 10 results, and three breakaways, over the course of the California tour. When they looked back at the CGM data, they were really pleased to see how well riders kept within target during rides and, during the seven days, there were almost no hypos. There was just one concerning issue – overnight there was a steady increase in below-target glucose for all the cyclists. “The use of CGM has really highlighted to us that we need to work on this post-exercise period to help recovery and, for safety, to avoid these night-time hypos,” Sam said.

So, CGM has been really important in working with these athletes. There are so many advantages associated with being able to see their data in real time and make short-term decisions, and going through data afterwards to learn and adjust strategies for future races and training. For instance, it helps adjust carbohydrate intake and monitor insulin needs. Meanwhile, CGM alarms are particularly useful, especially overnight for avoiding hypos.

The one drawback is the sensor time lag, which does become apparent during exercise at such high speeds and when prompt decisions about refuelling might be needed. Mike commented that this might be solved by developing different predictive algorithms built into CGMs, for when glucose might be rising or dropping during a sporting performance.

Meanwhile, from the medical side, Dr Federico Fontana, Head of Performance at Team Novo Nordisk, has been making use of all the different data streams coming from his cyclists. “We are trying to better merge training data with glucose data into a common display,” he explained. This, hopefully, will lead to better training, glucose management and control, and the ability to spot patterns and trends. They’ll be able to check out differences between race days, recovery days or training at home, using very simple displays. “The long- term aim is to develop some personalised approaches through a dashboard that can support the athlete with their personal decision-making, with the whole team supporting them in turn.”

So, after 100 years of athletes trying to compete on insulin, there have been some impressive achievements – and more to come.  “We know that some recent developments like closed-loop systems, digital pens, CGM and intermittently scanned glucose monitors have really shed light on the accomplishments of some of these athletes and their level of glycaemic control. The technology allows them to make critical on-the-minute decisions about nutrition, hydration or insulin therapy patterns and we think that emerging systems may help to further improve Time in Range in these athletes,” Mike said. “And, finally, from Team Novo Nordisk, we think that novel ways of displaying data to the athletes and the coaches might give a better glimpse on how to optimise performance in these incredible human beings.”

Recommended reading
Much of this new knowledge has been highlighted in a recent position statement on CGM and intermittent glucose monitoring by EASD/ISPAD, and endorsed by the American Diabetes Association (published in both Diabetologia and Paediatric Diabetes). This highly recommended reading sets out detailed information on when it is safe to exercise, how different types of exercise produce different glucose responses, and sets out glucose targets based on this. Access the position statement on the EASD website.

For more on this topic, see Professor Mike Riddell’s presentation in our Insulin@100 series, ‘Exercise and insulin: a potent synergy’.

You can also hear Mike in conversation with fellow cycling enthusiast Professor Miles Fisher in their contribution to our ‘The long and short of it’ series, ‘This sporting life’.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.

Listening to your feedback continues to be at the forefront of ensuring the EASD e-Learning programme is up to date, evidence based and meets the needs of our learners.

You may recently have read about some changes we made to the e-Learning platform to make it easier for you to let us know what you think about our courses and alert us to any technical problems. When you sign into the platform, to the right of the screen – wherever you are on the site – there is now a toolbar, which includes a number of options to help you communicate with us.

If something isn’t working the way you expect it to, you can click on Report a technical problem’ and a short form will be presented. This feedback is monitored on a daily basis during the week and you can expect a response within two working days.

Alternatively, if you notice something that needs changing in the content itself, or there are topics you would like to learn more about, you can use the ‘Feedback on course content’ button.

For other general enquiries, there’s a simple Contact us’ button.

To support the dialogue between us and our users further still, the toolbar contains a ‘Your messages’ button, where you can access correspondence about issues you’ve raised with the e-Learning team, all in one place.

And if all else fails, you can still use our original green ‘Provide course feedback’ button below the content ladder to the left of the page.

What happens to your feedback about a module?

Learner feedback for each module is reviewed on a monthly basis. A summary of the feedback for the month is produced and highlights are shared with module authors. A member of the feedback team may contact a learner who has provided their email address to respond to any specific queries.

All of the learner free-text feedback is collected and organised into themes and forms part of the periodic review process whereby each module is reviewed to ensure it is fit for purpose.

Module assessment

One significant theme we have seen in your learner feedback has been requests for more clinical case studies. To address this feedback we have been working with our authors and other experts to build up the number of self-assessed cases studies in each current module. It is expected that this project will be on-going until at least the end of the year but the work to add these to the e-Learning platform has begun. As we write, the following modules have had new case studies added to them:

  • Diabetes and the kidney: Module 1
  • Hypoglycaemia: Module 1
  • Insulin resistance: Module 1
  • Management of hyperglycaemia in type 2 diabetes – ADA/EASD consensus report (2018) and update (2019)
  • Non-alcoholic fatty liver disease: Module 1
  • Phenotypic variability: Module 1

Some of our learners have also asked for more assessment activities. This feedback, together with feedback from a review of our assessment strategy, led to us to begin a project four months ago to strengthen the end-of-module assessment and move from five questions to 10. In addition, many of the questions will be based on clinical scenarios to enable learners to apply their knowledge to clinical practice. The modules listed above have all moved to this new format.

Launch dates

We received learner feedback asking us to include the date on which individual modules were launched. In response to this, we have added launch dates retrospectively to all of our existing modules and will be including this information as we launch all new modules from now on.

New courses and modules

Many of you have put forward suggestions for new courses or new modules within existing courses. The e-Learning team review these suggestions regularly. So far in 2021 we have launched the following modules:

  • Cardiovascular health and diabetes. Module 7: Heart failure on trial – DAPA-HF and EMPEROR-Reduced
  • SGLT-2 inhibitors. Module 8: The VERTIS CV trial
  • SGLT-2 inhibitors. Module 9: Renal outcomes clinical trials update
  • Insulin resistance. Module 1: Insulin resistance, the metabolic syndrome and type 2 diabetes
  • Non-alcoholic fatty liver disease. Module 1: NAFLD – epidemiology, pathophysiology and diagnosis
  • Hypoglycaemia. Module 1: Reducing hypoglycaemia
  • Metabolic surgery. Module 1: Mechanisms of metabolic surgery
  • Metabolic surgery. Module 2: Metabolic surgery for obesity and type 2 diabetes

We continue to aim to launch one new module a month and, in September, at the 2021 Virtual EASD Annual Meeting, we will be launching new modules each day of the meeting. For more information please visit: https://www.easd.org/annual-meeting.html

Watch out for our latest module, Hypoglycaemia in older people, launching on 26th July.

The opinions expressed in this article are those of the author, Dr Eleanor D Kennedy.

If you want a deeper understanding of the COVID-19 vaccination landscape, Dr Marc Evans is here to help. This week on Horizons we’re launching part one of his two-part presentation, an in-depth survey of the various vaccination approaches and how each of them performs against new variants.

Dr Marc Evans’ research passions are real-world evidence, epidemiology and pharmacoepidemiology – making him perhaps the ideal guide on a tour of the current COVID-19 vaccine landscape. As he points out at the start of his first presentation, quoting respected Yale vaccine researcher Saad Omer: “this is an evolving science; it’s like watching sausages being made in front of the world’s eyes.”

The focus of this first installment is on the various vaccines that have already been produced – at remarkable speed and with a remarkable degree of efficacy – from this real-time sausage-making process. First, Marc examines the different approaches taken to induce an immune response against the SARS-CoV-2 virus – the various potential vaccine platforms.

“Typically we could use a whole pathogen, the live attenuated or inactivated approach, to induce an immune response,” says Marc. “We can use nucleic acid-based vaccines, either DNA or RNA based. We can generate antibodies against the toxoid antigen produced as a result of SARS-CoV-2 penetrating cells and that inflammatory response that is consequent on the toxoid. We can look at subunit recombinant protein-based antigens, targeting specific units – subunits – within the SARS-CoV-2 viral membrane. We can look at viral vector-based vaccines. We can generate vaccines against various polysaccharides within the membrane of the SARS-CoV-2 viral particle. Or we can look at polysaccharide conjugate-based vaccine platforms. Now, where we’re going at the moment is very much along the route of the messenger RNA (or mRNA) vaccines and there’s a lot of excitement and interest in this as a potential therapeutic modality.”

As Marc attests, this has been largely a success story – thus far. But there’s still a long way to go. “We have already seen a lot of data around the differing vaccine effects in terms of efficacy against severe COVID-19 and we can be fairly reassured that the various vaccine candidates actually provide fairly good protection against severe illness. But what we really want to now is, what might happen in the future with respect to these vaccines in terms of all the emerging variants.”

To find out more, click here and watch part one of Marc’s presentation – ‘Understanding the vaccine landscape’.

In next week’s film, Marc will be examining the epidemiology and future directions of the COVID-19 pandemic, sharing some modeling insights as to what we might expect to see in terms of implementation and rollout of vaccination across the world.

Look to the liver – for non-alcoholic fatty liver disease (NAFLD) has important links with type 2 diabetes and metabolic syndrome, and can worsen the risk of cardiovascular disease.

NAFLD is a multisystem disease that begins with fat accumulation in the liver. Once 5% or more of the liver cells contain fat, the person actually has NAFLD and they are looking at a serious health issue that is attracting increasing attention among healthcare professionals. According to Professor Chris Byrne, Southampton University, speaking at this year’s Advanced Technologies and Treatment for Diabetes meeting, NAFLD may progress to liver fibrosis, cirrhosis and liver cancer. It is also associated with an increased risk of chronic kidney disease, cardiovascular disease and type 2 diabetes. And, importantly, it is often found together with metabolic syndrome, which may provide a route into earlier diagnosis of NAFLD during routine checks; maybe something can be done before it progresses too far.

Links with type 2 diabetes

Professor Byrne describes NAFLD and type 2 diabetes as a “vicious spiral of worsening disease.” Over the last few years, she and others have published evidence that NAFLD increases the risk of type 2 diabetes more than two-fold, and the presence of type 2 diabetes then accelerates the rate of progression of NAFLD to liver fibrosis and maybe even hepatocellular carcinoma. Hence, a vicious spiral. Worse still, NAFLD also doubles the risk of cardiovascular disease and increases the risk of chronic kidney disease by 50%.

Here is some of that evidence. A meta-analysis published in 2018 and updated in 2020, covering half a million patients, showed that the presence of NAFLD doubled the risk of type 2 diabetes. This increased risk is likely driven by marked hepatic insulin resistance and increased hepatic glucose output in NAFLD.

Another study, involving paired liver biopsies separated by six years, showed that 56% of patients with type 2 diabetes and NAFLD progressed to liver fibrosis, compared with 21% of those with NAFLD but no diabetes.  This was confirmed by research based on European registry data covering 18 million individuals and showing that a history of diabetes at baseline was the strongest independent predictor of a diagnosis of cirrhosis or liver cancer.

NAFLD and cardiovascular risk

“Those people who are cynical about NAFLD being an independent risk factor for cardiovascular disease in patients who have already developed type 2 diabetes often say to me ‘well, there is co-existing type 2 diabetes in these individuals and that’s what’s driving the cardiovascular disease risk’,” said Professor Byrne. So, she addressed this question with Sarah Wild at Edinburgh University, drawing upon Scottish Diabetes Registry data, with its cohort of over 134,000 individuals. They were able to compare cardiovascular events in those with liver disease and diabetes and those with diabetes alone. This clearly showed that NAFLD is an independent risk factor for incident or recurrent cardiovascular disease (CVD).

Professor Byrne believes the link with cardiovascular disease comes from the atherogenic dyslipidaemia, involving very low-density lipoprotein particles, that occurs in the context of metabolic syndrome. “The actual mechanisms involved are very complicated and seem to involve the release of proinflammatory and prothrombotic factors as well.”

Once NAFLD has been diagnosed, the diabetes team should be very aware of the increased risk of CVD. Prof Byrne recommends using your local cardiovascular risk tool, and then doubling the score for the presence of NAFLD.  

Diagnosing NAFLD

So, hopefully, with raised awareness NAFLD will be spotted earlier and more often by both non-specialists and diabetologists. Professor Byrne thinks that, ideally, all patients with type 2 diabetes should be screened for the condition. Raised liver enzymes can be a sign, of course. And there are five easily measured features of metabolic syndrome that should set alarm bells ringing during routine tests – high blood pressure, increased triglycerides, low HDL, large waist circumference and glucose of 6 mmol/l or more. There’s usually insulin resistance and high fasting insulin too, and the above-mentioned atherogenic dyslipidaemia – so plenty to look out for.

At present, liver enzymes and metabolic syndrome markers are the mainstay of diagnosis of NAFLD and data can be fed into the established diagnostic tools ELF and FIB-4 to get a score. But what threshold score should be used to warrant further investigation by elastography – also known as Fibroscan – which assesses the degree of liver fibrosis?  “This is work in progress,” said Professor Byrne. “NICE recommends an ELF threshold of 10.5 to identify those with F3 and F4 fibrosis, but the lower grade F2 should not be ignored, so we go down to a threshold of 9. Then we find that hepatology can’t cope with all these referrals for elastography investigation, so we’ve adopted a threshold of around 10. Choose your thresholds in terms of what your local service can handle.” She added that she’s expecting elastography to find its way into more diabetes clinics in the not too distant future, which will make accurate diagnosis of NAFLD easier.

Treating – and preventing – NAFLD

So what about treatment? It’s so important to consider that cardiovascular risk. “Pioglitazone, which was licensed 20 years ago, has become the forgotten cost-effective and cardioprotective drug for type 2 diabetes,” said Professor Byrne. The good news is that randomised clinical trials have shown that pioglitazone has proven efficacy in resolving NAFLD in at least 50% of patients and it also has a well-established cardioprotective effect. Similar benefits can be had from the GLP-1 receptor agonists, with the added benefit of weight loss.  “The GLP-1 receptor agonists are going to become very popular in type 2 diabetes,” she added.  And weight loss, through diet and/or medication, is very effective at facilitating loss of liver fat (as Diabetes UK’s DiRECT trials have shown) so may help stop progression of NAFLD or even prevent it from developing in the first place.

So, there’s yet another reason to encourage weight loss in type 2 diabetes management: prevent NAFLD and you prevent so many other problems down the line.

For more on this topic enrol on our course ‘Non-alcoholic fatty liver disease’, written and presented by Professor Michael Roden.

Watch out for our forthcoming debate on screening for NAFLD between Professors Gianluca Perseghin and Ken Cusi, part of our series ‘The long and the short of it’.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.

The human microbiome, its role in diabetes and whether we can modify it with diet was the subject of two presentations at the 38th International Symposium on Diabetes and Nutrition.

As an increasing amount of research turns its attention to the human gut microbiome and its influence on disease prevention, yogurt consumption is in the spotlight.

Dr Kerstin Thriene, a postdoctoral researcher at the University Medical Center Freiburg in Germany, began by looking at previous research – for example, one study found that a higher intake of yogurt was associated with a reduced risk of type 2 diabetes, but the mechanisms are complex and were not addressed.

As a brief lesson on the human gut microbiota, she explained that it’s a complex ecosystem comprising bacteria, fungi viruses and so on, and they protect the human host from potential pathogenic colonisation. They also metabolise food components that can’t be digested by the host and produce advantageous metabolites, such as short chain fatty acids.

Recent research also supports the idea that human gut microbiota directly influence the immune system, but it’s a two-way relationship as the microbiota are dependent on our choices of food, lifestyle and medications.

Problems arise when the balance is disrupted (known as dysbiosis) and this is associated with inflammation and immune-mediated diseases. Various studies have suggested an altered gut microbiome composition in people with diabetes.

A recent review confirmed this dysbiosis – alterations in the gut microbiome impact on the immune system balance and it’s mediated by the production of metabolites from gut microbiota, such as short chain fatty acids.

A difference is also seen in the microbiota between type 1 and type 2 diabetes. There are quite a few studies, said Dr Thriene, that look at the influence of diet on type 2 diabetes and the microbiome, but the microbiota also play a role in the development of type 1 diabetes.

In type 1, the dysbiosis may occur very early in life, having a strong effect on the immune system and inflammation, even before onset of the actual disease. The suggestion is that establishing a healthy microbiota as early in life as possible may prevent the initiation and progression of type 1 diabetes. However, she said, it’s not yet clear whether this dysbiosis is a consequence of the disease phenotype or whether it’s actually involved in the pathophysiology.

Obesity is also often accompanied by chronic, low-grade inflammation and some studies show that obesity-related dysregulation of the gut microbiota is connected with impaired gut-barrier function. In a recent study, it was found that the microbiota impairs insulin clearance in obese mice and may therefore play a key role in obesity and diseases such as type 2 diabetes.

We may be able to influence the composition of the microbiota with diet and this is where yogurt comes in. So far, there are very few human intervention studies looking at whether yogurt consumption can play a role. The small number that have are promising and Dr Thriene is involved in an ongoing trial investigating the effects of yogurt consumption on the human gut microbiota in 100 healthy participants, using metagenomics and metabolomics analysis to unpick its effects.

While it’s a promising area, she sounded a warning on the huge number of products promising ‘good’ or ‘healthy’ bacteria, drawing from the NHS guidance on probiotics. It states that because of the way probiotics are regulated, we can’t always be sure that the product actually contains the bacteria, that it contains enough of it to have an effect and that the bacteria are able to survive long enough to reach the gut.

She concluded that if the effects of yogurt consumption appear to be positive, the gut microbiota might function as a mediator of the health benefits derived from yogurt consumption, but that the effects of yogurt consumption on human gut microbiota is not completely clear.

The case for casein

Yogurt and the microbiome were also covered by Dr André Marette from Laval University in Canada, who discussed the impact of dairy products on the development of type 2 diabetes. (He declared conflicts of interest in that some work presented was funded by the Dairy Producers of Canada and Danone Nutricia Research.)

Studies looking at diet and type 2 diabetes tend to focus on fats and carbohydrates, but we know much less about proteins and whether they protect from type 2 diabetes. In addition, most animal-model studies looking at protein only use casein and this is far from representative of the human diet, which contains many types of protein.

Dr Marette highlighted one study that evaluated casein versus other protein types typical in a human diet – such as eggs, meat and fish – on weight gain, metabolic health and gut microbiota in an obese mouse model.

The mice were either on a high-fat, high-sucrose diet (HFHS) or a low-fat, low-sucrose diet with each of the proteins added in (so four groups). It found that casein is protective against developing full-blown metabolic syndrome in the HFHS mice compared to a mix of different protein types, and the protein source modulates gut microbiota independent of dietary fat and carbohydrate. Casein, they concluded, is a key dairy protein that reduces the risk of type 2 diabetes compared with a mix of proteins in the human diet.

Yogurt is rich in casein and he drew attention to a systematic review that showed that yogurt is the dairy product most favourably associated with a reduction in incidence of type 2 diabetes.

The next study he highlighted looked at the effects of yogurt intake on whole-body and tissue-specific insulin resistance in a new mouse model of diet-induced obesity and type 2 diabetes, and the potential role of gut microbiota and specific metabolites in yogurt’s health effects.

The yogurt dosage was the equivalent to one serving per day for humans. It showed that yogurt improves body weight and reduces energy intake. The effect was more striking in its finding that yogurt intake improves insulin resistance. When looking at the effect on the microbiota, part of yogurt’s effect on insulin sensitivity appears to be related to the change in the gut microbiome.

When looking at liver metabolomic analyses, it shows that yogurt intake increases levels of branched chain hydroxy acids (BCHA) in plasma and metabolic tissues of HFHS-fed obese mice, and BCHA plasma levels correlate with metabolic benefits of yogurt treatment in obese mice and modulate hepatic glucose production. This suggests that the gut microbiota and fermentation-derived BCHA mediate the health benefits of yogurt consumption in obese mice. This study has been submitted for publication.

For more on the metabolic syndrome, enrol on our course ‘Insulin resistance’, written and presented by Professor Kåre Birkeland.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.

Early puberty timing is linked with type 2 diabetes and our increasing understanding of this could lead to targeted interventions in the future…

With type 2 diabetes on the rise, understanding the origins of the disease and whether we can tackle its causes earlier in life is key. At the 2021 Diabetes UK Professional Conference, Ken Ong, professor of paediatric epidemiology at the University of Cambridge, discussed the influence of puberty on metabolic dysfunction and diabetes.

Early puberty timing is actually part of a trajectory starting from low birthweight, moving through to rapid infancy growth and then childhood obesity. There is now a large body of literature, said Professor Ong, showing that early puberty timing is associated with a higher risk of a wide range of diseases later in life and all-cause mortality.

There is a wide variation in the timing of puberty. The onset of periods can happen from around 10 up to 18 (younger than 12 is considered early). This is a milestone that comes later in the two- to three-year process of puberty, known as menarche, and it’s a commonly used marker of puberty timing in many studies because it’s well recalled by women.

It’s highly heritable and it’s also influenced by socio-demographic factors – early menarche is significantly more likely in some ethnic groups (for example, girls of Indian descent are 3.5 times more likely to experience it than girls who are white) and girls from the poorest backgrounds are almost twice as likely to experience it.

A systematic review and meta-analysis looked at 28 observational studies linking early puberty timing with higher risk of type 2 diabetes, and concluded that it may contribute as much as 12% of the burden of type 2 diabetes. Around half of this is explained by higher body mass index (BMI) in adult life but a significant risk remains after controlling for adult BMI.

He also highlighted the InterAct study, which demonstrated an association between early menarche and increased risk of type 2 diabetes, with women who were between 8 and 11 years at the time of menarche having a 70% higher incidence of future diabetes than women who had menarche at the average age of 13.

Determinants of puberty timing

There have been a number of genes implicated in rare disorders of puberty. In the past 12 years, an increasing number of independent genetic signals have been identified that are strongly associated with puberty timing.

Higher BMI has a causal effect on early puberty timing in both sexes, but a larger effect is seen in females, which is consistent with observations in clinical practice.

In turn, a causal effect of early puberty timing on later overweight is also seen and it’s a bi-directional relationship, with early overweight leading to early puberty timing, which then amplifies the overweight. This seems to be one of the main mechanisms tying early puberty timing to later disease, such as type 2 diabetes, although there are other mechanisms.

When it comes to translating these observations into clinical practice, he highlighted two studies that have altered menarche timing. The Planet Health RCT looked at the effects of a school-based obesity-prevention intervention (diet and physical activity) on menarche. It was designed to avoid overweight in schoolgirls and it was effective in avoiding early menarche.

The second was a small RCT in which Professor Ong was involved, which used metformin therapy in girls who had low birthweight and had gone on to have early-normal puberty. Metformin was effective in delaying the progression to menarche. It also appeared to have a number of other benefits on body composition and metabolic markers.

He pointed out that this was not with a view to treating the population with metformin, as we need to find lifestyle interventions to do the same job. However, the barrier to translating observations in the origins of disease into interventions is that the time between  that intervention and its long-term benefit is very long.

Therefore, the intermediary benefits need to be highlighted. For puberty timing, this might be avoiding some the adverse socio-economic effects of early puberty, such as earlier age of sexual intercourse, risk-taking behaviour and poor educational performance. These are well-established associations.

He concluded that early puberty timing may make an appreciable contribution to the burden of type 2 diabetes and there’s a potential for interventions that target joint outcomes – tackling overweight and early puberty timing – to give both short-term and long-term benefits.

The views expressed in this article are those of the author, Dr Eleanor D Kennedy.