Category: Journals

A new paper in Diabetologia describes how a unique dataset of HbA1c measurements drawn from the UK Biobank reveals the extent of undiagnosed diabetes. The findings suggest that population-wide screening could lead to earlier clinical diagnosis, earlier intervention and, perhaps, fewer long-term complications. Dr Susan Aldridge reports.

Screening can detect undiagnosed diabetes earlier than either symptomatic or incidental diagnosis. This allows for earlier intervention – lifestyle change, medication or both – which may reduce the risk of later complications.

There are already diabetes screening programmes in many countries, which differ according to their eligibility criteria and population coverage. In England, there is the NHS Health Check, which was initiated in 2009 and provides screening for high-risk adults aged 40-74, while the American Diabetes Association (ADA) recommends that all US adults aged 35 or older be screened.

Studies on these programmes are important as they can tell us how many cases of undiagnosed diabetes are identified by screening. However, since there is a direct link between screening and diagnosis in these studies, they don’t measure how much earlier diagnosis by screening occurs compared with diagnosis in routine clinical care. This would reveal the reduction in the time people are living with undiagnosed diabetes that could be achieved by screening and help policymakers decide whether it is worth the investment.

The UK Biobank is a population-based cohort of over 500,000 UK residents aged 40-70 at enrolment (between 2006 and 2010). HbA1c is measured on enrolment, but the results are not fed back to participants or their clinicians. These measurements therefore represent a rich resource that uncouples screening from diagnosis because the Biobank is also linked to participants’ routine healthcare data up to 10 years post-enrolment. This allows assessment of the prospective time to diabetes diagnosis in routine care following an elevated (≥48 mmol/mol) HbA1c at enrolment among those who did not have a pre-existing diabetes diagnosis.

Dr Nicholas Thomas, Dr John Dennis and colleagues from the Exeter Centre of Excellence in Diabetes (EXCEED), UK, have used this UK Biobank data to estimate the reduction in time to diagnosis that could be achieved by implementing population-level HbA1c screening compared with routine care. They also looked at the participant characteristics associated with longer time to diagnosis.

Mining the UK Biobank

The study started with a cohort of 179,923 participants from the UK Biobank who had both an enrolment HbA1c measurement and available longitudinal primary care data up to 2016/2017. Of these, 13,077 proved to have a pre-existing diabetes diagnosis, leaving a study population of 166,846 participants.

Undiagnosed diabetes was defined as having an HbA1c measurement of ≥48 mmol/mol at enrolment. Time to diabetes diagnosis in routine care was calculated as the time between the HbA1c measurement and the date of a code for diabetes, prescription for glucose-lowering medication, HbA1c of ≥48 mmol/mol, fasting glucose of ≥7.0 mmol/l or random/two-hour postprandial glucose of ≥11.1 mmol/l in primary care medical records or records of a code for diabetes in secondary care medical records.

In total, 1% – 1703 – of the study group had undiagnosed diabetes, which is an extra 13% of diabetes cases relative to the 13,077 who had a pre-existing diagnosis. This gives us a rough idea of the possible extent of undiagnosed diabetes among the UK population. Compared with those in the study population with HbA1c <48 mmol/mol, those with undiagnosed diabetes were, on average, older, had a higher BMI, were more likely to be male, live in more deprived areas and self-report being of non-White ethnicity. They were similar in most respects to those with a pre-existing diagnosis, but were more likely to self-report being of non-White ethnicity (median 11.4% vs 9.8%) and had a slightly higher BMI (median 30.9 vs 30.1 kg/m²).

Time to diagnosis

So how did these participants with undiagnosed diabetes fare over the next few years? Most of them – 87.7% – did receive a clinical diagnosis of diabetes during the median of 7.3 years follow-up. During this time, HbA1c tended to increase – the median value for those who had it measured at diagnosis in primary care was 58.2 mmol/mol.

However, this increase wasn’t inevitable – 6.9% of the participants who had undiagnosed diabetes at enrolment in the Biobank subsequently had HbA1c below 48 mmol/mol recorded in primary care, but half of this group subsequently received a diabetes diagnosis.

Median time to diagnosis varied slightly with the year the participants had enrolled in the Biobank – for 2008, it was 2.3 years; for 2009, 2.2 years; for 2010, it was significantly shorter at 1.8 years. The EXCEED team quote 2.2 years as median delay time to diagnosis based on this study population. Having a higher BMI and higher enrolment HbA1c were both associated with a shorter time to diagnosis, but there was no clear evidence of an association between age, ethnicity or socioeconomic status and time to diabetes diagnosis.

The value of HbA1c screening

This is the first study to use real-world clinical data to show how much earlier a diabetes diagnosis might be made by implementing a population-based screening programme. It shows that HbA1c screening at UK Biobank enrolment could have identified these cases of undiagnosed diabetes a median of 2.2 years earlier before receiving a clinical diagnosis in routine care.

This finding is similar to that of the Ely study of 40-65 year olds, which compared outcomes for participants randomised to screening at five-yearly intervals with outcomes for those receiving no screening. The reduction in time to diagnosis was 3.3 years.

Meanwhile, the prevalence of undiagnosed diabetes of 1% found in this study population is similar to the 1.4% estimate derived by modelling done by Diabetes UK, confirmed by a 2003-2005 UK National Screening Committee (NSC) pilot, which also showed a prevalence of 1.4%. The prevalence of undiagnosed diabetes in older populations has been found to be higher, with the NSC study showing a prevalence of 2.8% in those over 40 and, in the Ely study, 4.5%.

The finding that male sex, higher HbA1c and BMI >30 kg/m² are associated with shorter time to diagnosis suggests that clinicians are more likely to screen men and those with obesity. The relative delay in diagnosis for women is interesting as it does not arise from differences in age, BMI, HbA1c deprivation or ethnicity. This association between sex and delayed diagnosis has not been observed in other studies, so maybe this is peculiar to UK primary care or to the UK Biobank cohort. The link with higher HbA1c and earlier diagnosis is easily explained by those with higher blood glucose being more likely to have diabetes symptoms earlier, prompting earlier diagnosis.

A key strength of this study was that the systematic baseline HbA1c assessment of UK Biobank participants was not fed back to either them or their clinicians, providing the EXCEED team with a unique dataset to evaluate the benefits of HbA1c screening on time to diagnosis compared with diagnosis in routine care. In this study, 87.7% of those with undiagnosed diabetes eventually received a clinical diagnosis of the condition, while only 6.9% reverted to an HbA1c below the diagnostic threshold.

A limitation is that the UK Biobank is not a representative UK cohort – previous studies show that participants have better health outcomes, are from less deprived areas and are more likely to be of White ethnicity than the general UK population. Given the known association between non-White ethnicity and higher social deprivation and increased risk of diabetes, the rate of undiagnosed diabetes is likely to be higher in the wider UK population than in the UK Biobank cohort.

In addition, those volunteering for the Biobank are likely to be more health conscious than average, as are volunteers in other research studies. This means they may have more healthcare appointments and are likely to be diagnosed sooner. This suggests that population-based screening initiatives could identify even more cases of undiagnosed diabetes and reduce time to diagnosis more than the 2.2 years seen in this study.

Finally, most of the cohort had not accumulated sufficient follow-up data to reliably evaluate the impact of delayed diagnosis upon diabetes complications. The UK Prospective Diabetes Study (UKPDS) showed that earlier intensive blood-glucose control reduces the risk of later complications. We would therefore expect earlier diagnosis to lead to fewer complications in the long term. However, thus far, trials of screening interventions have not shown a significant reduction in all-cause mortality. This is worthy of further exploration when more recent UK Biobank-linked primary care data become available.

To read this paper, go to: Young K, McGovern A, Barroso I, Hattersley A, Jones A, Shields B, Thomas N, Dennis J. The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis. Diabetologia online 22 November 2022. https://doi.org/10.1007/s00125-022-05824-0

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Diabetes in Europe has become a rapidly accelerating public health crisis. That is why the EASD and other major stakeholders have come together to form the European Diabetes Forum, which aims to translate research and best practice into policy that will achieve better diabetes care for people in Europe. A recent article in Diabetologia introduces the Forum and its strategic plans on integrated care, data and registries, and digital diabetes and self-management. Dr Susan Aldridge reports.

Professor Chantal Mathieu, President of EASD, and her colleagues introduce the European Diabetes Forum (EUDF) by explaining why the initiative is so necessary at this time. They describe diabetes in Europe as “an emergency hiding in plain sight”. One person in 11 (61 million people) lives with diabetes in Europe today. That is more than the population of Italy. Worse still, there is no sign of this public health crisis slowing down, for diabetes prevalence in the European region is set to grow by a further 13% by 2045, according to the latest data from the International Diabetes Federation (IDF).

In a statement that will strike a chord with all those who live with diabetes, the authors go on to say: “Diabetes remains one of the most undertreated and underestimated of all common medical conditions. Society has no real sense of what living with diabetes means: the sheer scale of the health indicators one must constantly track and trace; the omnipresent threat of complications; the fear and anxiety about the future.”

People with diabetes suffered disproportionately during the COVID-19 pandemic, being more likely to be hospitalised or die from the infection, as well as missing out on their regular health checks during lockdown. Diabetes also has a severe impact on healthcare economies, with an annual expenditure of around €170 billion. Indirect costs include decreased productivity, sick leave, disability, early retirement and premature death.

Meanwhile, type 2 diabetes is increasingly affecting people at a younger age, and young-onset diabetes is more aggressive. Furthermore, IDF data shows that the Europe region has the highest number of children and adolescents with type 1 diabetes, with a total of 295,000. 

Faced with this enormous challenge, the scientific and medical communities, and people with diabetes themselves, have of course approached policy makers. But they do so from different angles, which tends to dilute the overall message, leading to policy inertia rather than the urgent action that is needed, according to the authors.

The European Diabetes Forum

The EUDF emerged after several years of preparation and research by Dr John Nolan of EASD and was founded in 2019 as a non-profit organisation under Belgian law by the following organisations: EASD, EFSD (European Foundation for the Study of Diabetes), FEND (Federation of European Nurses in Diabetes) and JDRF (Juvenile Diabetes Research Foundation). After the launch, PDCE (Primary Care Diabetes Europe), SFD (Société Francophone du Diabète) IDF Europe and ISPAD (International Society for Pediatric and Adolescent Diabetes) joined as members. EUDF also has a number of pharmaceutical and medical technology companies as supporting collaborators.

The EUDF is a platform for bringing together stakeholders from across the European diabetes landscape to present a harmonised voice on the diabetes community’s needs to governments, regulators, payers and others. During the pandemic, non-communicable diseases like diabetes got less political attention. So EUDF action may be even more critical during the post-pandemic era to help push diabetes care back up the agenda. 

The mission of EUDF is “to ensure the translation of research and clinical evidence into policy actions towards better diabetes care at a national level.” As well as working at the European level, the EUDF also supports translation of its efforts to national and regional initiatives. At present, a number of national/regional forums are at various stages of development – successful examples are the Belgian and Romanian Forums at www.belgiandiabetesforum.be and www.forumdiabet.ro

So far, the EUDF has identified three main areas of policy focus: integrated care, data and registries and digitalisation and empowerment of self-care. To ensure delivery in these, three Strategic Forums were created during 2021 to generate policy recommendations. After appointing a chair and around 15 expert members, each Forum defined its work plan and key deliverables. All members and chairs are working as volunteers.

All recommendations from the three Forums can be found at https://www.eudf.org/our-work/recommendations

Integrated care

“Integrated care represents efficiency and value for money, and it needs to be at the foundation of diabetes healthcare in every setting and country in Europe.” (EUDF)

A number of models and pilot schemes around Europe show that integrated care plays an important role in the quality, efficacy and efficiency of diabetes management. However, there are still many gaps in the level of integration across care systems. In part, this reflects differences in infrastructure and resources across Europe. The failure to fully integrate care results in inefficiency and suboptimal clinical performance. This, in turn, drives up care costs and increases the health burden on people living with diabetes. 

The EUDF considers that diabetes care should be redesigned to better meet the needs of those living with the condition. The use of technology, addressing inequalities in diabetes care and addressing psychosocial concerns should be considered during such redesign. Healthcare professionals should focus more on supporting integrated care models and pathways, rather than just following routine. And, at the system level, this approach should be supported by constructing transferable principles that can be applied across divergent healthcare systems. 

With all the above in mind, the EUDF proposes strategies to improve integration in all diabetes care settings. These include implementing assessment models and developing patient-centred pathways for diabetes care. Also, educational curricula need to be revised and incentives put in place to encourage cooperation and teamwork within and between primary and secondary care settings.

Data and registries

“It takes more than a registry to improve care, we need to use data to raise awareness and initiate action to improve outcomes for people with diabetes.” (EUDF)

The EUDF is well aware that the diabetes community in Europe has launched several programmes over the last decades, including the St Vincent Declaration, with the vision of improving outcomes. These projects, although ambitious, generally resulted in only incremental improvements. One reason was that, in most countries, the outcomes of diabetes care could not be monitored accurately because of the absence of quality registries. In Europe today, most diabetes data are estimated, rather than robust, with a few exceptions. Registries, where they exist, are a source of valuable scientific data but are not applied as often as they perhaps could be to significantly improve diabetes care.

The Forum sets out what is needed to create a meaningful, working diabetes registry. First, decision-makers must accept that changes are needed. Second, a dedicated team should be given the authority to develop a registry at local or regional level and manage it, with the mandate to improve agreed standards of care. Finally, following successful regional efforts, a broader European registry should be rolled out.

Diabetes registries will help enable a more evidence-based and data-driven approach to diabetes management. For instance, they will contribute to quality control and better adherence to guidelines and track performance across clinics and regions, helping to identify reasons for variation in outcomes. All of this can help reduce costly complications. An example of a registry that works well is the global paediatric SWEET registry (www.sweet-project.org).

Policy makers, health authorities, healthcare professionals, industry and people with diabetes should work together to create registries throughout Europe, where they do not already exist, and expand and strengthen those that do. The EUDF has already set out recommendations on the governance of registries, on procedural aspects like data input and the indicators that should be included and implementation strategies. 

Digitalisation and empowerment of self-care

“Creating an environment where successful digital solutions can be easily shared throughout Europe to support their people with diabetes.” (EUDF)

At the moment, there are two distinct trends around the use of digital tools in diabetes care. On the one hand, physicians sometimes seem reluctant to introduce or use these tools. On the other hand, there is a rapid increase in the development of intuitive digital tools to meet the needs of people living with diabetes.

There is evidence that digital support via an app or online improves the empowerment of people with diabetes, leading to better self-management and decision-making. And improving self-management is the key to achieving a high level of compliance with therapy, which should lead to better health outcomes, with reduced risk of complications and a better quality of life. Here, digital tools, including apps, can serve as the patient-facing interface for digitally enabled care. They enable better day-to-day support, greater flexibility and connectedness, which can enable remote monitoring and more data-driven decision-making.

Many EU countries are starting to devise policy to support health and diabetes apps. The EUDF suggests creating an environment where digital solutions that prove successful for people with diabetes in one country can be shared easily with other countries, stakeholders and organisations to broaden their reach within Europe. The Forum wants to accelerate this process with recommendations on how to develop a user-centred app, implementing a best-access pathway for apps and supporting the integration and uptake of high-quality apps into the healthcare system.

The path forward for the EUDF

The EUDF has been working with the WHO and WHO Europe to align messages and discuss priorities and is accredited as a ‘non-state actor’ for WHO Europe. The EUDF has welcomed the WHO’s Global Diabetes Compact and wants to work further to refine its coverage targets to European standards.

Meanwhile, there are currently several opportunities in the European policy environment to advance this work. The European Commission has launched ‘Healthier Together – EU non-communicable diseases initiative’, which is a comprehensive roadmap to guide and support member states in addressing the challenge of highly prevalent non-communicable diseases, including diabetes. The EUDF and its members have given their input on the priorities of this initiative and provided examples of best practices. They are now working at member state level to implement these examples. Countries and stakeholders can apply for support for policy projects and interventions, via EU funding, mainly from EU4Health.

In addition, a Joint Action on cardiovascular disease and diabetes, funded under the 2022 EU4Health Work Programme has been launched. Member states can submit proposals to the European Commission for the development and implementation of the Programme. The EUDF will continue to engage with these opportunities and encourage country experts and its own partners to contribute.

In conclusion, although diabetes is one of the greatest health challenges that Europe faces today, we can address it by using the tools available and taking the necessary policy actions. All of Europe’s major diabetes stakeholders have now come together in the EUDF to generate ideas and recommendations. Driving forward solutions in integrated care, registries and digitalisation and self-care will promote a more person-centric and data-driven approach to diabetes management, which should result in fewer complications, improved quality of life and more efficient use of clinical resources.

The EUDF will continue to act as an expert partner to promote these efforts. The authors end by saying: “Our vision is to achieve better outcomes for people with diabetes and enable healthcare systems to cope with a devastating epidemic that can no longer be swept aside. The time to act is now.”

To read this article, go to: Mathieu C, Soderberg J, Del Prato S, Felton A-M, Cos X, de Beaufort C, Gautier J-F, Hauck B, Forbes A, Heine R, Schwarz P and Tobeyns B on behalf of the European Diabetes Forum. The European Diabetes Forum: a forum for turning the tide on diabetes in Europe. Diabetologia 17. November 2022. https://doi.org/10.1007/s00125-022-05831-1

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

SGLT-2 inhibitors and GLP-1 receptor agonists have benefits that go beyond glucose-lowering in diabetes. A new study, reported in Diabetologia, looked at the cost-effectiveness of these medications. The findings may lead to more widespread use and could reduce heart and kidney complications for those living with type 2 diabetes. Dr Susan Aldridge reports.

Recent clinical trials have shown that SGLT-2 inhibitors and GLP-1 receptor agonists reduce the incidence of cardiovascular and kidney disease in people with type 2 diabetes, independently of their glucose-lowering effect. For instance, SGLT-2 inhibitors reduce hospitalisation for heart failure (HF) by 33% and end-stage kidney disease (ESKD) by 35%, while GLP-1 receptor agonists reduce myocardial infarction (MI) by 10% and stroke by 17%. SGLT-2 inhibitors have also been shown to reduce the incidence of cardiovascular and kidney disease in people without diabetes as well, suggesting that their use has benefit independent of HbA1c levels.

In light of this evidence, the recently updated American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus guidelines for treatment of people with type 2 diabetes recommend the use of SGLT-2 inhibitors and GLP-1 receptor agonists for those with, or at risk of, cardiovascular and kidney disease. However, uptake of these medications, particularly the GLP-1 receptor agonists, among people with type 2 diabetes has been limited so far.

A crucial barrier is their high cost. Previous cost-effectiveness analyses of these medications have tended to focus on their glucose-lowering effect. To expand their use earlier in the course of diabetes, and irrespective of HbA1c, we really need to know how cost-effective they are in terms of their cardiovascular and kidney benefits.

Accordingly, Jedidiah Morton of Monash University, Australia, and colleagues, have constructed a model using a real-world population with type 2 diabetes to assess the cost-effectiveness of widespread use of SGLT-2 inhibitors and GLP-1 receptor agonists, considering only major cardiovascular and kidney outcomes.

Modelling the health economics of type 2 diabetes

The model used real-world, individual-level data capturing the probable incidence and costs of ESKD, non-fatal hospitalisations for MI, HF, stroke and all-cause mortality among people with type 2 diabetes in Australia from 2020 to 2040. This data came from the National Diabetes Services Scheme and national hospital and mortality data.

Baseline health states were assigned using data from 2010 to 2019 and the population was then ‘aged’ in yearly cycles, using probability data to track incidence of the above events (ESKD and so on) to build up the model. Additionally, a cohort of new-onset type 2 diabetes was added each year.

Outcomes were total probable cases of ESKD, hospitalisation for MI, HF and stroke, years of life lived, quality-adjusted life years (QALYs), healthcare costs and societal costs. The primary outcome was incremental cost-effectiveness ratio (ICER), which is the cost per QALY gained, with the willingness-to-pay threshold set at per QALY. Put simply, cost-effectiveness would be achieved if the ICER was less than or equal to $AU28,000.

Outcomes were evaluated in two different populations: the total population with type 2 diabetes and the secondary prevention population, which was everyone with type 2 diabetes who had prior cardiovascular disease (CVD) – either an actual admission from 2010 to 2019 or a modelled admission from 2020 to 2040 for MI, HF or stroke.

The researchers modelled four different scenarios. In the first two, the use of SGLT-2 inhibitors or GLP-1 receptor agonists was increased to 75% of the total type 2 diabetes. In the third and fourth scenarios, this increase was confined to the secondary prevention population. The four scenarios were compared with the use of these medications in 2019 – the last year for which data was available – which was around 20% for SGLT-2 inhibitors and 5% for GLP-1 receptor agonists. These figures were about the same for people with and without prior cardiovascular disease. The impact of the increased use of the two medications in the four scenarios was calculated using data from recent meta-analyses of major outcomes trials for SGLT-2 inhibitors and GLP-1 receptor agonists. 

Focus on cost-effectiveness

The prevalence of diabetes in Australia was projected to grow from 1.13 million in 2020 to 1.45 million in 2040. Compared with current use of 20% of SGLT-2 inhibitors, increasing their use to 75% in the total population with type 2 diabetes would result in a gain of 400,018 extra years of life and 176,446 QALYs, according to this model.

The corresponding ICER for healthcare costs would be AU$23,717, taking into account the cost of the medication and setting it against the healthcare cost reductions from having fewer diabetes complications. The secondary prevention population numbered 95,247 people and 75% SGLT-2 inhibitor use would lead to a gain of 29,357 QALYs and an ICER of AU$8878.

For GLP-1 receptor agonists, the corresponding figures for the whole type 2 diabetes population were 460,028 extra years of life and 200,932 QALYs. The ICER was calculated as $AU100,705, again taking into account a reduction in healthcare costs arising from wider use of these medications. For the secondary prevention population, GLP-1 receptor agonists used for 75% would lead to a gain of 36,090 QALYs and an ICER of AU$79,742.

These findings suggest that use of SGLT-2 inhibitors is probably cost-effective in both the total and secondary prevention populations. However, the analysis suggests that GLP-1 receptor agonists are not likely to be cost-effective from a healthcare or societal perspective at current prices. This has important policy implications, suggesting that reimbursement criteria that limit use of SGLT-2 inhibitors, where they exist, should perhaps be re-considered. Currently, too many people living with type 2 diabetes are missing out on the benefits of these medications, which this new study shows to be a worthwhile investment in their future health.

This is the first cost-effectiveness analysis of its kind. Other studies have excluded cardiovascular or kidney benefits or modelled the populations used in cardiovascular outcomes trials, which represent only 20 to 60% of people with type 2 diabetes. Most of those studies have also found SGLT-2 inhibitors to be cost-effective.

This new study extends these findings by showing cost-effectiveness of SGLT-2 inhibitors, regardless of their effects on glucose levels. This doesn’t mean everyone with type 2 should be on them, however, nor does this study address other considerations about their widespread use.

Interpretation of the findings on GLP-1 receptor agonists is more complex. If you look only at cardiovascular benefit, they are not cost-effective in either the total type 2 diabetes population or those with existing cardiovascular disease. However, GLP-1 receptor agonists lead to weight loss and have less risk of hypoglycaemia compared with sulphonylureas and insulin, and are very effective glucose-lowering medications. None of these benefits was considered in this study.

Further analyses taking a more detailed look at the GLP-1 receptor agonists’ cost-effectiveness are needed. This is important because there is already a high burden of CVD in type 2 diabetes and, with an ageing population, stroke in particular is becoming more common. These are outcomes that could be improved by an increased uptake of GLP-1 receptor agonists.

To read this paper, go to: Morton J, Marquina C, Shaw J, Lieu D, Polkinghorne K, Ademi Z, Magliano D. Projecting the incidence and costs of cardiovascular and kidney complications of type 2 diabetes with widespread SGLT2i and GLP-1 RA use: a cost-effectiveness analysis. Diabetologia online 21 November 2022. https://doi.org/10.1007/s00125-022-05832-0

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

A new study, reported in Diabetologia, shows that vigorous exercise on a bike or using a home video helps protect pancreatic beta cells from apoptosis induced by endoplasmic reticulum-induced stress. The benefits were seen in people with or without type 1 or type 2 diabetes, shedding light on the role of physical activity in preventing or delaying the onset of the condition. Dr Susan Aldridge reports.

Loss of functional pancreatic beta cells drives the development and progression of diabetes. In type 1 diabetes, research into therapies has focused on the immune system. For instance, teplizumab, an anti-CD3 antibody recently approved by the Food and Drug Administration (FDA), significantly delays the onset of the condition in high-risk individuals, buying them precious time without the burden of diabetes. However, many treated with teplizumab will still go on to develop type 1 diabetes, so there is clearly a need for other therapies that can protect beta cells in both type 1 and type 2 diabetes.

Signals of endoplasmic reticulum (ER) stress are present in the beta cells of people with type 1 and type 2 diabetes. And several forms of monogenic diabetes are caused by mutations in genes involved in the response to ER stress. The underlying mechanism of ER stress involves accumulation of mis-or unfolded proteins in the ER lumen, which leads to beta cell apoptosis if it continues. ER stress can be reproduced in vitro by exposing human islets to proinflammatory cytokines and chemical ER stressors such as thapsigargin.

Therefore, agents that can restore normal ER function could perhaps provide a therapeutic strategy in diabetes. Tauroursodeoxycholic acid and imatinib are two compounds that have already been shown to reduce ER stress and protect beta cells in pre-clinical models of diabetes. Imatinib also showed modest but transient protection of beta cells in a clinical trial in people with recent-onset type 1 diabetes.

Physical exercise is an important non-pharmacological element in diabetes prevention and management. It improves glycaemic control in people with type 1 and type 2 diabetes by improving insulin sensitivity, stimulating glucose uptake by skeletal muscle cells and reducing weight. It also decreases circulating lipids, blood pressure and risk of cardiovascular complications. A combination of aerobic and resistance exercise is recommended, with interval aerobic training probably being more beneficial than continuous aerobic training.

Studies in animal models and human islets have also suggested that physical exercise has a direct effect upon beta cells. In an earlier study, Alexandra Coomans de Brachène of the Université Libre de Bruxelles, along with her colleagues, have shown that serum from eight healthy young male participants who performed moderate-intensity continuous exercise training for eight weeks protected beta cells from proinflammatory cytokines and thapsigargin. This protection was observed in primary human islets and the human beta cell line EndoC-βH1.

They have now extended this study to assess the impact of different forms of exercise on ER-stressed human beta cells in a larger cohort of individuals with and without diabetes.

Exercising to protect beta cells

Two separate groups of participants took part in this study – a group of healthy younger people and a mixed group of older people with or without type 1 or type 2 diabetes, and of different ancestral origins. All participants had VO_2peak, their maximal oxygen uptake (a measure of aerobic fitness), measured on an exercise bike at the start of the study. The 46 healthy participants – 26 female, 20 male – were assigned to one of four different physical exercise regimes carried out three times a week over an eight-week period.

Another five healthy participants acted as controls, doing their normal physical activity only. The intervention groups consisted of stationary bike high-intensity interval training (HIIT), adapted sprint interval training (aSIT), vigorous-intensity continuous training (VICT) or high-intensity functional training performed at home (HIFT). The three bike-training regimes were carried out in the authors’ laboratory and differed with respect to the proportion of VO_2peak worked at. The HIIT regime consisted of six bouts of two minutes at a load of 90% VO_2peak interspersed with two minutes active rest at 50% VO_2peak. The aSIT regime was 12 bouts at 30 seconds at 125%VO_2peak interspersed with two minutes of active rest. And the VICT regime was 28 continuous minutes at a load of 70% VO_2peak.

Meanwhile, the HIFT consisted of videos with four bouts of 30 seconds of whole-body exercises such as squats, lunges and jumping jacks, interspersed with 30 seconds of active rest. The difficulty and number of repetitions of the exercises increased from video one to video four, and the participants progressed through the series during the eight-week intervention period.

To evaluate the possible impacts of diabetes and ancestry on the beta cell-protective effects of exercise, 36 individuals who had type 1 or type 2 diabetes or no diabetes and were of Belgian origin (European ancestry) or were Belgians of Moroccan, Turkish or African origin (non-European ancestry) participated in the study.

For comparison, participants without diabetes were matched to those with type 1 and type 2 diabetes based on sex and similar age. They took part in training three times a week for 12 weeks, consisting of stationary bike HIIT training, similar to that described above, and strength-training exercises involving the four main muscle groups – namely, chest press, lateral pulldown, leg press and leg curl. They did three sets of 10 repetitions of these.

Blood was collected from all participants prior to the study and after four, eight and 12 weeks of training to obtain serum. Then EndoC-βH1 cells were treated with thapsigargin in the presence of serum to see if this ‘exercised serum’ protected the cells from ER stress. Thapsigargin alone would have triggered ER stress and beta cell apoptosis.

Fluorescence microscopy was then used to count apoptotic cells after staining them with a DNA-binding dye and RNA was extracted from the beta cells to assess any changes in gene expression from exposure to ‘exercised serum’.  

Positive findings

In the experiments involving the younger, healthy volunteers, there was significant protection against thapsigargin-induced beta cell apoptosis after four weeks of exercise for the three exercise bike regimes and after eight weeks for the home exercise. Since no major differences were found between the different types of exercise, the results were pooled and re-analysed according to sex.

There was significant exercise-mediated beta cell protection with a 29-32% reduction in apoptosis in women and 27-40% decrease among men. When pooling results for all 46 participants, there was a 28-35% decrease in apoptosis at four and eight weeks. Serum was also collected from 13 of the participants two months after the training and the protective effects were still seen. Sera from the control group did not confer any protection against thapsigargin, confirming the role of exercise.

When it came to participants with diabetes, they were older than the healthy participants, had a lower starting VO_2peak  and those with type 2 diabetes were obese. Serum from the individuals in this group who did not have diabetes significantly protected human beta cells from thapsigargin-induced apoptosis after four, eight and 12 weeks of training. Furthermore, ‘exercised serum’ from participants with type 1 or type 2 diabetes was also protective, reducing apoptosis by 45% and 26%, respectively, after 12 weeks of training.

Finally, to determine whether ancestry affected the response, data was pooled from the three groups and split into those of European and non-European origins. Again, serum conferred significant protection against apoptosis. Therefore, neither the presence of diabetes nor ancestral origin influence the protective effects of physical exercise against ER stress-induced beta cell apoptosis. 

How exercise might protect beta cells

What about the mechanism driving the beta cell protection conferred by exercise? RNA analysis of the beta cells exposed to ‘exercised serum’ showed reduction in expression of two pro-apoptosis genes, CHOP and DP5,and in the XBP1s gene, which is involved in ER stress. These changes are consistent with exercise conferring protection on beta cells via reduction in ER stress and apoptosis.

When exercised, skeletal muscle and other tissues release substances called exerkines into the bloodstream. A recent study showed that one exerkine, known as clusterin, protects rodent beta cells from metabolic stress. The authors therefore carried out an additional experiment to see if clusterin could reproduce the beneficial effects of ‘exercised serum’ in human beta cells. They found that clusterin reduced thapsigargin-induced cell death by 31-42% at two concentrations.

The mRNA expression of DP5 was also significantly reduced at the higher dose of clusterin. Taken together, these findings suggest that the mechanism of beta cell protection afforded by exercise involves muscle or multi-organ crosstalk with beta cells, mediated by circulating exerkines. Further experiments will help clarify the molecular pathways involved in this mechanism.

In practical terms, the finding that home-based exercise protected beta cells as well as gym-based exercise is important, as people can access these benefits via videos or apps rather than needing access to equipment. In the four training regimes, participants spent at least 50% of their time at their maximum heart rate. Whether beta cell protection would also result from mild to moderate exercise, such as brisk walking, remains to be determined.

In summary, serum from people with or without type 1 or type 2 diabetes after eight to 12 weeks of regular vigorous exercise confers beta cell protection against ER stress. The benefit also persists after the intervention. This shows the unexpected potential of exercise training in preserving beta cells.

Exercise training should therefore be tested in larger trials for its benefits as a non-pharmacological intervention in people who are at risk of either type 1 or type 2 diabetes. This could prove to be an effective way of preserving endogenous insulin secretion and beta cell health, as well as having cardiovascular and other health benefits. 

To read this paper, go to: Coomans de Brachène A, Scoubeau C, Musuaya E, Costa-Junior JM, Castela A, Carpentier J, Faoro V, Klass M, Cnop M, Eizirik D. Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes. Diabetologia 19 November 2022. https://doi.org/10.1007/s00125-022-05837-9

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

A new study reported in Diabetologia looks at how breaks in sedentary behaviour and timing of physical activity affect liver fat and insulin resistance. The findings could inform lifestyle interventions to prevent type 2 diabetes. Dr Susan Aldridge reports.

Sedentary behaviour has been linked with an increased risk of cardiometabolic diseases, including type 2 diabetes. Several studies have shown that interrupting prolonged sitting with standing or light activity improves glycaemic responses and lipid levels. Meanwhile, moderate-to-vigorous-physical activity (MVPA) is associated with reduced liver fat, improved insulin sensitivity and reduced type 2 diabetes risk.

The timing of physical activity may also have an impact on metabolic health. 

People at risk of type 2 diabetes are often told to move more to help prevent or delay the onset of the condition. If breaking up sedentary time and planning the timing of physical activity do have an influence, incorporating this information into lifestyle intervention could help clarify goals, increase motivation and hopefully increase the success of type 2 diabetes prevention efforts.

Accordingly, Jeroen van der Velde of Leiden University Medical Center in The Netherlands, and colleagues have looked at whether breaks in sedentary time and the timing of physical activity influence liver fat content and insulin resistance in a group of people taking part in an obesity study. 

Measuring sedentary time and physical activity

The researchers studied 775 participants drawn from the Netherlands Epidemiology of Obesity study, involving men and women aged 45 to 65 with a BMI of 27kg/m² or more. This is a population-based prospective study looking at the pathways leading to obesity-related diseases.

Daily levels of activity, including sedentary time, were measured with a combined acceleration and heart-rate monitor. The participants wore these for four consecutive days and nights and carried on with their usual activities, so this was very much a study of everyday life without any particular lifestyle intervention. Levels of activity were defined as sedentary time, light physical activity (LPA) and MVPA. For timing of physical activity, morning was 06.00 to 12.00 hours, afternoon 12.00 to 18.00 hours and evening 18.00 to 00.00 hours. Blood samples were used to measure insulin resistance, while a subgroup of participants had their liver fat measured by MRI.

Sedentary time and breaks

This study found that neither the length of sedentary time nor the number of breaks were associated with a reduction in liver fat or insulin resistance, contrary to what might have been expected because of previous research. So why were no benefits observed here? The researchers suggest that experimental studies are usually set up to compare regular breaks in sedentary time with continuous sitting. This situation is not usual in the free-living situation that was being monitored in the present study. Another explanation could be that in this free-living situation, the intensity of the activity carried out in the breaks was too light to elicit any improvements in liver fat or insulin resistance.

Surprisingly, the number of activity breaks in sedentary time was even associated with an increase in liver fat – the opposite of what might have been expected. The researchers suggest that, since there wasn’t a corresponding increase in insulin resistance, the increase in liver fat might have occurred by chance, given that the sample size was relatively small, at 206 participants.

These findings add to the existing debate over the value of taking breaks during sedentary time. It may be that a longer trial – this study only lasted for four days – would reveal some benefit. And maybe boosting the intensity of the break activity would help too.

Timing of physical activity

As you might expect, higher overall physical energy expenditure and MVPA were both associated with reduced liver fat and insulin resistance, whereas no effect was seen for LPA. Timing of exercise is a relatively unexplored area in obesity and diabetes. In this study, MVPA in the afternoon and evening was associated with up to 25% reduced insulin resistance compared with MVPA in the morning or distributed evenly throughout the day. However, there was no impact of MVPA timing on liver fat.

These findings are supported by earlier research showing that, in men with type 2 diabetes, high-intensity exercise in the afternoon improved blood glucose more than high-intensity exercise in the morning. Another study showed that aerobic exercise in the evening, but not in the morning, decreased blood pressure in hypertensive men. And an analysis of data from the Look AHEAD trial of lifestyle intervention in people with type 2 diabetes showed that those doing MVPA in the morning had an increased risk of cardiovascular disease compared with those doing MVPA later in the day.

Taken together, all of these findings suggest benefit on metabolic health to physical activity later, rather than earlier, in the day. The underlying mechanisms remain unclear, however. It is possible that physical activity could activate body clock genes, enhancing our circadian rhythms, and this, in turn, improves metabolic factors like insulin resistance. This is supported by two earlier studies showing that metabolic responses vary with time of day and are regulated by clock genes. Furthermore, muscular strength and the function of mitochondria in skeletal muscle peak in early afternoon, which would also help maximise the impact of exercise. 

What does this mean for type 2 diabetes prevention?

This study did not show any metabolic benefit in taking breaks from sedentary behaviour. That was not surprising, given that it was short in duration and involved participants doing their usual activities. It would be interesting to see the impact of taking more structured and intense exercise breaks, such as running on the spot or doing squats and press-ups during the non-sedentary time. And a longer trial of weeks or months monitoring sedentary time and breaks may provide new insights.

The impact of timing of physical activity on insulin resistance is particularly interesting. Further studies are needed but it may be that advising people to be more active in the afternoon and evening, rather than in the morning, would be more effective in terms of type 2 diabetes prevention.

To read this paper, go to: van der Velde J, Boone S, Winters-van Eekelen E, Hesselink M, Schrauwen-Hinderling V, Schrauwen P, Lamb H, Rosendaal F, de Mutsert R. Timing of physical activity in relation to liver fat content and insulin resistance. Diabetologia online 1 November 2022.

https://link.springer.com/article/10.1007/s00125-022-05813-3

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

There are large differences among individuals with type 1 diabetes in their level of glycaemic control, as reflected by glucose variability. An imaging study, reported in a recent issue of Diabetologia, finds that residual beta cell mass plays a role in glucose variability, independent of beta cell function.

It is well known that, despite advances in treatment and technology, only a minority of people with type 1 diabetes actually reach their treatment targets. This is often because optimised glucose control carries a risk of hypoglycaemia. Some people with type 1 do have an HbA1c at or even below target levels without significant hypoglycaemia. Others, however, experience repeated hypos and have poor glycaemic control, including high glucose variability (HGV). While behavioural and psychological factors such as fear and avoidance of hypoglycaemia may account for some of these differences, the underlying mechanisms remain unknown.

The loss of insulin production in type 1 diabetes is generally attributed to destruction of beta cells via autoimmune attack. However, some beta cells do survive – even in longstanding diabetes – and some of them, at least, continue to produce insulin. Evidence of this is seen by the presence of low but detectable C-peptide in people with type 1 diabetes.

It is now possible to detect, monitor and quantify beta cell mass in vivo,with imaging that uses radiolabelled extendin to bind to the glucagon-like peptide 1 (GLP-1) receptor on the beta cell.

Marti Boss at Radboud University Medical Center in the Netherlands and colleagues previously used single photon emission computed tomography (SPECT) imaging to reveal persistent beta cell mass in people with type 1 diabetes of long duration. The extent to which these residual cells might contribute to glucose stability remains unknown, however. So, to investigate further, these researchers used positron emission tomography (PET), which is more accurate than SPECT, with radiolabelled extendin to quantify beta cell mass in people with type 1 diabetes and either low or high glucose variability profiles.

Measuring beta cell mass

Participants in the low glucose variability (LGV) group had HbA1c ≤53 mmol/mol, intact hypoglycaemia awareness and no severe hypos in the last year and no more than two such events overall. Those in the HGV group had either HbA1c ≥69 mmol/mol and reduced hypoglycaemic awareness and/or at least two severe hypos in the last year or HbA1c ≥64 mmol/mol and impaired hypoglycaemic awareness and/or at least two severe hypos in the last year.

Beta cell function was calculated from glucose and C-peptide levels measured after a mixed meal tolerance test (MMTT).

In addition, participants wore continuous glucose monitors for seven to eight days after the MMTT and before the PET scan. Radiolabelled extendin was injected and PET images of the abdomen, including the pancreas, were taken and analysed for the amount of label taken up by the pancreas. This mean standardised uptake value (SUVmean) is known to allow a reliable comparison between individuals and patients with different characteristics – in this study, LGV and HGV – and so was used as a measure of residual beta cell mass. There were nine participants in the LGV group and seven in the HGV group.

Beta cell mass and glucose variability

C-peptide levels as a measure of beta cell function were detectable in around half of all participants. SUVmean (residual beta cell mass) was significantly higher in the LGV group compared with the HGV group. Analysis of the CGM data showed that those in the LGV group also had significantly higher Time in Range and lower mean glucose values than those in the HGV group.

The relationship between beta cell mass and beta cell function was somewhat complex, however. For one of the individuals with LGV had no detectable C-peptide and a similar SUVmean to the individual in this group with the highest C-peptide. And this SUVmean was higher than that of a third individual in the LGV group with no detectable C-peptide. In other words, a high SUVmean did not necessarily correlate with a high C-peptide.

Finally, SUVmean correlated with Time in Range and was inversely correlated with mean glucose levels. However, there was no correlation between SUVmean and BMI, diabetes duration, age at disease onset and blood glucose levels prior to imaging.

The benefits of residual beta cell mass

People with LGV have a higher beta cell mass than those with HGV, according to extendin PET imaging. The findings support the view that preservation of beta cell mass benefits glycaemic stability in people with type 1 diabetes, independent of beta cell function.

There is increasing evidence that some beta cells do survive, even in longstanding type 1 diabetes. In this new study, pancreatic uptake of radiolabelled extendin, consistent with the presence of beta cells, was shown in most of the participants. Their diabetes duration ranged from two to 50 years.

Residual beta cell function, as measured by C-peptide, may contribute towards better glycaemic stability. However, it is unlikely that this explains all the observed benefits of residual beta cell mass because some of the LGV participants, as mentioned above, had undetectable C-peptide – so they enjoyed lower glycaemic variability in the absence of beta cell function. Residual beta cells do not necessarily produce insulin, yet their influence on glycaemic variability suggests some functionality.

The authors suggest that these residual beta cells might be suppressing glucagon release from nearby alpha cells or may induce a lower state of inflammation in the pancreas, both of which would be expected to improve glucose control. These ideas could be tested by experiments measuring glucagon and C-reactive protein in people with type 1 diabetes with different glucose variabilities.

It would also be interesting to measure alpha cell mass in vivo when exploring the association with beta cell mass and glucose variability. Pancreas volume decreases in type 1 diabetes but data from donor pancreases shows that alpha cell mass remains the same. The development of imaging techniques that can measure alpha cell mass is currently ongoing.

In summary, beta cell mass is higher among people with type 1 diabetes and relatively stable glucose control compared with those whose glucose levels are more variable. These findings suggest that residual beta cell mass may play a role in maintaining glycaemic stability and highlights the importance of preserving beta cells, even if they appear to be non-functional. Surviving beta cells are of great interest for novel and future interventions that could restore or extend their functionality, thereby improving glycaemic control. Extendin PET imaging is a valuable tool for detecting beta cells and could be used in future studies monitoring beta cell mass during the course of diabetes or in interventions aimed at preserving beta cell mass.

To read this paper, go to: Jansen T, Brom M, Boss M, Buitinga M, Tack C, van Meijel L, Galan, B, Gotthardt M. Importance of beta cell mass for glycaemic control in people with type 1 diabetes. Diabetologia 17 November 2022. https://link.springer.com/article/10.1007/s00125-022-05830-2

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

The use of SGLT-2 inhibitors in diabetes for cardiorenal protection, as well as for glucose lowering, is now backed by clinical guidelines. However, the heart and kidney benefits may actually arise from circulating ketones, which can also lead to diabetic ketoacidosis (DKA). A new paper in Diabetologia explores the benefits and risks of ketones in SGLT-2 inhibitors. Dr Susan Aldridge reports.

Recent clinical trials have shown that the benefits of the SGLT-2 inhibitors extend far beyond their glucose-lowering properties – they also have significant cardiorenal benefits. For example, empagliflozin and canagliflozin both decrease the risk of major adverse cardiovascular events (MACE – a composite of death from cardiovascular causes, non-fatal myocardial infarction or non-fatal stroke) in people with type 2 diabetes and either established cardiovascular disease (CVD) or at high CV risk.

Moreover, all the SGLT-2 inhibitors reduce the risk of hospitalisation for heart failure (HHF) in people with type 2 diabetes by 27-35%, even in those who did not have heart failure at baseline, suggesting a preventive effect. These benefits even extend to people without diabetes. As a result, SGLT-2 inhibitors are now recommended in type 2 diabetes guidelines for those with established CVD or at high CV risk.

Meanwhile, several trials have shown that SGLT-2 inhibitors can reduce the progression of chronic kidney disease (CKD). Some were designed to look at CV rather than renal outcomes. Then the CREDENCE trial, which had a composite renal endpoint as a primary outcome, showed that canagliflozin reduces serum creatinine, end-stage renal disease (ESRD) or death from renal causes by 34% in people with type 2 diabetes and CKD. Renal benefit was also seen for dapagliflozin in the DAPA-CKD trial, where the composite outcome of decline in estimated glomerular filtration rate (eGFR), end stage renal disease (ESRD) or death from renal or CV causes was reduced for those on the SGLT-2 inhibitor. Accordingly, SGLT-2 inhibitors are now recommended for people with CKD with and without type 2 diabetes.

Underlying mechanisms of cardiorenal benefits

The benefits of SGLT-2 inhibitors for the heart and kidneys are great news for people with and without type 2 diabetes. However, they were unexpected, so it’s not surprising that the underlying mechanisms are still a matter for debate and are likely to be multifactorial. One of the many proposals put forward is that the modest and transient elevation in ketones seen during SGLT-2 treatment may have therapeutic relevance to the benefits to the heart and kidney. 

Ketones – acetoacetate, β-hydroxybutyrate (β-OHB) and acetone – are byproducts of fat metabolism that can be used as a non-glucose fuel source during fasting and exercise. Put simply, chronic glycosuria from SGLT-2 inhibitor treatment favours ketogenesis. And this, in turn, may help the heart, which requires a large amount of ATP synthesis, some of which is obtained via the metabolism of ketones. In heart failure, the ‘energy-starved heart’ theory involves a lessening of glucose oxidation, but this energy deficit might be made up if there are ketones around. This idea is supported by a small study in which β-OHB was infused into patients with heart failure with reduced ejection fraction, producing a dose-dependent increase in stroke volume, cardiac output and left ventricular ejection fraction.

Ketones might also reduce oxidative stress by a number of pathways, which could help alleviate atherosclerosis. They may also play a role in lowering blood pressure by suppressing sympathetic nervous system activity and heart rate, via the action of β-OHB on G-protein coupled receptor 41.

As far as the kidney is concerned, ketones are also an energy-efficient fuel for renal tubular cells, so it may be that SGLT-2 inhibitors protect the kidney via the same mechanism that they protect the heart. Ketones may also inhibit rapamycin complex 1, known to be a mediator of kidney injury, at least in animal models.

So, in conclusion, there are several potential mechanisms by which the modest increase in ketones associated with SGLT-2 inhibitors could confer cardiorenal benefit. Further studies are now needed to clarify the relevance of these.

The downside of ketones – DKA

Most people on SGLT-2 inhibitors experience only a mild rise in circulating ketones. However, in some circumstances, there may be a greater increase. DKA is a well-known serious complication of type 1 diabetes occurring with the combination of hyperglycaemia, metabolic acidosis and elevated serum and/or urinary ketones. It can also occur in type 2 diabetes, typically when the person has a severe, acute illness.

Sometimes, however, DKA occurs when the blood glucose is high but not as high as typically seen in this condition. This has been termed euglycaemic DKA (eDKA). Before the widespread use of SGLT-2 inhibitors, eDKA accounted for 3% of all DKA cases. It is suspected that it occurs when there is impaired hepatic glucose production, as in chronic liver disease, or when there is excess glycosuria, as in pregnancy. eDKA has also been associated with SGLT-2 inhibitor treatment, as has traditional DKA. However, the underlying mechanisms of DKA with the use of SGLT-2 inhibitors are not completely understood, although a number of theories have been proposed and are still under investigation.

Fear of hypoglycaemia and weight gain can be barriers to the optimal use of insulin by people with type 1 diabetes. In such cases, SGLT-2 inhibitors can be a useful way of reducing HbA1c, body weight and insulin requirements without increasing the risk of hypoglycaemia. And there is no reason to think that people with type 1 diabetes would not also get cardiorenal benefit from the SGLT-2 inhibitors. Indeed, these drugs are increasingly being used off-label in type 1 diabetes. However, there is concern about the increased risk of DKA with their use.

These fears are not unfounded – a meta-analysis of randomised controlled trials showed that SGLT-2 inhibitors do indeed increase the risk of DKA in a dose-dependent fashion. At higher doses, there are 34 events per 1000 person-years and, at lower doses, seven events per 1000 person-years. In a study of people with type 1 diabetes treated with canagliflozin as an add-on to insulin, the incidence of DKA was 5.1% with the 100 mg dose and 9.4% with the 300 mg dose. All serious DKA episodes were associated with precipitating factors such as flu, pneumonia, pump failure or incorrect insulin dosing.

This means that, although SGLT-2 inhibitors are a potentially valuable adjunct therapy to insulin in type 1 diabetes, they should only be used in people who are well educated about the risks of DKA as well as prevention and treatment strategies. They should be willing and able to monitor ketones and seek urgent medical help if they are elevated.

SGLT-2 inhibitors and type 2 diabetes

SGLT-2 inhibitors are now used extensively in type 2 diabetes because, although their blood glucose-lowering effect is relatively modest, they induce weight loss, blood pressure-lowering and, of course, the cardiorenal benefits described above. Do these benefits outweigh the risks of DKA in type 2 diabetes?

In randomised controlled studies, the rate of DKA is much lower in type 2 diabetes than in type 1, being just 2.5 times higher than controls on either placebo or a comparator medication. Risk factors include autoimmune diabetes (misdiagnosed as type 2 diabetes), pregnancy, previous DKA and restricting carbohydrate intake. DKA can be precipitated by an acute event like surgery, trauma, infection, heart attack or, as in type 1 diabetes, inappropriate insulin dosing.

Presentation, prevention and treatment

People with SGLT-2 inhibitor-related DKA present with nausea, vomiting, abdominal pain and malaise. There will be acidosis and ketones but glucose concentrations may be below 13.9 mmol/l (eDKA). It is this absence of very elevated glucose levels that may delay recognition of the problem by patients and clinicians, particularly in a very busy A&E setting.

People with type 1 and type 2 diabetes should know that they need to monitor ketones if they are unwell. If they are positive, they need to follow the instructions they have been given by their diabetes team, seeking immediate medical help if necessary.  

Inpatient treatment involves administration of intravenous insulin and fluids to resolve acidosis. The insulin will suppress lipolysis and the formation of ketones.

To minimise the risk of DKA, SGLT-2 inhibitors should be stopped during acute illness and for at least three days before surgery. DKA has been shown to occur in people undergoing colonoscopy and should be stopped at least two days before the procedure. Finally, if someone does develop DKA in the setting of SGLT-2 inhibitor treatment, the drug should not be restarted immediately. There have been cases of recurrences of DKA with continuous SGLT-2 therapy. They should, therefore, only be restarted after careful consideration of the risk/benefit ratio – if the patient has established CKD or heart failure, for instance, and if they are well-educated in the use of the drugs.

In conclusion, SGLT-2 inhibitors, originally developed as glucose-lowering agents in type 2 diabetes, have recently been shown to have significant cardiorenal benefit. So they are now recommended to reduce heart and kidney complications in people with and even without type 2 diabetes. However, the mechanisms underlying these benefits are not completely understood. One proposed theory is that they arise from a modest increase in the level of circulating ketones but ketones are also linked with the significant side-effect of DKA, which may be under-recognised if it is euglycaemic. Thus, ketones are a ‘double-edged sword’ in the use of these increasingly popular medications and a careful analysis of their benefit/risk ratio is always needed.

To read this paper, go to: Lupsa B, Kibbey R, Inzucchi R. Ketones: the double-edge sword of SGLT-2 inhibitors. Diabetologia online 18 October 2022. https://link.springer.com/article/10.1007/s00125-022-05815-1

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Low birth weight (LBW) is associated with an increased risk of type 2 diabetes. At the recent EASD meeting in Stockholm, researchers at the Steno Diabetes Center in Copenhagen revealed that people with LBW are diagnosed at lower BMI and younger age than those of normal birthweight. They also reported that a high-carbohydrate diet has an adverse metabolic impact on those with LBW. Dr Susan Aldridge reports.

The risk for type 2 diabetes starts in the womb and, although obesity is a risk factor for type 2 diabetes for children and adults, the opposite is the case for babies. Low birth weight (LBW), linked to foetal malnutrition, is associated with a higher risk of type 2 diabetes, hypertension, cardiovascular disease and cancer. Dr Alexsander Lühr Hansen’s research on the Danish DD2 cohort explores what they believe to be a distinct type 2 diabetes phenotype associated with LBW.

“To do this, you need good birth data,” he said. “With older individuals, data don’t go that far back so we partnered with the Danish National Archives to digitise the original midwife records for the entire DD2 cohort.”

The study population was 6886 individuals newly diagnosed with type 2 diabetes either by the GP or at an outpatient clinic, divided into three birth weight categories – low (LBW – less than 3000g), normal (NBW – 3000g to 3700g) and high (HBW – more than 3700g).

The researchers looked at LBW versus NBW with respect to BMI and age at diagnosis. “We saw that low birth weight is associated with a higher prevalence of being under 45 or between 45 and 55 at diagnosis and lower prevalence of being diagnosed at age over 75 compared with those who had normal or high birth weight,” said Dr Lühr Hansen. “People with lower birth weight are also more likely to have a lower BMI of under 25 or between 25 and 30, and less likely to have a BMI over 40 at diagnosis.”

Other differences noted were that people with LBW had a lower waist circumference, a lower waist-hip and waist-height ratio and were less likely to have a family history of type 2 diabetes than those with higher birth weight. Finally, LBW was also associated with the presence of three or more comorbidities at diagnosis of type 2 diabetes. One of these was hypertension, with those with LBW being more likely to be on multiple hypertension medications than those of higher birth weight.

The researchers also explored the linearity of these associations. “For every kilogram of difference in birth weight, we see a 3.3 year difference in age of diagnosis,” said Dr Lühr Hansen. “And for BMI, the change per kilogram is 1.46 and for waist circumference it’s 3.9 cm.”

Finally, they looked at the possible role of genetic confounding. A polygenic risk score, including all the known genetic variants for type 2 diabetes, was worked out for a subgroup of participants. This was used as an exposure and LBW as the outcome. No specific associations were found, suggesting that genetic factors are not involved in the LBW phenotype. Studies are ongoing to shed light on the pathophysiology of the LBW phenotype – looking at, for instance, whether it is driven by beta cell deficiency.

Carb overfeeding study

“Low birth weight is a known risk factor for type 2 diabetes, especially when someone is exposed to affluent conditions and there is a mismatch between the foetal and the postnatal environment,” said senior researcher Charlotte Brøns. Accordingly, she and her team have been investigating the metabolic and physiological impact of various diets on people with LBW.

For instance, in one study, they showed that five days of high-fat overfeeding led to peripheral insulin resistance in lean young men. “In our most recent study, we showed that early middle-aged, non-obese, low birth weight men have significantly increased hepatic fat content compared with normal birth weight men,” Charlotte said. “And 20% of the low-birthweight men already had NAFLD.”  The reason is probably that diets high in simple carbohydrates, especially fructose, stimulate hepatic fat deposition and increase the risk of NAFLD through de novo lipogenesis.

To investigate the impact of carbohydrates in LBW individuals, they put together a new study. This involves four weeks overfeeding with simple carbohydrates to see if this is associated with differential changes in hepatic fat content, insulin resistance, whole-body energy metabolism, key metabolic hormones and metabolomic and lipidomic profiles in healthy, early middle-aged, LBW, non-obese men compared with NBW controls.

Data on 22 LBW and 21 NBW men with a mean age of 38 and no history of type 2 diabetes was drawn from the Danish Medical Birth Registry. The carbohydrate overfeeding consisted of giving the men packages containing 25% in excess of their daily calorie requirement in the form of fruit juice, sugar-sweetened soda and candy. As expected, they all increased their BMI as a result of overfeeding.

The LBW men had more hepatic fat than the NBW men at baseline and, in response to overfeeding, both groups had a similar increase in hepatic fat, but this did not affect the hepatic glucose production or hepatic insulin resistance. Both groups had an increase in fasting glucose and C-peptide, and an increase in energy expenditure.

With fasting plasma hormones, LBW individuals had lower levels of adiponectin, both at baseline and with overfeeding, while leptin levels were increased significantly in response to overfeeding, but it decreased in the NBW group. In the metabolomics part of the study, eight out of 65 metabolites responded differently to overfeeding in LBW men compared with NBW men. Further analysis revealed that these changes could increase reactive oxygen species and affect mitochondrial function in LBW individuals. And, in the lipidomics part of the study, the LBW group had a significantly higher number of lipids, including triglycerides and others known to be associated with the risk of NAFLD, insulin resistance and type 2 diabetes.

“We can speculate that with time and continued overfeeding, an increase in reactive oxygen species generation may lead to insulin resistance, mitochondrial damage and overt type 2 diabetes,” Charlotte concluded. “And the lipidomic signature is associated with insulin resistance, NAFLD and type 2 diabetes.” Further research into the impact of a high-carb diet on LBW individuals is needed, but the take-home message is that they need to take extra care to adhere to a healthy balanced diet if they want to mitigate their risk of type 2 diabetes.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

A new paper in Diabetologia shows that the incidence of childhood-onset type 1 diabetes in Sweden has levelled off over the past two decades, although it is still high. Increased immigration to Sweden by families at lower risk does not provide a complete explanation for this trend. Dr Susan Aldridge reports.

Mapping population-based trends of diseases such as type 1 diabetes is important for understanding the underlying causes and for healthcare planning. Between the early 1980s and the first years of the 21^st century, the incidence of childhood-onset type 1 diabetes doubled in Sweden. There were similar increases in many other countries around the world. The usual explanation for these increases is a change in environmental risk factors, such as lifestyle or exposure to infectious diseases, affecting the autoimmune pathogenesis of the condition.

In the 30-year follow-up of the nationwide Swedish Childhood Diabetes Registry (SCDR), there is a plateau in the incidence trend in the years 2002-2007. Some other population-based registers have reported a similar finding. Finland recently found a tendency towards a decrease, but the majority of study centres globally are still reporting an increase in type 1 diabetes incidence.

After Finland, Sweden has the second highest incidence of childhood-onset type 1 diabetes in the world, suggesting a strong genetic risk. Research from the USA has shown that the incidence and prevalence of type 1 and type 2 diabetes in young people differ between ethnic groups, with the highest prevalence of type 1 being in non-Hispanic white people.

Therefore, one factor that may affect diabetes incidence in a country could be migration, which could both introduce new lifestyle habits and change the genetic risk of the overall population. The number of people living in Sweden but born (or having parents born) outside Sweden has gone up from 11.3% in 2000 to 19.6% in 2019. Could this explain the plateau in incidence of type 1 in Sweden described above?

Ingrid Waernbaum at Uppsala University and colleagues at Umeå University, both in Sweden, have done a follow-up of the SCDR data, analysing trends by age, sex and parental country of birth to see whether the 2000 to 2007 plateau was stable during the following 12 years, in order to assess the impact of migration.

Investigating trends in type 1

The study population consisted of 23,143 type 1 diabetes cases recorded in the SCDR from January 1978 to December 2019. To investigate the impact of immigration on time trends, children born in Sweden with two parents born in Sweden were compared with the rest of the study population, consisting of those who had at least one parent who was not born in Sweden. The former (18,606 children) were termed ‘Swedish’, the latter (4527 children) ‘Other countries’.

In addition, a sub-group of Asian children (586 children, part of the ‘Other countries’ population) was analysed. This Asian group actually represented the most numerous immigrant group (3%) coming to Sweden from elsewhere.

The researchers used the data to describe the incidence trends by age and sex from 1978 to 2019 for the total, Swedish, Other countries and Asian populations. The incidence trends in the total population and in the Swedish population showed a steady increase until 2000 and then began to level off – this flattening off continued up to 2019. Trend curves were broadly similar for total, Swedish, Other and Asian populations, but overall higher for Swedish and lower for Other and Asian, compared with the total population.

Understanding the trends

This new follow-up study to 2019 reveals a prolongation of the levelling off in type 1 diabetes incidence in Sweden that was noted in the early 2000s. Incidence, however, is still high. Similar trends have been noted in Norway, Western Australia and Finland, although with shorter observation times.

The hypothesis being tested in this study was that increased immigration to Sweden over the past decades has caused the plateauing of the incidence rate of type 1 diabetes because of an increased fraction of children with fewer susceptible genetic traits. Put simply, Swedish children are more likely to develop type 1 diabetes than children from elsewhere, so if the balance shifts towards the latter, this could explain the development of the plateau. However, statistical analysis led the researchers to conclude that the hypothesis does not, in fact, fully explain the incidence trends.

Instead, the Swedish population displayed a similar slowing down in incidence to the total population. The generally lower incidence for children with immigrant parents shows that genetics determines the incidence level, but the actual trend is mainly due to exposure to environmental risk factors. This is illustrated by the low, but still increasing, incidence among Asian children. They have a low genetic risk for type 1 diabetes (contrasting, of course, with their risk of type 2 diabetes). And, since risk genes may differ in Asian children and may respond differently to environmental triggers, it would be interesting to continue follow-up of this sub-population.

Of the non-genetic risk factors that could be involved in type 1 diabetes, dietary patterns and early growth rate have been suggested as triggers and/or accelerators of beta cell destruction. In Sweden, as elsewhere, the prevalence of childhood obesity increased in the late 1990s, but this reached a plateau in the first decade of this century.

Another possible risk factor for type 1 diabetes in the Swedish setting is maternal BMI, particularly during the first trimester. However, a recent study suggests that there have been lower rates of increase in BMI and obesity prevalence among Swedish women since the early 2000s. It can therefore be concluded that incidence trends in childhood-onset diabetes in Sweden may partly depend on changes in childhood growth and weight.

One strength of this new study is that it is nationwide, population-based and has a long period of follow-up. Linking individual cases to their parents and country of birth provides us with new insights into the trends in type 1 diabetes incidence over time.

The authors conclude that, after more than 25 years of rapid increase in the 1980s and 1990s, the incidence of childhood-onset type 1 diabetes in Sweden has levelled off over the past two decades. This pattern does not depend upon increased immigration over this period, but its association with obesity is clearly of interest.

The number of cases of childhood-onset type 1 diabetes remains high in Sweden. Given that type 1 diabetes is a lifelong condition that may impose a considerable burden on the child and their family, it is important to keep monitoring trends and investigating the underlying risk factors. And, of course, efforts to improve lifestyle habits among young children and their families should be intensified.

To read this paper, go to: Waernbaum I, Lind T, Möllsten A, Dahlquist G. The incidence of childhood-onset type 1 diabetes, time trends and association with the population composition in Sweden: a 40-year follow-up. Diabetologia 20 October 2022. https://link.springer.com/article/10.1007/s00125-022-05816-0

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

As maternal glycaemic control has improved in women with type 1 diabetes before and during pregnancy, so too has birthweight and adiposity in their offspring, posing health risks later in life. A new theory was presented in a recent issue of Diabetologia. Dr Susan Aldridge reports.

The incidence of type 1 diabetes is rising all around the world. This suggests that there are increasing numbers of pregnant women with type 1 diabetes – a trend already reported in research from Canada and Scotland. Despite improvement in maternal glycaemic control in recent years, a type 1 pregnancy is still risky. While reduced in frequency, complications such as congenital malformations, pre-eclampsia, pre-term labour and stillbirth are still more prevalent among women with type 1 diabetes than in those without diabetes.

Foetal growth is also affected in pregnancies with type 1 diabetes. Up to the 1970s, overgrowth with signs of excessive fat accumulation was the main finding, although growth restriction was also noted. More recently, a paradoxical trend has been noted – babies born to women with type 1 diabetes increasingly show overgrowth, despite improved maternal glycaemic control. For instance, a continuous increase in the proportion of large-for-gestational-age (LGA) neonates born to women with type 1 diabetes was observed between 1992 and 2013 in Scotland, and between 1982 and 2007 in Sweden.

Meanwhile, the proportion of small-for-gestational-age (SGA) neonates born to women with type 1 diabetes remained stable at around 3-4% up to 2010, followed by a small increase to 6-7% in the last 10 years. In a recent large, multi-centre trial, rates for LGA offspring were 62-65% and SGA offspring 1-2%.

Foetal overgrowth increases the risk of shoulder dystocia, birth trauma and operative delivery. It is often based on birthweight and therefore defined as a foetus being LGA. However, in diabetes, foetal overgrowth tends to mean excessive fat deposition at various anatomical locations. It can occur not only in LGA infants, but in those of normal birthweight.

In the longer term, babies born to a woman with type 1 diabetes are more likely to become obese and have an increased risk of developing type 2 diabetes, cardiovascular disease and other features of the metabolic syndrome. It is likely that an adverse intrauterine environment sets up the foetus for these future problems, so it’s important to avoid foetal overgrowth during pregnancy.

Poor glycaemic control over a long period can lead to microangiopathy, expressed clinically as diabetic retinopathy and diabetic nephropathy. The presence of diabetic nephropathy in pregnancy is associated with a higher prevalence of SGA. Microangiopathy may impair placental development and growth which, in turn, leads to restricted foetal growth.

In a new review, Gernot Desoye of the Medical University of Graz, Austria, and colleagues elsewhere, argue that the increase in LGA neonates in recent years is actually a consequence of the corresponding improvement in glycaemic control in the pre- and periconceptional periods. Their hypothesis is based on the idea that it is now far less common for women to experience severe hyperglycaemia and so adverse processes in early pregnancy around placentation, including microangiopathy of maternal blood vessels, have decreased. Improved placentation leads to unimpeded foetal overnutrition via the still present, but milder, maternal hyperglycaemia.

What determines birthweight?

Birthweight is determined by the interplay between the genetics of the foetus and the supply of nutrients transferred from the mother via the placenta. Successful development of the placenta requires some significant changes in the maternal arteries around the uterus. Restricted growth due to foetal hypoxia may be seen when this remodelling is impaired in type 1 diabetes, particularly when the condition is long-standing and poorly controlled.

However, major advances in diabetes management among women with type 1 diabetes have resulted in pre- and periconceptional mean HbA1c decreasing from ≥ 59 mmol/mol in 1996-1999 to 52 mmol/mol in 2012-2016. Blood pressure control has also improved and smoking rates have decreased. All these changes may have impacted the remodelling of blood vessels, as mentioned above, resulting in improved placentation. This, in turn, improves oxygen delivery to the foetus, reducing the risk of growth restriction.

Measurement of first trimester concentrations of protein biomarkers related to placental size and function supports the idea that improved placentation may be leading to LGA babies in women with type 1 diabetes. Levels are lower in women with diabetes than in those without diabetes, which suggests poor placentation but, with the effect of hyperglycaemia, their babies were born with normal birthweights. And when women with type 1 diabetes had levels of these biomarkers the same as those without diabetes – suggesting a ‘healthy’ placenta – their babies were LGA, reflecting the contributing effect of hyperglycaemia.

Why are there more LGA babies today?

Early events in pregnancy that may impair placentation and foetal oxygenation are not the only factors affecting birthweight in pregnancies of women with type 1 diabetes. Despite improvements in glycaemic control, maternal and foetal glucose levels still tend to be elevated beyond what would be expected in a healthy pregnancy, leading to foetal overnutrition.

Sometimes poor placentation may initially impair foetal growth, but then hyperglycaemia results in the baby being born with normal birthweight. This actually represents a phenotype of overgrowth with excessive fat deposition. It resembles the ‘thin-fat’ phenotype often seen in Asian populations, where babies are born with a ‘normal’ birthweight but with disproportionately high body fat. However, if placentation has been adequate, then later hyperglycaemia, however subtle, may lead to an LGA neonate.

So there is an important distinction between overgrowth in normal and LGA babies. The authors note that the normalising of placentation resulting from improved glycaemic control may have unmasked the potential for overgrowth in the context of a maternal metabolism that is, in itself, still subject to hyperglycaemia because of type 1 diabetes. Here, the impact of foetal overnutrition because of elevated maternal macronutrients – particularly glucose – become obvious, leading to more LGA neonates than previously seen.

Blood glucose in early and later pregnancy

The CONCEPTT trial was a large, multi-centre, randomised controlled trial of continuous glucose monitoring (CGM) in women with type 1 diabetes who had a mean HbA1c level of 52 mmol/mol. The LGA rate was 53% in the women on CGM and 69% in those on routine capillary glucose monitoring. These rates were higher than the 46% reported in the National Pregnancy in Diabetes UK Audit, but the early mean HbA1c was higher, at 60 mmol/mol, than in the CONCEPTT trial.

These studies cannot be compared directly, but they perhaps illustrate the influence of early pregnancy blood glucose levels on birthweight. However, elevated blood glucose levels in the pre-and periconceptional period are not the only key factor. These early levels likely interact with the influence of glucose levels later in pregnancy to ultimately determine birthweight.

Meanwhile, the increase in obesity means that more women with type 1 diabetes enter pregnancy with a BMI that is in the overweight or obese range. This further increases the risk of having a LGA infant. The underlying reasons for this aren’t clear but may involve maternal hyperglycaemia arising from maternal insulin resistance.

Why foetal overgrowth matters

Foetal overgrowth can lead to excessive fat deposition, which can cause long-term harm to offspring. In more than 4800 mother-offspring pairs in the global Hyperglycaemia and Adverse Pregnancy Outcome study, neonatal fat was positively associated with obesity in the offspring at 11 years. Neonatal obesity was therefore the likely mediator between an unfavourable intrauterine environment and childhood obesity. This is important because individuals who have a higher number of adipocytes at the age of two will have a higher number of adipocytes throughout their lifespan. These adipocytes are ‘hungry’ and will fill up with triacylglycerols, which leads to excessive fat deposition and long-term obesity risk. Foetal overgrowth with excessive fat accumulation in pregnancies with type 1 diabetes may therefore lead to similar long-term consequences to the offspring of women who develop gestational diabetes.

Strict glycaemic control is necessary throughout pregnancy to avoid inappropriate foetal growth. Ideally, glucose levels should be as close as possible to normal physiological levels and daily glucose variability should also be taken into account – although the actual glucose level required to maintain foetal growth, without increased adiposity, is currently unknown.

CGM may improve glycaemic control by levelling out glucose fluctuations and perhaps reduce the number of LGA neonates. However, CGM is costly and not universally available – diet and weight management plans are cheaper alternatives. Excessive gestational weight gain in women with and without type 1 diabetes can lead to higher foetal growth, independent of glycaemic control. Therefore, women with type 1 diabetes should be advised about weight management during pregnancy, particularly if they already have overweight or obesity.

Future directions

The suitability of HbA1c as a pregnancy outcome predictor in type 1 diabetes has already been questioned. Also, there is mounting evidence of the importance of monitoring temporal glucose profiles during pregnancy and spending as much time in range as possible to improve pregnancy outcomes. Continuous glucose monitoring looks promising for achieving these goals, so it’s hoped that healthcare systems will support their use in pregnancy, as has been done in the UK.

As far as research is concerned, exploring the early growth of the foetus and how it is influenced by the maternal environment is an under-explored area. It is known that maternal diet in the pre- and periconceptional periods can influence the early growth of the embryo, foetus and placenta, but the impact of metabolic changes in the mother is less well understood. Therefore, one research priority should be this early pregnancy period and the factors affecting placental growth trajectories.

Also, to date, human studies have focused on the proportion of LGA babies born to women with type 1 diabetes. However, some have normal birthweight, but excessive adiposity. The focus on birthweight does not capture this, but no alternative classification system is currently available. Thus, it could be important to start measuring neonatal body composition, although this might be challenging to include in routine clinical practice. Skinfold thickness could be used as a starting point, although more advanced techniques, such as air displacement plethysmography or dual-energy x-ray absorptiometry, may be preferred where available.

Studies should also include biomarker measurement for placentation and blood-glucose levels throughout pregnancy and how they relate to the outcome of neonatal adiposity.

In conclusion, the authors are suggesting that improved glycaemic control among women with type 1 diabetes has led to improved placentation in early pregnancy. This sets the scene for foetal overgrowth later on, driven by maternal hyperglycaemia. It means that complex interactions of blood glucose levels at different stages of pregnancy determine foetal overgrowth in pregnancies complicated by type 1 diabetes.

Going forward, there needs to be more intensive efforts to bring blood-glucose levels closer to the physiological range during pregnancy, which may be achieved using CGM. More research is needed into the placentation phase and neonatal adiposity, as well as birthweight, should be routinely measured.

To read this paper, go to: Desoye G, Ringholm L, Damm P, Mathiesen ER, Van Poppel MNM. Secular trend for increasing birthweight in offspring of pregnant women with type 1 diabetes: is improved placentation the reason? Diabetologia 66, 33-43 (2023). https://link.springer.com/article/10.1007/s00125-022-05820-4

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy