Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes

Ware, J. et al | 2022 | Randomized Trial of Closed-Loop Control in Very Young Children with Type 1 Diabetes | N Engl J Med 2022| 386| P. 209-219 | DOI: 10.1056/NEJMoa2111673

This paper outlines the findings of a trial, at the outset the researchers hypothesized that use of the Cambridge closed-loop algorithm for 16 weeks in children 1 to 7 years of age with type 1 diabetes would improve glycemic control, as compared with sensor-augmented pump therapy, and have an acceptable safety profile.



The possible advantage of hybrid closed-loop therapy (i.e., artificial pancreas) over sensor-augmented pump therapy in very young children with type 1 diabetes is unclear.


In this multicenter, randomized, crossover trial, we recruited children 1 to 7 years of age with type 1 diabetes who were receiving insulin-pump therapy at seven centers across Austria, Germany, Luxembourg, and the United Kingdom. Participants received treatment in two 16-week periods, in random order, in which the closed-loop system was compared with sensor-augmented pump therapy (control). The primary end point was the between-treatment difference in the percentage of time that the sensor glucose measurement was in the target range (70 to 180 mg per deciliter) during each 16-week period. The analysis was conducted according to the intention-to-treat principle. Key secondary end points included the percentage of time spent in a hyperglycemic state (glucose level, more than180 mg per deciliter), the glycated hemoglobin level, the mean sensor glucose level, and the percentage of time spent in a hypoglycemic state (glucose level, less than 70 mg per deciliter). Safety was assessed.


A total of 74 participants underwent randomization. The mean (±SD) age of the participants was 5.6±1.6 years, and the baseline glycated hemoglobin level was 7.3±0.7 per cent. The percentage of time with the glucose level in the target range was 8.7 percentage points (95 per cent confidence interval [CI], 7.4 to 9.9) higher during the closed-loop period than during the control period (P less than 0.001). The mean adjusted difference (closed-loop minus control) in the percentage of time spent in a hyperglycemic state was −8.5 percentage points (95 per cent CI, −9.9 to −7.1), the difference in the glycated hemoglobin level was −0.4 percentage points (95 per cent CI, −0.5 to −0.3), and the difference in the mean sensor glucose level was −12.3 mg per deciliter (95 per cent CI, −14.8 to −9.8) (P less than0.001 for all comparisons). The time spent in a hypoglycemic state was similar with the two treatments (P equal to0.74). The median time spent in the closed-loop mode was 95 per cent (interquartile range, 92 to 97) over the 16-week closed-loop period. One serious adverse event of severe hypoglycemia occurred during the closed-loop period. One serious adverse event that was deemed to be unrelated to treatment occurred.


A hybrid closed-loop system significantly improved glycemic control in very young children with type 1 diabetes, without increasing the time spent in hypoglycemia.

Research summary is available from the NEJM

Full article available from NEJM

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data

Prof Dianna J Magliano, D. J. et al | 2021 | Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data | The Lancet Diabetes & Endocrinology | DOI:https://doi.org/10.1016/S2213-8587(21)00327-2



Population-level trends in mortality among people with diabetes are inadequately described. We aimed to examine the magnitude and trends in excess all-cause mortality in people with diabetes.


In this retrospective, multicountry analysis, we collected aggregate data from 19 data sources in 16 high-income countries or jurisdictions (in six data sources in Asia, eight in Europe, one from Australia, and four from North America) for the period from Jan 1, 1995, to Dec 31, 2016, (or a subset of this period) on all-cause mortality in people with diagnosed total or type 2 diabetes. We collected data from administrative sources, health insurance records, registries, and a health survey. We estimated excess mortality using the standardised mortality ratio (SMR).


In our dataset, there were approximately 21 million deaths during 0·5 billion person-years of follow-up among people with diagnosed diabetes. 17 of 19 data sources showed decreases in the age-standardised and sex-standardised mortality in people with diabetes, among which the annual percentage change in mortality ranged from –0·5 per cent (95 per cent CI –0·7 to –0·3) in Hungary to –4·2 per cent (−4·3 to –4·1) in Hong Kong. The largest decreases in mortality were observed in east and southeast Asia, with a change of –4·2 per cent (95 per cent CI –4·3 to –4·1) in Hong Kong, –4·0 per cent (−4·8 to –3·2) in South Korea, –3·5 per cent (−4·0 to –3·0) in Taiwan, and –3·6 per cent (−4·2 to –2·9) in Singapore. The annual estimated change in SMR between people with and without diabetes ranged from –3·0 per cent (95 per cent CI –3·0 to –2·9; US Medicare) to 1·6 per cent (1·4 to 1·7; Lombardy, Italy). Among the 17 data sources with decreasing mortality among people with diabetes, we found a significant SMR increase in five data sources, no significant SMR change in four data sources, and a significant SMR decrease in eight data sources.


All-cause mortality in diabetes has decreased in most of the high-income countries we assessed. In eight of 19 data sources analysed, mortality decreased more rapidly in people with diabetes than in those without diabetes. Further longevity gains will require continued improvement in prevention and management of diabetes.


US Centers for Disease Control and Prevention, Diabetes Australia Research Program, and Victoria State Government Operational Infrastructure Support Program

Trends in all-cause mortality among people with diagnosed diabetes in high-income settings: a multicountry analysis of aggregate data [abstract only]

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New Type 2 Diabetes Risk Factors Identified

Martin, S. et al | 2021| Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study | Diabetes Care | dc211262. https://doi.org/10.2337/dc21-1262

Type 2 diabetes (T2D) is associated with a number of risk factors and now new research, published in Diabetes Care, suggests that increased levels of liver fat and a smaller pancreas volume may also add to a greater risk of developing T2D.

The new study, conducted at Brunel University, used data collected from 32,859 people who underwent an MRI as part of the UK Biobank study. Data from 9358 participants with type 1 diabetes was also collected from various genome-wide association studies.

“People with type 2 diabetes usually have excess fat in their liver and pancreas, the two key organs in the maintenance of the normal level of blood sugar. The genetic analysis we used in this study is the best possible method to test this relationship,” says Dr Yaghootkar. (via MedScape).


Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations.


We used genetic variants associated (P less than 5 × 10−8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n equal to 32 859). We obtained summary-level data for risk of type 1 (9 358 cases) and type 2 (55 005 cases) diabetes from the largest available genome-wide association studies. We performed inverse–variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects.


Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 [2.02, 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 [1.08, 1.49] or 27 per cent increased risk and 0.76 [0.62, 0.94] or 24 per cent decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes.


Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.

MedScape New Type 2 Diabetes Risk Factors Identified

Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study [paper]

Reducing the risk of suicide in people with diabetes

Diabetes UK | 4 January 2022 | Reducing the risk of suicide in people with diabetes

Suicide and diabetes isn’t something that’s generally talked about. But we should be talking about it, says Simon O’Neill, Diabetes UK’s Director of Health Intelligence and Professional Liaison. Here he explains why and what to do if you need help or want to help a loved one.

Diabetes can be hard to live with. The daily grind of checking blood glucose levels, carb-counting, insulin adjustment and dealing with hypos and highs can take its toll. It’s relentless and there’s no day off. Unsurprisingly diabetes burnout, when you’ve just had enough, is common. We also know that depression is twice as likely if you have diabetes and that 60 per cent of people with diabetes struggle with their mental wellbeing at some point.

So it isn’t that surprising that people with diabetes have double the risk of suicide or intentional self injury compared with the general population. But that isn’t something that’s widely talked about.

The RESCUE collaborative community are trying to do just that – start talking about suicide and self harm in diabetes – and to make sure that help and support are there if people need it. I’m part of that collaborative, to ensure that the voices of people with diabetes are right at the heart of the conversation (Source: DiabetesUK).

Full details from Diabetes UK

Diabetic kidney disease in children and adolescents: an update

Lopez, L.N. et al | 2021 |  Diabetic kidney disease in children and adolescents: an update | Pediatric Nephrology | doi.org/10.1007/s00467-021-05347-7

The reviewers of this article review recent updates to the diagnosis and management of diabetic kidney disease (DKD) in children and adolescents.

The review makes the following key points:

  1. The incidence of diabetes, particularly type 2 diabetes, and its complications, are on the rise in children and adolescents, disproportionately affecting racial-ethnic minorities.
  2. The cornerstone in the prevention of diabetic kidney disease is optimal glycemic control, along with screening for and management of hypertension and albuminuria.
  3. GLP1 receptor agonists, in conjunction with metformin, have been shown to have a beneficial effect in reducing the incidence of adverse kidney outcomes, and are now approved for use in older children with type 2 diabetes.
  4. While many new therapies have been studied and approved for use in adults with diabetes and diabetic kidney disease, insufficient progress has been made in performing clinical trials in children and young adults.


Diabetic kidney disease (DKD), previously encountered predominantly in adult patients, is rapidly gaining center stage as a childhood morbidity and one that pediatric nephrologists are likely to encounter with increasing frequency. This is in large part due to the obesity epidemic and the consequent rise in type 2 diabetes in children and adolescents, as well as the more aggressive diabetes phenotype in today’s youth with more rapid beta-cell decline and faster development and progression of diabetes-related complications along with lower responsiveness to the treatments used in adults. DKD, an end-organ complication of diabetes, is at the very least a marker of, and more likely a predisposing factor for, the development of adverse cardiovascular outcomes and premature mortality in children with diabetes. On an optimistic note, several new therapeutic approaches are now available for the management of diabetes in adults, such as GLP1 receptor agonists, SGLT2 inhibitors, and DPP4 inhibitors, that have also been shown to have a favorable impact on cardiorenal outcomes. Also promising is the success of very low-energy diets in inducing remission of diabetes in adults. However, the addition of these pharmacological and dietary approaches to the management toolbox of diabetes and DKD in children and adolescents awaits thorough assessment of their safety and efficacy in this population. This review outlines the scope of diabetes and DKD, and new developments that may favorably impact the management of children and young adults with diabetes and diabetic kidney disease.

The full article is available from Pediatric Nephrology