To Örebro University

Background and aims: Young maternal age is thought to be associated with adverse metabolic outcomes in offspring that may persistin to adulthood. Previous studies have utilised longitudinal designs including cohort studies to assess these associations, but may have been limited by unmeasured or residual confounding. Here we use a longitudinal sibling comparison design (to tackle familial genetic and environmental confounding), to evaluate the association between maternal age <16 years at delivery and type 2 diabetes (T2D) in adult-hood among offspring.

Materials and methods: Using Swedish Register data from 1964 to 2018, we defined young mothers as maternal age at delivery <16 years and assessed T2D in offspring from 30 years. Demographic information was provided by Statistics Sweden; T2D by the Patient Register, Prescribed Drug Register, and Cause of Death Register using ICD 9 and ICD 10 codes; and death information by the Cause of Death Register. We estimated person-time from birth to diagnosis of T2D, emigration, death, loss to follow-up, or the end of the follow-up on December 31, 2018, whichever came first. After ruling out birth order effect, we associated maternal age at birth (<16 vs ≥16) with T2D, utilising Cox regression for conventional and models stratified by family (biological mother) for sibling comparison. We adjusted these models for sex (men vs women) and socioeconomic index (high, low, agriculture, and others vs middle).

Results: There were 5,719,176 mothers who gave birth to offspring comprising 2,661,535 groups of siblings. Of these, 6,020 children were born when their mothers were <16 years old; 13.93% developed T2D among these compared to 5,713,156 children who were born when their mothers were ≥ 16 years; 10.59% developed T2D among these. Using conventional analysis, both in unadjusted and adjusted analysis, offspring of young mothers compared with their siblings born after their mother was aged 16 years, had statistically significantly higher hazard ratios (with 95% confidence intervals) for T2D (HR [95% CI]: 1.63 [1.52, 1.75] and 1.52 [1.42, 1.65]). In comparison, sibling models ,both in unadjusted and adjusted analysis, found offspring of young mothers compared with their siblings born after their mother was aged 16 years, had significantly decreased hazard ratios for T2D (0.28 [0.21, 0.38] and 0.25 [0.20, 0.33]).

Conclusion: The raised risk of T2D born to young mothers compared with their siblings born after their mother was aged 16 years is confounded by familial characteristics.

AIMS/HYPOTHESIS: The risk of complications and medical consequences of type 2 diabetes are well known. Hospital costs have been identified as a key driver of total costs in studies of the economic burden of type 2 diabetes. Less evidence has been generated on the impact of individual diabetic complications on the overall societal burden. The objective of this study was to analyse costs of hospital-based healthcare (inpatient and outpatient care) and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016.

METHODS: Data for 2016 were retrieved from a Swedish national retrospective observational database cross-linking individual-level data for 1997-2016. The database contained information from population-based health, social insurance and socioeconomic registers for 392,200 people with type 2 diabetes and matched control participants (5:1). Presence of type 2 diabetes and of diabetes complications were derived using all years, 1997-2016. Costs of hospital-based care and of absence from work due to diabetes complications were estimated for the year 2016. Regression analysis was used for comparison with control participants to attribute absence from work to individual complications, and to account for joint presence of complications.

RESULTS: Use of hospital care for complications was higher in type 2 diabetes compared with control participants in 2016: 26% vs 12% had ≥1 hospital contact; there were 86,104 vs 24,608 outpatient visits per 100,000 people; and there were 9894 vs 2546 inpatient admissions per 100,000 people (all p < 0.001). The corresponding total costs of hospital-based care for complications were €919 vs €232 per person (p < 0.001), and 74.7% of costs were then directly attributed to diabetes (€687 per person). Regression analyses distributed the costs of days absent from work across diabetes complications per se, basic type 2 diabetes effect and unattributed causes. Diabetes complications amounted to €1317 per person in 2016, accounting for possible complex interactions (25% of total costs of days absent). Key drivers of costs were the macrovascular complications angina pectoris, heart failure and stroke; and the microvascular complications eye diseases, including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost an additional €579 per person and medications used in risk-factor treatment amounted to €418 per person.

CONCLUSIONS/INTERPRETATION: The economic burden of complications in type 2 diabetes is substantial. Costs of absence from work in this study were found to be greater than of hospital-based care, highlighting the need for considering treatment consequences in a societal perspective in research and policy. Graphical abstract.

Background and aims: Non-western immigrants to Europe are at high risk for type 2 diabetes (T2D). In this nationwide study including incident cases of T2D, the aim was to compare mortality in first- and second generation immigrants with native Swedes.

Materials and methods: Patients living in Sweden diagnosed with a new-onset pharmacologically treated T2D between 2006 to 2012 were identified through the Swedish Prescription Drug Register. Patients were followed until December 31, 2016 for all-cause mortality (ACM) and until December 31, 2012 for cause-specific mortality (CSM). Analyses were adjusted for age at diagnosis, sex, year of diagnosis, socioeconomy, education, treatment and region. Comparisons were assessed using coxregression analysis.

Results: In total, 169 300 individuals (129 533 (76.3%) native Swedes; 31 988 (18.9%) first-generation immigrants, and 7 799 (4.8%) second-generation immigrants with either one or both parents born outside Sweden) were diagnosed with T2D between 2006 and 2012 and fulfilled inclusion criteria. First-generation immigrants had lower ACM rate [hazard ratio (HR): 0.85, 95% CI 0.82 to 0.89] compared with native Swedes. The mortality was particularly low in persons born in the Middle East [0.45,0.40 to 0.51], Asia [0.56, 0.46 to 0.68], and Africa [0.88. 0.82 to 0.95]. Mortality rates decreased with older age at migration and shorter stay in Sweden, with the lowest rate in those originating from the Middle East living in Sweden <25 years [0.40, 0.34 to 0.46]. First-generation immigrants born in the Middle East (0.43; 0.30-0.62), and Asia (0.38; 0.19- 0.77) had lower cardiovascular disease related mortality rates compared with native Swedes. Middle Eastern immigrants further displayed lower cancer related mortality rate (0.59, 0.42 to 0.84) compared with native Swedes. Second generation immigrants displayed similar survival rates as native Swedes.

Conclusion: Our data indicate that in T2D patients, exposure to the Swedish environment seems to have a larger impact on mortality risk than region of origin. This study indicates protecting mechanisms on mortality related to the non-western environment.

AIMS/HYPOTHESIS: The AERx insulin Diabetes Management system (AERx iDMS) is a liquid aerosol device that enables insulin to be administered to the peripheral parts of the lung. This study aimed to compare the pharmacokinetic and pharmacodynamic properties of insulin which is inhaled using AERx iDMS with insulin which is subcutaneously administered.

METHODS: In total, 18 C-peptide negative patients with Type I (insulin-dependent) diabetes mellitus participated in this randomised, open-label, 5-period crossover trial. Human regular insulin was administered subcutaneously (0.12 U/kg body weight) or inhaled by means of the AERx iDMS (dosages 0.3, 0.6, 1.2, and 1.8 U/kg body weight). Thereafter plasma glucose was kept constant at 7.2 mmol/l for a 10-h period (glucose clamp technique).

RESULTS: Inhaled insulin provided a dose-response relation that was close to linear for both pharmacokinetic (AUC-Ins(0-10 h); Cmax-Ins) and pharmacodynamic (AUC-GIR(0-10 h); GIRmax) parameters. Time to maximum insulin concentration (Tmax-Ins) and time to maximum glucose infusion rate (TGIRmax) were shorter with inhaled insulin than with subcutaneous administration. The pharmacodynamic system efficiency of inhaled insulin (AUC-GIR(0-6 h) was 12.7% (95% C.I.: 10.2-15.6).

CONCLUSION/INTERPRETATION: The inhalation of soluble human insulin using the AERx iDMS is feasible and provides a clear dose response. Further long-term studies are required to investigate safety aspects, HbA1c values, incidence of hypoglycaemic events and the quality of life.

Background and aims: The prevalence of diabetes has increased rapidly over the last decades worldwide. The risk of complications and medical consequences is well known and identified as key driver of costs. Less evidence on the impact of individual diabetic complications on the societal burden is available. The objective was to analyse costs of hospital-based health care and work absence related to individual macrovascular and microvascular complications of type 2 diabetes in Sweden in 2016.

Materials and methods: The study used data from a Swedish retrospective observational database cross-linking 20 years of individual-level data (1997-2016) from national population-based health, social insurance and socio-economic registers for 392,200 people with type 2 diabetes and matched controls (5:1). Diabetes status and presence of 19 types of complications were derived from years 1997-2016 while the costs of hospital-based care and of production loss due to diabetes complications were estimated for 2016. Regression analysis was used for comparison to controls, to attribute production loss to individual complications, and to account for joint presence of complications.

Results: Complications are prevalent and patterns complex in type 2 diabetes (Fig. 1). Use of hospital care for complications was higher compared to controls: 86,104 vs 24,608 outpatient visits per 100,000 persons and 9,894 vs 2,546 inpatient admissions per 100,000 persons (p<0.001) in 2016. 26% vs 12% had ≥1 hospital contact. The corresponding total costs of hospital-based care fo rcomplications were EUR 91,875 vs EUR 23,222 per 100 persons (p<0.001) and 75% were directly attributed to diabetes (EUR 689/person). Regression analyses distributed the costs of days absent from work across diabetes complications, basic type 2 diabetes effect and unattributed causes: diabetes complications amounted to EUR 2,165/person in 2016. Key drivers of costs of production loss were macrovascular complications angina pectoris, heart failure and stroke, and microvascular complications eye disease including retinopathy, kidney disease and neuropathy. Early mortality in working ages cost additional EUR 579/person and medications used in risk-factor treatment amounted to EUR 418/person.

Conclusion: The economic burden of complications in type 2 diabetes is substantial. Costs of productivity loss in this study were found to be greater than those of hospital-based care highlighting the need for considering treatment consequences in a societal perspective in research and policy.

Background and aims: Multiple daily insulin injections are an integral part of life for patients with type 1 diabetes (T1D). Moreover, patients’ schedules can change from day-to-day, further complicating T1D management. This study aimed to analyze daily injection patterns for patients with T1D, thereby providing insights into patients’ behaviour.

Materials and methods: This post hoc observational study included children and adults with T1D from Sweden using NovoPen®6with bolus insulin (primarily insulin aspart) and/or basal insulin (primarily insulin degludec). Injection data were uploaded via the Glooko® cloud system. Daily bolus and basal injection timing profiles were documented, weighting each dose relative to the total daily dose. The time difference between two consecutive basal insulin injections was used to evaluate basal timing variation.

Results: Overall, 159 adults and 47 children were included in the analysis, with a total of 38678 days of bolus injections and 17869 days of basal injections. The mean bolus daily injection profile displayed peaks at typical mealtimes, but substantial variation was observed both across patients and between adults and children (Figure 1). In those receiving insulin degludec, the timing of consecutive basal injections differed by more than 6 hr in approximately 9% of the injections for adults and 7% of those for children.

Conclusion: These real-world data provide a unique insight into the everyday bolus and basal adherence of paediatric and adult patients with T1D. Furthermore, the results illustrate the flexibility needed for basal injections to enable optimal management of T1D.

AIMS/HYPOTHESIS: Ceramides and IL-6 have a role in immune-inflammatory responses and cardiovascular diseases, and are suggested to be involved in insulin and glucose metabolism. We sought to assess the associations of circulating levels of IL-6, TNF-alpha and high-sensitivity C reactive protein (hsCRP), which are inflammatory markers related to insulin resistance (IR), with the plasma lipid metabolites ceramides and diacylglycerols (DAG) in patients with CHD.

METHODS: Cross-sectional analyses were carried out on data from 33 patients with CHD. Serum levels of the inflammatory markers and plasma lipid metabolites (lipidomics approach performed by ultra-performance liquid chromatography coupled to electrospray ionisation MS) were measured at the same time point as insulin resistance (IR) (HOMA-IR index).

RESULTS: Serum circulating levels of IL-6 were strongly correlated with plasma ceramide concentrations (r = 0.59, p < 0.001). Adjustments for serum TNF-alpha or hsCRP levels, smoking, BMI, age, sex or HOMA-IR did not change the results (p < 0.001). After adjustments for the effect of serum inflammatory markers (TNF-alpha or hsCRP), HOMA-IR and BMI the correlation between plasma DAG and serum IL-6 (r = 0.33) was also significant (p < 0.03). In a linear regression model, circulating levels of both ceramides and TNF-alpha had a significant independent influence on circulating levels of IL-6, altogether accounting for 41% of its variation (p < 0.001).

CONCLUSIONS/INTERPRETATION: Our results strongly suggest that the link between ceramides, IR and inflammation is related to the inflammatory marker IL-6. Ceramides may contribute to the induction of inflammation involved in IR states that frequently coexist with CHD.

Background and aims: The Changing Diagnostic Criteria for Gestational Diabetes (GDM) study (CDC4G) is a stepped wedged randomized controlled trial in Sweden on the effects of introducing the 2013 WHO criteriaf or diagnosing GDM. Almost all Swedish pregnancies are registered in the Swedish Pregnancy Register (SPR). The CDC4G study provides a unique opportunity to validate the GDM diagnosis in the SPR. We aim to 1) validate the diagnosis of GDM in the SPR using the laboratory values from the oral glucose tolerance tests (OGTT) in the CDC4G study as the gold standard; 2) explore effects of change in diagnostic criteria on validity and prevalence of the diagnosis of GDM. Secondary aim is to investigate whether incident GDM diagnoses during pregnancy are recorded by the midwife when entering the follow-up postpartum registration in the SPR.

Materials and methods: Data from the SPR were compared with data from the CDC4G eCRF (gold standard measurements: venous OGTT values fasting, 1-h and 2-h) among 6080 screened individuals in 2018. We also investigated if the GDM diagnosis, set at the maternity ward was registered by the midwives at the postpartum follow-up (SPR tickbox). We present the sensitivity, specificity, positive (PPV) and negative (NPV) predictive value for each question. The study was approved by the Uppsala-Örebro regional Ethical Review board (2016/487), and by the Swedish Ethical Review Authority (2019/02148, 2020/02856, 2021/02055).

Results: Validating the ICD-code GDM (O24.4) in the Swedish Pregnancy Register resulted in 84.7% sensitivity, 96.7% specificity, PPV of 91.8%, and NPV of 93.5%. The prevalence of the GDM diagnosis more than tripled using the new criteria (Table 1). Both the sensitivity and specificity of the follow-up postpartum registration of GDM were considerably lower than for the GDM ICD-code, 76.6% and 87.6%, respectively. There were some minor differences in the accuracy of the registration before and after the switch to the new criteria for GDM, see table 1.

Conclusion: The coding of GDM in clinical practice, that is transferred to the SPR needs to be improved. We recommend researchers to use data based on ICD coding, instead of manually entered SPR data, until the quality of the variable has improved.

AIMS/HYPOTHESIS: High levels of cardiorespiratory fitness (CRF) and physical activity (PA) are associated with a favourable metabolic risk profile. However, there has been no thorough exploration of the independent contributions of cardiorespiratory fitness and subcomponents of activity (total PA, time spent sedentary, and time spent in light, moderate and vigorous intensity PA) to metabolic risk factors in children and the relative importance of these factors. METHODS: We performed a population-based, cross-sectional study in 9- to 10- and 15- to 16-year-old boys and girls from three regions of Europe (n = 1709). We examined the independent associations of subcomponents of PA and CRF with metabolic risk factors (waist circumference, BP, fasting glucose, insulin, triacylglycerol and HDL-cholesterol levels). Clustered metabolic risk was expressed as a continuously distributed score calculated as the average of the standardised values of the six subcomponents. RESULTS: CRF (standardised beta = -0.09, 95% CI -0.12, -0.06), total PA (standardised beta = -0.08, 95% CI -0.10, -0.05) and all other subcomponents of PA were significantly associated with clustered metabolic risk. After excluding waist circumference from the summary score and further adjustment for waist circumference as a confounding factor, the magnitude of the association between CRF and clustered metabolic risk was attenuated (standardised beta = -0.05, 95% CI -0.08, -0.02), whereas the association with total PA was unchanged (standardised beta = -0.08 95% CI -0.10, -0.05). CONCLUSIONS/INTERPRETATION: PA and CRF are separately and independently associated with individual and clustered metabolic risk factors in children. The association between CRF and clustered risk is partly mediated or confounded by adiposity, whereas the association between activity and clustered risk is independent of adiposity. Our results suggest that fitness and activity affect metabolic risk through different pathways.

AIMS/HYPOTHESIS: The aim of this study was to investigate the association between maternal diabetes in pregnancy and offspring cognitive ability and also to assess whether the association was due to intrauterine mechanisms or shared familial characteristics.

METHODS: We linked national registers and conducted a prospective cohort study of singleton Swedish-born men to explore associations between maternal pregnancy diabetes and educational achievement at age 16 years, the age of completing compulsory education in Sweden (n = 391,545 men from 337,174 families, graduating in 1988-1997 and n = 326,033 men from 282,079 families, graduating in 1998-2009), and intelligence quotient (IQ) at the mandatory conscription examination at 18 years of age (n = 664,871 from 543,203 families).

RESULTS: Among non-siblings, maternal diabetes in pregnancy was associated with lower offspring cognitive ability even after adjustment for maternal age at birth, parity, education, early-pregnancy BMI, offspring birth year, gestational age and birthweight. For example, in non-siblings, the IQ of men whose mothers had diabetes in their pregnancy was on average 1.36 points lower (95% CI -2.12, -0.60) than men whose mothers did not have diabetes. In comparison, we found no such association within sibships (mean difference 1.70; 95% CI -1.80, 5.21).

CONCLUSIONS/INTERPRETATION: The association between maternal diabetes in pregnancy and offspring cognitive outcomes is likely explained by shared familial characteristics and not by an intrauterine mechanism.

Background and aims: The development and application of digital technologies to healthcare is a key component in meeting the increasing demand from patients for chronic disease management. Healthcare payers need evidence to support value-based decisions on new technologies. Smart insulin pens record the timing and dose of insulin, and data can integrate with continuous glucose monitoring (CGM) to improve diabetes self-management. The present analysis assessed the cost-effectiveness of introducing a smart insulin pen from a Swedish public healthcare payer perspective.

Materials andmethods: The IQVIA CORE DiabetesModel was used to project clinical outcomes and healthcare costs (2018 Swedish krona [SEK]) over patients’ lifetimes in a Swedish type 1 diabetes (T1D) population. The model projected the development of complications, mortality, HbA1c, hypoglycaemia and insulin dosing to estimate cost effectiveness. Clinical model inputs were informed by an observational study of the introduction of an NFC-enabled smart insulin pen (NovoPen® 6) in 94 adults with T1D receiving basal-bolus insulin and using CGM. Smar tinsulin pen use (median follow up 7 months) was associated with an additional 1.89 h/day time in range (TIR 3.9-10.0 mmol/L [70-180 mg/dL]) compared with baseline. Change in TIR was converted to change in HbA1c using a published regression equation to allow long-term outcomes to be modelled based on published risk equations. Additional TIR with the smart insulin pen translated to a 0.62% (6.8 mmol/mol) HbA1c reduction and there were 33 fewer CGM-documented non-severe hypoglycaemic events/patient/year (≥15 min <3.0 mmol/L [54 mg/dL]) relative to baseline. Baseline characteristics were taken from the study cohort or, if unavailable, adults with T1D from the Swedish National Diabetes Register. Future costs and clinical benefits were discounted at 3% annually. Costs were converted to Euros (EUR) using a 0.091 SEK exchange rate.

Results: Over patients’ lifetimes, smart insulin pen use was associated with improved mean discounted quality-adjusted life expectancy (1.13 quality-adjusted life years) and cost savings (EUR11,091) vs standard care. Improvements in quality-adjusted life expectancy were driven by a lower frequency and delayed onset of complications predicted with the smart insulin pen relative to standard care. Higher treatment costs (due to the higher bolus insulin dose) with the smart insulin pen were offset by the lower cost of complications compared with standard care (Fig).

Conclusion: In this long-term modelling analysis, lifelong use of a smart insulin pen improved clinical outcomes at a lower cost relative to standard care in a T1D population, suggesting that the smart insulin pen represents an efficient use of Swedish public healthcare resources in this patient population.

Background and aims: To study the effects of obesity treatment with gastric bypass surgery on hospitalization for heart failure (HF) and atrial fibrillation (AF) in patients with type 2 diabetes (T2D) and obesity. We also studied the effects of gastric bypass surgery on mortality in a subgroup of individuals with preexisting heart failure.

Materials and methods: In this register-based nationwide cohort study we compared individuals with T2D and obesity that underwent Roux-en-Y gastric bypass surgery (RYGB) with matched individuals with T2D and obesity that did not undergo surgery. Data was gathered by linking the Swedish National Diabetes Register and Scandinavian Obesity Surgery Registry. Matching of individuals for age, gender, BMI and calendar time was done using a time updated propensity score. The main outcome measures were hospitalization for HF and/or AF, and mortality in patients with preexisting HF. The risk for heart failure, AF and death were assessed using a Cox-proportional hazards regression model that addressed measured confounding.

Results: We identified 5321 individuals with T2D and obesity that had undergone RYGB between January 2007 and December 2013 and 5321 matched controls. The individuals includedwere between 18 and 65 years old and had a BMI > 27.5 kg/m2. The follow-up time for hospitalization was until the end of 2015 (mean 4.5 years) and the end of 2016 for death. Our results show a 73% lower risk for HF (HR 0.27 (0.19, 0.38) p<0.001), 41% for AF (HF 0.59 (0.44, 0.78) p < 0.001), and 77% for concomitant AF and HF (HR0.23 (0.12, 0.46) p < 0.001) in the surgically treated group. In patients with preexisting HF we observed significantly lower mortality in the group that underwent surgery (HR0.23 (0.12, 0.43) p < 0.001).

Conclusion: Bariatric surgery may reduce risk for HF and AF in patients with T2D and obesity, speculatively via positive cardiovascular and renal effects. Obesity treatment with surgery may also be a valuable alternative in selected patients with T2D and HF.

Background and aims: Risk factors for lower limb amputation (LLA) in individuals with diabetes have been under-studied. We examined how demographic and socioeconomic, medical and life-style risk factors may be associated with LLA in people with newly diagnosed diabetes.

Materials and methods: We conducted a cohort study using Swedish national register-linked data. We identified, through the Swedish national diabetes register, all individuals 18 years or older with an incident diabetes diagnosis and no previous amputation from 2007 to 2016. These individuals were followed from the date of the diagnosis to amputation, emigration, death, or the end of the study in 2017, whichever occurred first. Several national Swedish registers were used to obtain data on incident LLA and potential risk factors, including demographic and socioeconomic, medical and lifestyle variables. Variables with more than 40% missing data were excluded from the analysis. The cohort consisted of 66,569 individuals, where of 133 hadan amputation. Cox proportional hazards models were used to obtain hazard ratio (HR) with 95% confidence interval (CI) for associations between demographic and socioeconomic, medical and lifestyle vari-ables and amputation risk. Both unadjusted and mutually adjusted models were fitted.

Results: During the median follow-up time of 4 years there were in total 133 LLA. Based on the model mutually adjusting for all variables, higher age, HR 1.08 (95% CI, 1.05 - 1.10) per year, and being divorced compared with being married, HR 1.67 (1.07 - 2.60) showed positive association. Male sex indicated higher risk, HR 1.57 (1.06 - 2.34). Individuals with an increased foot risk at baseline had increased risk for LLA compared to individuals with healthy feet (neuropathy/angiopathy, HR 4.12 (2.84 - 5.98), previous wounds, HR 8.26 (3.29 - 20.74), ongoing severe foot disease, HR 11.24 (4.82 - 26.23). Insulin treatment compared with diet-only treatment showed HR 2.03 (1.10 - 3.74). Hypertension and HbA1c were not statistically significantly associated with LLA risk. People with obesity had a statistically significant lower risk, HR 0.46 (0.29 - 0.75), compared with individuals with normal weight. Smoking was associated with an increased risk compared with no smoking, HR 1.99 (1.28 - 3.09). Finally, low physical activity (<1 time/week) was associated with an increased risk with a HR of 2.05 (1.30 - 3.23) compared with daily physical activity.

Conclusion: This study found a higher risk for LLA among people with higher age, male sex, who were divorced, who had a higher foot risk group, who were on insulin treatment, lower physical activity levels, and who were smoking. Obesity was associated with lower risk for LLA. Thus, these variables may have important roles in LLA risk among individuals with diabetes.

Increasing diabetes prevalence has been reported in most European countries in the last 20 years. In this study we report on the development of prevalence and incidence of diabetes from 1972 to 2001 in Laxa, a rural community in central Sweden. A diabetes register was established at the primary healthcare centre (PHCC) in Laxa, beginning in 1972 and based on data from clinical records at the PHCC, nearby hospitals and private practitioners in the area. In addition, case-finding procedures involving 85% of the residents aged 35 to 79 years old was performed from 1983 onwards. During the study period a total of 776 new diabetes cases was found, 36 type 1 diabetes mellitus and 740 type 2 diabetes mellitus. The age-standardised incidence rates for type 1 diabetes mellitus and type 2 diabetes mellitus were 0.15 and 3.03 cases per 1,000 population, respectively. No increase in incidence over time was detected for either forms of diabetes. Age-standardised prevalence for women and men increased from 28.3 and 25.9, respectively, per 1,000 in 1972 to 45 and 46.3 per 1,000 in 1988 (p < 0.0001), thereafter falling to a mean of 43.5 per 1,000 for women, while men had a mean of 44.9 per 1,000 for the rest of the study period. The prevalence of diabetes mellitus in Laxa is high, but has not increased during the last 13 years. The incidence rate was relatively stable over the whole 30-year period.

People living with diabetes have many medical devices available to assist with disease management. A critical aspect that must be considered is how systems for continuous glucose monitoring and insulin pumps communicate with each other and how the data generated by these devices can be downloaded, integrated, presented and used. Not only is interoperability associated with practical challenges, but also devices must adhere to all aspects of regulatory and legal frameworks. Key issues around interoperability in terms of data ownership, privacy and the limitations of interoperability include where the responsibility/liability for device and data interoperability lies and the need for standard data-sharing protocols to allow the seamless integration of data from different sources. There is a need for standardised protocols for the open and transparent handling of data and secure integration of data into electronic health records. Here, we discuss the current status of interoperability in medical devices and data used in diabetes therapy, as well as regulatory and legal issues surrounding both device and data interoperability, focusing on Europe (including the UK) and the USA. We also discuss a potential future landscape in which a clear and transparent framework for interoperability and data handling also fulfils the needs of people living with diabetes and healthcare professionals.

Background and aims: This 52 week, parallel-arm, open-label, phase 3 study compared two doses of the once weekly GLP-1 receptor agonist dulaglutide (DU) versus bedtime insulin glargine, all combined with pre-meal insulin lispro with or without metformin, in patients with type 2 diabetes mellitus inadequately controlled on conventional insulin therapy. Insulin glargine and insulin lispro were titrated to attempt to reach glycaemic targets.

Materials and methods: Patients (N = 884; mean baseline characteristics: age 59.4 years; duration of diabetes 12.7 years; HbA1c 8.5%; body weight 91.1 kg; BMI 32.5 kg/m2; total daily insulin dose 56 U) were randomised (1:1:1) to once weekly DU 1.5 mg, DU 0.75 mg, or bedtime insulin glargine titrated-to-target. The primary objective was to compare the change in HbA1c from baseline of DU 1.5 mg with insulin glargine at 26 weeks for noninferiority (margin 0.4%) and if met, then superiority was tested.

Results: At 26 and 52 weeks, both DU doses were statistically superior to insulin glargine for HbA1c change from baseline. Insulin glargine was associ-ated with greater fasting serum glucose reduction compared with both DU doses. The mean prandial insulin doses at 26 weeks were 93 U for DU 1.5 mg, 97 U for DU 0.75 mg, and 68 U for insulin glargine. The insulin glargine dose was 65 U. Similar insulin doses were observed at 52 weeks. Body weight decreased with DU 1.5 mg and increased with DU 0.75 mg and insulin glar-gine at 52 weeks. The rate of documented symptomatic hypoglycaemia (≤3.9 mmol/L) at 52 weeks was 31.0, 35.0,and 39.9 events/patient/year for DU 1.5 mg, DU 0.75 mg, and insulin glargine, respectively. The number of severe hypoglycaemia events was 11 for DU 1.5 mg, 15 for DU 0.75 mg, and 22 for insulin glargine. Nausea, diarrhoea, and vomiting were more common with DU 1.5 mg (25.8%, 16.6%, and 12.2%, respectively) and DU 0.75 mg (17.7%, 15.7%, and 10.6%) versus insulin glargine (3.4%, 6.1%, and 1.7%).

Conclusion: DU compared to insulin glargine, both combined with insu-lin lispro, resulted in better glycaemic control, less body weight gain, no in-creased risk of hypoglycaemia, and more common reporting of gastrointes-tinal adverse events.

Background and aims: Automated insulin delivery (AID) systems help people living with diabetes (PwD) manage their glucose levels using automated insulin dose adjustment. Numerous studies provide evidence on AID systems effectiveness and the significant improvement of glycemic outcomes across diverse PwD populations. The aim of this study is to assess both the clinical and economic impact of AID compared to multiple daily insulin (MDI) or continuous subcutaneous insulin infusion (CSII) treatments in conjunction with continuous glucose monitoring (CGM) in Sweden.

Materials and methods: The IQVIA Core Diabetes Model v.10 was used to simulate 1000 individuals from different groups; pediatrics with type 1 diabetes (T1D), adults with uncontrolled T1D and adults with uncontrolled type 2 diabetes (T2D) on MDI across several time horizons (5, 15, 30 and 50 years). The corresponding mean baseline HbA1c levels in each group were 7.30%, 9.04% and 9.13%. After being randomized to an AID system all groups showed significant reductions of HbA1c levels: -0.40% vs. CSII+CGM, -1.42% vs. MDI+CGM and -1.30% vs. MDI + CGM respectively.

Results: The results suggest that across all time horizons AID therapy was associated with increased quality-adjusted life years (QALYs), risk reductions for long-term complications and direct cost savings. At 50 years, 22% [standard deviation (sd): 1.9%], 41% [sd: 1.9%] and 24% [sd: 2.4%] of events were averted in the pediatrics T1D, uncontrolled adults T1D and uncontrolled adults with T2D respectively. Direct costs were also reduced for all groups ranging from -8% to -22%. Incremental cost effectiveness ratio (ICER) for a 50 years’ time horizon was calculated based on QALY gains and total accumulated costs, resulting in -225,260 SEK/QALY [95% CI: -423,819 to -26,701] for the pediatric group, 154,684 SEK/QALY [95% CI: 139,594 to 169,774] for the uncontrolled T1D group and 562,065 SEK/QALY [95% CI: 507,326 to 616,803] for the uncontrolled T2D.

Conclusion: From a clinical perspective the analyzed groups would benefit from the use of AID systems, with risk reductions in diabetes-related complications both in the short- and in the long term. From an economic perspective, at a willingness-to-pay threshold of 500,000 SEK per QALY, AID systems are a cost-effective alternative to CSII and MDI in the pediatrics T1D, and uncontrolled adults T1D, and possibly cost-effective for uncontrolled T2D patient populations in Sweden. Therefore, AID systems are the therapeutic option that offer the maximum health gain while balancing health care costs for pediatrics and uncontrolled T1D and T2D on MDI.

AIMS/HYPOTHESIS: The weak relationship between insulin resistance and total serum triacylglycerols (TGs) could be in part due to heterogeneity of TG molecules and their distribution within different lipoproteins. We determined concentrations of individual TGs and the fatty acid composition of serum and major lipoprotein particles and analysed how changes in different TGs and fatty acid composition are related to features of insulin resistance and abdominal obesity.

METHODS: We performed lipidomic analyses of all major lipoprotein fractions using two analytical platforms in 16 individuals, who exhibited a broad range of insulin sensitivity.

RESULTS: We identified 45 different TGs in serum. Serum TGs containing saturated and monounsaturated fatty acids were positively, while TGs containing essential linoleic acid (18:2 n-6) were negatively correlated with HOMA-IR. Specific serum TGs that correlated positively with HOMA-IR were also significantly positively related to HOMA-IR when measured in very-low-density lipoproteins (VLDLs), intermediate-density lipoproteins (IDLs) and LDL, but not in HDL subfraction 2 (HDL(2)) or 3 (HDL(3)). Analyses of proportions of esterified fatty acids within lipoproteins revealed that palmitic acid (16:0) was positively related to HOMA-IR when measured in VLDL, IDL and LDL, but not in HDL(2) or HDL(3). Monounsaturated palmitoleic (16:1 n-7) and oleic (18:1 n-9) acids were positively related to HOMA-IR when measured in HDL(2) and HDL(3), but not in VLDL, IDL or LDL. Linoleic acid was negatively related to HOMA-IR in all lipoproteins.

CONCLUSIONS/INTERPRETATION: Serum concentrations of specific TGs, such as TG(16:0/16:0/18:1) or TG(16:0/18:1/18:0), may be more precise markers of insulin resistance than total serum TG concentrations.

AIMS/HYPOTHESIS: Distinct DNA methylation patterns have recently been observed to precede type 1 diabetes in whole blood collected from young children. Our aim was to determine whether perinatal DNA methylation is associated with later progression to type 1 diabetes.

METHODS: Reduced representation bisulphite sequencing (RRBS) analysis was performed on umbilical cord blood samples collected within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Study. Children later diagnosed with type 1 diabetes and/or who tested positive for multiple islet autoantibodies (n = 43) were compared with control individuals (n = 79) who remained autoantibody-negative throughout the DIPP follow-up until 15 years of age. Potential confounding factors related to the pregnancy and the mother were included in the analysis.

RESULTS: No differences in the umbilical cord blood methylation patterns were observed between the cases and controls at a false discovery rate <0.05.

CONCLUSIONS/INTERPRETATION: Based on our results, differences between children who progress to type 1 diabetes and those who remain healthy throughout childhood are not yet present in the perinatal DNA methylome. However, we cannot exclude the possibility that such differences would be found in a larger dataset.

AIMS/HYPOTHESIS: Metabolic dysregulation may precede the onset of type 1 diabetes. However, these metabolic disturbances and their specific role in disease initiation remain poorly understood. In this study, we examined whether children who progress to type 1 diabetes have a circulatory polar metabolite profile distinct from that of children who later progress to islet autoimmunity but not type 1 diabetes and a matched control group.

METHODS: We analysed polar metabolites from 415 longitudinal plasma samples in a prospective cohort of children in three study groups: those who progressed to type 1 diabetes; those who seroconverted to one islet autoantibody but not to type 1 diabetes; and an antibody-negative control group. Metabolites were measured using two-dimensional GC high-speed time of flight MS.

RESULTS: In early infancy, progression to type 1 diabetes was associated with downregulated amino acids, sugar derivatives and fatty acids, including catabolites of microbial origin, compared with the control group. Methionine remained persistently upregulated in those progressing to type 1 diabetes compared with the control group and those who seroconverted to one islet autoantibody. The appearance of islet autoantibodies was associated with decreased glutamic and aspartic acids.

CONCLUSIONS/INTERPRETATION: Our findings suggest that children who progress to type 1 diabetes have a unique metabolic profile, which is, however, altered with the appearance of islet autoantibodies. Our findings may assist with early prediction of the disease.

Several environmental contaminants, such as polychlorinated biphenyls, dioxins, bisphenol A and phthalates, have been linked to diabetes. We therefore investigated whether other kinds of contaminants, perfluoroalkyl substances (PFAS), also called perfluorinated compounds (PFCs), are also associated with diabetes.

The Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study investigated 1,016 men and women aged 70 years. Seven PFAS were detected in almost all participant sera by ultra-high performance liquid chromatograph/tandem mass spectrometry. Diabetes was defined as use of hypoglycaemic agents or fasting glucose > 7.0 mmol/l.

114 people had diabetes. In the linear analysis, no significant relationships were seen between the seven PFAS and prevalent diabetes. However, inclusion of the quadratic terms of the PFAS revealed a significant non-linear relationship between perfluorononanoic acid (PFNA) and diabetes, even after adjusting for multiple confounders (OR 1.96, 95% CI 1.19, 3.22, p = 0.008 for the linear term and OR 1.25, 95% CI 1.08, 1.44, p = 0.002 for the quadratic term). Perfluorooctanoic acid (PFOA) also showed such a relationship (p = 0.01). PFOA was related to the proinsulin/insulin ratio (a marker of insulin secretion), but none of the PFAS was related to the HOMA-IR (a marker of insulin resistance) following adjustment for multiple confounders.

PFNA was related to prevalent diabetes in a non-monotonic fashion in this cross-sectional study, supporting the view that this perfluoroalkyl substance might influence glucose metabolism in humans at the level of exposure seen in the general elderly population.

Background and aims: In previous studies on environmental contaminants and diabetes only a limited number of contaminants have been evaluated. The aim with the present study is therefore to obtain a comprehensive picture of the relationships between a large number of environmental contaminants and prevalent diabetes.

Materials and methods: In 10 examination cycles in The National Health and Nutrition Examination Survey (NHANES) (1999-2017) altogether 116 different environmental contaminants were evaluated in the circulation or urine in relation to prevalent diabetes. Similar analyses were also performed in the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS) study (n=1016, all aged 70 years, 50% women, 42 contaminants). The logistic regression models were adjusted for age, sex, race, education, BMI, alcohol intake, smoking and lipids.

Results: In a meta-analysis of the 10 NHANES examinations, thirty-six contaminants were significantly related to prevalent diabetes. Those contaminants represent a number of different classes, such as metals, PCBs, dioxins, furans, pesticides, PFAS, phthalates, and phenols. Some of these relationships were inverse, such as lead, cadmium, mercury, barium, cesium and strontium, some PFAS and furans, as well as benzo-phenone-3. In the smaller PIVUS study (119 prevalent diabetes cases), significant relationships similar to NHANES were seen for some PCBs, p,p´-DDE and lead. PFHxS and PFOA, showed inverse relationships also in PIVUS. The same was seen for mercury and cadmium.

Conclusion: Many environmental contaminants were related to diabetes in the NHANES study. Some of these relationships, mainly some metals and PFAS, were negative. Many of these results were similar in the smaller PIVUS study. These findings need be evaluated in prospective studies.

To investigate the relation between diabetes mellitus and the risk of renal cell cancer we carried out a population-based retrospective cohort study. Patients identified in the Swedish Inpatient Register who were discharged from hospitals with a diagnosis of diabetes mellitus between 1965 and 1983 formed a cohort of 153852 patients (80005 women and 73847 men). The cohort members were followed up to 1989 by record linkage to three nation-wide registries. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were computed using age-specific sex-specific and period-specific incidence and mortality rates derived from the entire Swedish population. After exclusion of the first year of observation, a total of 267 incidences of renal cell cancer (ICD-7:180.0) occurred in diabetic patients compared with the 182.4 that had been expected. Increased risks were observed in both women (SIR = 1.7, 95% confidence interval, CI = 1.4-2.0) and men (SIR = 1.3; 95 % CI = 1.1-1.6) throughout the duration of follow-up (1-25 years). A higher risk was seen for kidney cancer (ICD-7:180) mortality (SMR = 1.9; 95% CI = 1.7-2.2, women; SMR 1.7, 95% CI = 1.4-1.9, men). In comparison with the general population, patients with diabetes mellitus have an increased risk of renal cell cancer.

Background and aims: People with type 1 diabetes are known to be at heightened risk of common mental health problems. However, it remains unknown whether genetic liability contributes to the elevated risk. This study aimed to investigate the association and familial co-aggregation of type 1 diabetes with depression, anxiety and stress-related disorders.

Materials and methods: Using multiple Swedish nationwide registers, we obtained a population sample of individuals born 1973-2007 and still residing in Sweden at age 5. Individuals were linked to their biological parents, full-siblings, half-siblings, full-cousins and half-cousins. We obtained information from the National Patient Register (since 1973) on the diagnoses of type 1 diabetes, depression, anxiety and stress-related disorders using ICD codes and from the Prescribed Drug Register (since 2005) on the prescribed antidepressants and anxiolytics using ATC codes. Primary outcomes were any or specific diagnosis of 1) depression, 2) anxiety and 3) stress-related disorders. We examined a secondary outcome of using antidepressants or anxiolytics in those who resided in Sweden after 2005.

Results: In this cohort study of about 3.5 million individuals, 20005 (53.9% male) were diagnosed with childhood-onset type 1 diabetes (< 18 years of age, the median age at onset: 9.7). We used Cox models to estimate the association between type 1 diabetes and each outcome. Individuals were regarded as unexposed before diagnosis and exposed after. During a median follow-up of 22.2 years, individuals with type 1 diabetes were at a higher risk of all outcomes after adjusting for sex and birth year: any diagnosis (HR [95%CI]: 1.73 [1.67-1.80]), depression (1.93 [1.84-2.02]), anxiety (1.41[1.33-1.50]), stress-related disorders (1.75 [1.62-1.89]) and using antidepressants or anxiolytics (1.30 [1.26-1.34]). Familial co-aggregation was evaluated using Cox models, where an individual’s relative was regarded unexposed before the individual’s diabetes diagnosis and exposed after. Overall, higher risks of all outcomes were observed in relatives of individuals with diabetes and declined proportionally with decreasing genetic relatedness. Highest HRs were found in parents: any diagnosis (1.21 [1.16, 1.26]), depression (1.20 [1.13-1.26]), anxiety (1.22 [1.15, 1.30]), stress-related disorders (1.25 [1.17-1.34]) and using antidepressants or anxiolytics (1.18 [1.16, 1.21]). HRs decreased but remained significant in full-siblings after adjusting for sex and birth year of the sibling: any diagnosis (1.11 [1.05, 1.17]), depression (1.11 [1.03-1.19]), anxiety (1.10 [1.02, 1.1]), stress-related disorders (1.20 [1.08-1.32]) and using antidepressants or anxiolytics (1.05 [1.01, 1.09]). HRs decreased and were not significant in maternal and paternal half-siblings (HRs 0.90-1.10; 1.00-1.11), full-cousins (HRs 0.98-1.05) and half-cousins (HRs 0.80-1.02).

Conclusion: Our findings support existing evidence that individuals with childhood-onset type 1 diabetes were at higher risks of depression, anxiety, stress-related disorders and using antidepressants and anxiolytics and suggest that familial liability may contribute to these associations. The results highlight the importance of family support integrated with pediatric diabetes care.

Aims/hypothesis: The aim of this study was to investigate the effect of childhood-onset type 1 diabetes on the risk of subsequent neurodevelopmental disorders, and the role of glycaemic control in this association. We hypothesised that individuals with poor glycaemic control may be at a higher risk of neurodevelopmental disorders compared with the general population, as well as compared with individuals with type 1 diabetes with adequate glycaemic control.

Methods: This Swedish population-based cohort study was conducted using data from health registers from 1973 to 2013. We identified 8430 patients with childhood-onset type 1 diabetes (diagnosed before age 18 years) with a median age of diabetes onset of 9.6 (IQR 5.9-12.9) and 84,300 reference individuals from the general population, matched for sex, birth year and birth county. Cox models were used to estimate the effect of HbA(1c) on the risk of subsequent neurodevelopmental disorders, including attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders (ASD) and intellectual disability.

Results: During a median follow-up period of 5.6 years, 398 (4.7%) individuals with type 1 diabetes received a diagnosis of any neurodevelopmental disorder compared with 3066 (3.6%) in the general population, corresponding to an adjusted HR (HRadjusted) of 1.31 (95% CI 1.18, 1.46) after additionally adjusting for other psychiatric morbidity prior to inclusion, parental psychiatric morbidity and parental highest education level. The risk of any neurodevelopmental disorder increased with HbA(1c) levels and the highest risk was observed in patients with mean HbA(1c) >8.6% (>70 mmol/mol) (HRadjusted 1.90 [95% CI 1.51, 2.37]) compared with reference individuals without type 1 diabetes. In addition, when compared with patients with diabetes with HbA(1c) <7.5% (<58 mmol/mol), patients with HbA(1c) >8.6% (>70 mmol/mol) had the highest risk of any neurodevelopmental disorder (HRadjusted 3.71 [95% CI 2.75, 5.02]) and of specific neurodevelopmental disorders including ADHD (HRadjusted 4.16 [95% CI 2.92, 5.94]), ASD (HRadjusted 2.84 [95% CI 1.52, 5.28]) and intellectual disability (HRadjusted 3.93 [95% CI 1.38, 11.22]).

Conclusions/interpretation: Childhood-onset type 1 diabetes is associated with an increased risk of neurodevelopmental disorders, with the highest risk seen in individuals with poor glycaemic control. Routine neurodevelopmental follow-up visits should be considered in type 1 diabetes, especially in patients with poor glycaemic control.

Background and aims: Patients with diabetes mellitus have a worse prognosis after acute coronary syndromes than patients without diabetes. Outcomes in patients with diabetes after ST-segment elevation myocar-dial infarction (STEMI) in the era of modern interventional treatment and antiplatelet therapy are less well studied. The aim is to characterise outcomes and complications in a contemporary population with diabetes and STEMI undergoing primary percutaneous coronary intervention (PCI).

Materials and methods: In the registry-based randomised Thrombus Aspiration in ST-Elevation myocardial infarction in Scandinavia (TASTE) trial, 7244 patients with STEMI were randomised to undergo manual thrombus aspiration followed by PCI or to undergo PCI alone. Thrombus aspiration did not affect mortality at one year in the 1005 patients (13.9%) with diabetes [Hazard ratio (HR) 1.04; CI 0.69-1.58,p=0.839]. Therefore, all patients with diabetes, irrespective ofrandomisation in TASTE, were studied as one cohort. All patients were followed for incidence of all-cause mortality, myocardial infarction or stent thrombosis until one year after index event. HRs were calculated using a Cox proportional hazard regression model adjusted for comorbidities.

Results: Patients with diabetes were older (mean age 67.6 vs 66.0 years, p<0.001), more often had a previous myocardial infarction (19.9 vs 10.3%, p<0.001) and undergone previous PCI (17.3 vs 8.4%, p<0.001). Thrombus grade did not differ between patients with and without diabetes (Grade 0 to Grade 5, p=0.909) and neither did the type of affected coronary vessel. Pharmacological cardiovascular treatment did not differ between groups, but the use of drug eluting stents was higher in patients with diabetes (59.0 vs 48.4%, p<0.001). After adjustment for comorbidities, diabetes independently increased the risk for mortality (HR 1.57; CI 1.23-2.00, p<0.001), but was not an independent risk factor for future myocardial infarction or stent thrombosis.

Conclusion: Diabetes remained an adverse prognostic risk factor in this contemporary setting, resulting in increased one-year mortality in a large cohort of patients with STEMI treated with PCI. This was not influenced by thrombus aspiration and not explained by a higher thrombus burden or differences in cardiovascular medical therapy compared to patients without diabetes.

Background and aims: Bariatric surgery (BS) is an effective treatment for long-term weight loss in people with type 2 diabetes (T2D) and obesity. However, long-term prospective data on the efficacy and safety of BS with roux-en-y gastric bypass or sleeve gastrectomy in T2D populations are limited. AIMS: Evaluate the long-term effects of BS in people with T2D up to 14 years after surgery.

Materials and methods: A nationwide, matched, longitudinal, retrospective study based on data from the Swedish National Diabetes Registry (NDR) and the Swedish Obesity Surgery Registry (SOReg). Both registries cover more than 95% of all individuals with T2D and bariatric surgeries, respectively. A cohort of 8399 individuals with T2D (SOReg) who had undergone BS between 2007 and 2020 was matched by sex, age and BMI, with a control group from NDR who had not had surgery (n=8399). This study assessed the 28-day mortality rate after a CVD event, the long-term incidence of heart and kidney failure, psychiatric disorders and nutritional deficiencies. Data on outcomes were collected as ICD codes from the Swedish National Patient Registry and the Cause of Death Registry. Risks were quantified using unadjusted Cox regression models, yielding HR with 95% CI.

Results: In total, 16798 individuals with overweight or obesity were included and followed for up to 14 years. The mean BMI at the start of follow-up was 41±6 kg/m 2 , with a mean age of 49±10 years for both groups. The mean duration of T2D at baseline was 6.1 years for the control group and 6.5 years for the surgery group. The surgical group had slightly higher HbA1 c levels and education, but were less often single and had lower nicotine use (standardised mean difference, SMD >0.1). No significant differences were observed in cholesterol, eGFR, the prevalence of CVD, heart and kidney failure, psychiatric disorders, or nutritional deficiencies at baseline (SMD<0.1). During follow-up, the risk of heart failure, kidney failure, and death within 28 days of a CVD event was up to 45% lower in the surgically treated group compared to the controls (p <0.0001). However, the risk of hospitalisation for psychiatric disorders was increased after surgery (HR 1.21; 95% CI 1.13-1.29; p<0.0001). The surgically treated individuals also had a twofold increased risk of developing nutritional deficiencies compared to controls (HR 2.06; CI 1.84-2.31; p<0.0001) during the follow-up period.

Conclusion: This nationwide study shows that the benefits of bariatric surgery on CVD death, and heart and kidney failure for people with T2D are maintained in the long term. However, surgery increases the risk of suffering from psychiatric disorders or nutritional deficiencies for these individuals.

Aims/hypothesis: Our aim was to study the risk of renal disease in patients with type 1 diabetes (T1D) and coexisting coeliac disease (CD).

Methods: Individuals with T1D were defined as having a diagnosis of diabetes recorded at <= 30 years of age in the Swedish Patient Register between 1964 and 2009. Individuals with CD were identified through biopsy reports with villous atrophy (Marsh stage 3) from 28 pathology departments in Sweden between 1969 and 2008. We identified 954 patients with both T1D and CD. For each patient with T1D + CD, we selected five age- and sex-matched reference individuals with T1D only (n = 4,579). Cox regression was used to estimate the following risks: (1) chronic renal disease and (2) end-stage renal disease in patients with CD + T1D compared with T1D patients only.

Results: Forty-one (4.3%) patients with CD + T1D and 143 (3.1%) patients with T1D only developed chronic renal disease. This corresponded to an HR of 1.43 for chronic renal disease (95% CI 0.94, 2.17) in patients with CD + T1D compared with T1D only. In addition, for end-stage renal disease there was a positive (albeit statistically non-significant) HR of 2.54 (95% CI 0.45, 14.2). For chronic renal disease, the excess risk was more pronounced after >10 years of CD (HR 2.03, 95% CI 1.08, 3.79). Risk estimates were similar when we restricted our cohort to the following T1D patients: (1) those who had an inpatient diagnosis of T1D; (2) those who had never received oral glucose-lowering medication; and (3) those who had not received their first diabetes diagnosis during pregnancy.

Conclusions/interpretation: Overall this study found no excess risk of chronic renal disease in patients with T1D and CD. However, in a subanalysis we noted a positive association between longstanding CD and chronic renal disease in T1D.

Aims/hypothesis: Not all obese individuals display the metabolic disturbances commonly associated with excess fat accumulation. Mechanisms maintaining this ‘metabolically healthy obesity’ (MHO) are as yet unknown. We aimed to study different fat depots and transcriptional pathways in subcutaneous adipose tissue (SAT) as related to the MHO phenomenon.

Methods: Sixteen rare young adult obesity-discordant monozygotic (MZ) twin pairs (intra-pair difference (∆) in BMI ≥3 kg/m²), aged 22.8–35.8 years, were examined for detailed characteristics of metabolic health (subcutaneous, intra-abdominal and liver fat [magnetic resonance imaging/spectroscopy]), OGTT, lipids, adipokines and C-reactive protein (CRP). Affymetrix U133 Plus 2.0 chips were used to analyse transcriptomics pathways related to mitochondrial function and inflammation in SAT.

Results: Based on liver fat accumulation, two metabolically different subgroups emerged. In half (8/16) of the pairs (∆weight 17.1 ± 2.0 kg), the obese co-twin had significantly higher liver fat (∆718%), 78% increase in AUC insulin during OGTT and CRP, significantly more disturbance in the lipid profile and greater tendency for hypertension compared with the lean co-twin. In these obese co-twins, SAT expression of mitochondrial oxidative phosphorylation, branched-chain amino acid catabolism, fatty acid oxidation and adipocyte differentiation pathways were downregulated and chronic inflammation upregulated. In the other eight pairs (∆weight 17.4 ± 2.8 kg), the obese co-twin did not differ from the non-obese co-twin in liver fat (∆8%), insulin sensitivity, CRP, lipids, blood pressure or SAT transcriptomics.

Conclusions/interpretation: Our results suggest that maintenance of high mitochondrial transcription and lack of inflammation in SAT are associated with low liver fat and MHO.

AIMS/HYPOTHESIS: We examined whether analysis of lipids by ultra-performance liquid chromatography (UPLC) coupled to MS allows the development of a laboratory test for non-alcoholic fatty-liver disease (NAFLD), and how a lipid-profile biomarker compares with the prediction of NAFLD and liver-fat content based on routinely available clinical and laboratory data.

METHODS: We analysed the concentrations of molecular lipids by UPLC-MS in blood samples of 679 well-characterised individuals in whom liver-fat content was measured using proton magnetic resonance spectroscopy ((1)H-MRS) or liver biopsy. The participants were divided into biomarker-discovery (n = 287) and validation (n = 392) groups to build and validate the diagnostic models, respectively.

RESULTS: Individuals with NAFLD had increased triacylglycerols with low carbon number and double-bond content while lysophosphatidylcholines and ether phospholipids were diminished in those with NAFLD. A serum-lipid signature comprising three molecular lipids ('lipid triplet') was developed to estimate the percentage of liver fat. It had a sensitivity of 69.1% and specificity of 73.8% when applied for diagnosis of NAFLD in the validation series. The usefulness of the lipid triplet was demonstrated in a weight-loss intervention study.

CONCLUSIONS/INTERPRETATION: The liver-fat-biomarker signature based on molecular lipids may provide a non-invasive tool to diagnose NAFLD, in addition to highlighting lipid molecular pathways involved in the disease.

Background and aims: Established cardiovascular disease (eCVD) is associated with need for healthcare interventions, reduced work capacity and excess mortality. People with type 2 diabetes have increased risk and earlier onset of eCVD compared to people in general. The objective was to assess the burden of hospital-based care, days absent from work, associated costs, and excess mortality for people with type 2 diabetes with and without eCVD with comparison to matched controls.

Materials and methods: The study used a Swedish retrospective data-base cross-linking longitudinal individual-level data (2007-2016) from national population-based health, social insurance, and socio-economic registers for 454,983 people with type 2 diabetes and their matched controls (5:1 on year of birth, sex, and region of residence). Statuse CVD (coronary artery disease, stroke, amputation, periphery vascular disease, non-fatal cardiac arrest, or related interventions) was derivedf rom retrospective data 1997-2006 and updated at change of status 2007-2016. Use of hospital-based care, days absent from work (calendar days) and mortality used data 2007-2016. Regression analysis accounting for individual-level clustering was used for comparison to controls and to attribute costs of hospital-based care and days absent from work to eCVD and to individual complications considering multimorbidity. Excess mortality adjusted for age, sex, and educational level was attributed to eCVD using Cox proportional hazards.

Results: Thirty percent (n=136,135) of people with type 2 diabetes up to age 70 years were observed with eCVD≥1 observation year in 2007-2016 (women 24% n=43,847; men 34% n=92,288). The mean annual costs of hospital-based care for diabetes complications were EUR 2,758 (95% CI 2,729 to 2,787) of which EUR 2,461 (95% CI 2,432 to 2,490)were attributed to people with eCVD (89%). Main drivers of costs of hospital-based care for people withe CVD were acute myocardial infarction, angina pectoris, and stroke; but also end-stage renal disease (ESRD) andeye disease confirming that eCVD is associated with an increased burden from other complications. eCVD was a leading cause behind work absence for both diabetes and controls. People with type 2 diabetes <66 years had on average 146 days absent (95% CI 145-147) of which 68 days (47%) were attributed to eCVD. Controls had 106 days absent of which 63 days (59%) were attributed to eCVD. The annual cost of eCVD work absence was EUR 9,337 (95% CI 9,150 to9,523) per individual. The highest work absence was attributed to ESRD, stroke, and heart failure. Type 2 diabetes without eCVD did not differ from controls regarding mortality risk, but type 2 diabetes with eCVD had a four-fold risk of death hazard rate 4.13 (95% CI 4.10 to 4.18) adjusting for age, sex, and educational level.

Conclusion: This study assessed the size of the burden of eCVD-status in people with type 2 diabetes in three measures: 1) eCVD was associated with excess mortality; 2) 9 out of 10 EUR spent on hospital-based care for diabetes complications; and 3) even higher costs of days absent from work in the long-run. Reducing the risks of living with eCVD and post-poning the onset of eCVD remain central goals to reduce the burden of type 2 diabetes on the individual and on society.

Background and aims: Individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) have higher prevalence of type 2 diabetes (T2D) and impaired fasting glycemia. Given the role of the liver as main contributor to endogenous glucose production (EGP), we investigated if hepatic glucose fluxes were increased with worsening of liver histology, from liver steatosis (SL) to MASH with advanced fibrosis, and the interplay with adipose tissue lipolysis.

Materials and methods: The cohort comprised n=260 subjects with liver biopsy from the EPoS cohort (92/168 Female/Male; 153/109 noT2D/T2D; 58/202 SL/MASH), of whom n=206 had transcriptomics of liver biopsy (EPoS-RNA) and n=68 (EPoS-flux) had measurement of fasting EGP and adipose tissue lipolysis by stable-isotope (6,6- 2 H 2 -glucose and U- 2 H 5 -glycerol infusion.). Intra-hepatic glucose fluxes were estimated using genome-scale metabolic modeling (GSMM) of transcriptomic data and results were validated vs tracer measurements.

Results: Tracer-measured EGP and hepatic insulin resistance were increased with histological severity (mainly with fibrosis and inflammation, Kruskal-Wallis’ test p< 0.05) and correlated with insulin resistance and tracer-measured adipose tissue lipolytic flux (Pearson’s test p<0.0001), even in absence of T2D. GSMM-analysis showed that high EGP was due to increased gluconeogenesis and anaplerosis and was associated with excess substrates uptake, rather than changes in the expression of glucogenic genes. However, hepatic expression of genes involved in insulin signaling (IRS1, IRS2, and AKT2) was reduced with the worsening of liver fibrosis and the presence of T2D (Kruskal-Wallis’ test p< 0.05).

Conclusion: In MASLD, not only lipids but also glucose metabolism is impaired. The dysregulation of EGP is due to the elevated release of gluconeogenic substrates from peripheral tissues and to the impairment in insulin signaling, and is associated with the severity of hepatic fibrosis and inflammation, rather than steatosis. These findings contribute to improve our understanding of the mechanisms underlying the increased risk of hyperglycemia and T2D in subjects with MASH.

AIMS/HYPOTHESIS: Previous metabolomics studies suggest that type 1 diabetes is preceded by specific metabolic disturbances. The aim of this study was to investigate whether distinct metabolic patterns occur in peripheral blood mononuclear cells (PBMCs) of children who later develop pancreatic beta cell autoimmunity or overt type 1 diabetes.

METHODS: In a longitudinal cohort setting, PBMC metabolomic analysis was applied in children who (1) progressed to type 1 diabetes (PT1D, n = 34), (2) seroconverted to ≥1 islet autoantibody without progressing to type 1 diabetes (P1Ab, n = 27) or (3) remained autoantibody negative during follow-up (CTRL, n = 10).

RESULTS: During the first year of life, levels of most lipids and polar metabolites were lower in the PT1D and P1Ab groups compared with the CTRL group. Pathway over-representation analysis suggested alanine, aspartate, glutamate, glycerophospholipid and sphingolipid metabolism were over-represented in PT1D. Genome-scale metabolic models of PBMCs during type 1 diabetes progression were developed by using publicly available transcriptomics data and constrained with metabolomics data from our study. Metabolic modelling confirmed altered ceramide pathways, known to play an important role in immune regulation, as specifically associated with type 1 diabetes progression.

CONCLUSIONS/INTERPRETATION: Our data suggest that systemic dysregulation of lipid metabolism, as observed in plasma, may impact the metabolism and function of immune cells during progression to overt type 1 diabetes.

DATA AVAILABILITY: The GEMs for PBMCs have been submitted to BioModels (www.ebi.ac.uk/biomodels/), under accession number MODEL1905270001. The metabolomics datasets and the clinical metadata generated in this study were submitted to MetaboLights (https://www.ebi.ac.uk/metabolights/), under accession number MTBLS1015.

Background and aims: Loss of a first-degree family member in childhood constitutes a major psychological stressor, and is associated both with subsequent psychiatric and somatic morbidity. The potential influence on type 1 diabetes risk has however not yet been fully elucidated. In this study we therefore aimed to investigate the impact of childhood bereavement on type 1 diabetes risk.

Materials and methods: We conducted a population-based study in Sweden, encompassing 2,321,318 children born in Sweden January 1 1990 to December 31 2012. The follow up ended December 31 2013, at death of the child, type 1 diabetes diagnosis, emigration or when the child turned 19 years. All children were followed from the age of one, with exposure defined as death of a mother, father, or sibling. Type 1 diabetes diagnoses were extracted from the National Patient Register. We applied Cox proportional hazards models with attained age as time scale and loss of family member as a time varying variable, adjusting for potential confounders including parental type 1 diabetes, parental country of birth, and region of residence. We further categorized child age at bereavement as pre-school (1-6 years), school age (7-12 years) and teenage (13-18 years).

Results: During follow-up (median 10.8 years), 50,253 (2.2%) children experienced loss of a family member. Median age at loss was 9.6 years, and 32% of all deaths were categorized as traumatic (accident, suicide, violence, or other sudden unnatural deaths). In total 10,965 children were diagnosed with type 1 diabetes during follow-up and median age at diagnosis was 8.5 years. We observed no overall association between childhood bereavement and type 1 diabetes risk (crude HR 1.00, 95% CI 0.86-1.18, adjusted HR 0.96, 95% CI 0.82 -1.13). The risk was not influenced by sex of the child, cause of death of family member, or familial relationship to the deceased. However, we noted an association when the exposure occurred during the teenage years (adjusted HR 1.67, 95% CI 1.15-2.43).

Conclusion: Overall, childhood bereavement was not associated with the risk of type 1 diabetes, but the impact of childhood loss on type 1 diabetes may be modified by age at bereavement.

AIMS/HYPOTHESIS: The potential impact of childhood bereavement-a severe psychological stressor-on childhood type 1 diabetes development remains unclear. Here, we aimed to bridge this knowledge gap and assess whether bereavement characteristics influenced any impact.

METHODS: We conducted a register-based cohort study encompassing 3,598,159 children born in Sweden between 1987 and 2020. Childhood bereavement was defined as the death of a biological mother, father or sibling. Diagnosis of type 1 diabetes in childhood (<18 years) was ascertained through the National Patient Register. We applied a Cox proportional hazards regression model to investigate the impact of childhood bereavement on type 1 diabetes, while adjusting for potential confounders (including parental type 1 diabetes status, country of birth and demographic characteristics).

RESULTS: During follow-up, 86,226 children (2.4%) lost a family member, and 18,817 children (0.52%) were diagnosed with type 1 diabetes (median age at onset 9.1 years). We did not detect any overall association between childhood bereavement and type 1 diabetes (adjusted HR 1.04; 95% CI 0.93, 1.17). We found no influence of age at loss, cause of death, familial relationship to the deceased, and time since loss.

CONCLUSIONS/INTERPRETATION: In this large population-based Swedish study, we observed no evidence supporting a link between childhood bereavement and type 1 diabetes.

AIMS/HYPOTHESIS: Virally induced inflammatory responses, beta cell destruction and release of beta cell autoantigens may lead to autoimmune reactions culminating in type 1 diabetes. Therefore, viral capability to induce beta cell death and the nature of virus-induced immune responses are among key determinants of diabetogenic viruses. We hypothesised that enterovirus infection induces a specific gene expression pattern that results in islet destruction and that such a host response pattern is not shared among all enterovirus infections but varies between virus strains.

METHODS: The changes in global gene expression and secreted cytokine profiles induced by lytic or benign enterovirus infections were studied in primary human pancreatic islet using DNA microarrays and viral strains either isolated at the clinical onset of type 1 diabetes or capable of causing a diabetes-like condition in mice.

RESULTS: The expression of pro-inflammatory cytokine genes (IL-1-α, IL-1-β and TNF-α) that also mediate cytokine-induced beta cell dysfunction correlated with the lytic potential of a virus. Temporally increasing gene expression levels of double-stranded RNA recognition receptors, antiviral molecules, cytokines and chemokines were detected for all studied virus strains. Lytic coxsackievirus B5 (CBV-5)-DS infection also downregulated genes involved in glycolysis and insulin secretion.

CONCLUSIONS/INTERPRETATION: The results suggest a distinct, virus-strain-specific, gene expression pattern leading to pancreatic islet destruction and pro-inflammatory effects after enterovirus infection. However, neither viral replication nor cytotoxic cytokine production alone are sufficient to induce necrotic cell death. More likely the combined effect of these and possibly cellular energy depletion lie behind the enterovirus-induced necrosis of islets.