Childhood-onset Type Research Articles

The relationship between islet autoantibody status and the genetic risk of type 1 diabetes in adult-onset type 1 diabetes

Aims/hypothesisThe reason for the observed lower rate of islet autoantibody positivity in clinician-diagnosed adult-onset vs childhood-onset type 1 diabetes is not known. We aimed to explore this by assessing the genetic risk of type 1 diabetes in autoantibody-negative and -positive children and adults.MethodsWe analysed GAD autoantibodies, insulinoma-2 antigen autoantibodies and zinc transporter-8 autoantibodies (ZnT8A) and measured type 1 diabetes genetic risk by genotyping 30 type 1 diabetes-associated variants at diagnosis in 1814 individuals with clinician-diagnosed type 1 diabetes (1112 adult-onset, 702 childhood-onset). We compared the overall type 1 diabetes genetic risk score (T1DGRS) and non-HLA and HLA (DR3-DQ2, DR4-DQ8 and DR15-DQ6) components with autoantibody status in those with adult-onset and childhood-onset diabetes. We also measured the T1DGRS in 1924 individuals with type 2 diabetes from the Wellcome Trust Case Control Consortium to represent non-autoimmune diabetes control participants.ResultsThe T1DGRS was similar in autoantibody-negative and autoantibody-positive clinician-diagnosed childhood-onset type 1 diabetes (mean [SD] 0.274 [0.034] vs 0.277 [0.026], p=0.4). In contrast, the T1DGRS in autoantibody-negative adult-onset type 1 diabetes was lower than that in autoantibody-positive adult-onset type 1 diabetes (mean [SD] 0.243 [0.036] vs 0.271 [0.026], p<0.0001) but higher than that in type 2 diabetes (mean [SD] 0.229 [0.034], p<0.0001). Autoantibody-negative adults were more likely to have the more protective HLA DR15-DQ6 genotype (15% vs 3%, p<0.0001), were less likely to have the high-risk HLA DR3-DQ2/DR4-DQ8 genotype (6% vs 19%, p<0.0001) and had a lower non-HLA T1DGRS (p<0.0001) than autoantibody-positive adults. In contrast to children, autoantibody-negative adults were more likely to be male (75% vs 59%), had a higher BMI (27 vs 24 kg/m2) and were less likely to have other autoimmune conditions (2% vs 10%) than autoantibody-positive adults (all p<0.0001). In both adults and children, type 1 diabetes genetic risk was unaffected by the number of autoantibodies (p>0.3). These findings, along with the identification of seven misclassified adults with monogenic diabetes among autoantibody-negative adults and the results of a sensitivity analysis with and without measurement of ZnT8A, suggest that the intermediate type 1 diabetes genetic risk in autoantibody-negative adults is more likely to be explained by the inclusion of misclassified non-autoimmune diabetes (estimated to represent 67% of all antibody-negative adults, 95% CI 61%, 73%) than by the presence of unmeasured autoantibodies or by a discrete form of diabetes. When these estimated individuals with non-autoimmune diabetes were adjusted for, the prevalence of autoantibody positivity in adult-onset type 1 diabetes was similar to that in children (93% vs 91%, p=0.4).Conclusions/interpretationThe inclusion of non-autoimmune diabetes is the most likely explanation for the observed lower rate of autoantibody positivity in clinician-diagnosed adult-onset type 1 diabetes. Our data support the utility of islet autoantibody measurement in clinician-suspected adult-onset type 1 diabetes in routine clinical practice.Graphical abstract

The incidence of childhood-onset type 1 diabetes, time trends and association with the population composition in Sweden: a 40 year follow-up

Aims/hypothesisDuring the 1980s and 1990s, the incidence of childhood-onset type 1 diabetes more than doubled in Sweden, followed by a plateau. In the present 40 year follow-up, we investigated if the incidence remained stable and whether this could be explained by increased migration from countries reporting lower incidences.MethodsWe used 23,143 incident cases of childhood-onset type 1 diabetes reported between 1978 and 2019 to the nationwide, population-based Swedish Childhood Diabetes Registry and population data from Statistics Sweden. Generalised additive models and ANOVA were applied to analyse the effects of onset age, sex, time trends and parental country of birth and interaction effects between these factors.ResultsThe flattening of the incidence increase seems to remain over the period 2005–2019. When comparing the incidence of type 1 diabetes for all children in Sweden with that for children with both parents born in Sweden, the trends were parallel but at a higher level for the latter. A comparison of the incidence trends between individuals with Swedish backgrounds (high diabetes trait) and Asian backgrounds (low diabetes trait) showed that the Asian subpopulation had a stable increase in incidence over time.Conclusions/interpretationIn Sweden, the increase in incidence of childhood-onset type 1 diabetes in the late 20th century has been approaching a more stable albeit high level over the last two decades. Increased immigration from countries with lower incidences of childhood-onset type 1 diabetes does not provide a complete explanation for the observed levelling off.Graphical abstract

Pantoprazole Induced Acute Interstitial Nephritis in a Patient with Diabetic Ketoacidosis.

Childhood-onset type 1 diabetes mellitus (DM) is a common chronic metabolic disease associated with life-threatening complications. Diabetic ketoacidosis (DKA) is an acute complication of type 1 DM that has significant mortality mostly due to cerebral edema. Other putative complications of DKA include hypokalemia, hypophosphatemia, hypoglycemia, intracerebral and peripheral venous thrombosis, rhabdomyolysis, acute pancreatitis, and acute kidney injury (AKI) (Murdoch IA et al., Acta Paediatr 1993; 82:498-500).

Childhood-onset type 1 diabetes and attention-deficit/hyperactivity disorder with educational attainment: A population-based sibling-comparison study.

To examine the association of childhood-onset type 1 diabetes (T1D) and attention-deficit/hyperactivity disorder (ADHD) with educational outcomes from compulsory school to university. Using multiple Swedish nationwide registers, we followed up on 1,474,941 individuals born in Sweden from 1981-1995 to December 31, 2013. Associations of T1D and ADHD with achieving educational milestones (from compulsory school to university) and school performances were estimated using logistic and linear regression models and sibling comparison models. Compared to their peers, children with both T1D and ADHD were less likely to achieve any of the educational attainments, including completing compulsory school (adjusted OR [aOR] [95% CI]: 0.43 [0.26, 0.72]), be eligible to and finishing upper secondary school (0.26 [0.19, 0.36], 0.24 [0.17, 0.35], respectively), and starting university (0.38 [0.17, 0.90]). The odds of achieving these educational milestones were substantially lower in children with ADHD alone (aORs: 0.14-0.44), but were slightly worse or no differences in children with T1D alone (aORs: 0.86-1.08). All associations above remained similar in the sibling comparison models. Children and adolescents with both T1D and ADHD had long-term educational underachievement, with ADHD being the major contributor. Our findings suggest the importance of assessing ADHD in children with T1D and targeted support for minimising the education gap between the affected children and their peers.

Association and Familial Coaggregation of Childhood-Onset Type 1 Diabetes With Depression, Anxiety, and Stress-Related Disorders: A Population-Based Cohort Study.

OBJECTIVETo estimate the association and familial coaggregation of childhood-onset type 1 diabetes with depression, anxiety, and stress-related disorders.RESEARCH DESIGN AND METHODSThis was a population-based cohort study with use of data from Swedish nationwide registers. A total of ∼3.5 million individuals born in Sweden 1973–2007 were linked to their biological parents, full siblings and half-siblings, and cousins. Cox models were used to estimate the association and familial coaggregation of type 1 diabetes with depression, anxiety, and stress-related disorders.RESULTSIndividuals diagnosed with childhood-onset type 1 diabetes (n = 20,005) were found to be at greater risks of all outcomes: any psychiatric diagnosis (adjusted hazard ratio [aHR] 1.66 [95% CI 1.59–1.72]) or specific diagnoses of depression (1.85 [1.76–1.94]), anxiety (1.41[1.33–1.50]), and stress-related disorders (1.75 [1.62–1.89]), as well as use of antidepressants or anxiolytics (1.30 [1.26–1.34]), compared with individuals without type 1 diabetes. Overall, relatives of individuals with type 1 diabetes were at elevated risks of developing these outcomes, with the highest risks seen in parents (aHRs 1.18–1.25), followed by full siblings (aHRs 1.05–1.20), and the magnitudes of risk estimates appear proportional to familial relatedness.CONCLUSIONSThese results support existing evidence that children and adolescents with type 1 diabetes are at greater risks of developing depression, anxiety, and stress-related disorders and indicate that shared familial factors might contribute to these elevated risks. Our findings highlight the need for psychological consulting for children and their families in diabetes care. Quantitative and molecular genetic studies are warranted to further understand the etiology of these psychiatric disorders in type 1 diabetes.

IgA-Type Enterovirus Antibodies Are Increased among Adults and Children with Recently Diagnosed Type 1 Diabetes.

Enteroviruses (EV) are among the leading environmental triggers of childhood-onset type 1 diabetes (T1D). Our aim was to determine the prevalence of antibodies against EV and their association with T1D in different age groups (n = 62), including young adults, and to compare these data with results from HLA-matched control participants (n = 62). IgA, IgG, and IgM antibodies against EV were detected. IgA EV antibodies were present in 46.8% of participants with T1D (median level 10.9 EIU) and in 11.3% of controls (median level 3.4 EIU). IgA EV positivity and higher level of IgA EV antibodies were both significant risk factors for T1D (odds ratio (OR) 8.33; 95% confidence interval (CI) 2.52–27.6; p = 0.0005 and OR 1.04; 95% CI 1.01–1.06; p = 0.0105, respectively). Importantly, the prevalence of IgA EV antibodies in the subgroups of both children and young adults was also significantly different between participants with T1D and their matched controls (p = 0.0089 and p = 0.0055, respectively). Such differences were not seen for IgG and IgM EV antibodies. However, IgG EV antibodies were associated with 65 kDa glutamic acid decarboxylase antibodies, but not with zinc transporter 8 and protein tyrosine phosphatase IA2 antibodies. The genotype frequency of PTPN22 (rs2476601) and IFIH1 (rs1990760) was not associated with EV positivity. This study showed that EV infections may be an important disease-promoting factor of T1D not only in childhood-onset but also in adult-onset T1D. However, to further confirm this association, direct virological studies are needed in the latter T1D group.

Childhood and adolescent onset type 2 diabetes mellitus (CAT2DM): The yoke of the young diabetics

AimsTo study the prevalence, clinical characteristics, complications, and treatment pattern of childhood – and adolescent-onset type 2 diabetes among young diabetes patients (<25 years at diagnosis). MethodsWe conducted an observational retro-prospective study among young diabetics at a tertiary care hospital between January 2012 and December 2020. A detailed medical assessment, laboratory evaluation, and screening for complications were done in all patients. ResultsWe analyzed a total of 130 patients, with a mean age of 23 years. Forty-seven (36.2%) had a family history. Osmotic symptoms and weight loss were the predominant features, 4 had ketosis, but 34.65% were detected incidentally. Seventy-two (55.2%) were overweight and obese. Most of the patients were uncontrolled, with a mean HbA1c of 9.4 ± 2.8%. There were 1.5%, 1.5%, and 2.3% of retinopathy, nephropathy, and neuropathy cases detected at evaluation. Seventy-nine (60.8%) patients were controlled on oral hypoglycemic agents (OHAs) alone, and 45 (34.5%) needed insulin at onset for control. ConclusionThis study on CAT2DM emphasizes the fact that diabetes has emerged over the past decade among young adults. Screening may be needed in high-risk groups, and prompt, effective treatment may change prognosis significantly.

Long term risk of heart failure in individuals with childhood-onset type 1 diabetes

BackgroundWe aimed to evaluate the risk of heart failure in young adults with childhood-onset type 1 diabetes from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study. We also examined risk factors and microvascular disease burden associated with the incidence of heart failure. MethodsParticipants in the EDC study without known baseline heart failure (n = 655) were enrolled and then followed for 25 years. “Any” heart failure comprised the underlying cause of death, primary reason for hospitalization, EDC clinic examination findings or self-report of a physician diagnosis. “Hard” heart failure was determined only by the underlying cause of death or primary reason for hospitalization. Incidence rates for heart failure were estimated using Poisson models. Cox models were constructed to examine the associations between risk factors and microvascular disease burden with incident heart failure. ResultsThe mean baseline age and diabetes duration were 27(8) years and 19 (8) years. Incidence for any and hard heart failure were 3.4 and 1.8/1000 person-years. Diabetes duration, ever smoking and triglycerides were significant risk factors of any heart failure; longer diabetes duration, lower estimated glomerular filtration rate and higher white blood cell count significantly predicted hard heart failure. A gradient association was observed between the number of microvascular disease (from 0 to 3) and “hard” heart failure endpoint but not “any” clinically defined heart failure. ConclusionYoung adults with long-duration type 1 diabetes had a high risk of heart failure. As microvascular disease burden increases so does the risk of heart failure independently of diabetes duration, A1c and coronary artery disease.

Adequate metabolic control at early stages of childhood onset type 1 diabetes prevent diabetic neuropathy: a 30 year follow up study

Adequate metabolic control at early stages of childhood onset type 1 diabetes prevent diabetic neuropathy: a 30 year follow up study

Child Neurology: A Case Series of Heterogeneous Neuropsychiatric Symptoms and Outcome in Very Early-Onset Narcolepsy Type 1.

Narcolepsy type 1 is a central disorder of hypersomnolence characterized by excessive daytime sleepiness, cataplexy (i.e., sudden loss of muscle tone during wakefulness triggered by emotions), and REM sleep-related manifestations that can present with a peculiar phenotype when arising at a pediatric age. Several features of childhood-onset narcolepsy type 1 are also common in neuropsychiatric conditions; discrete neuropsychiatric comorbidity has also been demonstrated. Here, we report on 3 children with very early narcolepsy type 1. All 3 patients had psychiatric features at the time of symptom onset coupled with peculiar motor disturbances. The course of narcolepsy symptoms also paralleled neuropsychiatric symptoms, suggesting a possible intrinsic link between sleep and psychological features. Multidisciplinary management is mandatory for pediatric narcolepsy type 1 since prompt disease management addressing neuropsychiatric symptoms could lead to better clinical outcomes and quality of life.

End-stage renal disease: incidence and prediction by coronary heart disease, and educational level. Follow-up from diagnosis of childhood-onset type 1 diabetes throughout Norway 1973–2017

To investigate incidence of end-stage renal disease (ESRD), and the association of education and coronary heart disease (CHD) with ESRD, in subjects throughout Norway followed from the diagnosis of childhood-onset type 1 diabetes. All new onset cases of type 1 diabetes 1973-2016 were followed for CHD and ESRD in nation-wide registries through 2017. Ten matched controls per case were selected from the National Population Register. Cox regression was used to estimate hazard ratios, and probabilities were estimated by the cumulative incidence function accounting for competing risk. Among 9311 patients with type 1 diabetes, 130 developed ESRD with a probability of ESRD after 40 years of 5.5%. The rate was 35-fold higher than in controls (aHR=35.5, 95% CI 23.1 - 54.6). Higher education was associated with lower risk of ESRD compared to low education (aHR=0.14, 95% CI 0.07 - 0.27). Diagnosed CHD was associated with 14-fold increased rate of ESRD (aHR=14.3, 95% CI 9.2 - 22.2). The hazard rate of ESRD was 35-fold higher in cases compared to controls. CHD was associated with a 14-fold increased rate of subsequent ESRD, while higher education was associated with substantially lower rate of ESRD.

Selection bias and multiple inclusion criteria in observational studies

Abstract Objectives Spurious associations between an exposure and outcome not describing the causal estimand of interest can be the result of selection of the study population. Recently, sensitivity parameters and bounds have been proposed for selection bias, along the lines of sensitivity analysis previously proposed for bias due to unmeasured confounding. The basis for the bounds is that the researcher specifies values for sensitivity parameters describing associations under additional identifying assumptions. The sensitivity parameters describe aspects of the joint distribution of the outcome, the selection and a vector of unmeasured variables, for each treatment group respectively. In practice, selection of a study population is often made on the basis of several selection criteria, thereby affecting the proposed bounds. Methods We extend the previously proposed bounds to give additional guidance for practitioners to construct i) the sensitivity parameters for multiple selection variables and ii) an alternative assumption free bound, producing only logically feasible values. As a motivating example we derive the bounds for causal estimands in a study of perinatal risk factors for childhood onset Type 1 Diabetes Mellitus where selection of the study population was made by multiple inclusion criteria. To give further guidance for practitioners, we provide a data learner in R where both the sensitivity parameters and the assumption-free bounds are implemented. Results The assumption-free bounds can be both smaller and larger than the previously proposed bounds and can serve as an indicator of settings when the former bounds do not produce feasible values. The motivating example shows that the assumption-free bounds may not be appropriate when the outcome or treatment is rare. Conclusions Bounds can provide guidance in a sensitivity analysis to assess the magnitude of selection bias. Additional knowledge is used to produce values for sensitivity parameters under multiple selection criteria. The computation of values for the sensitivity parameters is complicated by the multiple inclusion/exclusion criteria, and a data learner in R is provided to facilitate their construction. For comparison and assessment of the feasibility of the bound an assumption free bound is provided using solely underlying assumptions in the framework of potential outcomes.

A comparative study on the incidence of type 1 diabetes mellitus between children of North African migrants and Italian children in Emilia-Romagna region, Italy.

Evaluate the incidence of type 1 diabetes in North African vs Italian children aged 0-14years from 1 January 2015, to 31st December 2018, in Emilia-Romagna region, Italy. Clinical and epidemiological data about childhood onset type 1 diabetes in Emilia Romagna region were retrospectively collected by the regional centers of pediatric diabetology and matched using 3 different data sources. 365 new cases were diagnosed. Total cumulative incidence was 15.4/100,000/year. North African cases showed a cumulative incidence of 53.8/100,000/year, statistically significant compared to cumulative incidence of the Italian cases alone 13.1/100,000/year (p value < 0.001). The annual incidence did not differ in the 4years for both groups. Conclusion: The incidence of type 1 diabetes in the pediatric age (0 14 years) was significantly higher in the North African population than in the Italian one, suggesting that a mix of genetic and environmental factors may have caused the increase in newly diagnosed cases. • The incidence of type 1 diabetes largely varies worldwide. • Study on immigrants helped to better understand the interplay role between genetics and environment. • This is the first study focused on the incidence of children and adolescents of North African migrants in Italy. • The incidence of children and adolescents of North African migrants in Emilia Romagna region, Italy, seems to be higher than that reported in the host countries, and, above all, than that reported in highest-incidence countries in Europe and in the world.

Risk of cancer in young and middle‐aged adults with childhood‐onset type 1 diabetes in Sweden—A prospective cohort study

In persons with type 1 diabetes, the risk of cancer remains controversial. We wanted to examine the excess risk of cancer in a large population-based cohort diagnosed with type 1 diabetes before 15years of age. From 1July 1977 to 31 December 2013, we prospectively and on a national scale included 18,724 persons (53% men) with childhood-onset type 1 diabetes. For each person with type 1 diabetes, we selected four referents, matched for the date at birth and municipality of living at the time when the case developed diabetes. Cases and referents were linked to national registers of cancer and of the cause of death. A total of 125 persons (61% women) with diabetes had 135 different cancers, all diagnosed after the diabetes diagnosis. The median duration from diabetes diagnosis to first cancer diagnosis was 19years (interquartile range 10-26). The median age at cancer diagnosis in the diabetes group was 28years (interquartile range 20-35). The overall standardized incidence ratio (95%), using the Swedish general population as referents for women with diabetes was 1.28 (1.02, 1.58) and when comparing women with diabetes with matched referents, we found a hazard ratio of 1.42 (1.10, 1.85). No elevated risk was seen for men. Cancers of the breast and testis were the most common types in women and men respectively. Women with childhood-onset type 1 diabetes had a small but significantly elevated risk of cancer. No such tendency was seen for men. The reason behind this is unclear.

Alarming increase in ketoacidosis in children and adolescents with newly diagnosed type 1 diabetes during the first wave of the COVID-19 pandemic in Israel.

To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel. A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position. During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P= 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P= 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P= 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P= 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P= 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P= 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P= 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P= 0.002). The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

30-Year Cardiovascular Disease in Type 1 Diabetes: Risk and Risk Factors Differ by Long-term Patterns of Glycemic Control.

We hypothesized that there is heterogeneity in long-term patterns of glycemic control with respect to cardiovascular disease (CVD) development in type 1 diabetes and that risk factors for CVD differ by glycemic control pattern. Thus, we estimated associations between data-derived latent HbA1c trajectories and 30-year CVD risk in the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset (<17 years old) type 1 diabetes. Participants (n = 536 with two or more HbA1c measurements [median 6] and CVD-free at baseline; mean age 27 and diabetes duration 18 years) were followed from 1986 to 1988 to 2016 to 2018 to ascertain CVD incidence (CVD death, myocardial infarction, stroke, coronary revascularization or blockage ≥50%, ischemic electrocardiogram, or angina). Latent HbA1c trajectories and their association with time-to-CVD incidence were simultaneously assessed using joint latent class mixed models. Two HbA1c trajectories with respect to differential CVD risk were identified: low (HbA1c ∼8% [64 mmol/mol] and improving over follow-up, 76% of cohort) and high (HbA1c ∼10% [86 mmol/mol] and stable, 24%). Overall, 30-year CVD incidence was 47.4% (n = 253); major adverse cardiovascular event incidence was 31.0% (n = 176). High HbA1c was associated with threefold increased CVD risk versus low HbA1c. Both groups had similar age and diabetes duration. Non-HDL cholesterol and estimated glomerular filtration rate were associated with CVD risk only in low HbA1c; albumin excretion rate was associated with CVD risk only in high HbA1c. These risk factor differences suggest that pathways to CVD may differ by glycemic control, potentially resulting in important implications for prognosis in type 1 diabetes.

Neural correlates of slower gait in middle-aged persons with childhood-onset type 1 diabetes mellitus: The impact of accelerated brain aging

AimsWe aimed to determine if neuroimaging characteristics of gray and white matter are associated with gait speed in middle-aged individuals with childhood-onset type 1 diabetes (T1D), and whether associations are independent of diabetic peripheral neuropathy (DPN) status. MethodsIn a cohort of 100 middle-aged adults with childhood-onset T1D (aged 49.2 ± 7.0 years, 50F/50M), we assessed cross-sectional associations of DPN, severity of white matter hyperintensities (WMH; Fazekas score), and regional gray matter volume (GMV) with gait speed. Associations were tested separately and combined in linear regression models adjusted for diabetes duration and locomotor risk factors. ResultsAverage gait speed was 1.3 m/s, with 52% of participants walking below the age-appropriate range of 1.3–1.5 m/s. In separate models, higher WMH severity (β = −0.27, p = 0.01) and smaller caudate GMV (β = −0.21, p = 0.04), but not DPN (β = −0.20, p = 0.08) were associated with slower gait speed. When combined, only WMH severity remained significant (β = −0.22, p = 0.04). ConclusionsMore than half of participants walked more slowly than expected based on age. Gait speed was slower among those with more severe WMH independent of locomotor risk factors. Gait slowing in middle-aged persons with T1D may reflect brain changes, and thus, deserve further attention.

Adult-Onset Type 1 Diabetes: Current Understanding and Challenges.

Recent epidemiological data have shown that more than half of all new cases of type 1 diabetes occur in adults. Key genetic, immune, and metabolic differences exist between adult- and childhood-onset type 1 diabetes, many of which are not well understood. A substantial risk of misclassification of diabetes type can result. Notably, some adults with type 1 diabetes may not require insulin at diagnosis, their clinical disease can masquerade as type 2 diabetes, and the consequent misclassification may result in inappropriate treatment. In response to this important issue, JDRF convened a workshop of international experts in November 2019. Here, we summarize the current understanding and unanswered questions in the field based on those discussions, highlighting epidemiology and immunogenetic and metabolic characteristics of adult-onset type 1 diabetes as well as disease-associated comorbidities and psychosocial challenges. In adult-onset, as compared with childhood-onset, type 1 diabetes, HLA-associated risk is lower, with more protective genotypes and lower genetic risk scores; multiple diabetes-associated autoantibodies are decreased, though GADA remains dominant. Before diagnosis, those with autoantibodies progress more slowly, and at diagnosis, serum C-peptide is higher in adults than children, with ketoacidosis being less frequent. Tools to distinguish types of diabetes are discussed, including body phenotype, clinical course, family history, autoantibodies, comorbidities, and C-peptide. By providing this perspective, we aim to improve the management of adults presenting with type 1 diabetes.

Data driven patterns of nutrient intake and coronary artery disease risk in adults with type 1 diabetes.

Dietary intake provides a potential intervention target to reduce the high risk for coronary artery disease (CAD) in type 1 diabetes. This effort aimed to identify patterns of nutrient intake in young/middle-aged adults with type 1 diabetes and to examine associations between those patterns and development of CAD. Principal component analysis was used to derive nutrient intake patterns among 514 individuals with childhood-onset (<17years old) type 1 diabetes aged 18+ years and free of CAD (defined as CAD death, myocardial infarction, revascularization, ischemia, or study physician diagnosed angina). Cox models were used to assess the association between nutrient patterns and CAD incidence over 30-years of follow-up. Three nutrient principal components (PC) were identified: PC1 (high caffeine and saccharin intake), PC2 (high alcohol and caffeine, lower intake of essential nutrients) and PC3 (higher fiber/micronutrients, low alcohol). In unadjusted Cox models, only PC1 (negatively) and PC2 (positively) were associated with CAD risk. These associations were no longer significant after adjusting for diabetes duration. Important dietary components underlying the three patterns identified may have been influenced by diabetes duration or age. Future research can continue to explore patterns of nutrient intake over time and CAD development in type 1 diabetes.

CONGENITAL MUSCULAR DYSTROPHIES: EP.69 LAST STRONG: LAMA2 and SELENON to study trial readiness, outcome measures and natural history

SELENON (SEPN1)-related myopathy (SELENON-RM) is a rare congenital myopathy characterized by slowly progressive proximal muscle weakness, early onset rigidity of the spine and respiratory insufficiency. Patients with mutations in LAMA2 gene causing merosin-deficient congenital muscular dystrophy (LAMA2-MD) have a similar clinical phenotype, with a heterogenous disease spectrum ranging from a severe, early-onset congenital (complete laminin α2 deficiency) to a mild, childhood-onset limb-girdle type muscular dystrophy (partial laminin α2 deficiency). For both SELENON-RM and LAMA2-MD, no curative treatment options exist, yet promising preclinical studies are ongoing. Currently, there is a paucity on natural history data. Appropriate clinical and functional outcome measures need to be selected to reach trial readiness. We are performing a natural history study in Dutch-speaking patients diagnosed with SELENON-RM (n=10, mean age=18 (3-50) years, F=3, M=7) and LAMA2-MD (n=20, mean age=19 (3-50) years, F=15; M=5). Patients have four visits over a period of 1.5 year, with an interval of six months. At all visits, they undergo standard neurological examination, hand-held dynamometry (age≥5 years), functional measurements, questionnaires (patient report and/or parent proxy; age≥2 years), muscle ultrasound including ultrasound of the diaphragm, pulmonary function tests (spirometry, maximal inspiratory and expiratory pressure, sniff nasal inspiratory pressure; age≥5 years), and accelerometry for eight days; at visit one and three, they undergo cardiac evaluation (electrocardiogram, echocardiography), X-ray of the spine (age≥2 years), Dual-energy X-ray absorptiometry (DEXA-)scan (age≥2 years) and full body magnetic resonance imaging (MRI) (age≥10 years). Hereby we aim to describe the natural history of patients diagnosed with SELENON-RM or LAMA2-MD and to select outcome measures for future clinical trials. Our natural history study is an essential step to reach trial readiness.