Abstract
Aim
Links between autism spectrum disorder (ASD) and autoimmune diseases, including Type 1 diabetes have been proposed. This study assessed the frequency of ASD in children with Type 1 diabetes in the T1D Exchange (T1DX) registry and the impact of ASD on characteristics of children with Type 1 diabetes.
Methods
Analysis included 10 032 participants aged < 18 years (median Type 1 diabetes duration 6.5 years, 48% female, 77% non-Hispanic White). Diagnosis of ASD was defined as autism, Asperger’s or pervasive developmental disorder.
Results
A diagnosis of ASD was recorded for 159 (1.58%) participants. Those with ASD were predominantly male (88% vs. 51% of those without ASD, P < 0.001) and slightly older (median 14 vs. 13 years, P = 0.022). Occurrence of diabetic ketoacidosis at Type 1 diabetes diagnosis was similar (35% vs. 41%, P = 0.161). Pump use was lower in those with ASD (51% vs. 63%, P = 0.005) but continuous glucose monitor use was similar (24% vs. 27%, P = 0.351). Median HbA1c was slightly lower in those with ASD [68 vs. 69 mmol/mol (8.4% vs. 8.5%), P = 0.006]. This difference was more pronounced after adjusting for confounders.
Conclusions
The frequency of ASD in the T1DX registry was similar to that in the general population. These data show that despite deficits in communication, occurrence of diabetic ketoacidosis was similar in youth with and without ASD. Pump use was less frequent in those with ASD, possibly due to sensory issues, although CGM use did not differ. The lower HbA1c may be due to a more regimented routine with ASD. Because comorbidities such as ASD complicate care of patients with Type 1 diabetes, further research is needed to support these children.
Introduction
Both Type 1 diabetes and autism spectrum disorder (ASD) are common chronic conditions that may present during childhood [1]. Both conditions have increased significantly in prevalence over the past several decades [2–6]. The prevalence of Type 1 diabetes has increased from 1 in 670 in 2001 to 1 in 515 in 2009 (30% increase in 8 years), while the estimated prevalence of ASD in the USA has increased from 1 in 68 in 2012 to 1 in 59 in 2014 (15% increase in 2 years) with a male preponderance of 4:1 [3,6–8]. The rising incidence of ASD may be attributed to changes in the criteria for diagnosis, increased awareness, increased prevalence, differences in study design or all these factors [2,3]. Criteria for the diagnosis of ASD, a neurodevelopmental disorder, in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) include both a social (pragmatic) communication disorder and restricted interests and repetitive behaviours [9]. In addition, people with ASD may have disturbances in sensory function that present as sensory hypersensitivity, sensory hyposensitivity or sensory-seeking behaviour [10]. Given the high prevalence of ASD and the extra challenges facing individuals with the condition, it is important to identify with which comorbidities ASD is associated. Individuals with ASD have higher rates of comorbidities including a number of autoimmune diseases [11–19]. Some of these studies have shown an increased prevalence of ASD in children with Type 1 diabetes compared with the general population, whereas others have shown no difference. Recently, the German/Austrian Diabetes Patient Follow-Up registry (DPV) examined clinical characteristics and metabolic control in youth (1–20 years) enrolled in the DPV registry with Type 1 diabetes and ASD [20]. The DPV data did not demonstrate a difference in prevalence of ASD in the youth with Type 1 diabetes. Given the challenges faced by children with ASD, we investigated how the dual diagnoses of Type 1 diabetes and ASD affect metabolic control, treatment or presentation of diabetes. Data from the T1D Exchange Clinic Network (T1DX) demonstrate that, in the USA, very few children with Type 1 diabetes are meeting HbA1c targets [21,22]. The DPV data, when controlled for age, gender, duration of diabetes and year of observation, show that Type 1 diabetes metabolic control is not affected by the additional diagnosis of ASD. However, the prevalence of ASDs is much lower in the DPV compared with the T1DX cohort [3,8,20,23].
The aims of this study were to estimate the frequency of ASD in youth with Type 1 diabetes enrolled in the T1DX registry and to assess the demographic and clinical characteristics of these youth compared with those without ASD. Specifically, does the diagnosis of ASD affect metabolic control or the treatment of Type 1 diabetes.
Participants and methods
The T1DX clinic network includes > 80 US-based paediatric and adult endocrinology practices. Details on eligibility criteria, informed consent process and data collection for the T1DX clinic registry have been published previously [22,24].
For this analysis, we included data on 10 032 T1DX clinic registry participants < 18 years old who underwent routine clinical examination between 1 June 2016 and 1 September 2017. Diagnosis of ASD was defined as a report of one or more of the following medical conditions in the clinic chart: ASD, autism, Asperger’s or pervasive developmental disorder. Pervasive development disorder includes disorders that result in delays in socialization and communication. Age, duration of diabetes, diabetes management characteristics, occurrence of diabetic ketoacidosis, occurrence of severe hypoglycaemia (defined as seizure or loss of consciousness), and diagnosis of concomitant diseases were obtained from clinic medical chart data extraction. Demographic information was reported by the participant or parent of the participant through completion of a comprehensive questionnaire.
Statistical analysis
Associations between ASD status and participant characteristics (demographic characteristics, duration of diabetes) were assessed using Fisher’s exact (categorical characteristics) and Wilcoxon rank-sum tests (continuous characteristics). Multivariable regression models were used to assess the association of ASD with diabetes management characteristics and the diagnosis of concomitant diseases. Where appropriate, the following factors were assessed for potential confounding with each outcome through a stepwise selection procedure: age, duration of diabetes, sex, race/ethnicity, socio-economic status and device use.
Data analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA). In view of the multiple comparisons, only P-values < 0.01 were considered statistically significant.
Results
Among the 10 032 participants, 159 (1.58%) had a diagnosis of ASD. Participants with ASD were slightly older (median 14 vs. 13 years, P = 0.022) and were more likely to be male (88% vs. 51%, P < 0.001) than those without ASD. (Table 1). A diagnosis of ASD was not associated with race/ethnicity, socio-economic status or diabetes duration (P ≥ 0.10 for all).
Table 1.
Association between autism spectrum disorder status and participant characteristics
| Overall (N = 10 032) | Autism spectrum disorder (n = 159) | No autism spectrum disorder (n = 9873) |
P-value* | |
|---|---|---|---|---|
| Participant characteristics | ||||
| Age (years); median (Q1, Q3) | 13 (10, 16) | 14 (12,16) | 13 (10,16) | 0.022 |
| Type 1 diabetes duration (years); median (Q1, Q3) | 6.5 (4.0, 9.2) | 6.8 (4.5, 9.2) | 6.5 (4.0, 9.2) | 0.369 |
| Sex (men) | 5184 (52) | 140 (88) | 5044 (51) | <0.001 |
| Race/ethnicity | 0.889 | |||
| White non-Hispanic | 7690 (77) | 123 (78) | 7567 (77) | |
| Black non-Hispanic | 653 (7) | 12 (8) | 641 (7) | |
| Hispanic or Latino | 1061 (11) | 16 (10) | 1045 (11) | |
| Other race/ethnicity | 549 (6) | 7 (4) | 542 (6) | |
| Annual household income ($) | 0.143 | |||
| < 50 000 | 2421 (32) | 46 (38) | 2375 (32) | |
| 50 000 to <75 000 | 1271 (17) | 24 (20) | 1247 (17) | |
| ≥ 75 000 | 3820 (51) | 51 (42) | 3769 (51) | |
| Parent education | 0.461 | |||
| Less than high school graduate | 962 (10) | 14 (9) | 948 (10) | |
| High school graduate/GED | 2676 (28) | 44 (29) | 2632 (28) | |
| Associate or bachelor’s degree | 3716 (39) | 65 (43) | 3651 (39) | |
| Masters, professional or doctorate degree | 2197 (23) | 27 (18) | 2170 (23) | |
| Insurance status | 0.781 | |||
| Private | 6634 (71) | 106 (72) | 6528 (71) | |
| Other | 2642 (28) | 40 (27) | 2602 (28) | |
| None | 95 (1) | 2 (1) | 93 (1) | |
| Clinical characteristics | ||||
| Diabetic ketoacidosis present at diagnosis | 3586 (41) | 47 (35) | 3539 (41) | 0.161 |
| ≥ 1 severe hypoglycaemic event in previous 12 months | 111 (1) | 3 (2) | 108 (1) | 0.423 |
| ≥ 1 diabetic ketoacidosis event in previous 12 months | 556 (6) | 11 (7) | 545 (6) | 0.410 |
| Pump use | 6201 (63) | 81 (52) | 6120 (63) | 0.005 |
| CGM use | 2565 (27) | 38 (24) | 2527 (27) | 0.351 |
| HbA1c; median (Q1, Q3) | 0.006 | |||
| HbA1c (mmol/mol) | 69 (61, 81) | 68 (60, 78) | 69 (61, 83) | |
| HbA1c (%) | 8.5 (7.7, 9.6) | 8.4 (7.6, 9.3) | 8.5 (7.7, 9.7) | |
| Blood glucose checks per day†; median (Q1, Q3) | 4.0 (3.0, 6.0) | 4.2 (3.9, 5.0) | 4.0 (3.0, 6.0) | 0.011 |
| Total cholesterol (mmol/mol); mean (sd) | 4.31 (0.87) | 4.06 (0.67) | 4.34 (0.87) | 0.070 |
| Total daily insulin per kg; mean (sd) | 0.9 (0.3) | 0.9 (0.4) | 0.9 (0.3) | 0.790 |
| Diagnosis of coeliac disease | 789 (8) | 13 (8) | 776 (8) | 0.408 |
| Diagnosis of thyroid disease | 1314 (13) | 22 (14) | 1292 (13) | 0.258 |
Unless otherwise stated, values are given as n (%).
GED, General Education Diploma; CGM, continuous glucose monitoring.
P-values for participant characteristics were calculated using Fisher’s exact and Wilcoxon rank-sum tests. P-values for clinical characteristics were calculated using a regression model adjusted for confounders.
CGM users have been excluded from blood glucose checks/day.
Participants with missing data: age (0%), Type 1 diabetes duration (0%), sex (0%), race/ethnicity (1%), annual household income (25%), parent education (5%), insurance status (7%), diabetic ketoacidosis at diagnosis (13%), ≥ 1 severe hypoglycaemic event (1%), ≥ 1 diabetic ketoacidosis event (<1%), pump use (2%), CGM use (4%), HbA1c (3%), blood glucose checks/day (11%), total cholesterol (65%), celiac disease (0%), thyroid disease (0%).
Frequency of diabetic ketoacidosis at diagnosis was similar in participants with ASD and those without (35% vs. 41%, respectively, P = 0.161), as shown in Table 1. Similarly, post diagnosis, the occurrences of diabetic ketoacidosis and severe hypoglycaemia within the past 12 months were not associated with ASD status (P = 0.426 and 0.410, respectively).
Participants with ASD were less likely to use an insulin pump (52% vs. 63%, respectively, P = 0.005); however, there was no difference in continuous glucose monitor (CGM) use (24% vs. 27% in participants without ASD, P = 0.351).
The difference in HbA1c between those with and without ASD was confounded by the significant difference in pump use and age between the two groups. Therefore, although the overall median HbA1c was only slightly lower [68 vs. 69 mmol/mol (8.4% vs. 8.5%)] in participants with ASD compared with those without, this difference was significant after adjusting for confounders (P = 0.006). Among those using both CGM and a pump, median HbA1c was 58 vs. 64 mmol/mol (7.5% vs. 8.0%) in those with and without ASD, respectively (Table 2). Among adolescents aged 13 years or over, HbA1c was 69 mmol/mol (8.5%) in those with ASD compared with 73 mmol/mol (8.8%) in those without (Table 3).
Table 2.
HbA1c by autism spectrum disorder status and device use
| Autism spectrum disorder | No autism spectrum disorder | |||
|---|---|---|---|---|
| N | Median (Q1, Q3) | N | Median (Q1, Q3) | |
| Device | ||||
| Pump and CGM | 26 | 2091 | ||
| HbA1c (mmol/mol) | (54, 74) | 64 (56, 72) | ||
| HbA1c (%) | 7.5 (7.1, 8.9) | 8.0 (7.3, 8.7) | ||
| Pump only | 49 | 3614 | ||
| HbA1c (mmol/mol) | 69 (64, 81) | 72 (63, 83) | ||
| HbA1c (%) | 8.5 (8.0, 9.6) | 8.7 (7.9, 9.7) | ||
| CGM only | 9 | 340 | ||
| HbA1c (mmol/mol) | 62 (54, 69) | 65 (57, 73) | ||
| HbA1c (%) | 7.8 (7.1, 8.5) | 8.1 (7.4, 8.8) | ||
| None | 65 | 2994 | ||
| HbA1c (mmol/mol) | 72 (64, 78) | 75 (64, 90) | ||
| HbA1c (%) | 8.7 (8.0, 9.3) | 9.0 (8.0, 10.4) | ||
CGM, continuous glucose monitoring.
Table 3.
Participant characteristics by age group and autism spectrum disorder status
| <13 years | ≥13 years | |||
|---|---|---|---|---|
| Autism spectrum disorder (n = 57) | No autism spectrum disorder (n = 4097) | Autism spectrum disorder (n = 102) | No autism spectrum disorder (n = 5776) | |
| Age (years); median (Q1, Q3) | 10 (8, 12) | 10 (7, 11) | 16 (14, 17) | 15 (14, 16) |
| Type 1 diabetes duration (years); median (Q1, Q3) | 5 (4, 8) | 5 (3, 7) | 8 (6, 10) | 8 (6, 11) |
| Pump use; n (%) | 33 (59) | 2611 (65) | 48 (48) | 3509 (62) |
| CGM use; n (%) | 21 (38) | 1364 (35) | 17 (17) | 1163 (21) |
| HbA1c; median (Q1, Q3) | ||||
| HbA1c (mmol/mol) | 66 (56, 76) | 67 (60, 76) | 69 (63, 80) | 73 (63, 87) |
| HbA1c (%) | 8.2 (7.3, 9.1) | 8.3 (7.6, 9.1) | 8.5 (7.9, 9.5) | 8.8 (7.9, 10.1) |
| Blood glucose checks/day; median (Q1, Q3) | 5.0 (4.0, 7.0) | 5.0 (4.0, 7.0) | 4.0 (3.0, 5.0) | 4.0 (2.0, 5.0) |
| Total cholesterol (mmol/mol); mean (sd) | 3.95 (20) | 166 (28) | 158 (28) | 169 (37) |
| Total daily insulin per kg; mean (sd) | 0.8 (0.4) | 0.8 (0.3) | 1.0 (0.3) | 0.9 (0.3) |
The median number of blood glucose checks/day was higher (4.2 vs. 4.0, P = 0.011) and mean total cholesterol tended to be lower (4.06 vs. 4.36 mmol/mol, P = 0.070) in participants with ASD compared with those without. ASD status was not associated with total daily dose of insulin/kg or concomitant thyroid or coeliac disease (Table 1). Table 3 summarizes the characteristics of the subgroups of children (<13 years) and adolescents (≥13 years) by ASD diagnosis.
Discussion
Because youth with Type 1 diabetes visit a healthcare provider more frequently than healthy youth, one would expect that ASD might be diagnosed more often in youth with Type 1 diabetes. However, at 1.58%, the frequency of ASD in T1DX participants was similar to the general US population rate of 1.69% [3,8]. The DPV data also demonstrated a similar frequency of ASD in those with Type 1 diabetes compared with the general population (0.24% vs. 0.38%, respectively). However, the frequency of ASD in the German/Austrian population is 0.38%, much lower than in the USA [23]. Interestingly, our data show a male to female ratio of 7.4:1 in participants in the T1DX compared with 4:1 in the general US population for ASD diagnosis [3,8]. The DPV data showed a 5.8:1 ratio of males to females in youth with ASD and Type 1 diabetes compared with a 2–3:1 ratio of males to females in the general German population with ASD [20,23].
Despite difficulties with social communication, the data from both the T1DX and DPV studies demonstrated no difference in diabetic ketoacidosis at presentation and during treatment, as well as no differences in severe hypoglycaemia events. These data may reflect increased parental involvement and monitoring of youth with ASD and Type 1 diabetes. Given the developmental challenges and mental health problems associated with ASD, it is not surprising that pump use is less frequent in those with ASD in the T1DX registry. The fact that there was no significant difference in CGM use may be a reflection of the overall low CGM use among children, or the reduced potential for safety concerns with these devices. The lower HbA1c, higher number of daily blood glucose checks and trend toward lower cholesterol might suggest that those with ASD are more regimented in their diabetes and dietary management or that those with ASD are more likely to have an adult manage their diabetes through adolescence.
One major limitation of these findings is that the T1DX registry does not represent all children in the USA. The T1DX consists of more than 76 sites that were invited to participate in the registry representing 33 states [22]. Thirty-eight sites are primarily paediatric, 21 care for both paediatrics and adults, and 58 sites are academic. Also, because of the high representation of academic centres, there may be an over-representation of children with the dual diagnosis of Type 1 diabetes and ASD, or over-representation of children who are more difficult to manage. By contrast, there may also be an over-representation of families who have access to or are aware of the latest technologies. Another limitation to the interpretation of our data is the fact that the diagnosis of ASD, autism, Asperger’s or pervasive developmental disorder was based on reports by the participants’ families or primary care provider.
In the T1DX, the frequency of ASD is similar to the prevalence in the general US population, although with a higher male to female ratio. Our data combined with the DPV data suggest that there is not a link between ASD and Type 1 diabetes. Both sets of data showed a higher male prevalence for both ASD and Type 1 diabetes than seen in the population of ASD without Type 1 diabetes. Future studies should aim to look for a genetic link between Type 1 diabetes and ASD that would be seen only in males. Despite challenges associated with a diagnosis of ASD, these children with both ASD and Type 1 diabetes have better HbA1c than children without ASD, without an increase in occurrence of diabetic ketoacidosis or severe hypoglycaemia. This may reflect increased parental involvement with these youth or may be a reflection of their tendency for increased regimentation. Future studies should evaluate the factors, whether behavioural or genetic, that may affect the better HbA1c seen in children with Type 1 diabetes and ASD.
What’s new?
Type 1 diabetes and autism spectrum disorder are common chronic diseases that present in childhood; their combined presence adds challenges to care.
This is the first large study of the co-existence of both diseases in the USA. The data demonstrate a frequency of autism spectrum disorder in participants in a large national diabetes database that is similar to that in the general population.
Further research on the effect autism has on the management of diabetes is needed.
Acknowledgements
Supported through the Leona M. and Harry B. Helmsley Charitable Trust.
Funding sources
Funding for the study was provided by the Leona M. and Harry B. Charitable Trust.
Grant number: P30DK036836
Footnotes
Competing interests
None declared.
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