Abstract
Context
Normal growth throughout childhood and adolescence is considered an indicator of adequate glycaemic control in patients with type 1 diabetes. While it has been suggested that growth in type 1 diabetes is reduced, the literature is conflicting and differences in final adult height and the risk of short stature depending on glycaemic control remain largely unexplored.
Objective
This work aims to assess adult height outcomes across levels of glycemic control in children and adolescents with type 1 diabetes, as well as to investigate the effect of sex, age at disease onset, and timing of glycemic control in relation to puberty.
Methods
In this population-based Swedish cohort study, we collected data on glycemic control and height from specialist health-care visits of all individuals with childhood-onset type 1 diabetes in the National Diabetes Register. Using linear and logistic regression, we compared suboptimal (glycated hemoglobin A1c [HbA1c] 53-75 mmol/mol [7.0-9.0%]) and poor (HbA1c > 75 mmol/mol [>9.0%]) to optimal (HbA1c < 53 mmol/mol [<7.0%]) glycemic control in relation to final adult height and the risk of short stature.
Results
Poor glycemic control was associated with lower final adult height (−2.91 cm [95% CI, –3.48 to −2.33] for males, −1.83 cm [−2.42 to −1.23] for females) as well as a higher risk of short stature in males (odds ratio 1.90 [1.07-3.35]) but not in females (0.73 [0.36-1.51]). For females, adult height was lower only among those with type 1 diabetes since before puberty and if the poor glycemic control occurred before puberty. For males, adult height was lower irrespective of their age at diabetes onset, but only if they had poor glycemic control during or after puberty.
Conclusion
Poor glycemic control after the onset of type 1 diabetes, compared to optimal control, is associated with lower adult height in males and females. The prepubertal period seems to be more critical for females than males.
Keywords: epidemiology, type 1 diabetes, childhood, glycemic control, height
Type 1 diabetes is one of the most common chronic diseases of childhood, characterized by insulin deficiency due to autoimmune-mediated β-cell destruction. Insulin therapy aims to mitigate the arising increased glucose levels that, if sustained, lead to worsened symptoms in the short term and are associated with potentially irreversible consequences in the long-term such as macrovascular or microvascular complications, or impaired linear growth (1, 2).
While it is established that rapid early life or infant weight gain can be a risk factor for the development of type 1 diabetes (3), evidence also suggests that growth after disease onset is altered (4), for instance in relation to height velocity (5, 6) and pubertal growth (7). However, it is still uncertain if these growth impairments affect the potential of reaching full expected adult height. Results are conflicting; some have shown that children with type 1 diabetes are shorter in adult age (8-10), others have found no major effect on adult height (11-13). Recent reviews argue that children with type 1 diabetes may reach normal or only slightly lower final adult height, potentially thanks to adequate treatment especially in those with optimal glycemic control, routinely measured as glycated hemoglobin A1c (HbA1c) (2, 4, 14).
Poor glycemic control is associated with reduced growth and height velocity throughout childhood and puberty in individuals with type 1 diabetes (2). Moreover, following an increasing compared to a stable HbA1c trajectory in childhood seems to be linked to a lower z score for height (15). Less is known, however, on the relationship between poor glycemic control and adult height, although negative correlations between HbA1c and adult height have been shown (9). Additionally, the effect of sex, age at disease onset, and timing of glycemic control in relation to puberty remains to be further investigated. These factors are important to understand given biological differences in physiological growth between the sexes, a potentially more severe disease phenotype associated with an earlier onset of disease, as well as reports of delayed puberty and reduced pubertal growth spurt among those with type 1 diabetes, due to hormonal dysregulation such as increased insulin resistance (4, 16, 17).
Furthermore, previous studies on type 1 diabetes, glycemic control, and adult height suffer from limitations such as selected and small sample sizes, older retrospective studies not reflecting current clinical practice, resource-poor settings that might not equate to Western health-care systems where pediatric diabetes is managed in tertiary care, and lack of adjustments for confounding factors in statistical models. These issues could potentially be circumvented using prospectively collected data from national health-care and quality registers containing a wide range of information on the entire Swedish pediatric type 1 diabetes population.
The aim of this study was therefore to examine the association between glycemic control throughout childhood or adolescence and adult height outcomes in individuals with type 1 diabetes in a nationwide cohort. Also, we aimed to report sex-specific associations throughout as well as to investigate the effect of age at disease onset and timing of glycemic control in relation to puberty.
Materials and Methods
Study Design and Participants
This register-based cohort study was composed of all individuals with childhood type 1 diabetes registered in the National Diabetes Register (NDR); a nationwide Swedish quality register that collects clinical measurements and registrations from each health-care visit for diabetes, starting in 2000 in patients younger than 18 years, with increasing coverage on inclusion of each pediatric clinic in Sweden and near full coverage since 2005 (18).
By linking to other national sociodemographic and health-care registers (Fig. 1), we had access to routinely and prospectively collected data through 2020 on birth country, death and migration (Total Population Register), parental information (Multi-generation Register), and educational attainments (Longitudinal integrated database for labor market studies), all from Statistics Sweden, as well as diagnoses from inpatient (1987 to present) and outpatient (2001 to present) hospital care (National Patient Register [NPR]), medication prescriptions (Prescribed Drug Register [PDR]), and information on the pregnancy and perinatal period of each individual (Medical Birth Register), all from the National Board of Health and Welfare.
Figure 1.
Flowchart of study sample formation based on linkage of national registers. LISA is the Swedish acronym for the Longitudinal integrated database for labor market studies held by Statistics Sweden.
The Swedish Ethical Review Authority approved the study and waived the requirement for informed consent from study participants due to its register-based nature with data linked using individuals' unique personal identification numbers but pseudonymized for research purposes. Furthermore, children or their parents have the choice to opt out of the NDR.
For our study sample (see Fig. 1), we included individuals born in Sweden between 1982 and 2002 who were registered in the NDR during childhood. Date of their type 1 diabetes onset was defined as first registration of type 1 diabetes in the NDR, first diagnosis of type 1 diabetes in the NPR, or first insulin prescription in the PDR, whichever came first. For this study, follow-up started at the first registration of type 1 diabetes in the NDR and ended at the age by which final height is expected to have been reached, that is, age 20 years for males and age 18 years for females (henceforth used as the definition of adult age) (19). Thus, only individuals having at least one specialist visit registered in the NDR at adult age by the end of data availability (through 2020) were included (n = 12 623). Those with height values missing in all registrations at adult age (n = 445) were excluded, alongside those who had any emigration or immigration record before adult age (n = 83) to only include those who remained in Sweden during the entire follow-up.
Exposure
From health-care visits for type 1 diabetes (including routine checkups in specialist outpatient clinics recommended for children in Sweden every 3-6 months and all hospitalizations), HbA1c values from blood tests were routinely transferred to the NDR. Based on these values, we determined glycemic control as the mean HbA1c value during follow-up, time-weighted by averaging annual HbA1c means for each individual patient. HbA1c is measured in mmol/mol (International Federation of Clinical Chemistry and Laboratory Medicine calibrated). As recommended, we also report HbA1c in percentages according to the National Glycohemoglobin Standardization Program (20). Mean HbA1c was further categorized based on target values for glycemic control from the International Society for Pediatric and Adolescent Diabetes guidelines (21): optimal control less than 53 mmol/mol (<7.0%), suboptimal control 53 to 75 mmol/mol (7.0%-9.0%), and poor control greater than 75 mmol/mol (>9.0%), henceforth referred to as “category of mean HbA1c.”
Several measures of glycemic control were used. The main exposure was category of mean HbA1c over the entire follow-up. Three additional secondary exposures were 1) mean HbA1c values as a continuous variable to understand changes in height associated with smaller increments of HbA1c; 2) time with poor glycemic control (total number of years during follow-up) as a way of measuring cumulative exposure to high HbA1c levels (mean >75 mmol/mol [>9.0%]); 3) category of glycemic control based on mean HbA1c values before, during, or after puberty, to understand if timing of exposure in relation to puberty (and thereby to pubertal growth) is of importance. Since individual-level information on puberty is not recorded in the NDR, we defined the pubertal window as aged 10 to 15 years for girls and 11 to 16 years for boys, based on pubertal growth models for a Swedish population (19).
Outcome
Our primary outcome was final adult height (cm), measured any time during adult age and registered in the NDR. Values below 100 cm, or above 225 cm for women and 240 cm for men, were considered incorrect and disregarded (22).
The secondary outcome was short stature (0/1) defined as a z score for final adult height less than −2 SDs (23), calculated based on Swedish reference values (24). For a subgroup of the study sample with a registration of height at type 1 diabetes onset recorded in the NDR, an additional secondary outcome was change in z score for height, that is, the difference in height z score at disease onset and the z score for attained final adult height.
Covariates
Directed acyclic graphs (25) based on a priori subject-matter knowledge informed our choice of additionally including covariates related to the individual's disease (age at and calendar year of type 1 diabetes onset), their comorbidities (any other autoimmune disease, asthma), or their parents’ characteristics (type 1 diabetes, maternal height, country of birth, highest level of educational attainment). Age at type 1 diabetes onset was treated continuously in years but also categorized if disease first occurred before, during, or after puberty using the aforementioned pubertal definition. Any other autoimmune disease, asthma, and parental type 1 diabetes were defined using previously used and well-validated definitions based on diagnoses in the NPR or medication prescriptions in the PDR (26-29). Maternal height (cm) in adult age was retrieved from antenatal care records in the Medical Birth Register. Parental country of birth was categorized as both parents born in Sweden, one parent born abroad, or both parents born abroad. Highest level of parental educational attainment was defined as the highest category of completed education (compulsory, secondary, or university) in mothers or fathers.
Statistical Analysis
Descriptive statistics are presented as means with SD for continuous variables, and frequencies and percentages for categorical variables, all stratified by category of mean HbA1c and separately for males and females. Associations between all measures of glycemic control and height outcomes were estimated using linear regression (final adult height and change in z score for height) and logistic regression (short stature) models, yielding mean differences and odds ratios (ORs), respectively, with 95% CIs. All models were adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal adult height, parental type 1 diabetes, parental country of birth, and highest parental educational attainment. All analyses are presented separately for males and females. Sex differences were assessed using likelihood ratio tests comparing models with and without interaction terms for sex. Similarly, we tested for effect modification by category of age at type 1 diabetes onset in relation to puberty. To more flexibly model the association between mean HbA1c and final adult height without assuming linearity, we also used restricted cubic splines with 6 knots placed at each HbA1c quintile (with additional knots at 30 and 90 mmol/mol) to allow for nonlinearity between low and high HbA1c levels.
Sensitivity Analyses
A sensitivity analysis was performed to evaluate the robustness of the definition of puberty using 3 alternative windows of puberty. First, using the same definition for boys and girls (aged 10-15 years) to ensure that any potential sex differences were not explained by differing age intervals between the sexes. Second, using an extended window of puberty (aged 10-17 for boys and 9-16 years for girls) to more certainly capture both earlier onset and the later end of puberty. Third, using a shifted window of puberty (aged 12-17 for boys, 11-16 years for girls), allowing for a cleaner prepubertal group and representing the delayed pubertal onset that may occur due to type 1 diabetes.
Statistical significance levels were set at a 2-sided P value of less than .05, and all analyses were conducted in Stata Statistical Software: release 17 (StataCorp LLC).
Results
After the exclusion of 528 individuals (see Fig. 1), the final study sample (n = 12 095) consisted of 6699 (55.4%) males and 5396 (44.6%) females. Of those with poor glycemic control during follow-up (HbA1c > 75 mmol/mol [>9.0%], n = 2156), 51.9% were male, and 48.1% were female. In comparison to optimal glycemic control, individuals with suboptimal or poor control were younger at onset of type 1 diabetes, were diagnosed in earlier calendar years, had more concomitant autoimmune disease or asthma, and more often had parents with type 1 diabetes, parents born abroad, or with a lower level of educational attainment (Table 1). Background characteristics were in general comparable among males and females, although females had an earlier onset of diabetes. For instance, whereas mean age at diagnosis for males with poor glycemic control was 9.8 years (SD 4.6), females were diagnosed earlier (8.7 years, SD 3.8), with a lower proportion diagnosed after puberty (5.1% in females compared to 9.9% in males).
Table 1.
Characteristics of the study sample, presented according to glycemic control during follow-up, stratified by sex
| Category of mean HbA1ca, n (%) | |||
|---|---|---|---|
| Optimal < 53 mmol/mol (<7.0%) | Suboptimal 53-75 mmol/mol (7.0-9.0%) |
Poor > 75 mmol/mol (>9.0%) |
|
| A. Males (n = 6699) | 1309 (60.7) | 4271 (54.9) | 1119 (51.9) |
| Age at type 1 diabetes onset, mean (SD), y | 14.4 (3.8) | 10.2 (4.7) | 9.8 (4.6) |
| Before pubertyb | 213 (16.3) | 2283 (53.5) | 636 (56.8) |
| During pubertyb | 570 (43.5) | 1527 (35.8) | 372 (33.2) |
| After pubertyb | 526 (40.2) | 461 (10.8) | 111 (9.9) |
| Calendar year of type 1 diabetes onset | |||
| 1982-1989 | 8 (0.6) | 114 (2.7) | 55 (4.9) |
| 1990-1999 | 115 (8.8) | 1214 (28.4) | 467 (41.7) |
| 2000-2009 | 644 (49.2) | 2340 (54.8) | 490 (43.8) |
| 2010-2020 | 542 (41.4) | 603 (14.1) | 107 (9.6) |
| Any other autoimmune disease | 68 (5.2) | 528 (12.4) | 134 (12.0) |
| Asthma | 35 (2.7) | 203 (4.8) | 57 (5.1) |
| Parental factors | |||
| Type 1 diabetes (maternal or paternal) | 106 (8.1) | 459 (10.8) | 131 (11.7) |
| Country of birth | |||
| Both parents in Sweden | 1158 (88.5) | 3703 (86.7) | 939 (83.9) |
| One parent outside Sweden | 99 (7.6) | 374 (8.8) | 116 (10.4) |
| Both parents outside Sweden | 44 (3.4) | 177 (4.1) | 59 (5.3) |
| Missing | 8 (0.6) | 17 (0.4) | 5 (0.5) |
| Highest level of education (maternal or paternal) |
|||
| Compulsory | 29 (2.2) | 117 (2.7) | 73 (6.5) |
| Upper-secondary | 520 (39.7) | 1947 (45.6) | 652 (58.3) |
| University | 760 (58.1) | 2206 (51.7) | 394 (35.2) |
| Missing | 0 (0.0) | 1 (0.02) | 0 (0.0) |
| Maternal adult height, mean (SD), cm | 167.2 (5.9) | 166.8 (5.9) | 166.1 (6.1) |
| Missing | 65 (5.0) | 256 (6.0) | 73 (6.5) |
| Height outcomes | |||
| Adult height, mean (SD), cm | 181.7 (7.4) | 180.7 (7.1) | 178.8 (7.5) |
| Short staturec | 21 (1.6) | 99 (2.3) | 54 (4.8) |
| B. Females (n = 5396) | 847 (39.3) | 3512 (45.1) | 1037 (48.1) |
| Age at type 1 diabetes onset, mean (SD), y | 13.1 (3.6) | 9.0 (3.9) | 8.7 (3.8) |
| Before pubertyb | 156 (18.4) | 2024 (57.6) | 622 (60.0) |
| During pubertyb | 370 (43.7) | 1270 (36.2) | 362 (34.9) |
| After pubertyb | 321 (37.9) | 218 (6.2) | 53 (5.11) |
| Calendar year of type 1 diabetes onset | |||
| 1982-1989 | 1 (0.1) | 62 (1.8) | 50 (4.8) |
| 1990-1999 | 70 (8.3) | 989 (28.2) | 470 (45.3) |
| 2000-2009 | 380 (44.9) | 1977 (56.3) | 449 (43.3) |
| 2010-2020 | 396 (46.8) | 484 (13.8) | 68 (6.6) |
| Any other autoimmune disease | 68 (8.0) | 580 (16.5) | 182 (17.6) |
| Asthma | 29 (3.4) | 182 (5.2) | 61 (5.9) |
| Parental factors | |||
| Type 1 diabetes (maternal or paternal) | 65 (7.7) | 363 (10.3) | 143 (13.8) |
| Country of birth | |||
| Both parents in Sweden | 744 (87.8) | 3061 (87.2) | 845 (81.5) |
| One parent outside Sweden | 67 (7.9) | 282 (8.0) | 112 (10.8) |
| Both parents outside Sweden | 30 (3.5) | 159 (4.5) | 76 (7.3) |
| Missing | 6 (0.7) | 10 (0.3) | 4 (0.4) |
| Highest level of education (maternal or paternal) |
|||
| Compulsory | 15 (1.8) | 89 (2.5) | 69 (6.7) |
| Upper-secondary | 318 (37.5) | 1590 (45.3) | 599 (57.8) |
| University | 514 (60.7) | 1830 (52.1) | 369 (35.6) |
| Missing | 0 (0.0) | 3 (0.1) | 0 (0.0) |
| Maternal adult height, mean (SD), cm | 167.2 (6.0) | 166.9 (6.0) | 166.4 (6.0) |
| Missing | 45 (5.3) | 174 (5.0) | 70 (6.8) |
| Height outcomes | |||
| Adult height, mean (SD), cm | 167.7 (6.6) | 167.2 (6.7) | 165.8 (6.3) |
| Short staturec | 19 (2.2) | 74 (2.1) | 24 (2.3) |
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Glycemic control defined as mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood.
b Puberty categorized as before puberty, younger than 11 years for boys, younger than 10 years for girls; during puberty aged 11 to 16 years for boys, aged 10 to 15 years for girls; after puberty older than 16 years for boys, older than 15 years for girls.
c Short stature defined as a z score for final adult height less than −2 SDs.
Glycemic Control During Entire Follow-up and Final Adult Height
Both males and females with poor glycemic control during follow-up were shorter during adult age (mean adult height 178.8 cm in males, 166.4 cm in females) compared to those with optimal control (181.7 cm in males, 167.2 cm in females; see Table 1). Crude difference in mean adult height was −2.91 cm (95% CI, −3.48 to −2.33) for males and −1.83 cm (−2.42 to −1.23) for females (P for sex difference = .02). Results were not entirely attenuated after adjustment, including for age at onset (adjusted mean difference −1.59 cm [−2.16 to −1.01] for males and −0.94 cm [−1.54 to −.34] for females; Table 2).
Table 2.
Association between measures of glycemic control and final adult height using linear regression models stratified by sex
| Measure of glycemic control | Crude mean differenceb in adult height (95% CI), cm | Adjustedc mean differenceb in adult height (95% CI), cm | P test for sex interaction | ||
|---|---|---|---|---|---|
| Males | Females | Males | Females | ||
| Category of mean HbA1ca | |||||
| Suboptimal | −0.98 (−1.42 to −0.53) | −0.51 (−1.01 to −0.02) | −0.07 (−0.51 to 0.37) | −0.08 (−0.56 to 0.41) | .02 |
| Poor | −2.91 (−3.48 to −2.33) | −1.83 (−2.42 to −1.23) | −1.59 (−2.16 to −1.01) | −0.94 (−1.54 to −0.34) | |
| Mean HbA1c, mmol/mol | −0.7 (−0.8 to −0.6) | −0.5 (−0.6 to −0.3) | −0.4 (−0.6 to −0.3) | −0.3 (−0.4 to −0.1) | <.01 |
| Time with poor glycemic control, y | −0.42 (−0.49 to −0.34) | −0.42 (−0.51 to −0.32) | −0.27 (−0.35 to −0.20) | −0.27 (−0.36 to −0.17) | .30 |
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0%-9.0%), and poor greater than 75 mmol/mol (>9.0%).
b Mean difference in adult height, comparing suboptimal/poor to optimal glycemic control (category of mean HbA1c), per 10-unit increase (mean HbA1c), per additional 1 year (time with poor glycemic control).
c Models are adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
In terms of effect modification by age at onset, estimates were similar for males irrespective of when onset of type 1 diabetes occurred in relation to puberty (P for interaction with age at onset = .08; Table 3). In contrast, for females, poor glycemic control was associated with lower adult height only in those with type 1 diabetes onset before puberty (adjusted mean difference −3.01 cm [−4.09 to −1.94]; P < .001 for age at onset interaction).
Table 3.
Association between glycemic control and final adult height in males and females comparing suboptimal/poor to optimal glycemic control, stratified by age at onset of type 1 diabetes in relation to puberty
| Category of mean HbA1ca | Mean difference (95% CI) in adult height (cm) stratified by age at type 1 diabetes onset in relation to pubertyb | P test for age at onset interaction | |||||
|---|---|---|---|---|---|---|---|
| Before pubertyb | During pubertyb | After pubertyb | |||||
| Crude | Adjustedc | Crude | Adjustedc | Crude | Adjustedc | ||
| A. Males | |||||||
| Suboptimal | −1.06 (−2.08 to −.05) |
−0.63 (−1.56 to .30) |
−0.74 (−1.44 to −.05) |
−0.26 (−0.90 to .39) |
−0.54 (−1.45 to .36) |
0.02 (−.82 to .86) |
.08 |
| Poor | −3.52 (−4.65 to −2.40) |
−2.57 (−3.61 to −1.53) |
−1.86 (−2.80 to −.91) |
−0.93 (−1.81 to −.04) |
−1.93 (−3.41 to −.45) |
−1.64 (−3.00 to −.28) |
|
| B. Females | |||||||
| Suboptimal | −2.06 (−3.13 to −.99) |
−1.81 (−2.79 to −.83) |
0.25 (−.51 to 1.01) |
0.49 (−.20 to 1.18) |
−0.95 (−2.08 to .18) |
−0.46 (−1.49 to .58) |
<.001 |
| Poor | −3.87 (−5.02 to −2.72) |
−3.01 (−4.09 to −1.94) |
−0.72 (−1.67 to .23) |
−0.23 (−1.11 to .65) |
1.13 (−.78 to 3.04) |
1.68 (−.06 to 3.42) |
|
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0-9.0%), and poor greater than 75 mmol/mol (>9.0%).
b Puberty categorized as before puberty, younger than 11 years for boys, younger than 10 years for girls; during puberty aged 11 to 16 years for boys, 10 to 15 years for girls; after puberty older than 16 years for boys, older than 15 years for girls.
c Models are adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
Mean HbA1c during follow-up as a continuous variable was similarly associated with adult height (see Table 2). Per 10 mmol/mol increase in HbA1c, males were on average 0.7 cm (−0.8 to −0.6) shorter, and females 0.5 cm (−0.6 to −0.4) shorter (P < .001 for sex difference). However, using cubic splines we visualized the relationship between mean HbA1c and adult height, showing that the magnitude of reduction in height was not the same across the span of HbA1c values (Fig. 2). Between HbA1c 50 to 75 mmol/mol mean adult height was lower per mmol/mol HbA1c than for values greater than 75 mmol/mol. Using time with poor glycemic control as an alternative measure, we did not observe sex differences (P = .30 for sex interaction). For each additional year of poor glycemic control, males had a mean adult height difference of −0.42 cm (−0.49 to −0.34), which was not different from females’ mean difference of −0.42 cm (−0.51 to −0.32; see Table 2). All results remained of similar magnitude in adjusted models.
Figure 2.
Association between mean glycated hemoglobin A1c (HbA1c) (mmol/mol) during follow-up and final adult height in A, males and B, females, modeled using regression with restricted cubic splines and adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal adult height, parental type 1 diabetes, parental country of birth, and highest parental educational attainment. The dashed line displays the 95% CIs of the mean adult height.
Glycemic Control Before, During, or After Puberty, and Adult Height
For the association between glycemic control before, during, or after puberty, and final adult height, poor glycemic control before puberty (adjusted mean difference −2.06 cm [−3.21 to −0.91 cm]), but not during (−0.44 cm [−1.24 to 0.36 cm] or after puberty (−0.24 cm [−1.03 to 0.35 cm]) was associated with adult height in females (Table 4). Oppositely, for males, poor glycemic control before puberty (−0.29 cm [−1.56 to 0.97 cm]) was not associated with adult height; however, poor glycemic control during (−1.16 cm [−1.99 to −0.33 cm]) or after puberty (−1.24 cm [−1.90 to −0.58 cm]) was associated with adult height.
Table 4.
Association between category of mean glycated hemoglobin A1c levels before, during, or after puberty and final adult height comparing suboptimal/poor to optimal glycemic control in linear regression models stratified by sex
| Category of mean HbA1ca | Crude mean difference (95% CI) | Adjustedb mean difference (95% CI) | Fully adjustedc mean difference (95% CI) | P test for sex interaction | |
|---|---|---|---|---|---|
| Before puberty d | |||||
| Suboptimal | Males | −0.85 (−1.30 to −.40) | −0.55 (−1.06 to −.04) | 0.03 (−.58 to .65) | .54 |
| Females | −0.52 (−.96 to −.08) | −0.51 (−1.00 to −.02) | −0.63 (−1.21 to −.05) | ||
| Poor | Males | −2.32 (−3.62 to −1.20) | −0.93 (−2.23 to .36) | −0.29 (−1.56 to .97) | |
| Females | −2.72 (−3.90 to −1.53) | −2.38 (−3.60 to −1.16) | −2.06 (−3.21 to −.91) | ||
| During puberty d | |||||
| Suboptimal | Males | −0.71 (−1.11 to −.31) | −0.08 (−.58 to .42) | 0.10 (−0.41 to 0.62) | .02 |
| Females | −0.35 (−.78 to .08) | −0.01 (−.51 to .54) | −0.04 (−.55 to .47) | ||
| Poor | Males | −3.06 (−3.67 to −2.45) | −1.57 (−2.43 to −.70) | −1.16 (−1.99 to −.33) | |
| Females | −1.76 (−2.39 to −1.14) | −0.64 (−1.49 to .22) | −0.44 (−1.24 to .36) | ||
| After puberty d | |||||
| Suboptimal | Males | −1.03 (−1.49 to −.58) | −0.47 (−1.00 to .06) | −0.09 (−.58 to .41) | .02 |
| Females | −0.21 (−.72, .31) | 0.16 (−.43 to .75) | 0.37 (−.17 to .91) | ||
| Poor | Males | −2.72 (−3.28 to −2.17) | −1.72 (−2.42 to −1.01) | −1.24 (−1.90 to −.58) | |
| Females | −1.35 (−1.94 to −.75) | −0.81 (−1.55 to −.06) | −0.24 (−1.03 to .35) | ||
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Mean HbA1c levels of all measurements of HbA1c within named pubertal category are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0-9.0%), or poor greater than 75 mmol/mol (>9.0%).
b Models are adjusted for mean HbA1c levels in all other pubertal categories, for example, adjusted for during and after puberty if modeling before puberty.
c Models are additionally adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
d Puberty categorized as before puberty, younger than 11 years for boys, younger than 10 years for girls; during puberty aged 11 to 16 years for boys, 10 to 15 years for girls; after puberty older than 16 years for boys, older than 15 years for girls.
Glycemic Control and Short Stature
For the secondary outcome, poor glycemic control was associated with a higher risk for short stature in males (adjusted OR 1.90 [1.07-3.35]) but not in females (0.73, [0.36-1.51]; P = .01) for sex difference. Consistently, other measures of glycemic control were associated with short stature in males, but a higher risk in females was not apparent (Table 5).
Table 5.
Association between measures of glycemic control and short stature using logistic regression models stratified by sex
| Measure of glycemic control | Crude ORb of short statured (95% CI) | Adjustedc ORb of short statured (95% CI) | P test for sex interaction | ||
|---|---|---|---|---|---|
| Males | Females | Males | Females | ||
| Category of mean HbA1ca | |||||
| Suboptimal | 1.46 (.91-2.34) | 0.94 (.56-1.56) | 0.95 (.56-1.59) | 0.80 (.44-1.43) | .01 |
| Poor | 3.11 (1.87-5.18) | 1.03 (.56-1.90) | 1.90 (1.07-3.35) | 0.73 (.36-1.51) | |
| Mean HbA1c, mmol/mol | 1.31 (1.18-1.45) | 1.10 (.96-1.26) | 1.23 (1.08-1.40) | 1.04 (.88-1.22) | .02 |
| Time with poor glycemic control, y | 1.13 (1.07-1.19) | 1.05 (.96-1.16) | 1.08 (1.02-1.14) | 1.00 (.89-1.12) | .08 |
Abbreviations: HbA1c, glycated hemoglobin A1c; OR, odds ratio.
a Mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0-9.0%), or poor greater than 75 mmol/mol (>9.0%).
b Odds ratio for short stature, comparing suboptimal/poor to optimal glycemic control (category of mean HbA1c), per 10-unit increase (mean HbA1c), per additional 1 year (time with poor glycemic control).
c Models are adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
d Short stature defined as a z score for final adult height less than −2 SDs.
Glycemic Control and Change in z Score for Height
For the subgroup with height registrations at the onset of type 1 diabetes (n = 7670 [4227 males, 3443 females]), we observed that males had a greater z score for height at disease onset than females, but that values were similar across all levels of glycemic control. Both in males and females, z scores for adult height seemed to remain unchanged in those with optimal glycemic control and were similar or lower in those with suboptimal or poor control (Table 6).
Table 6.
Characteristics presented according to glycemic control, stratified by sex, in a subgroup of the study sample with height registrations at onset of type 1 diabetes
| Category of mean HbA1ca, n (%) | |||
|---|---|---|---|
| Optimal < 53 mmol/mol (<7.0%) | Suboptimal 53-75 mmol/mol (7.0-9.0%) |
Poor >75 mmol/mol (>9.0%) |
|
| A. Males (n = 4227) | 1116 (59.1) | 2643 (53.8) | 468 (53.8) |
| Age at type 1 diabetes onset, mean (SD), y | 15.0 (3.2) | 11.9 (4.1) | 12.6 (4.0) |
| Before pubertyb | 126 (11.3) | 1022 (38.7) | 149 (31.8) |
| During pubertyb | 503 (45.1) | 1209 (45.7) | 224 (47.9) |
| After pubertyb | 487 (43.6) | 412 (15.6) | 95 (20.3) |
| Calendar year of type 1 diabetes onset | |||
| 1990-1999 | 27 (2.4) | 192 (7.3) | 47 (10.0) |
| 2000-2009 | 557 (49.9) | 1861 (70.4) | 315 (67.3) |
| 2010-2020 | 532 (47.7) | 590 (22.3) | 106 (22.7) |
| Any other autoimmune disease | 57 (5.1) | 259 (9.8) | 38 (8.1) |
| Asthma | 25 (2.2) | 102 (3.9) | 17 (3.6) |
| Parental factors | |||
| Type 1 diabetes (maternal or paternal) | 85 (7.6) | 279 (10.6) | 57 (12.2) |
| Country of birth | |||
| Both parents in Sweden | 986 (88.4) | 2284 (86.4) | 393 (84.0) |
| One parent outside Sweden | 84 (7.5) | 230 (8.7) | 45 (9.6) |
| Both parents outside Sweden | 39 (3.5) | 122 (4.6) | 29 (6.2) |
| Missing | 7 (0.6) | 7 (0.3) | 1 (0.2) |
| Highest level of education (maternal or paternal) | |||
| Compulsory | 22 (2.0) | 63 (2.4) | 24 (5.1) |
| Upper-secondary | 453 (40.6) | 1224 (46.3) | 281 (60.0) |
| University | 641 (57.4) | 1356 (51.3) | 163 (34.8) |
| Maternal adult height | 167.2 (5.9) | 166.8 (6.0) | 166.4 (6.0) |
| Missing | 51 (4.6) | 114 (4.3) | 21 (4.5) |
| Height outcomes | |||
| Adult height, mean (SD), cm | 181.7 (7.1) | 181.0 (7.1) | 179.7 (7.6) |
| Short staturec | 17 (1.5) | 50 (1.9) | 16 (3.4) |
| Change in z score for height | 0.0 (0.8) | −0.1 (0.8) | −0.3 (0.9) |
| B. Females (n = 3443) | 774 (41.0) | 2267 (46.2) | 402 (46.2) |
| Age at type 1 diabetes onset, mean (SD), y | 13.5 (3.3) | 10.2 (3.7) | 10.8 (3.4) |
| Before pubertyb | 117 (15.1) | 1044 (46.1) | 151 (37.6) |
| During pubertyb | 346 (44.7) | 1017 (44.9) | 204 (50.8) |
| After pubertyb | 311 (40.2) | 206 (9.1) | 47 (11.7) |
| Calendar year of type 1 diabetes onset | |||
| 1990-1999 | 26 (3.4) | 170 (7.5) | 37 (9.2) |
| 2000-2009 | 353 (45.6) | 1617 (71.3) | 297 (73.9) |
| 2010-2020 | 395 (51.0) | 480 (21.2) | 68 (16.9) |
| Any other autoimmune disease | 54 (7.0) | 311 (13.7) | 58 (14.4) |
| Asthma | 24 (3.1) | 112 (4.9) | 21 (5.2) |
| Parental factors | |||
| Type 1 diabetes (maternal or paternal) | 61 (7.9) | 230 (10.2) | 66 (16.4) |
| Country of birth | |||
| Both parents in Sweden | 682 (88.1) | 1966 (86.7) | 305 (75.9) |
| One parent outside Sweden | 58 (7.5) | 179 (7.9) | 52 (12.9) |
| Both parents outside Sweden | 28 (3.6) | 113 (5.0) | 44 (11.0) |
| Missing | 6 (0.8) | 9 (0.4) | 1 (0.3) |
| Highest level of education (maternal or paternal) | |||
| Compulsory | 12 (1.6) | 42 (1.9) | 29 (7.2) |
| Upper-secondary | 292 (37.7) | 1037 (45.7) | 237 (59.0) |
| University | 470 (60.7) | 1185 (52.3) | 136 (33.8) |
| Missing | 0 (0.0) | 3 (0.1) | 0 (0.0) |
| Maternal adult height | 167.2 (5.8) | 166.8 (5.9) | 166.5 (6.4) |
| Missing | 34 (4.4) | 88 (3.9) | 15 (3.7) |
| Height outcomes | |||
| Adult height, mean (SD), cm | 167.6 (6.6) | 167.2 (6.6) | 165.9 (6.4) |
| Short staturec | 18 (2.3) | 42 (1.9) | 8 (2.0) |
| Change in z score for height | 0.1 (0.6) | 0.0 (0.8) | −0.2 (0.7) |
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood.
b Puberty categorized as before puberty, younger than 11 years for boys, younger than 10 years for girls; during puberty aged 11 to 16 years for boys, 10 to 15 years for girls; after puberty older than 16 years for boys, older than 15 years for girls.
c Short stature defined as a z score for final adult height less than −2 SDs.
Poor glycemic control had a negative effect on change in z score for height from diabetes onset to adulthood both in males and females. On average, in adjusted models, z score was −0.19 SD (−0.26 to −0.12) less for males and −0.12 SD (−0.19 to −0.04) for females (P = .12 for sex difference) comparing individuals with poor vs optimal glycemic control. The same pattern was present irrespective of the measure of glycemic control (Table 7).
Table 7.
Association between measures of glycemic control and change in z score for height from onset of type 1 diabetes to adulthood using linear regression models stratified by sex in a subgroup of the study sample with height measurements at onset of type 1 diabetes
| Measure of glycemic control | Crude mean differenceb in z score change (95% CI), cm | Adjustedc mean differenceb in z score change (95% CI), cm | P test for sex interaction | ||
|---|---|---|---|---|---|
| Males | Females | Males | Females | ||
| Category of mean HbA1ca | |||||
| Suboptimal | −0.09 (−.14 to −.05) | −0.05 (−.10 to .01) | −0.04 (−.09 to .01) | −0.03 (−.09 to .03) | .12 |
| Poor | −0.24 (−.30 to −.18) | −0.13 (−.20 to −.07) | −0.19 (−.26 to −.12) | −0.12 (−.19 to −.04) | |
| Mean HbA1c, mmol/mol | −0.06 (−.07 to −.04) | −0.03 (−.05 to −.02) | −0.05 (−.07 to −.03) | −0.03 (−.05 to −.02) | .07 |
| Time with poor glycemic, y | −0.05 (−.06 to −.04) | −0.05 (−.06 to −.04) | −0.04 (−.05 to −.03) | −0.04 (−.06 to −.03) | .73 |
Abbreviation: HbA1c, glycated hemoglobin A1c.
a Mean HbA1c levels of all measurements during follow-up from first registration of HbA1c after onset of diabetes to adulthood are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0-9.0%), or poor greater than 75 mmol/mol (>9.0%).
b Mean difference in change in z score for height, comparing suboptimal/poor to optimal glycemic control (category of mean HbA1c), per 10-unit increase (mean HbA1c), per additional 1 year (time with poor glycemic control).
c Models are adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
Sensitivity Analyses
For the relationship between glycemic control before, during, or after puberty, and final adult height, using alternative ages of the pubertal categories did not alter the interpretation of results (Table 8).
Table 8.
Sensitivity analysis for the association between category of mean glycated hemoglobin A1cb levels before, during, and after puberty and final adult height, comparing suboptimal/poor to optimal glycemic control in linear regression models stratified by sex. Models are presented using alternative definitions of pubertya
| Category of mean HbA1cb | Crude mean difference (95% CI) | Adjustedc mean difference (95% CI) | Fully adjustedd mean difference (95% CI) | P test for sex interaction | ||
|---|---|---|---|---|---|---|
|
Alternative puberty definition I:
Same for males and females |
Before puberty a | |||||
| Suboptimal | Males | −0.92 (−1.41 to −0.43) | −0.60 (−1.16 to −0.04) | −0.35 (−1.00 to 0.31) | .26 | |
| Females | −0.52 (−.96 to −.08) | −0.51 (−1.00 to −0.02) | −0.63 (−1.21 to −0.05) | |||
| Poor | Males | −3.15 (−4.63 to −1.67) | −1.57 (−3.13 to −0.02) | −0.57 (−2.09 to 0.94) | ||
| Females | −2.72 (−3.90 to −1.53) | −2.38 (−3.60 to −1.16) | −2.06 (−3.21 to −0.91) | |||
| During puberty a | ||||||
| Suboptimal | Males | −0.65 (−1.04 to −0.25) | −0.07 (−.57 to .43) | 0.06 (−.47 to .60) | <.01 | |
| Females | −0.35 (−.78 to .08) | −0.01 (−.51 to .54) | −0.04 (−.55 to .47) | |||
| Poor | Males | −3.30 (−3.95 to −2.65) | −2.10 (−3.02 to −1.18) | −1.86 (−2.76 to −0.97) | ||
| Females | −1.76 (−2.39 to −1.14) | −0.64 (−1.49 to 0.22) | −0.44 (−1.24 to 0.36) | |||
| After puberty a | ||||||
| Suboptimal | Males | −1.11 (−1.56 to −0.66) | −0.57 (−1.10 to −0.04) | −0.16 (−.65 to .33) | <.01 | |
| Females | −0.21 (−.72 to .31) | 0.16 (−.43 to.75) | 0.37 (−.17 to. 91) | |||
| Poor | Males | −2.81 (−3.36 to −2.26) | −1.41 (−2.12 to −0.69) | −0.97 (−1.63 to −0.30) | ||
| Females | −1.35 (−1.94 to −0.75) | −0.81 (−1.55 to −0.06) | −0.24 (−1.03 to 0.35) | |||
|
Alternative puberty definition II:
Extended window of puberty |
Before puberty a | |||||
| Suboptimal | Males | −0.92 (−1.41 to −0.43) | −0.75 (−1.28 to −0.22) | −0.37 (−1.02 to −0.29) | .31 | |
| Females | −0.36 (−.83 to .12) | −0.39 (−.90 to 0.12) | −0.58 (−1.19 to 0.04) | |||
| Poor | Males | −3.15 (−4.63 to −1.67) | −2.28 (−3.81 to −0.76) | −1.14 (−2.63 to 0.36) | ||
| Females | −2.20 (−3.67 to −0.73) | −1.80 (−3.29 to −0.31) | −2.34 (−3.75 to −0.93) | |||
| During puberty a | ||||||
| Suboptimal | Males | −0.65 (−1.04 to −0.24) | 0.05 (−.46 to .55) | 0.39 (−.13 to .91) | .29 | |
| Females | −0.13 (−.58 to .32) | 0.24 (−.32 to .79) | 0.14 (−.39 to .66) | |||
| Poor | Males | −2.59 (−3.17 to −2.01) | −0.75 (−1.57 to .06) | −0.36 (−1.16 to .44) | ||
| Females | −1.88 (−2.48 to −1.28) | −0.94 (−1.77 to −0.10) | −0.70 (−1.48 to .09) | |||
| After puberty a | ||||||
| Suboptimal | Males | −1.01 (−1.46 to −.56) | −0.55 (−1.09 to −.02) | −0.28 (−.78 to .22) | .06 | |
| Females | −0.34 (−.83 to .16) | −0.23 (−.81 to .36) | 0.05 (−.49 to .58) | |||
| Poor | Males | −2.56 (−3.11 to −2.02) | −1.66 (−2.39 to −.93) | −1.24 (−1.92 to −.56) | ||
| Females | −1.24 (−1.81 to −.67) | −0.59 (−1.35 to .17) | −0.33 (−1.02 to .36) | |||
|
Alternative puberty definition III:
Shifted with later onset of puberty |
Before puberty a | |||||
| Suboptimal | Males | −0.88 (−1.31, −.46) | −0.75 (−1.24, −.27) | −0.12 (−0.71, .47) | .13 | |
| Females | −0.21 (−.62, .21) | −0.03 (−.49, .44) | −0.16 (−.72, .40) | |||
| Poor | Males | −3.35 (−4.36 to −2.34) | −2.40 (−2.49 to −1.31) | −1.43 (−2.53 to −.34) | ||
| Females | −2.30 (−3.31 to −1.29) | −1.48 (−2.54 to −.42) | −1.38 (−2.40 to −.36) | |||
| During puberty a | ||||||
| Suboptimal | Males | −0.63 (−1.04 to −.22) | 0.30 (−.23 to .82) | 0.59 (.07 to 1.11) | .60 | |
| Females | −0.20 (−.65 to .26) | −0.07 (−.64 to .51) | −0.09 (−.63 to .44) | |||
| Poor | Males | −2.47 (−3.04 to −1.90) | −0.56 (−1.40 to .28) | −0.22 (−1.02 to.58) | ||
| Females | −1.97 (−2.55 to −1.38) | −1.62 (−2.47 to −.76) | −1.25 (−2.04 to −.46) | |||
| After puberty a | ||||||
| Suboptimal | Males | −1.01 (−1.46 to −.56) | −0.56 (−1.09 to −.02) | −0.32(−0.82 to .18) | .02 | |
| Females | 0.23 (−.83 to .16) | −0.04 (−.63 to .55) | 0.26 (−.27 to .80) | |||
| Poor | Males | −2.56 (−3.11 to −2.02) | −1.78 (−2.51 to −1.05) | −1.31 (−1.99 to −.63) | ||
| Females | −1.24 (−1.81 to −.67) | −0.30 (−1.07 to .47) | 0.05 (−.66 to .75) | |||
a Alternative puberty definitions are I) same window of puberty for boys and girls aged 10 to 15 years; II) extended window of puberty, aged 10 to 17 years for boys, 9 to 16 years for girls; and III) shifted window of puberty with later onset, aged 12 to 17 years for boys, 11 to 16 years for girls.
b Mean HbA1c levels of all measurements of HbA1c within named pubertal category are categorized as optimal less than 53 mmol/mol (<7.0%), suboptimal 53 to 75 mmol/mol (7.0-9.0%), or poor greater than 75 mmol/mol (>9.0%)
c Models are adjusted for mean HbA1c levels in all other pubertal categories, for example, adjusted for during and after puberty if modeling before puberty.
d Models are additionally adjusted for age at onset of diabetes, calendar year of onset, any other autoimmune disease, asthma, maternal height, parental type 1 diabetes, parental country of birth, and highest level of parental education.
Discussion
In this nationwide study of children with type 1 diabetes in Sweden, we found an association between poor glycemic control and adult height outcomes. The relationship displayed certain sex differences: Reductions in final adult height were slightly more pronounced for males than females, and males, but not females, with poor glycemic control had a higher risk of short stature. Interestingly, associations were not explained by the age at onset of type 1 diabetes (ie, longer duration of diabetes) but their strengths differed depending on the age at onset. This was particularly apparent for females, among whom poor glycemic control was associated with adult height only in those with onset before puberty. Lastly and similarly, final adult height differed depending on mean HbA1c before, during, or after puberty. For females, poor glycemic control before puberty seemed to be of importance, whereas for males, during or after puberty accounted for more of the association.
While several studies have investigated if individuals with type 1 diabetes are shorter than their disease-free peers (14), we aimed to bridge the knowledge gap regarding the effect of glycemic control on height since HbA1c is a modifiable and clinically used biomarker. In this largest study reported to date, we found that poor glycemic control was associated with adult height outcomes including final adult height, short stature, and change in z score for height from diabetes onset to adulthood. Results remained statistically significant after adjustments for potential confounders, demonstrating that although individuals with poor compared to optimal control differed in baseline characteristics, factors such as younger age at onset, less recent year of diagnosis, more concomitant autoimmune disease/asthma or parental origin, education, or type 1 diabetes status, did not entirely explain why they were shorter in adult age. Our findings are similar to, but more extensive than, a German and Austrian study of 1685 patients with near-adult height data that found a 0.3-unit reduction in z score for adult height among patients with HbA1c greater than 8.0% (9). Older studies, as outlined in a narrative review by Santi et al (2), also point to an association between poor glycemic control and growth outcomes in adolescence, although samples were much smaller than ours and they did not specifically assess final adult height nor approximate sex differences. Additionally, in our study, poor glycemic control seemed to affect growth in both sexes, but potentially more in males than females, with lower attained height and higher risk of short stature reflecting the magnitude of height loss in males. To the best of our knowledge, no other study has examined the association between glycemic control and short stature in patients with type 1 diabetes.
Using time with poor glycemic control as a secondary exposure, we further showed that final adult height was lower for each added year of poor glycemic control. Previous research has indeed shown an association between longer duration of diabetes (ie, younger age at onset) and reduced growth (6, 8, 13, 30). Yet, our results remained relatively unchanged in models adjusting for age at diabetes onset, thereby demonstrating that the effect of the time spent living with poor disease control is not entirely explained by the duration of the disease itself. This should be reassuring in terms of being able to modify clinical outcomes, even in children with diabetes onset earlier in life. Moreover, time with poor glycemic control had a similar effect on height for males and females, underscoring the importance of optimal control over time for all patients.
This study also assessed the association between glycemic control and adult height in relation to puberty. To start, we uncovered differences in final adult height depending on if onset of diabetes occurred before, during, or after puberty. Next, we separately estimated associations between the glycemic control before, during, or after puberty and final adult height. For females, results differed depending on age at onset with final height reduction present only in those with a prepubertal onset. In males, HbA1c during or after puberty were risk factors for worse height outcomes, irrespectively of when onset occurred. Studies stratifying by sex have found that pubertal growth velocity is reduced in females with type 1 diabetes compared to males, and is less in both sexes when contrasting poor to optimal glycemic control (7, 12, 31). It is also well known that peak growth velocity is reached earlier in puberty in girls than in boys (32). This could explain why we saw a reduction in adult height among females with diabetes onset before puberty, as well as an association with their HbA1c before puberty, but not among males. Correspondingly, an older study of 436 children found that final adult height in those with prepubertal onset diabetes was lower than in those with onset during or after puberty (30). They also described a decrease in standardized height over the course from diabetes onset to adulthood compared to a reference population but did not investigate according to glycemic control as we did.
In terms of mechanisms, growth impairment in type 1 diabetes is thought to be related to changes in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis due to lower insulin concentrations with subsequent decreased IGF-1 levels and hypersecretion of GH (2, 17). Furthermore, in line with our findings, puberty is an important period of hormonal change affecting growth. Known effects on puberty among those with diabetes include delayed age at menarche or attenuated pubertal growth spurt (8, 16, 33). These changes have been suggested to be mediated either via disruption of gonadotropin-releasing hormone neuronal signaling or through GH/IGF-1 axis suppression (4).
A major strength of this study is the large sample size with high generalizability, made possible by collection of data from nationwide sources, including the entire Swedish pediatric diabetes population, with information on a wide range of potential confounders, enabling important statistical adjustments. Thanks to the unique national personal identity number issued to all citizens, all data sources were unequivocally linked. As far as we know, this is the first study combining clinical measures of glycemic control with adult height data on a population-based scale. Advantageously, 96.5% of the study population before exclusions had adult height registrations. In addition, 63% of the final study sample had height measurements recorded at diabetes onset, which enabled comparisons of z score over the trajectory from onset to adulthood.
Certain weaknesses must be highlighted, especially in relation to data availability. We were limited to clinical data reported to the quality register and did not have access to growth charts for calculation of height velocity nor information on pubertal stage. We could therefore not determine if the association found between poor glycemic control and adult height was explained by reduced pubertal growth velocity. Also, information on parental height was not available, making it impossible to study outcomes related to target height based on mid-parental height calculations, or to entirely adjust for the inherent height potential of each study participant. Although it is an important predictor of the outcome, we do not believe that parental height confounds the demonstrated association since it ought not to affect the child's glycemic control. From medical birth records, we had access to maternal height and adjusting for that did not change the results. Lastly, we lacked information on the genetic background of our study sample. Adjusting for parental country of birth or parental type 1 diabetes (ie, an increased genetic risk for the disease) did not, however, alter the findings.
In summary, poor glycemic control after the onset of type 1 diabetes in childhood or adolescence is associated with lower adult height in men and women, and a higher risk of short stature in men, even after adjusting for measurable differences in baseline characteristics between glycemic control groups. Age at disease onset and timing of glycemic control in relation to puberty are factors of importance. These findings add to the body of literature on long-term outcomes of type 1 diabetes and can be useful for clinicians in contributing to patient and caregiver education.
Acknowledgments
We wish to thank Aki Tuilainen for data management support, and Drs Emma Caffrey Osvald and Samuel Rhedin for contributions to data collection, all at the Department of Medical Epidemiology and Biostatistics, Karolinska Institutet. We acknowledge the National Diabetes Register in Sweden for access to data.
Abbreviations
- GH
growth hormone
- HbA1c
glycated hemoglobin A1c
- IGF-1
insulin-like growth factor-1
- NDR
National Diabetes Register
- NPR
National Patient Register
- OR
odds ratio
- PDR
Prescribed Drug Register
Contributor Information
Awad I Smew, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Cecilia Lundholm, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Tong Gong, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Paul Lichtenstein, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden.
Lars Sävendahl, Department of Women's and Children's Health, Karolinska Institutet, 171 77 Stockholm, Sweden; Pediatric Endocrinology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Catarina Almqvist, Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 171 77 Stockholm, Sweden; Pediatric Allergy and Pulmonology Unit, Astrid Lindgren Children's Hospital, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Funding
This work was supported by the Swedish Research Council (grant Nos. 2018-02640 and 2023-02327), the Strategic Research Program in Epidemiology at Karolinska Institutet, the Swedish Heart-Lung Foundation (grant Nos. 2018-0512 and 2021-0416), the Swedish Asthma and Allergy Association (grant No. 2020-0008), the Foundation “Frimurare Barnhuset Stockholm”, and “H.K.H. Kronprinsessan Lovisas förening för barnasjukvård”. A.I.S. was supported by funding from the Clinical Scientist Training Programme and Medical Research Internship, both at Karolinska Institutet. The study funders were not involved in the design of the study; the collection, analysis, or interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.
Disclosures
None of the authors report any conflict of interest.
Data Availability
The data used in this study are available from the respective sources outlined in the article, but restrictions due to Swedish data storage law apply and are therefore not publicly available. Requests can be made to the data providers after approval from the Swedish Ethical Review Authority. Pseudonymized data may be provided by the corresponding author on reasonable request and if an appropriate data-sharing agreement with the Karolinska Institutet is established.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data used in this study are available from the respective sources outlined in the article, but restrictions due to Swedish data storage law apply and are therefore not publicly available. Requests can be made to the data providers after approval from the Swedish Ethical Review Authority. Pseudonymized data may be provided by the corresponding author on reasonable request and if an appropriate data-sharing agreement with the Karolinska Institutet is established.
