Introduction: Adult women with Turner syndrome (TS) have a high prevalence of diabetes and β-cell dysfunction that increases morbidity and mortality, but it is unknown if there is β-cell dysfunction present in youth with TS. This study aimed to determine the prevalence of β-cell dysfunction in youth with TS and the impact of traditional therapies on insulin sensitivity (SI) and insulin secretion. Methods: Cross-sectional, observational study recruited 60 girls with TS and 60 healthy controls (HC) matched on pubertal status. Each subject had a history, physical exam, and oral glucose tolerance test (OGTT). Oral glucose and c-peptide minimal modeling was used to determine β-cell function. Results: Twenty-one TS girls (35%) met criteria for prediabetes. Impaired fasting glucose was present in 18% of girls with TS and 3% HC (p value = 0.02). Impaired glucose tolerance was present in 23% of TS girls and 0% HC (p value <0.001). The hemoglobin A1c was not different between TS and HC (median 5%, p = 0.42). Youth with TS had significant reductions in SI, β-cell responsivity (Φ), and disposition index (DI) compared to HC. These differences remained significant when controlling for body mass index z-score (p values: 0.0006, 0.002, <0.0001 for SI, Φ total, DI, respectively). Conclusions: β-Cell dysfunction is present in youth with TS compared to controls. The presence of both reduced insulin secretion and SI suggest a unique TS-related glycemic phenotype. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in TS youth.

Turner syndrome (TS) is defined as the complete or partial absence of the second sex chromosome in a phenotypic female, and has a prevalence of 1 in 2,000–1 in 4,000 [1]. TS is associated with specific clinical features, such as short stature, ovarian failure, and cardiovascular disease.

Diabetes mellitus is 4 times more common in adult TS women than the general population, and contributes to their increased morbidity and mortality [2-4]. Previous studies have shown evidence of hyperinsulinemia, impaired glucose tolerance (IGT), and β-cell dysfunction in adult TS women compared to healthy controls [5-7]. Studies in youth with TS have focused on the effect of growth hormone (GH) on glucose homeostasis and showed mild reductions in insulin sensitivity (SI) without evidence of diabetes [8-11]. This study aimed to evaluate the prevalence of β-cell dysfunction in young individuals with TS.

Adult TS women have a high prevalence of impaired glucose tolerance (up to 70%) and up to 25% have diabetes mellitus [6, 7]. An increased relative risk (RR) of developing both type 1 (RR = 11.6) and type 2 diabetes (RR = 4.4) in the TS population across all age groups has been reported [12]. One study evaluated TS adults before and during HRT using oral and intravenous glucose tolerance testing (IVGTT) [6]. Before HRT, 50% of the TS women had impaired glucose tolerance by oral glucose tolerance testing (OGTT). Women with TS also had a diminished first phase insulin response by IVGTT compared to controls. Treatment with estrogen (oral or transdermal) for 6 months was associated with further deterioration in oral glucose tolerance [6].

Hjerrild et al. [5] evaluated the roles of β-cell function and SI on glucose homeostasis in adult women with TS. They showed increased glucose concentrations during OGTT and IVGTT concurrent with an insufficient increase in insulin concentration in women with TS [5]. These data contrast with data from studies that demonstrated a hyperinsulinemic response to glucose loading [8, 13, 14]. In addition to abnormalities in glucose homeostasis, TS patients also have abnormalities in liver function and lipid metabolism that may further influence SI and β-cell function [15, 16].

Many studies evaluating glucose metabolism in youth with TS have centered on the effect of GH on SI and glycemia. Using a euglycemic insulin clamp model, Caprio et al. [10] showed that insulin resistance is an early metabolic abnormality in TS. These investigators also used a hyperglycemic glucose clamp model to study 7 adolescents with TS and 7 controls before and during treatment with GH therapy. They found an increase in glucose-stimulated insulin release in TS patients compared to controls, as well as an increase in fasting plasma insulin after 6–12 months of GH treatment [8]. A recent retrospective study by Baronio et al. [11] evaluated the influence of GH on glucose homeostasis in TS girls using OGTT and showed no change in SI or β-cell secretory capacity over 7 years.

β-cell dysfunction can be detected before overt glucose intolerance or diabetes is diagnosed [17]. The oral c-peptide and glucose minimal models can be used with an OGTT to determine β-cell responsivity, SI and the disposition index (DI) (the product of SI and insulin response). These measurements are used to determine if a patient’s insulin secretion is appropriate for the degree of SI present. The goal of this study was to determine the prevalence of β-cell dysfunction in children and adolescents with TS and the impact of traditional therapies on SI and insulin secretion.

Participants

The study was approved by the Cincinnati Children’s Hospital Medical Center (CCHMC) and Children’s Mercy Hospital (CMH, Kansas City) Institutional Review Boards and all participants/legal guardians gave written consent (written assent was obtained from participants aged <18 years). The study was registered with clinical trials #NCT02160717. The study population consisted of 60 female youth age 6–22 years with TS recruited from the Cincinnati Center for Pediatric and Adult Turner Syndrome Care at CCHMC and the Great HeighTS Clinic at CMH. All TS participants met the following inclusion criteria: phenotypic females (1) had a karyotype that met the definition of TS [1] and (2) were on standard treatment with GH only, or were on GH plus estrogen, or were on estrogen and progesterone [1]. Exclusion criteria were diagnosis of diabetes mellitus, pregnancy, not on standard HRT for age, treatment with oxandrolone, metformin, glucocorticoids, or other medications known to alter glycemic control.

The control population consisted of 60 healthy female youth recruited from the greater Cincinnati, Ohio area. All controls were overall healthy without any chronic medical conditions. Exclusion criteria were diagnosis of diabetes mellitus, obesity, pregnancy, irregular menstrual cycles, delayed puberty, and taking any medication known to influence the glycemic control. Controls and TS participants were frequency matched for the pubertal status within the 3 groups: (1) pre-pubertal healthy control and pre-pubertal TS on GH; (2) pubertal healthy controls and pubertal TS on GH plus estrogen; all pre-menstrual and (3) post-menarche healthy controls and “post-menarche” TS on HRT with estrogen plus progesterone. Each participant underwent a comprehensive medical and family history, and physical exam with Tanner staging by a pediatric endocrinologist to include standard auxology, heart rate, temperature, and manual blood pressure assessment. Other clinical information was obtained from the TS database at CCHMC and the electronic medical record at CCHMC or CMH. The participant and/or the legal guardian provided the type and dose of any concurrent medications, which was confirmed via the electronic medical records at CCHMC or CMH.

Oral Glucose Tolerance Test

After a 10-h overnight fast, each participant completed a 2-h, 7-sample OGTT [18]. A single intravenous catheter was placed into an antecubital vein. The blood sampling arm was heated to obtain venous blood samples more in line with arterial blood. At time 0, after the blood draw, participants were presented with Glucola® (Azer Scientific, Morgantown, PA, USA), 1.75 g/kg (max of 75 g) consumed within 5 min. Blood samples were collected at time 0, and 10, 20, 30, 60, 90, and 120 min after Glucola® administration, for measurement of serum glucose, insulin, and c-peptide concentrations. Impaired fasting glucose (IFG) was defined as fasting glucose ≥100 mg/dL and IGT was defined as glucose ≥140 on an OGTT in accordance with American Diabetes Association definitions [19]. In addition, liver function tests (aspartate aminotransferase (ALT), alanine aminotransferase (AST), and gamma-glutamyl transferase, hemoglobin A1c (HbA1c), low-density lipoprotein (LDL), high-density lipoprotein (HDL), total cholesterol, and triglycerides (TGs) were collected at time zero. Islet cell antibody screen for GAD-65, insulin autoantibodies (IAA), islet antigen-2 autoantibodies (IA2), and zinc transporter 8 autoantibody (ZnT8) were obtained at time zero for all TS participants. After the OGTT was complete, the participant was given a meal and discharged home.

Biochemical Analyses

Serum glucose testing was performed in duplicate at the bedside on the YSI Analyzer (Yellow Springs Instrument Company, model # 2300 STAT Plus). The point of care HbA1c was performed on the Siemens DCA Vantage Analyzer during the study visit. The lipid panel, liver enzymes, insulin, and c-peptide were performed in the core research laboratory at CCHMC. Serum insulin and c-peptide were measured by electrochemiluminescence immunoassay using the Roche cobas e 411 analyzer (Indianapolis, IN, USA). Serum total cholesterol, HDL, LDL, and TG were measured by colorimetric method using the Roche cobas c 311 analyzer (Indianapolis, IN, USA). The liver enzymes, ALT and AST, were measured in the serum using a kinetic test on the cobas c 311 analyzer. Islet cell antibody screen for all 4 antibodies (IAA, GAD-65, IA2, and ZnT8) was performed using radiobinding assay at the Barbara Davis Center (Aurora, CO, USA).

Determination of β-Cell Function

The oral glucose minimal model of c-peptide secretion and kinetics originally applied to intravenous glucose-graded infusion data has been applied to assess β-cell secretion during an oral glucose perturbation [20]. C-peptide kinetics is described using the well-known 2-compartment model originally proposed by Eaton et al [21]. SI is estimated from plasma glucose and insulin concentrations measured during the 2 h OGTT using the oral glucose minimal model [18]. The oral glucose minimal model measures the overall effect of insulin on stimulating glucose disposal and inhibiting glucose production in the liver and periphery. The oral glucose minimal model has been validated against the euglycemic clamp [18]. β-cell responsivity (how well the β-cell secretes insulin in response to glucose), Φ, is estimated from plasma glucose and c-peptide concentrations measured during the OGTT, by using the oral c-peptide minimal model [20]. β-cell responsivity is expressed as β-cell response to glucose at basal conditions, during the dynamic phase (Φd) of response to an acute increase in glucose, and the static phase (Φs) of c-peptide secretion per unit glucose averaged across the entire test. Overall β-cell responsivity index designated as Φ, is the average increase in insulin secretion above basal insulin secretion (combines the static and dynamic phase responses). From the SI and the β-cell responsivity index, the DI can be calculated: DI = Φ × Si [20, 22]. The DI is an effective way to express β-cell function in relation to the degree of SI.

Statistical Analysis

All clinical and laboratory data were collected and managed in a REDCap database. The de-identified data from the OGTT was stored in a secure password protected Excel file and was sent to the University Of Alabama Diabetes Research Center, Core for Human Physiology (Barbara Gower, PhD, Director for the Metabolism Core Laboratory) for input into the minimal modeling program as described previously [18]. For analysis, de-identified data were imported into SAS® and merged using the unique identifiers.

All data were checked univariately and bivariately for outliers and inconsistent values, using 1 and 2-way plots, and frequency tables. Distributional properties of the continuous variables were checked, and appropriate transformations applied for analysis of the dependent variables. Insulin and glucose variables, including DI, were skewed and a log transformation was used for analysis. Means and associated standard deviations or medians and the 25th and 75th percentiles (interquartile range [IQR]) or frequencies are reported. Analysis of variance or Wilcoxon rank sum test was used to examine the difference between the TS participants and the controls, as appropriate. A generalized linear model was used when incorporating covariates and examining the interaction of group (TS or control) and pubertal status. A Tukey-Kramer correction was applied to adjust for multiple comparisons. The generalized linear model approach allowed for analysis of both continuous and binary outcomes by applying the appropriate link function. A p value of <0.05 was considered as statistically significant.

Participant Characteristics

Demographic and clinical data of the participants are presented in Table 1. A total of 120 females completed the study. The mean ± standard deviation age in the TS group was 14.2 ± 3.5 years compared to the healthy controls (HC) that were slightly younger, 12.5 ± 3.6 years. The majority of the participants were non-Hispanic white (90%). The TS participants were significantly shorter than the HC (144.4 ± 10.7 cm vs. 150.7 ± 16.3 cm, p = 0.01). Body mass index (BMI) z-score was also significantly higher in the TS participants (1.42 ± 0.74 vs. 0.69 ± 1.06, p < 0.001). Systolic and diastolic blood pressures were all within normal range based on pediatric guidelines [23]. Systolic z-score was not significantly higher in TS girls but diastolic z-score was higher in TS than HC (0.19 ± 1.32 vs. −0.19 ± 0.95 and 0.54 ± 1.01 vs. 0.07 ± 0.76, respectively) p values 0.07 and 0.004. Participants with TS were on medications including levothyroxine (14%), medications to treat attention-deficit/hyperactivity disorder (10%), β-blockers (5%), and allergy medications (17%). Two HC participants (3%) were on allergy medication and 1 HC participant (2%) was on medication for attention-deficit/hyperactivity disorder.

Table 1.

Demographics of participants

Demographics of participants
Demographics of participants

Specific details of the participants with TS are presented in Table 2. The majority of the TS participants had a 45,X karyotype (50%). The remainder of the karyotypes was mosaic with 46XX, isochromosome X and ring X material. The median age at diagnosis of TS was 2.0 years (IQR 0–9). Almost all TS participants (98%) were treated with GH at the time of study participation or had been in the past. The median length of time of GH exposure was 80.5 months (IQR 44–124). The mean dose of GH was 0.316 ± 0.071 mg/kg/week. Of TS participants in puberty, 95% of them required estrogen replacement for initiation of puberty. The majority (23/38 or 61%) of TS girls were started on estrogen between 12 and 14 years of age, with a median age of 13.0 years. The median length of time on estrogen was 23.2 months. Of the girls on estrogen, 50% were treated with transdermal estrogens and the remainder used an oral estrogen preparation.

Table 2.

Clinical characteristics of TS participants

Clinical characteristics of TS participants
Clinical characteristics of TS participants

OGTT Results

The results of the OGTT are demonstrated in Figure 1 and Table 3. IFG was present in 18% (11/60) of participants with TS, and in 2 HC participant (p value = 0.02). IGT was present in 23% (14/60) of TS girls and in no HC (p value <0.001). Four girls with TS had both IFG and IGT. Twenty-one TS girls (35%) met criteria for prediabetes (presence of IGT or IFG). The mean glucose, insulin, and c-peptide were higher in TS participants than in the HC at all time points and significantly higher at 30, 60, 90, and 120 min (all p values <0.05).

Table 3.

Metabolic outcomes in TS and HC

Metabolic outcomes in TS and HC
Metabolic outcomes in TS and HC
Fig. 1.

Glucose versus time during OGTT (a), insulin versus time during OGTT (b), C-peptide versus time during OGTT (c). OGTT, oral glucose tolerance test; TS, Turner syndrome; HC, healthy control.

Fig. 1.

Glucose versus time during OGTT (a), insulin versus time during OGTT (b), C-peptide versus time during OGTT (c). OGTT, oral glucose tolerance test; TS, Turner syndrome; HC, healthy control.

Close modal

The mean fasting glucose was similar between groups; 89 mg/dL in HC versus 91 mg/dL in TS participants (Table 3). The fasting serum insulin was significantly higher in the TS participants (7.4 μU/mL in HC vs. 12.4 μU/mL in TS, p = 0.003). In addition, the 2-h serum insulin was significantly higher in the TS participants (35.5 μU/mL in HC vs. 65.7 μU/mL in TS, p < 0.0001). The HbA1c was not different between TS and HC (median 5.0% for both groups, p = 0.42).

Within the TS participant groups, the mean 2-h serum glucose was the highest in the TS girls treated with GH and estrogen (Table 3). IFG was significantly more prevalent (35% vs. 10%) in the GH only group. There was no significant difference in prevalence of IFG or impaired glucose tolerance between 45,X and the other TS karyotypes.

The islet cell antibody screen for ZnT8, IAA, IA2, and GAD-65 were negative in all TS participants except in 1 individual with positive GAD-65 titer of 60 (normal <25). Total cholesterol, LDL, HDL, and TG were normal in all participants (TS and controls), using American Heart Association definitions [24]. The gamma-glutamyl transferase and ALT were significantly higher in TS group than HC, but still all within normal range (<50 mg/dL), and AST values were comparable and normal in both groups (<50 mg/dL).

β-Cell Function by Oral Minimal Model

Youth with TS had statistically significant reductions in SI, β-cell responsivity, and DI compared to HC (Fig. 2). These differences remained statistically significant even when controlling for BMI z-score (p values are 0.0006, 0.002, <0.0001 for SI, Φ total, and DI, respectively).

Fig. 2.

Minimal model indices in HC versus TS. TS, Turner syndrome; HC, healthy control; SI, insulin sensitivity; DI, disposition index.

Fig. 2.

Minimal model indices in HC versus TS. TS, Turner syndrome; HC, healthy control; SI, insulin sensitivity; DI, disposition index.

Close modal

The SI index was lowest in the pubertal subgroup for both the TS and the HC. The TS girls had significantly reduced SI index compared to the HC in all 3 subgroups (Fig. 3a). Total β-cell responsivity was lower in TS girls than HC in all 3 subgroups. β-cell responsivity increased with age (Fig. 3b). The DI was significantly lower in the TS girls within each subgroup, than the HC (Fig. 3c).

Fig. 3.

Minimal model indices based on pubertal status. ISI (a), β cell responsivity (b), and DI (c). TS, Turner syndrome; HC, healthy control; ISI, SI index; DI, disposition index; GH, growth hormone.

Fig. 3.

Minimal model indices based on pubertal status. ISI (a), β cell responsivity (b), and DI (c). TS, Turner syndrome; HC, healthy control; ISI, SI index; DI, disposition index; GH, growth hormone.

Close modal

The TS girls with IFG or IGT had significantly lower SI and DI than TS girls with normal glucose (p value = 0.006 for SI and for DI). The TS girls with normal glucose tolerance had a longer duration of GH therapy (84 months vs. 49 months p = 0.07) compared to the TS girls with prediabetes. There was no difference in glucose tolerance based on duration of estrogen therapy. There was also no difference in BMI or BMI z-score between TS girls with prediabetes compared to TS girls with normal glucose. The TS girls with prediabetes were more likely to have an elevated LDL (>130 mg/dL; p = 0.41) and TG (>200 mg/dL; p = 0.23), but this was not statistically significant. There was no difference in liver transaminases between TS girls with and without prediabetes.

This study demonstrated that β-cell dysfunction is present in youth with TS. TS girls have a significant reduction in SI and a reduced and inadequate insulin secretion in response to a glucose load. Furthermore, 35% of TS youth had IFG or IGT with normal HbA1c. Girls with TS had a significantly lower DI than HC indicating the presence of β-cell dysfunction. Similar to previous studies in adults with TS [5, 7, 25, 26]; this study also showed reduced and inadequate insulin secretion in TS girls. In contrast to previous studies in youth with TS that showed only reduced SI, our data established both reduced SI and an inadequate β-cell response, leading to a lower oral DI [27] and therefore reduced β-cell function. Studies in adults have shown that a low DIo increases the risk of progression to overt diabetes in 10 years [17]. The DIo has also been studied in pediatric populations [28, 29] and was shown to be a simple surrogate of β-cell function and predictive of the 2-h glucose concentration. The low DIo in the TS girls in this study correlates with the known increased risk of development of diabetes in the future observed clinically and confirmed in prior studies with adults [30]. The fact that we were able to demonstrate β-cell dysfunction in girls with TS as young as 6 years points toward potential genetic differences in SI and secretion innate to TS. Further studies are needed to assess young TS girls prior to GH initiation to support this statement.

Previous studies have found mixed results regarding SI in TS girls and women [5, 10, 30-32]. Similar to several past studies, this study documented a clear and significant reduction in SI in girls with TS compared to controls [10, 32, 33] that was not related to BMI or BMI z-score. TS girls also had reduced SI across all ages and therapies with the lowest SI in those receiving both GH and estrogen.

Prior reports documented a prevalence of IFG and IGT ranging from 8.7 to 40% [11, 14, 33]. In this study 35% of youth with TS had prediabetes (IFG or IGT). Moreover, 23% had IGT, despite a normal HbA1c. These data are similar to the results reported by Cicognani et al. [33] in 1988, but a higher prevalence of IGT than in more recent studies in youth with TS [11, 14]. Of note, in this study girls with IGT had significantly lower SI than TS girls with normal glucose tolerance. The girls in this study with IGT also had fewer months of GH treatment. Wooten et al. [9] showed that TS girls not treated with GH have a higher risk of insulin resistance and an increased risk of diabetes development. The latter was associated with increased abdominal and liver adiposity. While GH inhibits insulin stimulated glucose uptake by muscle and reduces liver SI, these effects are thought to be outweighed by the positive effects of GH on reducing adiposity, and improving lean (muscle) mass and overall body composition. Therefore, our data, similar to that of Wooten et al. [9], show that GH may have a protective effect on glucose tolerance and may reduce the risk of diabetes.

Bondy was able to show an increased risk of diabetes with trisomy for Xq or monosomy for Xp [30]. We did not observe a correlation between a particular karyotype and β-cell dysfunction, likely due to having inadequate power to detect a difference, given the wide range of karyotypes observed in a relatively small number of study subjects.

This study has the following strengths. First, this study has a large number of participants (healthy controls and TS girls = 120) with a wide range of nonadult ages. Second, this study examines the impact of accepted therapeutic interventions. Third, this study employed state of the art techniques (frequently sampled OGTT with oral and c-peptide minimal modeling) to determine SI, β-cell responsivity, and DIo. The oral glucose and c-peptide minimal model has been validated against IVGTT and 5-h OGTT and could be relatively easily performed in the clinical setting [18]. In addition, previous reports suggested that OGTT is not useful in TS and suggested that a fasting glucose, insulin, and HgbA1c are adequate for detecting abnormal glucose metabolism. Furthermore, the most recent 2017 guidelines for care of patients with TS recommend obtaining an HbA1c with or without fasting glucose starting at age 10 years [1]. The data in this study strongly suggest that fasting glucose and HgbA1c are inadequate and would not have identified the 14 girls with IGT. Early identification of IGT is needed in order to start treatment to prevent or slow the progression to diabetes mellitus.

This study has the following limitations. First, this study employs a cross-sectional design preventing assessment of changes in β-cell function over time. Second, participants were not matched based on BMI, as BMI is not the best measure of adiposity in TS girls given their short stature. Third, compliance with therapeutic interventions was not assessed formally. Fourth, the HC participants were younger than the TS girls as they were matched based on pubertal status in order to assess glucose homeostasis in the setting of estrogen and GH. In addition, TS girls were treated with exogenous GH and/or estrogen as part of standard therapy for TS which are known to lower SI. Finally, this study recruited patients from 2 centers in the Midwest of the USA which may limit the generalizability of the findings.

In conclusion, our study demonstrated that β-cell dysfunction is present in youth with TS compared to controls. In addition, 35% of youth with TS have prediabetes. The presence of both reduction in insulin secretion and SI suggest a unique TS-related glycemic phenotype. Further investigation is required to define the mechanism, rate of decline, and potential interventions to limit/prevent the progression of β-cell dysfunction in youth with TS. Based on the data from this study, we strongly suggest that providers employ serial OGTT to screen for glucose abnormalities in young adolescents with TS.

The authors would like to acknowledge the following organizations that contributed to this research: TS Center of Cincinnati, Children’s Mercy Kansas City, Gower lab, specifically Francesca Piccinni, PhD, at Cedars Sinai Medical Center, the Cincinnatus Foundation for Research and Education in Turner Syndrome, and the patients and families.

This study protocol was reviewed and approved by IRB at Cincinnati Children’s Hospital, approval number 2012-2788. Written informed consent was obtained from participants (or their parent/legal guardian/next of kin) to participate in the study.

Joseph Cernich has a consulting agreement with Novo-Nordisk. The remaining authors have no disclosures.

Research reported in this publication was supported in part by internal funds from the Division of Endocrinology at Cincinnati Children’s Hospital Medicine Center, a Behavioral Medicine, NIH Grant #5T32DK063929-10, a T32 in Environmental Health NIEHS Grant #T32ES10957-14, a local Arnold Strauss Research Fellowship Award, and the National Center for Advancing Translational Sciences of the National Institutes of Health, under Award Number UL1TR001425. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Drs Sheanon, Backeljauw, and Elder conceived this research project and were integral in the design of the study. Dr. Sheanon conducted the majority of the study visits at CCHMC, and Dr. Cernich was responsible for the study visits at CMH. Dr. Sheanon wrote the manuscript. Dr. Khoury performed all of statistical analysis. All authors were involved in analysis and interpretation of the work, revising the manuscript for intellectual content, and final approval of the manuscript.

All datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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