Catherine Pihoker

The SEARCH for Diabetes in Youth study: rationale, findings, and future directions.

The SEARCH for Diabetes in Youth (SEARCH) study was initiated in 2000, with funding from the Centers for Disease Control and Prevention and support from the National Institute of Diabetes and Digestive and Kidney Diseases, to address major knowledge gaps in the understanding of childhood diabetes. SEARCH is being conducted at five sites across the U.S. and represents the largest, most diverse study of diabetes among U.S. youth. An active registry of youth diagnosed with diabetes at age <20 years allows the assessment of prevalence (in 2001 and 2009), annual incidence (since 2002), and trends by age, race/ethnicity, sex, and diabetes type. Prevalence increased significantly from 2001 to 2009 for both type 1 and type 2 diabetes in most age, sex, and race/ethnic groups. SEARCH has also established a longitudinal cohort to assess the natural history and risk factors for acute and chronic diabetes-related complications as well as the quality of care and quality of life of persons with diabetes from diagnosis into young adulthood. Many youth with diabetes, particularly those from low-resourced racial/ethnic minority populations, are not meeting recommended guidelines for diabetes care. Markers of micro- and macrovascular complications are evident in youth with either diabetes type, highlighting the seriousness of diabetes in this contemporary cohort. This review summarizes the study methods, describes key registry and cohort findings and their clinical and public health implications, and discusses future directions.

Assessment and monitoring of glycemic control in children and adolescents with diabetes

Marian J Rewersa, Kuben Pillayb, Carine de Beaufortc, Maria E Craigd, Ragnar Hanase, Carlo L Acerinif and David M Maahsa aBarbara Davis Center, University of Colorado Denver, Aurora, CO, USA; bWestville Hospital, Durban, South Africa; cDECCP, Clinique Pediatrique/CHL, Luxembourg, Luxembourg; dInstitute of Endocrinology and Diabetes, Westmead, Australia; eDepartment of Pediatrics, Uddevalla Hospital, Uddevalla, Sweden and fDepartment of Pediatrics, University of Cambridge, Cambridge, UK

Glycemic control in youth with diabetes: the SEARCH for diabetes in Youth Study.

OBJECTIVE To assess correlates of glycemic control in a diverse population of children and youth with diabetes. STUDY DESIGN This was a cross-sectional analysis of data from a 6-center US study of diabetes in youth, including 3947 individuals with type 1 diabetes (T1D) and 552 with type 2 diabetes (T2D), using hemoglobin A(1c) (HbA(1c)) levels to assess glycemic control. RESULTS HbA(1c) levels reflecting poor glycemic control (HbA(1c) >or= 9.5%) were found in 17% of youth with T1D and in 27% of those with T2D. African-American, American Indian, Hispanic, and Asian/Pacific Islander youth with T1D were significantly more likely to have higher HbA(1c) levels compared with non-Hispanic white youth (with respective rates for poor glycemic control of 36%, 52%, 27%, and 26% vs 12%). Similarly poor control in these 4 racial/ethnic groups was found in youth with T2D. Longer duration of diabetes was significantly associated with poorer glycemic control in youth with T1D and T2D. CONCLUSIONS The high percentage of US youth with HbA(1c) levels above the target value and with poor glycemic control indicates an urgent need for effective treatment strategies to improve metabolic status in youth with diabetes.

The Effector T Cells of Diabetic Subjects Are Resistant to Regulation via CD4+FOXP3+ Regulatory T Cells

Defects in immune regulation have been implicated in the pathogenesis of diabetes in mouse and in man. In vitro assays using autologous regulatory (Treg) and responder effector (Teff) T cells have shown that suppression is impaired in diabetic subjects. In this study, we addressed whether the source of this defect is intrinsic to the Treg or Teff compartment of diabetic subjects. We first established that in type 1 diabetes (T1D) individuals, similar levels of impaired suppression were seen, irrespective of whether natural (nTreg) or adaptive Treg (aTreg) were present. Then using aTreg, we examined the ability of T1D aTreg to suppress Teff of healthy controls, as compared with the ability of control aTreg to suppress Teff of diabetic subjects. Taking this approach, we found that the aTregs from T1D subjects function normally in the presence of control Teff, and that the T1D Teff were resistant to suppression in the presence of control aTreg. This escape from regulation was seen with nTreg as well and was not transferred to control Teff coincubated with T1D Teff. Thus, the “defective regulation” in T1D is predominantly due to the resistance of responding T cells to Treg and is a characteristic intrinsic to the T1D Teff. This has implications with respect to pathogenic mechanisms, which underlie the development of disease and the target of therapies for T1D.

Defects in IL-2R Signaling Contribute to Diminished Maintenance of FOXP3 Expression in CD4+CD25+ Regulatory T-Cells of Type 1 Diabetic Subjects

OBJECTIVE In humans, multiple genes in the interleukin (IL)-2/IL-2 receptor (IL-2R) pathway are associated with type 1 diabetes. However, no link between IL-2 responsiveness and CD4+CD25+FOXP3+ regulatory T-cells (Tregs) has been demonstrated in type 1 diabetic subjects despite the role of these IL-2–dependent cells in controlling autoimmunity. Here, we address whether altered IL-2 responsiveness impacts persistence of FOXP3 expression in Tregs of type 1 diabetic subjects. RESEARCH DESIGN AND METHODS Persistence of Tregs was assessed by culturing sorted CD4+CD25hi natural Tregs with IL-2 and measuring FOXP3 expression over time by flow cytometry for control and type 1 diabetic populations. The effects of IL-2 on FOXP3 induction were assessed 48 h after activation of CD4+CD25− T-cells with anti-CD3 antibody. Cytokine receptor expression and signaling upon exposure to IL-2, IL-7, and IL-15 were determined by flow cytometry and Western blot analysis. RESULTS Maintenance of FOXP3 expression in CD4+CD25+ Tregs of type 1 diabetic subjects was diminished in the presence of IL-2, but not IL-7. Impaired responsiveness was not linked to altered expression of the IL-2R complex. Instead, IL-2R signaling was reduced in Tregs and total CD4+ T-cells of type 1 diabetic subjects. In some individuals, decreased signal transducer and activator of transcription 5 phosphorylation correlated with significantly higher expression of protein tyrosine phosphatase N2, a negative regulator of IL-2R signaling. CONCLUSIONS Aberrant IL-2R signaling in CD4+ T-cells of type 1 diabetic subjects contributes to decreased persistence of FOXP3 expression that may impact establishment of tolerance. These findings suggest novel targets for treatment of type 1 diabetes within the IL-2R pathway and suggest that an altered IL-2R signaling signature may be a biomarker for type 1 diabetes.

Presence of Diabetic Ketoacidosis at Diagnosis of Diabetes Mellitus in Youth: The Search for Diabetes in Youth Study

OBJECTIVE. The purpose of this work was to determine the prevalence and predictors of diabetic ketoacidosis at the diagnosis of diabetes in a large sample of youth from the US population. PATIENTS AND METHODS. The Search for Diabetes in Youth Study, a multicenter, population-based registry of diabetes with diagnosis before 20 years of age, identified 3666 patients with new onset of diabetes in the study areas in 2002–2004. Medical charts were reviewed in 2824 (77%) of the patients in a standard manner to abstract the results of laboratory tests and to ascertain diabetic ketoacidosis at the time of diagnosis. Diabetic ketoacidosis was defined by blood bicarbonate <15 mmol/L and/or venous pH < 7.25 (arterial/capillary pH < 7.30), International Classification of Diseases, Ninth Revision, code 250.1, or listing of diabetic ketoacidosis in the medical chart. RESULTS. More than half (54%) of the patients were hospitalized at diagnosis, including 93% of those with diabetic ketoacidosis and 41% without diabetic ketoacidosis. The prevalence of diabetic ketoacidosis at the diagnosis was 25.5%. The prevalence decreased with age from 37.3% in children aged 0 to 4 years to 14.7% in those aged 15 to 19 years. Diabetic ketoacidosis prevalence was significantly higher in patients with type 1 (29.4%) rather than in those with type 2 diabetes (9.7%). After adjusting for the effects of center, age, gender, race or ethnicity, diabetes type, and family history of diabetes, diabetic ketoacidosis at diagnosis was associated with lower family income, less desirable health insurance coverage, and lower parental education. CONCLUSION. At the time of diagnosis, 1 in 4 youth presents with diabetic ketoacidosis. Those with diabetic ketoacidosis were more likely to be hospitalized. Diabetic ketoacidosis was a presenting feature of <10% of youth with type 2. Young and poor children are disproportionately affected.

Prevalence of Diabetes in U.S. Youth in 2009: The SEARCH for Diabetes in Youth Study

OBJECTIVE To estimate the prevalence of diabetes in U.S. youth aged <20 years in 2009 and to estimate the total number of youth with diabetes in the U.S. by age, race/ethnicity, and diabetes type. RESEARCH DESIGN AND METHODS To address one of its primary aims, the SEARCH for Diabetes in Youth Study identified youth aged <20 years on 31 December 2009 with physician-diagnosed diabetes in selected areas of Colorado, Ohio, South Carolina, and Washington, among health plan members of Kaiser Permanente Southern California and among American Indians living on reservations in Arizona and New Mexico. Diabetes was classified as type 1, type 2, or other. Race/ethnicity was by self-report. RESULTS From a population of 3,458,974 youth aged <20 years, 7,695 youth with diabetes were identified (2.22/1,000): 6,668 with type 1 diabetes (1.93/1,000), 837 with type 2 diabetes (0.24/1,000), and 190 (0.05/1,000) with other diabetes types. Prevalence increased with age, was slightly higher in females than males, and was most prevalent in non-Hispanic White and least prevalent in Asian/Pacific Islanders, with Native American and black youth having the highest prevalence of type 2 diabetes. An estimated 191,986 U.S. youth aged <20 years have diabetes; 166,984 type 1 diabetes, 20,262 type 2 diabetes, and 4,740 other types. CONCLUSIONS Diabetes, one of the leading chronic diseases in childhood, affects >190,000 (1 of 433) youth aged <20 years in the U.S., with racial and ethnic disparities seen in diabetes prevalence, overall and by diabetes type.

Incidence Trends of Type 1 and Type 2 Diabetes among Youths, 2002-2012.

BACKGROUND Diagnoses of type 1 and type 2 diabetes in youths present a substantial clinical and public health burden. The prevalence of these diseases increased in the 2001–2009 period, but data on recent incidence trends are lacking. METHODS We ascertained cases of type 1 and type 2 diabetes mellitus at five study centers in the United States. Denominators (4.9 million youths annually) were obtained from the U.S. Census or health‐plan member counts. After the calculation of annual incidence rates for the 2002–2012 period, we analyzed trends using generalized autoregressive moving‐average models with 2‐year moving averages. RESULTS A total of 11,245 youths with type 1 diabetes (0 to 19 years of age) and 2846 with type 2 diabetes (10 to 19 years of age) were identified. Overall unadjusted estimated incidence rates of type 1 diabetes increased by 1.4% annually (from 19.5 cases per 100,000 youths per year in 2002–2003 to 21.7 cases per 100,000 youths per year in 2011–2012, P=0.03). In adjusted pairwise comparisons, the annual rate of increase was greater among Hispanics than among non‐Hispanic whites (4.2% vs. 1.2%, P<0.001). Overall unadjusted incidence rates of type 2 diabetes increased by 7.1% annually (from 9.0 cases per 100,000 youths per year in 2002–2003 to 12.5 cases per 100,000 youths per year in 2011–2012, P<0.001 for trend across race or ethnic group, sex, and age subgroups). Adjusted pairwise comparisons showed that the relative annual increase in the incidence of type 2 diabetes among non‐Hispanic whites (0.6%) was lower than that among non‐Hispanic blacks, Asians or Pacific Islanders, and Native Americans (P<0.05 for all comparisons) and that the annual rate of increase among Hispanics differed significantly from that among Native Americans (3.1% vs. 8.9%, P=0.01). After adjustment for age, sex, and race or ethnic group, the relative annual increase in the incidence of type 1 diabetes was 1.8% (P<0.001) and that of type 2 diabetes was 4.8% (P<0.001). CONCLUSIONS The incidences of both type 1 and type 2 diabetes among youths increased significantly in the 2002–2012 period, particularly among youths of minority racial and ethnic groups. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and the Centers for Disease Control and Prevention.)

Transition From Pediatric to Adult Care for Youth Diagnosed With Type 1 Diabetes in Adolescence

OBJECTIVE: Youth with type 1 diabetes mellitus are at risk for poor glycemic control as they age into adulthood. The aim of this study was to describe sociodemographic and clinical correlates of poor glycemic control associated with the transfer of care from pediatric to adult diabetes providers among a cohort of youth with type 1 diabetes diagnosed in adolescence. METHODS: Analyses included 185 adolescent participants with recently diagnosed type 1 diabetes in the SEARCH for Diabetes in Youth Study with pediatric care at baseline who were age ≥18 years at follow-up. Demographic and clinical factors were measured by survey and laboratory results. Survival analysis was used to estimate the age of transition. Logistic regression analysis assessed the association of demographic and clinical factors with the transition of care and poor glycemic control at follow-up. RESULTS: Fifty-seven percent of participants had transitioned to adult diabetes care providers by the follow-up visit. The estimated median age of transition of care was 20.1 years (95% confidence interval 19.8–20.4). Older age, lower baseline glycosylated hemoglobin, and less parental education were independently associated with increased odds of transition. The odds of poor glycemic control at follow-up were 2.5 times higher for participants who transitioned to adult care compared with those who remained in pediatric care. CONCLUSIONS: Transferring from pediatric to adult care, experienced by more than half the sample, was associated with an increased risk of poor glycemic control at follow-up. These findings suggest that young adults need additional support when moving to adult care.

Obesity and hypertension among children after treatment for acute lymphoblastic leukemia

The purpose was to determine the prevalence and treatment‐related risk factors for obesity and hypertension among childhood acute lymphoblastic leukemia (ALL) survivors treated with contemporary therapy.