Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009.

IMPORTANCE: Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups. OBJECTIVE: To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009. DESIGN, SETTING, AND PARTICIPANTS: Case patients were ascertained in 4 geographic areas and 1 managed health care plan. The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan. MAIN OUTCOMES AND MEASURES: Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTS: In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE: Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases.

Permanent neonatal diabetes mellitus: prevalence and genetic diagnosis in the SEARCH for Diabetes in Youth Study.

BACKGROUND: Neonatal diabetes mellitus (NDM) is defined as diabetes with onset before 6 months of age. Nearly half of individuals with NDM are affected by permanent neonatal diabetes mellitus (PNDM). Mutations in KATP channel genes (KCNJ11, ABCC8) and the insulin gene (INS) are the most common causes of PNDM. OBJECTIVE: To estimate the prevalence of PNDM among SEARCH for Diabetes in Youth (SEARCH) study participants (2001-2008) and to identify the genetic mutations causing PNDM. METHODS: SEARCH is a multicenter population-based study of diabetes in youth <20 yr of age. Participants diagnosed with diabetes before 6 months of age were invited for genetic testing for mutations in the KCNJ11, ABCC8, and INS genes. RESULTS: Of the 15,829 SEARCH participants with diabetes, 39 were diagnosed before 6 months of age. Thirty-five of them had PNDM (0.22% of all diabetes cases in SEARCH), 3 had transient neonatal diabetes that had remitted by 18 months and 1 was unknown. The majority of them (66.7%) had a clinical diagnosis of type1 diabetes by their health care provider. Population prevalence of PNDM in youth <20 yr was estimated at 1 in 252 000. Seven participants underwent genetic testing; mutations causing PNDM were identified in five (71%), (two KCNJ11, three INS). CONCLUSIONS: We report the first population-based frequency of PNDM in the US based on the frequency of PNDM in SEARCH. Patients with NDM are often misclassified as having type1 diabetes. Widespread education is essential to encourage appropriate genetic testing and treatment of NDM.

Ambiguous genitalia: what prenatal genetic testing is practical?

Concern for ambiguous genitalia or chromosome-phenotype discordance detected in a prenatal setting has increased over the last two decades. Practitioners faced with this prenatal finding have a variety of genetic tests available to them; however, it is unclear to what extent prenatal testing for disorders of sex development (DSD) is useful or practical. We undertook a retrospective review of the medical records of 140 individuals evaluated through the DSD clinic at Seattle Children's Hospital with birthdates from 01/01/1994 through 08/16/2011 to determine the rate of prenatal detection of ambiguous genitalia in individuals with DSD, what prenatal diagnostic workup was undertaken, and the postnatal outcome, including whether a postnatal genetic diagnosis was confirmed. Of all 140 subjects, 34 (24%) were identified prenatally. The most common postnatal diagnoses were penoscrotal hypospadias with transposition of the scrotum with no known genetic cause (24/140; 17%) and 21-hydroxylase deficiency (20/140; 14%). Apart from these, no single diagnosis comprised more than a few cases. Prenatal diagnostic testing varied widely, from no tests to multiple molecular tests with amniotic fluid hormone concentrations. In the absence of other fetal anomalies or growth retardation on ultrasound, prenatal karyotype with fluorescence in situ hybridization for the SRY gene is the most useful test when ambiguous genitalia is suspected. Further prenatal testing for Smith-Lemli-Opitz syndrome in 46,XY individuals and congenital adrenal hyperplasia in 46,XX individuals may be considered. However, targeted molecular testing for rare DSD conditions in the absence of a family history of DSD has a low yield.

Type 2 diabetes in childhood: clinical characteristics and role of ß-cell autoimmunity.

The global obesity epidemic has led to dramatic increases in the incidence and prevalence of type 2 diabetes mellitus (T2DM) among youth worldwide. In today's clinical practice it has become increasingly difficult to distinguish type 1 diabetes mellitus (T1DM) from T2DM as many children with T1DM are overweight at diagnosis. Numerous recent publications note a significant proportion of physician-diagnosed T2DM youth with evidence of pancreatic autoimmunity, exemplifying the challenges in distinguishing between T1DM and T2DM. The clinical implications of the phenomenon of antibody positivity in phenotypic T2DM youth, also referred to as "type 1.5 diabetes" (T1.5 DM), "double diabetes," "latent autoimmune diabetes in youth" (LADY), and "hybrid diabetes," are unclear at present. Current and future work should determine if the presence of autoantibodies in phenotypic T2DM youth/children affects clinical course; this will facilitate the development of optimal treatment strategies.

Sequential comparisons of one-month and three-month depot leuprolide regimens in central precocious puberty.

BACKGROUND: Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses. OBJECTIVES: In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses. METHODS: Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection. RESULTS: Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels. CONCLUSIONS: Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.

Alternatives to growth hormone stimulation testing in children.

Despite more than 40 years of pediatric growth hormone (GH) replacement, we are still limited in our ability to make a definitive diagnosis of GH deficiency (GHD) in children. Historically, GH stimulation tests (GHSTs) have been used to discriminate between GHD and idiopathic short stature. Over the years, increases in the peak diagnostic GH cutoffs and the proliferation of GH assays have fundamentally changed the nature of the GHST. In our opinion, today's GHSTs lack reproducibility and accuracy, are expensive, and can be dangerous. Moreover, newer diagnostic tools, such as high-resolution neuroimaging, measurements of serum insulin-like growth factor 1 and insulin-like growth factor-binding protein 3, and an increasing number of genetic tests, have emerged. We believe that it is no longer appropriate to use GHSTs to diagnose childhood GHD. Instead, diagnosis should be based on a combination of auxological, biochemical, neuroradiological and genetic considerations. Here, we examine the alternatives to the GHST that are currently available and literature that supports their use. We believe that these alternative methods should replace the GHST.

Association of parental history of diabetes with cardiovascular disease risk factors in children with type 2 diabetes.

AIMS: Determine if parental diabetes (DM) is associated with unhealthier cardiovascular disease (CVD) risk profiles in youth with type 2 diabetes (T2D), and whether associations differed by race/ethnicity. METHODS: Family history was available for 382 youth with T2D from 2001 prevalent and 2002-2005 incident SEARCH for Diabetes in Youth cohorts. Parental DM was evaluated in two ways: two-category-any parent vs. no parent DM (evaluated overall and stratified by race/ethnicity); and four-category-both parents, mother only, father only, or no parent DM (evaluated overall only). Associations with hemoglobin A1c (HbA1c), fasting lipids, blood pressure (BP), and urine albumin:creatinine ratio (ACR) were examined using regression models. RESULTS: Overall, sample characteristics included: 35.9% male, 19.1% non-Hispanic white (NHW), mean T2D duration 26.6±22.2months, mean HbA1c 7.9%±2.5% (62.6±27.8mmol/mol). Unadjusted two-category comparisons showed that youth with parental DM had higher HbA1c, higher DBP, and higher frequency of elevated ACR. Adjusted two-category comparisons showed associations remaining in non-stratified analysis for ACR [OR (95% CI)=2.3 (1.1, 5.0)] and in NHW youth for HbA1c [6.8%±0.4 vs. 8.0±0.4 (51.1±4.8 vs. 63.9±4.2mmol/mol), p=.015], DBP (67.7%±4.5 vs. 76.9±4.4mm Hg, p=.014) and lnTG (4.7±0.3 vs. 5.3±0.3, p=.008). There were no significant findings in the adjusted four-category evaluation. CONCLUSIONS: Parental history of diabetes may be associated with unhealthier CVD risk factors in youth with T2D.

Correlates of treatment patterns among youth with type 2 diabetes.

OBJECTIVE To describe treatment regimens in youth with type 2 diabetes and examine associations between regimens, demographic and clinical characteristics, and glycemic control. RESEARCH DESIGN AND METHODS This report includes 474 youth with a clinical diagnosis of type 2 diabetes who completed a SEARCH for Diabetes in Youth study visit. Diabetes treatment regimen was categorized as lifestyle alone, metformin monotherapy, any oral hypoglycemic agent (OHA) other than metformin or two or more OHAs, insulin monotherapy, and insulin plus any OHA(s). Association of treatment with demographic and clinical characteristics (fasting C-peptide [FCP], diabetes duration, and self-monitoring of blood glucose [SMBG]), and A1C was assessed by χ(2) and ANOVA. Multiple linear regression models were used to evaluate independent associations of treatment regimens and A1C, adjusting for demographics, diabetes duration, FCP, and SMBG. RESULTS Over 50% of participants reported treatment with metformin alone or lifestyle. Of the autoantibody-negative youth, 40% were on metformin alone, while 33% were on insulin-containing regimens. Participants on metformin alone had a lower A1C (7.0 ± 2.0%, 53 ± 22 mmol/mol) than those on insulin alone (9.2 ± 2.7%, 77 ± 30 mmol/mol) or insulin plus OHA (8.6 ± 2.6%, 70 ± 28 mmol/mol) (P < 0.001). These differences remained significant after adjustment (7.5 ± 0.3%, 58 ± 3 mmol/mol; 9.1 ± 0.4%, 76 ± 4 mmol/mol; and 8.6 ± 0.4%, 70 ± 4 mmol/mol) (P < 0.001) and were more striking in those with diabetes for ≥2 years (7.9 ± 2.8, 9.9 ± 2.8, and 9.8 ± 2.6%). Over one-half of those on insulin-containing therapies still experience treatment failure (A1C ≥8%, 64 mmol/mol). CONCLUSIONS Approximately half of youth with type 2 diabetes were managed with lifestyle or metformin alone and had better glycemic control than individuals using other therapies. Those with longer diabetes duration in particular commonly experienced treatment failures, and more effective management strategies are needed.

Insulin regimens and clinical outcomes in a type 1 diabetes cohort: the SEARCH for Diabetes in Youth study.

OBJECTIVE: To examine the patterns and associations of insulin regimens and change in regimens with clinical outcomes in a diverse population of children with recently diagnosed type 1 diabetes. RESEARCH DESIGN AND METHODS: The study sample consisted of youth with type 1 diabetes who completed a baseline SEARCH for Diabetes in Youth study visit after being newly diagnosed and at least one follow-up visit. Demographic, diabetes self-management, physical, and laboratory measures were collected at study visits. Insulin regimens and change in regimen compared with the initial visit were categorized as more intensive (MI), no change (NC), or less intensive (LI). We examined relationships between insulin regimens, change in regimen, and outcomes including A1C and fasting C-peptide. RESULTS: Of the 1,606 participants with a mean follow-up of 36 months, 51.7% changed to an MI regimen, 44.7% had NC, and 3.6% changed to an LI regimen. Participants who were younger, non-Hispanic white, and from families of higher income and parental education and who had private health insurance were more likely to be in MI or NC groups. Those in MI and NC groups had lower baseline A1C (P = 0.028) and smaller increase in A1C over time than LI (P < 0.01). Younger age, continuous subcutaneous insulin pump therapy, and change to MI were associated with higher probability of achieving target A1C levels. CONCLUSIONS: Insulin regimens were intensified over time in over half of participants but varied by sociodemographic domains. As more intensive regimens were associated with better outcomes, early intensification of management may improve outcomes in all children with diabetes. Although intensification of insulin regimen is preferred, choice of insulin regimen must be individualized based on the child and family's ability to comply with the prescribed plan.