Faculty Bibliography

The SEARCH for Diabetes in Youth Study prospectively identified youth aged <20 years with physician-diagnosed diabetes. Annual type 1 diabetes (T1D) incidence per 100,000 person-years (95% CI) overall, by age-group, and by sex were calculated for at-risk non-Hispanic white (NHW) youth from 2002 through 2009. Joinpoint and Poisson regression models were used to test for temporal trends. The age- and sex-adjusted incidence of T1D increased from 24.4/100,000 (95% CI 23.9-24.8) in 2002 to 27.4/100,000 (26.9-27.9) in 2009 (P for trend = 0.0008). The relative annual increase in T1D incidence was 2.72% (1.18-4.28) per year; 2.84% (1.12-4.58) per year for males and 2.57% (0.68-4.51) per year for females. After adjustment for sex, significant increases were found for youth aged 5-9 years (P = 0.0023), 10-14 years (P = 0.0008), and 15-19 years (P = 0.004) but not among 0-4-year-olds (P = 0.1862). Mean age at diagnosis did not change. The SEARCH study demonstrated a significant increase in the incidence of T1D among NHW youth from 2002 through 2009 overall and in all but the youngest age-group. Continued surveillance of T1D in U.S. youth to identify future trends in T1D incidence and to plan for health care delivery is warranted.

OBJECTIVE:To describe the prevalence of access and process barriers to health care and to examine their relationship to sociodemographic and disease factors in a large and diverse cohort of US youth with type 1 diabetes. STUDY DESIGN/METHODS:A cross-sectional analysis of 780 youth who participated in the SEARCH for Diabetes in Youth Study and were diagnosed with type 1 diabetes in 2002-2005. Experience of barriers to care was collected from parent report on questionnaires. Analyses included multivariate regression models to predict the presence of specific barriers to care. RESULTS:Overall, 81.7% of participants reported at least one barrier; the 3 most common were costs (47.5%), communication (43.0%), and getting needed information (48.4%). Problems with access to care, not having a regular provider, and receiving contextual care (care that takes into account personal and family context) were associated with poorer glycated hemoglobin levels. Adjusted multivariate models indicated that barriers related to access (regular provider, cost) were most likely for youth with low family income and those without public health insurance. Barriers associated with the processes of quality care (contextual care, communication) were more likely for Hispanic youth and those whose parents had less education. CONCLUSIONS:This study indicates that a large proportion of youth with type 1 diabetes experience substantial barriers to care. Barriers to access and those associated with processes of quality care differed by sociodemographic characteristics. Future investigators should expand knowledge of the systemic processes that lead to disparate outcomes for some youth with diabetes and assess potential solutions.

OBJECTIVE:To examine the longitudinal associations between sex, diabetes self-care, and the health-related quality of life (HRQL) of children and adolescents with type 1 or type 2 diabetes. STUDY DESIGN/METHODS:The sample included 910 participants with type 1 and 241 participants with type 2, ages 10-22 years at baseline, from the SEARCH for Diabetes in Youth Study, a longitudinal observational study. The primary outcome measure was the Pediatric Quality of Life Inventory. Repeated measures, mixed-model regression analysis was conducted with the use of data from baseline and at least one follow-up assessment, spanning approximately 4 years. RESULTS:HRQL was greater among those with type 1 versus type 2 diabetes. Among participants with type 1, greater (better) Pediatric Quality of Life Inventory total scores over time were related to greater parent education (P = .0007), lower glycated hemoglobin values (P < .0001), and greater physical activity during the past 7 days (PÂ = .0001). There was a significant interaction between sex and age (P < .0001); girls' HRQL remained stable or decreased over time, whereas males' HRQL increased. For participants with type 2 diabetes, there was no significant interaction by age and sex, but lower total HRQL was related to being female (P = .011) and greater body mass index z-scores (P = .014). CONCLUSIONS:HRQL in this cohort varied by diabetes type. The interaction between sex and age for type 1 participants, coupled with poorer HRQL among female than male participants with type 2 diabetes, suggests the impacts of diabetes on HRQL differ by sex and should be considered in clinical management. Encouraging physical activity and weight control continue to be important in improving HRQL.

IMPORTANCE/OBJECTIVE: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/METHODS: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/METHODS: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/CONCLUSIONS: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.

BACKGROUND:Two APOL1 nephropathy variants confer substantial risk for non-diabetic end-stage kidney disease (ESKD) in African Americans (AAs). Since not all genetically high-risk individuals develop ESKD, modifying factors likely contribute. Forty-two potentially interactive single nucleotide polymorphisms (SNPs) from a genome-wide association study in non-diabetic ESKD were tested for interaction with APOL1 to identify genes modifying risk for non-diabetic nephropathy. METHODS:SNPs were examined in an expanded sample of 1367 AA non-diabetic ESKD cases and 1504 AA non-nephropathy controls, with validation in an independent family-based cohort containing 608 first-degree relatives of index cases with non-diabetic ESKD. Logistic regression and mixed models were fitted to test for interaction effects with APOL1 on ESKD, estimated kidney function and albuminuria. RESULTS:Among ESKD samples, 14 of 42 SNPs demonstrated suggestive APOL1 interaction with P-values <0.05. After Bonferroni correction, significant interactions with APOL1 were seen with SNPs in podocin (rs16854341; NPHS2, P = 8.0 × 10(-4)), in SDCCAG8 (rs2802723; P = 5.0 × 10(-4)) and near BMP4 (rs8014363; P = 1.0 × 10(-3)); with trends for ENOX1 (rs9533534; P = 2.2 × 10(-3)) and near TRIB1 (rs4457349; P = 5.7 × 10(-3)). The minor allele in NPHS2 markedly changed the APOL1-ESKD association odds ratio (OR) from 7.03 to 1.76 (∼50% reduction in effect per copy of the minor allele), rs2802723 changed the OR from 5.1 to 10.5, and rs8014363 increased the OR from 4.8 to 9.5. NPHS2 (P = 0.05) and SDCCAG8 (P = 0.03) SNPs demonstrated APOL1 interaction with albuminuria in independent family-based samples. CONCLUSIONS:Variants in NPHS2, SDCCAG8 and near BMP4 appear to interact with APOL1 to modulate the risk for non-diabetic ESKD in AAs.

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/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.

In 2013, substantial progress was made in uncovering the genetic basis of a variety of kidney and urological disorders, including congenital and developmental diseases. The new findings will lead to an increased understanding of the pathophysiology of these diseases, improved risk prediction and the development of novel therapies.

BACKGROUND:SUDOSCAN® non-invasively measures peripheral small fiber and autonomic nerve activity using electrochemical skin conductance. Since neuropathy and nephropathy are microvascular Type 2 diabetes (T2D) complications, relationships between skin conductance, estimated glomerular filtration rate (eGFR), and urine albumin:creatinine ratio (UACR) were assessed. METHODS:Two hundred five African Americans (AA) with T2D, 93 AA non-diabetic controls, 185 European Americans (EA) with T2D, and 73 EA non-diabetic controls were evaluated. Linear models were fitted stratified by population ancestry and T2D, adjusted for covariates. RESULTS:Relative to EA, AA had lower skin conductance (T2D cases p<0.0001; controls p<0.0001). Skin conductance was also lower in T2D cases vs. controls in each population (p<0.0001, AA and EA). Global skin conductance was significantly associated with eGFR in AA and EA with T2D; adjusting for age, gender, BMI, and HbA1c, positive association was detected between skin conductance and eGFR in AA T2D cases (parameter estimate 3.38, standard error 1.2; p=5.2E(-3)), without association in EA T2D cases (p=0.22). CONCLUSIONS:Noninvasive measurement of skin conductance strongly associated with eGFR in AA with T2D, replicating results in Hong Kong Chinese. SUDOSCAN® may prove useful as a low cost, non-invasive screening tool to detect undiagnosed diabetic kidney disease in populations of African ancestry.

CONTEXT/BACKGROUND:Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification. OBJECTIVE:Our objective was to assess the relationships between sclerostin, BMD, and CP. DESIGN/METHODS:Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP. PARTICIPANTS/METHODS:A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years. MAIN OUTCOME MEASURES/METHODS:Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured. RESULTS:Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm3, lumbar vBMD was 180.7/47.0/179.0 mg/cm3, coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0, and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women (P<.0001). Before and after adjusting for age, sex, body mass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbar vertebrae vBMD (P<.0001). Sex-stratified analyses verified significant relationships in both men and women (both P<.001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P=.03). CONCLUSIONS:In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP.