Association between fear of hypoglycemia and physical activity in youth with type 1 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Youth with type 1 diabetes (T1D) are encouraged to participate in physical activity (PA). Studies have identified fear of hypoglycemia (FOH) as a barrier to participating in PA. OBJECTIVES: To examine (a) PA patterns in youth with T1D by age group and (b) the relationship between both parental and youth FOH and youth PA. METHODS: A cross-sectional analysis from the SEARCH cohort study visit of youth ages 10 to 17 years with T1D (n = 1129) was conducted. Linear regression models estimated the association between self-reported number of days of vigorous PA (VPA) and moderate PA (MPA) and both youth- and parent-reported FOH. Multivariable models were adjusted for age, sex, race, duration of T1D, HbA1c, use of continuous glucose monitoring (CGM), recent severe hypoglycemia, primary insulin regimen, and BMI. RESULTS: Participants were 52% female, had mean (sd) age 14.4 (4.2) years, diabetes duration 7.5 years (1.8), HbA1c 9.2% (1.7). Older youth were less likely to engage in VPA (P < .01), or sports teams (P < .01), but more likely to engage in MPA (P < .01). Higher youth FOH (behavior subscale) was associated with increased levels of VPA (ß (se) 0.30 (0.11), P = .01) but not significantly associated with MPA (P = .06). There was no statistically significant association between parental FOH and youth PA. CONCLUSIONS: In SEARCH participants with T1D, VPA, and team sports participation declined with age, while MPA increased. We observed that higher scores on the youth FOH behavioral subscale were associated with increased VPA levels, suggesting that FOH may be less of a barrier to PA than previously thought.

Family involvement with the diabetes regimen in young people: the role of adolescent depressive symptoms.

AIMS: In young people with Type 1 diabetes, depressive symptoms and shared responsibility for management of diabetes impact upon diabetes management and control. However, the simultaneous effects of both depressive symptoms and parental involvement on diabetes self-care and glycaemic control have not been examined. Thus, the aim of the current study was to examine the relationships between parental involvement and adolescent depressive symptoms in predicting blood glucose monitoring and glycaemic control. METHODS: One hundred and fifty young people with Type 1 diabetes (mean age 15.3 years) and their parents completed responsibility sharing and depressive symptom assessments, meter assessment of blood glucose monitoring and HbA(1c) at baseline and then 6, 12 and 18 months. RESULTS: Parental involvement affected HbA1c through blood glucose monitoring only at low levels of adolescent depressive symptoms (score ≤ 6), which made up only 20% of the sample. In the presence of more depressive symptoms, parental involvement no longer was related to HbA1c through blood glucose monitoring. This was the relationship in the majority of the sample (80%). CONCLUSIONS: While most young people in this sample are not showing evidence of high levels of depressive symptoms, even modest levels of distress interfere with parental involvement in diabetes management. By addressing adolescent depressive symptoms, interventions promoting parental involvement in these families may be more effective.

Insulin resistance and arterial stiffness in healthy adolescents and young adults.

AIMS/HYPOTHESIS: Increased arterial stiffness is a risk factor for adverse cardiovascular events in adults with obesity-related insulin resistance (IR) or type 2 diabetes mellitus. Adolescents with type 2 diabetes have stiffer vessels. Whether stiffness is increased in obesity/IR in youth is not known. We sought to determine if IR was a determinant of arterial stiffness in youth, independent of obesity and cardiovascular risk factors. METHODS: We measured cardiovascular risk factors, IR, adipocytokines and arterial stiffness (brachial artery distensibility [BrachD], pulse wave velocity [PWV]) and wave reflection (augmentation index [AIx]) in 343 adolescents and young adults without type 2 diabetes (15-28 years old, 47% male, 48% non-white). Individuals <85th percentile of BMI were classified as lean (n = 232). Obese individuals were grouped by HOMA index as not insulin resistant (n = 46) or insulin resistant (n = 65) by the 90th percentile for HOMA for lean. Mean differences were evaluated by ANOVA. Multivariate models evaluated whether HOMA was an independent determinant of arterial stiffness. RESULTS: Risk factors deteriorated from lean to obese to obese/insulin resistant (all p ≤ 0.017). Higher AIx, lower BrachD and higher PWV indicated increased arterial stiffness in obese and obese/insulin-resistant participants. HOMA was not an independent determinant. Age, sex, BMI and BP were the most consistent determinants, with HDL-cholesterol playing a role for BrachD and leptin for PWV (AIx R²= 0.34; BrachD R² = 0.37; PWV R² = 0.40; all p ≤ 0.02). CONCLUSIONS/INTERPRETATION: Although IR is associated with increased arterial stiffness, traditional cardiovascular risk factors, especially obesity and BP, are the major determinants of arterial stiffness in healthy young people.

Clinical evolution of beta cell function in youth with diabetes: the SEARCH for Diabetes in Youth study.

AIMS/HYPOTHESIS: Few studies have explored the epidemiology of beta cell loss in youth with diabetes. This report describes the evolution and major determinants of beta cell function, assessed by fasting C-peptide (FCP), in the SEARCH for Diabetes in Youth study. METHODS: Participants were 1,277 youth with diabetes (948 positive for diabetes autoantibodies [DAs] and 329 negative for DAs), diagnosed when aged <20 years, who were followed from a median of 8 months post diagnosis, for approximately 30 months. We modelled the relationship between rate of change in log FCP and determinants of interest using repeated measures general linear models. RESULTS: Among DA-positive youth, there was a progressive decline in beta cell function of 4% per month, independent of demographics (age, sex, race/ethnicity), genetic susceptibility to autoimmunity (HLA risk), HbA(1c) and BMI z score, or presence of insulin resistance. Among DA-negative youth, there was marked heterogeneity in beta cell loss, reflecting an aetiologically mixed group. This group likely includes youths with undetected autoimmunity (whose decline is similar to that of DA-positive youth) and youth with non-autoimmune, insulin-resistant diabetes, with limited decline (~0.7% per month). CONCLUSIONS/INTERPRETATION: SEARCH provides unique estimates of beta cell function decline in a large sample of youth with diabetes, indicating that autoimmunity is the major contributor. These data contribute to a better understanding of clinical evolution of beta cell function in youth with diabetes, provide strong support for the aetiological classification of diabetes type and may inform tertiary prevention efforts targeted at high-risk groups.

The effects of obesity and type 2 diabetes mellitus on cardiac structure and function in adolescents and young adults.

AIMS/HYPOTHESIS: We sought to evaluate the effects of obesity and obesity-related type 2 diabetes mellitus on cardiac geometry (remodelling) and systolic and diastolic function in adolescents and young adults. METHODS: Cardiac structure and function were compared by echocardiography in participants who were lean, obese or obese with type 2 diabetes (obese diabetic), in a cross sectional study. Group differences were assessed using ANOVA. Independent determinants of cardiac outcome measures were evaluated with general linear models. RESULTS: Adolescents with obesity and obesity-related type 2 diabetes were found to have abnormal cardiac geometry compared with lean controls (16% and 20% vs <1%, p < 0.05). These two groups also had increased systolic function. Diastolic function decreased from the lean to obese to obese diabetic groups with the lowest diastolic function observed in the obese diabetic group (p < 0.05). Regression analysis showed that group, BMI z score (BMIz), group × BMIz interaction and systolic BP z score (BPz) were significant determinants of cardiac structure, while group, BMIz, systolic BPz, age and fasting glucose were significant determinants of the diastolic function (all p < 0.05). CONCLUSIONS/INTERPRETATION: Adolescents with obesity and obesity-related type 2 diabetes demonstrate changes in cardiac geometry consistent with cardiac remodelling. These two groups also demonstrate decreased diastolic function compared with lean controls, with the greatest decrease observed in those with type 2 diabetes. Adults with diastolic dysfunction are known to be at increased risk of progressing to heart failure. Therefore, our findings suggest that adolescents with obesity-related type 2 diabetes may be at increased risk of progressing to early heart failure compared with their obese and lean counterparts.

Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth.

AIM/HYPOTHESIS: Common variants in the transcription factor 7-like 2 (TCF7L2) gene have been associated with type 2 diabetes in adults. However, it is not known whether TCF7L2 variation increases the risk of early onset type 2 diabetes. Using a case-control design, we examined whether the reported variants [rs12255372 (T/G) and rs7903146 (T/C)] are associated with type 2 diabetes in SEARCH for Diabetes in Youth study participants. METHODS: Variants were genotyped in 694 non-Hispanic white (NHW) youth (86 cases, mean age 15.5 years, mean BMI 34.8; and 608 controls, mean age 14.4 years, mean BMI 22.3) and 545 African-American (AA) youth (154 cases, mean age 15.9, mean BMI 37; and 391 controls, mean age 14.8, mean BMI 23.8). Logistic regression adjusted for age, sex, BMI and West African ancestry. RESULTS: The association of the risk T allele with case/control status was different in AA and NHW youth (p = 0.025). Among AA youth, each copy of the T allele (rs7903146) was associated with a 1.97-fold (1.37, 2.82) increased odds for type 2 diabetes (p < 0.0001), after adjustment for age, sex, BMI and African ancestry. No significant association was detected in NHW youth (adjusted OR, 1.14; 0.73, 1.79). CONCLUSION/INTERPRETATION: TCF7L2 variation is associated with an increased risk of early-onset type 2 diabetes among AA youth, and the association appears to be stronger in AA than NHW youth. This suggests potential different contributions of genetic and environmental factors to early-onset type 2 diabetes by race.

Gender differences in the relationships among obesity, adiponectin and brachial artery distensibility in adolescents and young adults.

BACKGROUND: Obesity-related cardiovascular diseases (CVDs) are a major cause of cardiovascular (CV) mortality. Obesity-related reduction in vascular protective adipose-derived proteins, such as adiponectin (APN), has an important role. METHODS: We compared brachial artery distensibility (BrachD) with APN, the level of adiposity and other CV risk factors (CVRFs) in 431 post-pubertal subjects (mean 17.9 years). Gender differences in average values were examined by t-tests. Correlations among BrachD, obesity and other CVRFs were examined. Regression analysis was performed to determine whether APN provided an independent contribution to BrachD, while controlling for obesity and other CVRFs. RESULTS: Male subjects had lower BrachD (5.72+/-1.37 vs 6.45+/-1.60% change per mm Hg, P<0.0001) and lower APN (10.50+/-4.65 vs 13.20+/-6.53; all P<0.04) than female subjects. BrachD correlated with APN (r=0.25, P< 0.0001). Both BrachD and APN correlated with measures of body size, including height, weight and body mass index (BMI). Both correlated with higher systolic blood pressure, glucose, insulin and lower high-density lipoprotein cholesterol (all P<0.01). In multivariate analysis, APN, gender, APN*gender and BMI z-score predicted BrachD (r(2)=0.305). On the basis of gender difference, only BMI z-score was significant for male subjects (r(2)=0.080), whereas APN and BMI z-score contributed for female subjects (r(2)=0.242, all P<0.0001). CONCLUSIONS: BrachD is independently influenced by obesity in both male and female subjects. In female subjects, APN exerts an additional independent effect even after adjusting for blood pressure (BP), lipid levels and insulin. Differences in the effect of the APN-adiposity relationship on obesity-related vascular disease may be one reason for gender differences in the development and progression of atherosclerosis.

Urinary symptoms and quality of life in women following urogenital fistula repair: a long-term follow-up study.

Using the Bristol Female Lower Urinary Tract Symptom questionnaire, we have investigated urinary and sexual symptoms and quality of life in a group of 31 women 50 months (median) after successful repair of urogenital fistula. All had undergone urodynamic investigation prior to their repair surgery, and only 36% had normal findings. Almost all women reported one or more symptoms, and for 65%, these caused at least 'a bit of a problem', although 87% said that their urinary symptoms had little or no impact on their quality of life. Symptoms were similar in urethrovaginal and vesicovaginal fistulae and were not significantly associated with prior functional abnormality.

Genotoxicity and carcinogenicity in rats and mice of 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7- one: an intestinal bacterial metabolite of 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline.

BACKGROUND: Compounds formed on the surface of fried or grilled meat and fish may be associated with increased risk of colon cancer. Normal intestinal bacteria can convert one of these compounds, 2-amino-3-methyl-3H-imidazo[4,5-f]quinoline (IQ), to the 7-hydroxy metabolite, 2-amino-3,6-dihydro-3-methyl-7H-imidazolo[4,5-f]quinolin-7-o ne (7-OHIQ), a direct-acting mutagen. PURPOSE: We studied the genotoxicity and carcinogenicity of 7-OHIQ to determine if it is responsible for the colon-specific activity of IQ. METHODS: The effects of pure, synthetic 7-OHIQ on DNA were evaluated in the Ames Salmonella typhimurium TA98 test, with and without an induced rat liver S9 fraction, and in the Williams DNA repair test using freshly explanted rat hepatocytes. 7-OHIQ was also subjected to an in vivo bioassay for 21 months by long-term intrarectal infusion in male F344 rats, using IQ and N-nitrosomethylurea (NMU) given intrarectally as positive tumor-producing controls. The standard NIH-07 rodent diet was supplemented with 15% corn oil to maximize any effect of the infused materials on the colon. A parallel bioassay involved intraperitoneal injection of 7-OHIQ in newborn mice, followed by dietary administration from week 11 to week 67. Again, IQ and NMU were used as positive controls. RESULTS: We confirmed that 7-OHIQ is a direct-acting mutagen in the Ames test, with added S9 liver fraction giving higher mutagenicity. 7-OHIQ was negative in the Williams test, whereas IQ was positive. 7-OHIQ did not induce colon cancer in rats, and in the newborn mouse test it produced only a low incidence of liver neoplasms. CONCLUSIONS: 7-OHIQ is not genotoxic, for to be so classified it must be definitely positive in both the Ames and Williams tests; moreover, it is not carcinogenic, in marked contrast to IQ and NMU.

Diabetic ketoacidosis among obese African-American adolescents with NIDDM.

OBJECTIVE: To determine whether ketosis at the time of presentation occurs among African-American adolescents with NIDDM. RESEARCH DESIGN AND METHODS: We reviewed the charts of all islet cell antibody (ICA) negative patients diagnosed with NIDDM at Children's Hospital Medical Center (CHMC) between 1982 and 1995. RESULTS: Between 1982 and 1985, 70 adolescents were diagnosed with NIDDM. Of these, ICA determinations were available and negative on 42 subjects (28 African-American, 12 white). Twelve of 28 (42%) African-American patients presented with ketonuria, and seven of 28 (25%) presented with DKA. In comparison, none of the 12 white adolescents with NIDDM had ketonuria at presentation or during their subsequent course. Mean follow-up time for patients with ketosis at presentation was 24 months. There was no difference between the age, BMI, or sex distribution of patients with and without ketosis. Previously diagnosed hypertension was present in 42% of patients presenting with ketosis, compared with 17% of the general NIDDM population at CHMC. CONCLUSIONS: We conclude that ketosis may occur among African-American adolescents with NIDDM, as has been previously reported among African-American adults with NIDDM. Therefore, ketosis in obese young African-American patients with new-onset diabetes does not necessarily imply the presence of IDDM and insulin dependence.