Given the current childhood obesity epidemic, insulin resistance in children is an important issue confronting health care professionals. There are no clear criteria to define insulin resistance in children, and surrogate markers such as fasting insulin are poor measures of insulin sensitivity. Based on current screening criteria and methodology, there is no justification for screening children for insulin resistance. Lifestyle interventions including diet and exercise can improve insulin sensitivity, whereas drugs should be implemented only in selected cases.

Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near (rs9942471, = 4.5 × 10) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at and, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.

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Obese boys and girls presented an earlier onset of puberty and completion of puberty and an impaired height gain during puberty.

OBJECTIVE -To explore the prevalence of lipid abnormalities and their relationship with albumin excretion and microalbuminuria in adolescents with type 1 diabetes.RESEARCH DESIGN AND METHODS -The study population comprised 895 young subjects with type 1 diabetes (490 males); median age at the baseline assessment was 14.5 years (range 10 -21.1), and median diabetes duration was 4.8 years (0.2-17). A total of 2,194 nonfasting blood samples were collected longitudinally for determination of total cholesterol, LDL cholesterol, HDL cholesterol, TG, and non-HDL cholesterol. Additional annually collected data on anthropometric parameters, A1C, and albumin-to-creatinine ratio (ACR) were available.RESULTS -Total cholesterol, LDL cholesterol, HDL cholesterol, and non-HDL cholesterol were higher in females than in males (all P Ͻ 0.001). A significant proportion of subjects presented sustained lipid abnormalities during follow-up: total cholesterol Ͼ5.2 mmol/l (18.6%), non-HDL cholesterol Ͼ3.4 mmol/l (25.9%), TG Ͼ1.7 mmol/l (20.1%), and LDL cholesterol Ͼ3.4 mmol/l (9.6%). Age and duration were significantly related to all lipid parameters (P Ͻ 0.001); A1C was independently related to all parameters (P Ͻ 0.001) except HDL cholesterol, whereas BMI SD scores were related to all parameters (P Ͻ 0.05) except total cholesterol. Total cholesterol and non-HDL cholesterol were independently related to longitudinal changes in ACR (B coefficient Ϯ SE): 0.03 Ϯ 0.01/1 mmol/l, P ϭ 0.009, and 0.32 Ϯ 0.014/1 mmol/l, P ϭ 0.02, respectively. Overall mean total cholesterol and non-HDL cholesterol were higher in microalbuminuria positive (n ϭ 115) than in normoalbuminuric subjects (n ϭ 780): total cholesterol 4.7 Ϯ 1.2 vs. 4.5 Ϯ 0.8 mmol/l (P ϭ 0.04) and non-HDL cholesterol 3.2 Ϯ 1.2 vs. 2.9 Ϯ 0.8 mmol/l (P ϭ 0.03).CONCLUSIONS -In this longitudinal study of adolescents with type 1 diabetes, sustained lipid abnormalities were related to age, duration, BMI, and A1C. Furthermore, ACR was related to both total cholesterol and non-HDL cholesterol, indicating a potential role in the pathogenesis of diabetic nephropathy.

Oxidant-antioxidant status was investigated in a group of severely obese prepubertal children in comparison with healthy subjects and in relation to a dietary restriction-weight loss program. All subjects underwent anthropometric measurements and determination of lipid profile, lag phase, malondialdehyde (MDA), and vitamin E. Compared with controls, obese children had a significantly higher body mass index (BMI) (28.97 +/- 2.42 vs. 16.03 +/- 1.88 kg/m2; P = 0.0002) and waist-to-hip ratio (WHR) (0.89 +/- 0.03 vs. 0.80 +/- 0.01; P = 0.0004); lag phase and vitamin E levels were significantly decreased [24.05 +/- 16.21 vs. 43.16 +/- 10 min (P = 0.004) and 21.12 +/- 14.96 vs. 35.54 +/- 13.62 micromol/liter (P = 0.02), respectively], whereas MDA was significantly increased (0.90 +/- 0.31 vs. 0.45 +/- 0.24 nmol/mg; P = 0.001). Both lag phase and MDA significantly correlated with BMI [respectively, r = -0.34 (P = 0.004) and r = 0.57 (P = 0.002)] and WHR [respectively, r = -0.63 (P = 0.0001) and r = 0.38 (P = 0.04)]. Oxidant status normalized after 6 months of dietary restriction [lag phase, 59.11 +/- 14.74 min (P = 0.002); MDA, 0.47 +/- 0.09 nmol/mg (P = 0.003)], which was associated with a reduction of BMI (27.34 +/- 1.87 kg/m2; P = 0.003), WHR (0.87 +/- 0.02; P = 0.001), and fat mass (34.49 +/- 2.68%; P = 0.008), but returned to baseline levels together with fatness indexes after another 6 months of free diet. Altered oxidant-antioxidant status is already present in prepubertal severely obese children and is reversible with a dietary restriction-weight loss program, which should be highly encouraged and maintained over time in this age group.

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10) and the risk of type 2 diabetes (P=6.1×10) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10), and pentose and glucuronate interconversions (P=3.0×10) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.

OBJECTIVETo assess the potential association between A1C variability (A1C-SD) and microalbuminuria in young people with type 1 diabetes.RESEARCH DESIGN AND METHODSSerially collected samples for A1C measurement were available for 1,232 subjects with childhood-onset type 1 diabetes recruited to the Oxford Regional Prospective Study and the Nephropathy Family Study.RESULTSThe median (range) number of A1C assessments was 4 (2–16). Mean intrapersonal A1C was 9.5% and A1C-SD was 0.91. Mean A1C and A1C-SD values were higher in subjects with microalbuminuria (n = 227) than in those with normoalbuminuria (10.3 vs. 9.4%; 1.12 vs. 0.86, P < 0.001). In a Cox regression model, A1C-SD was independently associated with microalbuminuria (hazard ratio 1.31 [95% CI 1.01–1.35]).CONCLUSIONSIn the current study, A1C variability was an independent variable that added to the effect of A1C on the risk for microalbuminuria in youth with type 1 diabetes, a population highly vulnerable to vascular complications.