Gut dysbiosis has been linked to type 1 diabetes (T1D); however, microbial capacity in T1D remains unclear. Here, we integratively profiled gut microbial functional and metabolic alterations in children with new-onset T1D in independent cohorts and investigated the underlying mechanisms. In T1D, the microbiota was characterized by decreased butyrate production and bile acid metabolism and increased lipopolysaccharide biosynthesis at the species, gene, and metabolite levels. The combination of 18 bacterial species and fecal metabolites provided excellently discriminatory power for T1D. Gut microbiota from children with T1D induced elevated fasting glucose levels and declined insulin sensitivity in antibiotic-treated mice. In streptozotocin-induced T1D mice, butyrate and lipopolysaccharide exerted protective and destructive effects on islet structure and function, respectively. Lipopolysaccharide aggravated the pancreatic inflammatory response, while butyrate activated Insulin1 and Insulin2 gene expression. Our study revealed perturbed microbial functional and metabolic traits in T1D, providing potential avenues for microbiome-based prevention and intervention for T1D.

OBJECTIVE Type 1 diabetes (T1D) is a highly heritable disease with much lower incidence but more adult-onset cases in the Chinese population. Although genome-wide association studies (GWAS) have identified >60 T1D loci in Caucasians, less is known in Asians. RESEARCH DESIGN AND METHODS We performed the first two-stage GWAS of T1D using 2,596 autoantibody-positive T1D case subjects and 5,082 control subjects in a Chinese Han population and evaluated the associations between the identified T1D risk loci and age and fasting C-peptide levels at T1D diagnosis. RESULTS We observed a high genetic correlation between children/adolescents and adult T1D case subjects (r_g = 0.87), as well as subgroups of autoantibody status (r_g ≥ 0.90). We identified four T1D risk loci reaching genome-wide significance in the Chinese Han population, including two novel loci, rs4320356 near BTN3A1 (odds ratio [OR] 1.26, P = 2.70 × 10⁻⁸) and rs3802604 in GATA3 (OR 1.24, P = 2.06 × 10⁻⁸), and two previously reported loci, rs1770 in MHC (OR 4.28, P = 2.25 × 10⁻²³²) and rs705699 in SUOX (OR 1.46, P = 7.48 × 10⁻²⁰). Further fine mapping in the MHC region revealed five independent variants, including another novel locus, HLA-C position 275 (omnibus P = 9.78 × 10⁻¹²), specific to the Chinese population. Based on the identified eight variants, we achieved an area under the curve value of 0.86 (95% CI 0.85–0.88). By building a genetic risk score (GRS) with these variants, we observed that the higher GRS were associated with an earlier age of T1D diagnosis (P = 9.08 × 10⁻¹¹) and lower fasting C-peptide levels (P = 7.19 × 10⁻³) in individuals newly diagnosed with T1D. CONCLUSIONS Our results extend current knowledge on genetic contributions to T1D risk. Further investigations in different populations are needed for genetic heterogeneity and subsequent precision medicine.

Objective Putative changes in the prevalence of obesity in Chinese children and adolescents in Shanghai, one of the most urbanized areas in China, were analyzed in a cross‐sectional manner in 2003–2008. Methods One urban and one suburban district were randomly selected. 70 582 students in 2003 and 86 355 students in 2008 from schools from within the two districts were examined. Anthropometric parameters were measured in all. Adiposity status was estimated using body mass index according to International Obesity Task Force standards. The prevalence of obesity was analyzed. Results The standardized prevalence of overweight significantly increased from 12.75 to 14.2% (p < 0.01), and the prevalence of obesity significantly increased from 3.35 to 3.94% (p < 0.01) during the study period. In contrast to data from developed countries, the prevalence of obesity decreased with age in both boys and girls. The prevalence of obesity and overweight in boys was significantly higher than that in girls (p < 0.01). Interestingly, the prevalence of overweight and obesity in the urban area was also significantly higher than that in suburb area (p < 0.01). Conclusion Over a 5‐yr period, there was a significant increase in the prevalence of obesity in children and adolescents in Shanghai. The high percentage of overweight and obesity in the young age groups is of particular concern. Urbanization might be a causative factor for the increase in obesity prevalence in Chinese children in the Shanghai area.

Objective IGF1R gene mutations have been associated with varying degrees of intrauterine and postnatal growth retardation, as well as microcephaly. Both autosomal dominant and autosomal recessive inheritance patterns have been reported. This study aimed to analyze the IGF1R gene in children with growth impairment using whole exome sequencing (WES) and to assess the clinical features with the autosomal dominant and recessive models. Methods We performed WES in 28 unrelated patients and found 3 children harboring IGF1R gene variants. We compared the clinical findings in our cases carrying IGF1R mutations to those in patients reported in the HGMD database. Results We identified four novel IGF1R gene variations by WES in 3 unrelated patients, including one missense variant (c.3740T>C (p.M1247T)) (Patient 1) inherited from an affected mother, one missense variant (c.744T>G (p.C248W)) (Patient 2) inherited from an affected father, and two compound heterozygous variations (c.2305G>C (p.E769Q); c.2684G>A (p.R895Q)) (Patient 3). To date, twenty-two patients have been described as harboring pathogenic variations in IGF1R in the HGMD database. We found that patients with compound heterozygous or homozygous variations displayed more severe phenotypes that were mainly characterized by developmental and speech delays, as well as mental retardation. Conclusion We identified four novel pathogenic variations in the IGF1R gene, which expanded the known mutation spectrum. Through a comparison among patients with reported IGF1R pathogenic variations, this study determined that an autosomal recessive inheritance model of the IGF1R gene may result in a more severe phenotype with developmental and speech delays, as well as mental retardation.