Search

Objective: Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals., Methods: Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays., Results: The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function., Conclusions: In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Objectives: Animal models indicate that hepatic insulin resistance (IR) promotes cholesterol gallstone disease (GSD). We sought to determine whether hepatic and whole-body IR are associated with incident GSD., Methods: At baseline, 450 Southwestern Indigenous American adults without GSD were included. Participants had a 2-step hyperinsulinemic-euglycemic clamp with glucose tracer at submaximal and maximal insulin stimulation (240 and 2400 pmol/m2/min) for whole-body IR (M-low and M-high) and hepatic glucose production (HGP) before and during submaximal insulin infusion (HGP-basal and HGP-insulin). Incident GSD was identified during follow-up visits conducted at ∼2-year intervals. The associations of HGP (basal, insulin, and % suppression), M-low, and M-high with risk of GSD were assessed by Cox regression models adjusted for age, sex, body fat (%), glucose, and insulin., Results: Sixty participants (13%) developed GSD (median follow-up: 11.6 years). Participants who developed GSD were of similar age and whole-body IR as those who did not (p's> 0.07), but were more likely to be female, have higher body fat, higher HGP-basal, and HGP-insulin, and lower % suppression of HGP (p's<0.02). In separate adjusted models, higher HGP-insulin and lower % suppression of HGP were associated with increased risk for GSD (hazard ratio [HR] per SD: HR 1.38, 95% CI 1.12, 1.69, p=0.002; HR 1.41 95% CI 1.16-1.72, p=0.0007). HGP-basal, M-low, and M-high were not associated with GSD in adjusted models (p's>0.22)., Conclusions: Resistance to insulin suppression of HGP increases risk for GSD. Hepatic IR is a link between GSD and other conditions of the metabolic syndrome., (Copyright © 2024 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Genetic determinants of interindividual differences in energy expenditure (EE) are largely unknown. Sphingolipids, such as ceramides, have been implicated in the regulation of human EE via mitochondrial uncoupling. In this study, we investigated whether genetic variants within enzymes involved in sphingolipid synthesis and degradation affect EE and insulin-related traits in a cohort of American Indians informative for 24-h EE and glucose disposal rates during a hyperinsulinemic-euglycemic clamp. Association analysis of 10,084 genetic variants within 28 genes involved in sphingolipid pathways identified a missense variant (rs267738, A>C, E115A) in exon 4 of CERS2 that was associated with higher sleeping EE (116 kcal/day) and increased rates of endogenous glucose production during basal (5%) and insulin-stimulated (43%) conditions, both indicators of hepatic insulin resistance. The rs267738 variant did not affect ceramide synthesis in HepG2 cells but resulted in a 30% decrease in basal mitochondrial respiration. In conclusion, we provide evidence that the CERS2 rs267738 missense variant may influence hepatic glucose production and postabsorptive sleeping metabolic rate., (© 2024 by the American Diabetes Association.)

Context: The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism., Objective: To determine biological mechanisms that govern diverse functions of this locus., Methods: Genotypes for 491,265 variants in 7,000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5,205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for LDL-C levels identified a variant in CELSR2 and the molecular impact of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay., Results: A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 also associated with increased oxidative phosphorylation gene expression; CELSR2 as a regulator of these genes, suggests potential influence on energy metabolism through muscle oxidative capacity., Conclusion: Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling., (Published by Oxford University Press on behalf of the Endocrine Society 2024.)

We sought to identify genetic/immunologic contributors of type 2 diabetes (T2D) in an indigenous American community by genotyping all study participants for both high-resolution HLA-DRB1 alleles and SLC16A11 to test their risk and/or protection for T2D. These genes were selected based on independent reports that HLA-DRB1*16:02:01 is protective for T2D and that SLC16A11 associates with T2D in individuals with BMI <35 kg/m2. Here, we test the interaction of the two loci with a more complete data set and perform a BMI sensitivity test. We defined the risk protection haplotype of SLC16A11, T-C-G-T-T, as allele 2 of a diallelic genetic model with three genotypes, SLC16A11*11, *12, and *22, where allele 1 is the wild type. Both earlier findings were confirmed. Together in the same logistic model with BMI ≥35 kg/m2, DRB1*16:02:01 remains protective (odds ratio [OR] 0.73), while SLC16A11 switches from risk to protection (OR 0.57 [*22] and 0.78 [*12]); an added interaction term was statistically significant (OR 0.49 [*12]). Bootstrapped (b = 10,000) statistical power of interaction, 0.4801, yielded a mean OR of 0.43. Sensitivity analysis demonstrated that the interaction is significant in the BMI range of 30-41 kg/m2. To investigate the epistasis, we used the primary function of the HLA-DRB1 molecule, peptide binding and presentation, to search the entire array of 15-mer peptides for both the wild-type and ancient human SLC16A11 molecules for a pattern of strong binding that was associated with risk and protection for T2D. Applying computer binding algorithms suggested that the core peptide at SLC16A11 D127G, FSAFASGLL, might be key for moderating risk for T2D with potential implications for type 1 diabetes., (© 2024 by the American Diabetes Association.)

Most genetic variants associated with adult height have been identified through large genome-wide association studies (GWASs) in European-ancestry cohorts. However, it is unclear how these variants influence linear growth during adolescence. This study uses anthropometric and genotypic data from a longitudinal study conducted in an American Indian community in Arizona between 1965-2007. Growth parameters (i.e. height, velocity, and timing of growth spurt) were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, in 787 participants with height measurements spanning the whole period of growth. Heritability estimates suggested that genetic factors could explain 25% to 71% of the variance of pubertal growth traits. We performed a GWAS of growth parameters, testing their associations with 5 077 595 imputed or directly genotyped variants. Six variants associated with height at peak velocity (P < 5 × 10-8, adjusted for sex, birth year and principal components). Implicated genes include NUDT3, previously associated with adult height, and PACSIN1. Two novel variants associated with duration of growth spurt (P < 5 × 10-8) in LOC105375344, an uncharacterized gene with unknown function. We finally examined the association of growth parameters with a polygenic score for height derived from 9557 single nucleotide polymorphisms (SNPs) identified in the GIANT meta-analysis for which genotypic data were available for the American Indian study population. Height polygenic score was correlated with the magnitude and velocity of height growth that occurred before and at the peak of the adolescent growth spurt, indicating overlapping genetic architecture, with no influence on the timing of adolescent growth., (Published by Oxford University Press 2024.)

Aim: Reduced renal insulin signalling is implicated in the pathogenesis of albuminuria. We sought to investigate whether insulin action and secretion, measured before diabetes onset, are associated with the development of albuminuria after diabetes onset., Materials and Methods: Baseline body composition, insulin sensitivity by hyperinsulinaemic-euglycaemic clamp at submaximal and maximal insulin stimulation (240 and 2400 pmol/m 2 /min; M-low and M-high), and insulin secretion by intravenous glucose tolerance test [acute insulin response (AIR)] were measured in 170 Southwestern Indigenous American adults who subsequently developed diabetes. After diabetes onset and during the median follow-up of 13.6 years, 81 participants (48%) developed albuminuria (urine albumin-to-creatinine ratio ≥30 mg/g). Separate associations of M-low, M-high and AIR (per 1-SD change) with the risk of albuminuria were assessed by Cox regression models adjusted for age, sex and body fat (%)., Results: Participants who developed albuminuria were of similar age (26.4 ± 5.4 vs. 27.5 ± 6.1 years), sex (46% vs. 48% male), body fat (36.4 ± 7.5 vs. 35.7 ± 7.9%) and AIR [2.3 ± 0.3 vs. 2.3 ± 0.3, pmol/L (log)] as those who did not develop albuminuria but had lower insulin sensitivity [M-low: 0.33 ± 0.08 vs. 0.36 ± 0.12, p = .03; M-high: 0.87 ± 0.11 vs. 0.91 ± 0.12, p = .02; mg/kg-metabolic body size/min (log)]. In separate adjusted models, lower M-low and M-high were both associated with an increased risk for albuminuria [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.14, 2.00, p = .004; HR 1.31, 95% CI 1.06, 1.63, p = .01), whereas AIR was not (HR 1.15, 95% CI 0.87, 1.56, p = .3)., Conclusions: Lower insulin sensitivity is associated with the development of albuminuria, suggesting a role for insulin signalling in the pathogenesis of proteinuria., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank., Results: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation., Conclusion: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern., (© 2023. The Author(s).)

Introduction: The ABCC8 gene regulates insulin secretion and plays a critical role in glucose homeostasis. The effects of an ABCC8 R1420H loss-of-function variant on beta-cell function, incidence of type 2 diabetes, and age-at-onset, prevalence, and progression of diabetes complications were assessed in a longitudinal study in American Indians., Research Design and Methods: We analyzed beta-cell function through the relationship between insulin secretion and insulin sensitivity in members of this population without diabetes aged ≥5 years using standard major axis regression. We used hierarchical logistic regression models to study cross-sectional associations with diabetes complications including increased albuminuria (albumin-to-creatinine ratio (ACR) ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), reduced estimated glomerular filtration rate (eGFR <60 mL/min/1.73 m 2 ), and retinopathy. This study included 7675 individuals (254 variant carriers) previously genotyped for the R1420H with available phenotypic data and with a median follow-up time of 13.5 years (IQR 4.5-26.8)., Results: Variant carriers had worse beta-cell function than non-carriers (p=0.0004; on average estimated secretion was 22% lower, in carriers), in children and adults, with no difference in insulin sensitivity (p=0.50). At any body mass index and age before 35 years, carriers had higher type 2 diabetes incidence. This variant did not associate with prevalence of increased albuminuria (OR 0.87, 95% CI 0.66 to 1.16), severe albuminuria (OR 0.96, 95% CI 0.55 to 1.68), or reduced eGFR (OR 0.44, 95% CI 0.18 to 1.06). By contrast, the variant significantly associated with higher retinopathy prevalence (OR 1.74, 95% CI 1.19 to 2.53) and this association was only partially mediated (<11%) by glycemia, duration of diabetes, risk factors of retinopathy, or insulin use. Retinopathy prevalence in carriers was higher regardless of diabetes presence., Conclusions: The ABCC8 R1420H variant is associated with increased risks of diabetes and of retinopathy, which may be partially explained by higher glycemia levels and worse beta-cell function., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Remission of type 2 diabetes can occur as a result of weight loss and is characterised by liver fat and pancreas fat reduction and recovered insulin secretion. In this analysis, we aimed to investigate the mechanisms of weight loss- induced remission in people with prediabetes., Methods: In this prespecified post-hoc analysis, weight loss-induced resolution of prediabetes in the randomised, controlled, multicentre Prediabetes Lifestyle Intervention Study (PLIS) was assessed, and the results were validated against participants from the Diabetes Prevention Program (DPP) study. For PLIS, between March 1, 2012, and Aug 31, 2016, participants were recruited from eight clinical study centres (including seven university hospitals) in Germany and randomly assigned to receive either a control intervention, a standard lifestyle intervention (ie, DPP-based intervention), or an intensified lifestyle intervention for 12 months. For DPP, participants were recruited from 23 clinical study centres in the USA between July 31, 1996, and May 18, 1999, and randomly assigned to receive either a standard lifestyle intervention, metformin, or placebo. In both PLIS and DPP, only participants who were randomly assigned to receive lifestyle intervention or placebo and who lost at least 5% of their bodyweight were included in this analysis. Responders were defined as people who returned to normal fasting plasma glucose (FPG; <5·6 mmol/L), normal glucose tolerance (<7·8 mmol/L), and HbA 1c less than 39 mmol/mol after 12 months of lifestyle intervention or placebo or control intervention. Non-responders were defined as people who had FPG, 2 h glucose, or HbA 1c more than these thresholds. The main outcomes for this analysis were insulin sensitivity, insulin secretion, visceral adipose tissue (VAT), and intrahepatic lipid content (IHL) and were evaluated via linear mixed models., Findings: Of 1160 participants recruited to PLIS, 298 (25·7%) had weight loss of 5% or more of their bodyweight at baseline. 128 (43%) of 298 participants were responders and 170 (57%) were non-responders. Responders were younger than non-responders (mean age 55·6 years [SD 9·9] vs 60·4 years [8·6]; p<0·0001). The DPP validation cohort included 683 participants who lost at least 5% of their bodyweight at baseline. Of these, 132 (19%) were responders and 551 (81%) were non-responders. In PLIS, BMI reduction was similar between responders and non-responders (responders mean at baseline 32·4 kg/m 2 [SD 5·6] to mean at 12 months 29·0 kg/m 2 [4·9] vs non-responders 32·1 kg/m 2 [5·9] to 29·2 kg/m 2 [5·4]; p=0·86). However, whole-body insulin sensitivity increased more in responders than in non-responders (mean at baseline 291 mL/[min × m 2 ], SD 60 to mean at 12 months 378 mL/[min × m 2 ], 56 vs 278 mL/[min × m 2 ], 62, to 323 mL/[min × m 2 ], 66; p<0·0001), whereas insulin secretion did not differ within groups over time or between groups (responders mean at baseline 175 pmol/mmol [SD 64] to mean at 12 months 163·7 pmol/mmol [60·6] vs non-responders 158·0 pmol/mmol [55·6] to 154·1 pmol/mmol [56·2]; p=0·46). IHL decreased in both groups, without a difference between groups (responders mean at baseline 10·1% [SD 8·7] to mean at 12 months 3·5% [3·9] vs non-responders 10·3% [8·1] to 4·2% [4·2]; p=0·34); however, VAT decreased more in responders than in non-responders (mean at baseline 6·2 L [SD 2·9] to mean at 12 months 4·1 L [2·3] vs 5·7 L [2·3] to 4·5 L [2·2]; p=0·0003). Responders had a 73% lower risk of developing type 2 diabetes than non-responders in the 2 years after the intervention ended., Interpretation: By contrast to remission of type 2 diabetes, resolution of prediabetes was characterised by an improvement in insulin sensitivity and reduced VAT. Because return to normal glucose regulation (NGR) prevents development of type 2 diabetes, we propose the concept of remission of prediabetes in analogy to type 2 diabetes. We suggest that remission of prediabetes should be the primary therapeutic aim in individuals with prediabetes., Funding: German Federal Ministry for Education and Research via the German Center for Diabetes Research; the Ministry of Science, Research and the Arts Baden-Württemberg; the Helmholtz Association and Helmholtz Munich; the Cluster of Excellence Controlling Microbes to Fight Infections; and the German Research Foundation., Competing Interests: Declaration of interests SKab receives grants from the German Diabetes Association, Wilhelm-Doerenkamp-Foundation, and California Walnut Commission and lecture fees from Sanofi, Boehringer Ingelheim, Berlin-Chemie, Lilly Deutschland, and Juzo Akademie. RW receives lecture fees from Eli Lilly, Novo Nordisk, and Sanofi and participates in a Data Safety Monitoring Board and Advisory Board for Eli Lilly. AL receives grants from Helmholtz Munich and Ludwig Maximilian University Klinikum München. NP receives lecture fees from NovoNordisk and Gesellschaft für Wissenschaftstransfer Dresden; advisory board fees from Bayer Vital; and holds patent WO 2021/092265A1 for diagnosis and treatment of non-alcoholic fatty liver disease and liver fibrosis. VN is the founder and equity owner of sThesis, iThera Medical, Spear UG, and I3. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To examine the role of glycemic measures performed during childhood in predicting future diabetes-related nephropathy and retinopathy in a high-risk indigenous American cohort., Research Design and Methods: We studied associations between glycated hemoglobin (HbA1c) and 2-h plasma glucose (PG), measured during childhood (age 5 to <20 years) in a longitudinal observational study of diabetes and its complications (1965-2007), and future albuminuria (albumin creatinine ratio [ACR] ≥30 mg/g), severe albuminuria (ACR ≥300 mg/g), and retinopathy (at least one microaneurysm or hemorrhage or proliferative retinopathy on direct ophthalmoscopy). Areas under the receiver operating characteristic curve (AUCs) for childhood glycemic measures when predicting nephropathy and retinopathy were compared., Results: Higher baseline levels of HbA1c and 2-h PG significantly increased the risk of future severe albuminuria (HbA1c: hazard ratio [HR] 1.45 per %; 95% CI 1.02-2.05 and 2-h PG: HR 1.21 per mmol/L; 95% CI 1.16-1.27). When categorized by baseline HbA1c, children with prediabetes had a higher incidence of albuminuria (29.7 cases per 1,000 person-years [PY]), severe albuminuria (3.8 cases per 1,000 PY), and retinopathy (7.1 cases per 1,000 PY) than children with normal HbA1c levels (23.8, 2.4, and 1.7 cases per 1,000 PY, respectively); children with diabetes at baseline had the highest incidence of the three complications. No significant differences were observed between AUCs for models with HbA1c, 2-h PG, and fasting PG when predicting albuminuria, severe albuminuria, or retinopathy., Conclusions: In this study, higher glycemia levels ascertained by HbA1c and 2-h PG during childhood were associated with future microvascular complications; this demonstrates the potential utility of screening tests performed in high-risk children in predicting long-term health outcomes., (© 2023 by the American Diabetes Association.)

Early puberty onset is associated with higher risk of diabetes, but most studies have not accounted for childhood factors that may confound the association. Using data from a study conducted in an Indigenous community in Arizona (1965-2007), we examined associations of timing and velocity of the adolescent growth spurt with type 2 diabetes, and whether these associations are mediated by childhood body mass index and insulinemia. Adolescent growth parameters were derived from the Preece-Baines growth model, a parametric growth curve fitted to longitudinal height data, for 861 participants with height measurements spanning the whole period of growth. In males, older age at take-off, age at peak velocity, and age at maturation were associated with decreased prevalence of diabetes (odds ratio (OR) = 0.43 per year, 95% confidence interval (CI): 0.27, 0.69; OR = 0.50, 95% CI: 0.35, 0.72; OR = 0.58, 95% CI: 0.41, 0.83, respectively), while higher velocity at take-off was associated with increased risk (OR = 3.47 per cm/year, 95% CI: 1.87, 6.42) adjusting for age, birth year, and maternal diabetes. Similar results were observed with incident diabetes. Our findings suggest that an early and accelerated adolescent growth spurt is a risk factor for diabetes, at least in males. These associations are only partially explained by measures of adiposity and insulinemia., (Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 10-9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, β = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10-12). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, β = -7.55 [95% CI -9.88, -5.22]; P = 3.2 × 10-10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10-4]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy., (© 2023 by the American Diabetes Association.)

Background: Genome-wide association studies have shown that body mass index (BMI), an estimate of obesity, is highly polygenic. Individual variants typically have small effect sizes, making it challenging to identify unique loci in under-represented ethnic groups which lack statistical power due to their small sample size. Yet obesity is a major health disparity and is particularly prevalent in southwestern American Indians. Here, we identify and characterize a new locus for BMI that was detected by analyzing moderate associations with BMI obtained in a population-based sample of southwestern American Indians together with the well-powered GIANT dataset., Methods: Genotypes for 10.5 million variants were tested for association with BMI in 5870 American Indians and 2600 variants that showed an association P < 10 -3 in the American Indian sample were combined in a meta-analysis with the BMI data reported in GIANT (N = 240,608). The newly identified gene, NFIA-AS2 was functionally characterized, and the impact of its lead associated variant rs1777538 was studied both in-silico and in-vitro., Results: Rs1777538 (T/C; C allele frequency = 0.16 in American Indians and 0.04 in GIANT, meta-analysis P = 5.0 × 10 -7 ) exhibited a large effect in American Indians (1 kg/m 2 decrease in BMI per copy of C allele). NFIA-AS2 was found to be a nuclear localized long non-coding RNA expressed in tissues pertinent to human obesity. Analysis of this variant in human brown preadipocytes showed that NFIA-AS2 transcripts carrying the C allele had increased RNA degradation compared to the T allele transcripts (half-lives = 9 h, 13 h respectively). During brown adipogenesis, NFIA-AS2 featured a stage-specific regulation of nearby gene expression where rs1777538 demonstrated an allelic difference in regulation in the mature adipocytes (the strongest difference was observed for L1TD1, P = 0.007)., Conclusion: Our findings support a role for NFIA-AS2 in regulating pathways that impact BMI., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Epigenetic markers are potential biomarkers for diabetes and related complications. Using a prospective cohort from the Hong Kong Diabetes Register, we perform two independent epigenome-wide association studies to identify methylation markers associated with baseline estimated glomerular filtration rate (eGFR) and subsequent decline in kidney function (eGFR slope), respectively, in 1,271 type 2 diabetes subjects. Here we show 40 (30 previously unidentified) and eight (all previously unidentified) CpG sites individually reach epigenome-wide significance for baseline eGFR and eGFR slope, respectively. We also develop a multisite analysis method, which selects 64 and 37 CpG sites for baseline eGFR and eGFR slope, respectively. These models are validated in an independent cohort of Native Americans with type 2 diabetes. Our identified CpG sites are near genes enriched for functional roles in kidney diseases, and some show association with renal damage. This study highlights the potential of methylation markers in risk stratification of kidney disease among type 2 diabetes individuals., (© 2023. The Author(s).)

Aims/hypothesis: There is limited information on how polygenic scores (PSs), based on variants from genome-wide association studies (GWASs) of type 2 diabetes, add to clinical variables in predicting type 2 diabetes incidence, particularly in non-European-ancestry populations., Methods: For participants in a longitudinal study in an Indigenous population from the Southwestern USA with high type 2 diabetes prevalence, we analysed ten constructions of PS using publicly available GWAS summary statistics. Type 2 diabetes incidence was examined in three cohorts of individuals without diabetes at baseline. The adult cohort, 2333 participants followed from age ≥20 years, had 640 type 2 diabetes cases. The youth cohort included 2229 participants followed from age 5-19 years (228 cases). The birth cohort included 2894 participants followed from birth (438 cases). We assessed contributions of PSs and clinical variables in predicting type 2 diabetes incidence., Results: Of the ten PS constructions, a PS using 293 genome-wide significant variants from a large type 2 diabetes GWAS meta-analysis in European-ancestry populations performed best. In the adult cohort, the AUC of the receiver operating characteristic curve for clinical variables for prediction of incident type 2 diabetes was 0.728; with the PS, 0.735. The PS's HR was 1.27 per SD (p=1.6 × 10 -8 ; 95% CI 1.17, 1.38). In youth, corresponding AUCs were 0.805 and 0.812, with HR 1.49 (p=4.3 × 10 -8 ; 95% CI 1.29, 1.72). In the birth cohort, AUCs were 0.614 and 0.685, with HR 1.48 (p=2.8 × 10 -16 ; 95% CI 1.35, 1.63). To further assess the potential impact of including PS for assessing individual risk, net reclassification improvement (NRI) was calculated: NRI for the PS was 0.270, 0.268 and 0.362 for adult, youth and birth cohorts, respectively. For comparison, NRI for HbA 1c was 0.267 and 0.173 for adult and youth cohorts, respectively. In decision curve analyses across all cohorts, the net benefit of including the PS in addition to clinical variables was most pronounced at moderately stringent threshold probability values for instituting a preventive intervention., Conclusions/interpretation: This study demonstrates that a European-derived PS contributes significantly to prediction of type 2 diabetes incidence in addition to information provided by clinical variables in this Indigenous study population. Discriminatory power of the PS was similar to that of other commonly measured clinical variables (e.g. HbA 1c ). Including type 2 diabetes PS in addition to clinical variables may be clinically beneficial for identifying individuals at higher risk for the disease, especially at younger ages., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

The Phoenix Epidemiology and Clinical Research Branch of the National Institute of Diabetes and Digestive and Kidney Diseases has conducted prospective studies of diabetes and its complications in the Pima Indians living in Arizona, USA for over 50 years. In this review we highlight areas in which these studies provided vital insights into the criteria used to diagnose type 2 diabetes, the pathophysiologic changes that accompany the development of type 2 diabetes, and the course and determinants of diabetes complications-focusing specifically on diabetic kidney disease. We include data from our longitudinal population-based study of diabetes and its complications, studies on the role of insulin resistance and insulin secretion in the pathophysiology of type 2 diabetes, and in-depth studies of diabetic kidney disease that include measures of glomerular function and research kidney biopsies. We also focus on the emerging health threat posed by youth-onset type 2 diabetes, which was first seen in the Pima Indians in the 1960s and is becoming an increasing issue worldwide., Competing Interests: Disclosure of interest The authors declare that they have no competing interests., (Published by Elsevier Masson SAS.)

Context: Insulin secretion and sensitivity regulate glycemia, with inadequately compensated deficiencies leading to diabetes., Objective: We investigated effects of weight loss, an intensive lifestyle intervention (ILS), and metformin on the relationship between insulin secretion and sensitivity using repository data from 2931 participants in the Diabetes Prevention Program clinical trial in adults at high risk of developing type 2 diabetes., Methods: Insulin secretion and sensitivity were estimated from insulin and glucose concentrations in fasting and 30-minute postload serum samples at baseline and 1, 2, and 3 years after randomization, during the active intervention phase. The nonlinear relationship of secretion and sensitivity was evaluated by standardized major axis regression to account for variability in both variables. Insulin secretory demand and compensatory insulin secretion were characterized by distances along and away from the regression line, respectively., Results: ILS and metformin decreased secretory demand while increasing compensatory insulin secretion, with greater effects of ILS. Improvements were directly related to weight loss; decreased weight significantly reduced secretory demand (b=-0.144 SD; 95% CI (-0.162, -0.125)/5 kg loss) and increased compensatory insulin secretion (b = 0.287 SD, 95% CI (0.261, 0.314)/5 kg loss). In time-dependent hazard models, increasing compensatory insulin secretion (hazard ratio [HR] = 0.166 per baseline SD, 95% CI 0.133, 0.206) and weight loss (HR = 0.710 per 5 kg loss, 95% CI 0.613, 0.819) predicted lower diabetes risk., Conclusion: Diabetes risk reduction was directly related to the amount of weight loss, an effect mediated by lowered insulin secretory demand (due to increased insulin sensitivity) coupled with improved compensatory insulin secretion., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Insulin-like growth factor binding protein 4 (IGFBP4) is involved in adipogenesis, and IGFBP4 null mice have decreased body fat through decreased PPAR-γ expression. In the current study, we assessed whether variation in the IGFBP4 coding region influences body mass index (BMI) in American Indians who are disproportionately affected by obesity. Whole exome sequence data from a population-based sample of 6779 American Indians with longitudinal measures of BMI were used to identify variation in IGFBP4 that associated with BMI. A novel variant that predicts a p.Ser76Thr in IGFBP4 (Thr-allele frequency = 0.02) was identified which associated with the maximum BMI measured during adulthood (BMI 39.8 kg/m 2 for Thr-allele homozygotes combined with heterozygotes vs. 36.2 kg/m 2 for Ser-allele homozygotes, β = 6.7% per Thr-allele, p = 8.0 × 10 -5 , adjusted for age, sex, birth-year and the first five genetic principal components) and the maximum age- and sex-adjusted BMI z-score measured during childhood/adolescence (z-score 0.70 SD for Thr-allele heterozygotes vs. 0.32 SD for Ser-allele homozygotes, β = 0.37 SD per Thr-allele, p = 8.8 × 10 -6 ). In vitro functional studies showed that IGFBP4 with the Thr-allele (BMI-increasing) had a 55% decrease (p = 0.0007) in FOXO-induced transcriptional activity, reflecting increased activation of the PI3K/AKT pathway mediated through increased IGF signaling. Over-expression and knock-down of IGFBP4 in OP9 cells during differentiation showed that IGFBP4 upregulates adipogenesis through PPARγ, CEBPα, AGPAT2 and SREBP1 expression. We propose that this American Indian specific variant in IGFBP4 affects obesity via an increase of IGF signaling., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Growth abnormalities in childhood have been related to later cardiometabolic risks, but little is known about these associations in populations at high risk of type 2 diabetes., Objectives: We examined the associations of patterns of growth, including weight and height at ages 1-59 months, with cardiometabolic risk factors at ages 5-16 years., Methods: We linked anthropometric data collected at ages 1-59 months to cardiometabolic data obtained from a longitudinal study in a southwestern American Indian population at high risk of diabetes. Analyses included 701 children with ≥1 follow-up examination at ages 5-16 years. We derived age- and sex-specific weight-for-height z-scores (WHZ) and height-for-age z-scores (HAZ) at ages 1-59 months. We selected the highest observed WHZ and the lowest observed HAZ at ages 1-59 months and analyzed associations of z-scores and categories of WHZ and HAZ with cardiometabolic outcomes at ages 5-16 years. We used linear mixed-effects models to account for repeated measures., Results: Overweight/obesity (WHZ >2) at ages 1-59 months was significantly associated with increased BMI, fasting and 2-hour postload plasma glucose, fasting and 2-hour insulin, triglycerides, systolic blood pressure, diastolic blood pressure, and decreased HDL cholesterol at ages 5-16 years relative to normal weight (WHZ ≤1). For example, at ages 5-9 years, 2-hour glucose was 10.4 mg/dL higher (95% CI: 5.6-15.3 mg/dL) and fasting insulin was 4.29 μU/mL higher (95% CI: 2.96-5.71 μU/mL) in those with overweight/obesity in early childhood. Associations were attenuated and no longer significant when adjusted for concurrent BMI. A low height-for-age (HAZ < -2) at ages 1-59 months was associated with 5.37 mg/dL lower HDL (95% CI: 2.57-8.17 mg/dL) and 27.5 μU/mL higher 2-hour insulin (95% CI: 3.41-57.6 μU/mL) at ages 10-16 years relative to an HAZ ≥0., Conclusions: In this American Indian population, findings suggest a strong contribution of overweight/obesity in early childhood to cardiometabolic risks in later childhood and adolescence, mediated through persistent overweight/obesity into later ages. Findings also suggest potential adverse effects of low height-for-age, which require confirmation., (Published by Oxford University Press on behalf of the American Society for Nutrition 2022.)

Clinical and biomarker phenotypic associations for carriers of protein function-altering variants may help to elucidate gene function and health effects in populations. We genotyped 1127 Strong Heart Family Study participants for protein function-altering single nucleotide variants (SNV) and indels selected from a low coverage whole exome sequencing of American Indians. We tested the association of each SNV/indel with 35 cardiometabolic traits. Among 1206 variants (average minor allele count = 20, range of 1 to 1064), ~ 43% were not present in publicly available repositories. We identified seven SNV-trait significant associations including a missense SNV at ABCA10 (rs779392624, p = 8 × 10 -9 ) associated with fasting triglycerides, which gene product is involved in macrophage lipid homeostasis. Among non-diabetic individuals, missense SNVs at four genes were associated with fasting insulin adjusted for BMI (PHIL, chr6:79,650,711, p = 2.1 × 10 -6 ; TRPM3, rs760461668, p = 5 × 10 -8 ; SPTY2D1, rs756851199, p = 1.6 × 10 -8 ; and TSPO, rs566547284, p = 2.4 × 10 -6 ). PHIL encoded protein is involved in pancreatic β-cell proliferation and survival, and TRPM3 protein mediates calcium signaling in pancreatic β-cells in response to glucose. A genetic risk score combining increasing insulin risk alleles of these four genes was associated with 53% (95% confidence interval 1.09, 2.15) increased odds of incident diabetes and 83% (95% confidence interval 1.35, 2.48) increased odds of impaired fasting glucose at follow-up. Our study uncovered novel gene-trait associations through the study of protein-coding variants and demonstrates the advantages of association screenings targeting diverse and high-risk populations to study variants absent in publicly available repositories., (© 2022. The Author(s).)

Introduction: We estimated the effects of cardiorespiratory fitness (CRF) and body mass index (BMI) at baseline on mortality and cardiovascular disease events in people with type 2 diabetes who participated in the Look AHEAD randomized clinical trial., Methods: Look AHEAD compared effects of an intensive lifestyle intervention with diabetes support and education on cardiovascular disease events in 5145 adults age 45-76 yr with overweight/obesity and type 2 diabetes. In 4773 participants, we performed a secondary analysis of the association of baseline CRF during maximal treadmill test (expressed as metabolic equivalents (METs)) on mortality and cardiovascular disease events during a mean follow-up of 9.2 yr., Results: The mean (SD) CRF was 7.2 (2.0) METs. Adjusted for age, sex, race/ethnicity, BMI, intervention group, and β-blocker use, all-cause mortality rate was 30% lower per SD greater METs (hazard ratio (HR) = 0.70 (95% confidence interval, 0.60 to 0.81); rate difference (RD), -2.71 deaths/1000 person-years (95% confidence interval, -3.79 to -1.63)). Similarly, an SD greater METs predicted lower cardiovascular disease mortality (HR, 0.45; RD, -1.65 cases/1000 person-years) and a composite cardiovascular outcome (HR, 0.72; RD, -6.38). Effects of METs were homogeneous on the HR scale for most baseline variables and outcomes but heterogeneous for many on the RD scale, with greater RD in subgroups at greater risk of the outcomes. For example, all-cause mortality was lower by 7.6 deaths/1000 person-years per SD greater METs in those with a history of cardiovascular disease at baseline but lower by only 1.6 in those without such history. BMI adjusted for CRF had little or no effect on these outcomes., Conclusions: Greater CRF is associated with reduced risks of mortality and cardiovascular disease events., (Copyright © 2022 Written work prepared by employees of the Federal Government as part of their official duties is, under the U.S. Copyright Act, a “work of the United States Government” for which copyright protection under Title 17 of the United States Code is not available. As such, copyright does not extend to the contributions of employees of the Federal Government.)

Aims: Hormone sensitive lipase (HSL), encoded by the LIPE gene, is involved in lipolysis. Based on prior animal and human studies, LIPE was analysed as a candidate gene for the development of type 2 diabetes (T2D) in a community-based sample of American Indians., Materials and Methods: Whole-exome sequence data from 6782 participants with longitudinal clinical measures were used to identify variation in LIPE., Results: Amongst the 16 missense variants identified, an Arg611Cys variant (rs34052647; Cys-allele frequency = 0.087) significantly associated with T2D (OR [95% CI] = 1.38 [1.17-1.64], p = 0.0002, adjusted for age, sex, birth year, and the first five genetic principal components) and an earlier onset age of T2D (HR = 1.22 [1.09-1.36], p = 0.0005). This variant was further analysed for quantitative traits related to T2D. Amongst non-diabetic American Indians, those with the T2D risk Cys-allele had increased insulin levels during an oral glucose tolerance test (0.07 SD per Cys-allele, p = 0.04) and a mixed meal test (0.08 log 10 µU/ml per Cys-allele, p = 0.003), and had increased lipid oxidation rates post-absorptively and during insulin infusion (0.07 mg [kg estimated metabolic body size {EMBS}] -1  min -1 per Cys-allele for both, p = 0.01 and 0.009, respectively), compared to individuals with the non-risk Arg-allele. In vitro functional studies showed that cells expressing the Cys-allele had a 17.2% decrease in lipolysis under isoproterenol stimulation (p = 0.03) and a 21.3% decrease in lipase enzyme activity measured by using p-nitrophenyl butyrate as a substrate (p = 0.04) compared to the Arg-allele., Conclusion: The Arg611Cys variant causes a modest impairment in lipolysis, thereby affecting glucose homoeostasis and risk of T2D., (© 2021 John Wiley & Sons Ltd. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Objective: This study aimed to identify genetic variants enriched in Southwest American Indian (SWAI) individuals that associate with BMI., Methods: Whole genome sequencing data (n = 296) were used to identify potentially functional variants that are common in SWAI individuals (minor allele frequency ≥10%) but rare in other ethnic groups (minor allele frequency < 0.1%). Enriched variants were tested for association with BMI in 5,870 SWAI individuals. One variant was studied using a luciferase reporter, and haplotypes that included this variant were analyzed for association with various measures of obesity (n = 917-5,870), 24-hour energy expenditure (24-h EE; n = 419), and skeletal muscle biopsy expression data (n = 207)., Results: A 5' untranslated region variant in cytochrome b5 type A (CYB5A), rs548402150, met the enrichment criteria and associated with increased BMI (β = 2%, p = 0.004). Functionally, rs548402150 decreased luciferase expression by 30% (p = 0.003) and correlated with decreased skeletal muscle CYB5A expression (β = -0.5 SD, p = 0.0008). Combining rs548402150 with two splicing quantitative trait loci in CYB5A identified a haplotype carried almost exclusively in SWAI individuals that associated with increased BMI (β = 3%, p = 0.0003) and decreased CYB5A expression, whereas the most common haplotype in all ethnic groups associated with lower BMI and percentage of body fatness, increased 24-h EE, and increased CYB5A expression., Conclusions: Further studies on the effects of CYB5A on 24-h EE and BMI may provide insights into obesity-related physiology., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society (TOS).)

Purpose of Review: The present review focuses on the epidemiology of type 2 diabetes (T2D) in Indigenous communities in the continental United States (U.S.)-including disease prevention and management-and discusses special considerations in conducting research with Indigenous communities., Recent Findings: Previous studies have reported the disparately high prevalence of diabetes, especially T2D, among Indigenous peoples in the U.S. The high prevalence and incidence of early-onset T2D in Indigenous youth relative to that of all youth in the U.S. population pose challenges to the prevention of complications of diabetes. Behavioral, dietary, lifestyle, and genetic factors associated with T2D in Indigenous communities are often investigated. More limited is the discussion of the historical and ongoing consequences of colonization and displacement that impact the aforementioned risk factors. Future research is necessary to assess community-specific needs with respect to diabetes prevention and management across the diversity of Indigenous communities in the U.S., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia., (© 2021 by the American Diabetes Association.)

We assessed whether the relationship between insulin secretion and sensitivity predicted development of type 2 diabetes in American Indians participating in a longitudinal epidemiologic study. At baseline, when all subjects did not have diabetes, 1566 participants underwent oral tests and 420 had intravenous measures of glucose regulation with estimates of insulin secretion and sensitivity. Standardized major axis regression was used to study the relationship of secretion and sensitivity. Distances away from and along the regression line estimated compensatory insulin secretion and secretory demand, respectively. This relationship differed according to glucose tolerance and BMI categories. The distance away from the line is similar to the disposition index (DI) defined as the product of estimated secretion and sensitivity, but the regression line may differ from a line with constant DI (i.e., it is not necessarily hyperbolic). Subjects with the same DI but different levels of insulin secretion and sensitivity had different incidence rates of diabetes; lower sensitivity with higher secretory demand was associated with greater diabetes risk. Insulin secretion and insulin sensitivity, analyzed together, predict diabetes better than DI alone. Physiologically, this may reflect long-term risk associated with increased allostatic load resulting from the stimulation of insulin hypersecretion by increased glycemia., (© 2021 by the American Diabetes Association.)

Emerging antimicrobial drug resistance is increasing the complexity involved in treating critical conditions such as bacterial induced sepsis. Methods for diagnosing specific drug resistance tend to be rapid or sensitive, but not both. Detection methods like sequence-specific single-molecule analysis could address this concern if they could be adapted to work on smaller targets similar to those produced in traditional clinical situations. In this work we demonstrate that a 120 bp double stranded polynucleotide with an overhanging single stranded 25 bp probe sequence can be created by immobilizing DNA with a biotin/streptavidin magnetic bead system, labeling with SYBR Gold, and rinsing the excess away while the probe retains multiple fluorophores. These probes with multiple fluorophores can then be used to label a bacterial plasmid target in a sequence-specific manner. These probes enabled the detection of 1 pM plasmid samples containing a portion of an antibiotic resistance gene sequence. This system shows the possibility of improving capture and fluorescence labeling of small nucleic acid fragments, generating lower limits of detection for clinically relevant samples while maintaining rapid processing times.

While the samples and data from the Pima Indians of the Gila River Indian Community have been included in many international HLA workshops and conferences and have been the focus of numerous population reports and the source of novel alleles at the classical HLA loci, they have not been studied for the non-classical loci. In order to expand our HLA-disease association studies, we typed over 300 whole genome sequences from full Pima heritage members, controlled for first degree relationship, and employed recently developed computer algorithms to resolve HLA alleles. Both classical-HLA-A, -B, and -C- and non-classical- HLA-E, -F, -G, -J, -L, -W, -Y, -DPA2, -DPB2, -DMA, -DMB, -DOA, -DRB2, -DRB9, TAP1- loci were typed at the 4-field level of resolution. We present allele and selected haplotype frequencies, test the genotype distributions for population structure, discuss the issues that are created for tests of Hardy-Weinberg equilibrium over the four sample spaces of high resolution HLA typing, and address the implications for the evolution of non-classical pseudogenes that are no longer expressed in a phenotype subject to natural selection., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Objective: In an ongoing effort to identify the genetic variation that contributes to obesity in American Indians, known Bardet-Biedl syndrome (BBS) genes were analyzed for an effect on BMI and leptin signaling., Methods: Potentially deleterious variants (Combined Annotation Dependent Depletion score > 20) in BBS genes were identified in whole-exome sequence data from 6,851 American Indians informative for BMI. Common variants (detected in ≥ 10 individuals) were analyzed for association with BMI; rare variants (detected in < 10 individuals) were analyzed for mean BMI of carriers. Functional assessment of variants' effect on signal transducer and activator of transcription 3 (STAT3) activity was performed in vitro., Results: One common variant, rs59252892 (Thr549Ile) in BBS9, was associated with BMI (P = 0.0008, β = 25% increase per risk allele). Among rare variants for which carriers had severe obesity (mean BMI > 40 kg/m 2 ), four were in BBS9. In vitro analysis of BBS9 found the Ile allele at Thr549Ile had a 20% increase in STAT3 activity compared with the Thr allele (P = 0.01). Western blot analysis showed the Ile allele had a 15% increase in STAT3 phosphorylation (P = 0.006). Comparable functional results were observed with Ser545Gly and Val209Leu but not Leu665Phe and Lys810Glu., Conclusions: Potentially functional variants in BBS genes in American Indians are reported. However, functional evidence supporting a causal role for BBS9 in obesity is inconclusive., (© 2021 Regeneron Pharmaceuticals Inc. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

Microbial resistance to currently available antibiotics poses a great threat in the global fight against infections. An important step in determining bacterial antibiotic resistance can be selective DNA sequence capture and fluorescence labeling. In this paper, we demonstrate the fabrication of simple, robust, inexpensive microfluidic devices for DNA capture and fluorescence detection of a model antibiotic resistance gene sequence. We laser micromachined polymethyl methacrylate microchannels and enclosed them using pressure-sensitive adhesive tapes. We then formed porous polymer monoliths with DNA capture probes in these microchannels and used them for sequence-specific capture, fluorescent labeling, and laser-induced fluorescence detection of picomolar (pM) concentrations of synthetic and plasmid antibiotic resistance gene targets. The relative fluorescence for the elution peaks increased with loaded target DNA concentration. We observed higher fluorescence signal and percent recovery for synthetic target DNA compared to plasmid DNA at the same loaded target concentration. A non-target gene was used for control experiments and produced < 3% capture relative to the same concentration of target. The full analysis process including device fabrication was completed in less than 90 min with a limit of detection of 30 pM. The simplicity of device fabrication and good DNA capture selectivity demonstrated herein have potential for application with processes for bacterial plasmid DNA extraction and single-particle counting to facilitate determination of antibiotic susceptibility. Graphical abstract.

Insulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m -2 ) or obese (BMI ≥ 30 kg m -2 ) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.

Background: Genetic factors that influence kidney traits have been understudied for low frequency and ancestry-specific variants., Methods: We combined whole genome sequencing (WGS) data from 23,732 participants from 10 NHLBI Trans-Omics for Precision Medicine (TOPMed) Program multi-ethnic studies to identify novel loci for estimated glomerular filtration rate (eGFR). Participants included European, African, East Asian, and Hispanic ancestries. We applied linear mixed models using a genetic relationship matrix estimated from the WGS data and adjusted for age, sex, study, and ethnicity., Findings: When testing single variants, we identified three novel loci driven by low frequency variants more commonly observed in non-European ancestry (PRKAA2, rs180996919, minor allele frequency [MAF] 0.04%, P = 6.1 × 10 -11 ; METTL8, rs116951054, MAF 0.09%, P = 4.5 × 10 -9 ; and MATK, rs539182790, MAF 0.05%, P = 3.4 × 10 -9 ). We also replicated two known loci for common variants (rs2461702, MAF=0.49, P = 1.2 × 10 -9 , nearest gene GATM, and rs71147340, MAF=0.34, P = 3.3 × 10 -9 , CDK12). Testing aggregated variants within a gene identified the MAF gene. A statistical approach based on local ancestry helped to identify replication samples for ancestry-specific variants., Interpretation: This study highlights challenges in studying variants influencing kidney traits that are low frequency in populations and more common in non-European ancestry., Competing Interests: Declaration of Competing Interest GRA is employed by Regeneron Pharmaceuticals and he owns stock and stock options for Regeneron Pharmaceuticals. BMP serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. BMP reports serving on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. Y-DIC, LRY, JCM, BDM, JIR, KDT, JPL, EB, JAS, GRA report grants from NIH during the conduct of the study. Remaining authors have nothing to disclose., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims/hypothesis: Prevalence of type 2 diabetes differs among human ancestry groups, and many hypotheses invoke differential natural selection to account for these differences. We sought to assess the potential role of differential natural selection across major continental ancestry groups for diabetes and related traits, by comparison of genetic and phenotypic differences., Methods: This was a cross-sectional comparison among 734 individuals from an urban sample (none of whom was more closely related to another than third-degree relatives), including 83 African Americans, 523 American Indians and 128 European Americans. Participants were not recruited based on diabetes status or other traits. BMI was calculated, and diabetes was diagnosed by a 75 g oral glucose tolerance test. In those with normal glucose tolerance (n = 434), fasting insulin and 30 min post-load insulin, adjusted for 30 min glucose, were taken as measures of insulin resistance and secretion, respectively. Whole exome sequencing was performed, resulting in 97,388 common (minor allele frequency ≥ 5%) variants; the coancestry coefficient (F ST ) was calculated across all markers as a measure of genetic divergence among ancestry groups. The phenotypic divergence index (P ST ) was also calculated from the phenotypic differences and heritability (which was estimated from genetic relatedness calculated empirically across all markers in 761 American Indian participants prior to the exclusion of close relatives). Under evolutionary neutrality, the expectation is P ST  = F ST , while for traits under differential selection P ST is expected to be significantly greater than F ST. A bootstrap procedure was used to test the hypothesis P ST  = F ST. RESULTS: With adjustment for age and sex, prevalence of type 2 diabetes was 34.0% in American Indians, 12.4% in African Americans and 10.4% in European Americans (p = 2.9 × 10 -10 for difference among groups). Mean BMI was 36.3, 33.4 and 33.0 kg/m 2 , respectively (p = 1.9 × 10 -7 ). Mean fasting insulin was 63.8, 48.4 and 45.2 pmol/l (p = 9.2 × 10 -5 ), while mean 30 min insulin was 559.8, 553.5 and 358.8 pmol/l, respectively (p = 5.7 × 10 -8 ). F ST across all markers was 0.130, while P ST for liability to diabetes, adjusted for age and sex, was 0.149 (p = 0.35 for difference with F ST ). P ST was 0.094 for BMI (p = 0.54), 0.095 for fasting insulin (p = 0.54) and 0.216 (p = 0.18) for 30 min insulin. For type 2 diabetes and BMI, the maximum divergence between populations was observed between American Indians and European Americans (P ST-MAX  = 0.22, p = 0.37, and P ST-MAX  = 0.14, p = 0.61), which suggests that a relatively modest 22% or 14% of the genetic variance, respectively, can potentially be explained by differential selection (assuming the absence of neutral drift)., Conclusions/interpretation: These analyses suggest that while type 2 diabetes and related traits differ significantly among continental ancestry groups, the differences are consistent with neutral expectations based on heritability and genetic distances. While these analyses do not exclude a modest role for natural selection, they do not support the hypothesis that differential natural selection is necessary to explain the phenotypic differences among these ancestry groups. Graphical abstract.

Background: Obesity and energy expenditure (EE) are heritable and genetic variants influencing EE may contribute to the development of obesity. We sought to identify genetic variants that affect EE in American Indians, an ethnic group with high prevalence of obesity., Methods: Whole-exome sequencing was performed in 373 healthy Pima Indians informative for 24-hour EE during energy balance. Genetic association analyses of all high-quality exonic variants (≥5 carriers) was performed, and those predicted to be damaging were prioritized., Results: Rs752074397 introduces a premature stop codon (Cys264Ter) in DAO and demonstrated the strongest association for 24-hour EE, where the Ter allele associated with substantially lower 24-hour EE (mean lower by 268 kcal/d) and sleeping EE (by 135 kcal/d). The Ter allele has a frequency = 0.5% in Pima Indians, whereas is extremely rare in most other ethnic groups (frequency < 0.01%). In vitro functional analysis showed reduced protein levels for the truncated form of DAO consistent with increased protein degradation. DAO encodes D-amino acid oxidase, which is involved in dopamine synthesis which might explain its role in modulating EE., Conclusion: Our results indicate that a nonsense mutation in DAO may influence EE in American Indians. Identification of variants that influence energy metabolism may lead to new pathways to treat human obesity., Clinical Trial Registration Number: NCT00340132., (Published by Oxford University Press on behalf of the Endocrine Society 2020.)

Aims/hypothesis: The aim of this work was to examine the associations of average weight and weight velocity in three growth periods from birth through adolescence with type 2 diabetes incidence., Methods: Child participants were selected from a 43 year longitudinal study of American Indians to represent three growth periods: pre-adolescence (birth to ~8 years); early adolescence (~8 to ~13 years); and late adolescence (~13 to ~18 years). Age-, sex- and height-standardised weight z score mean and weight z score velocity (change/year) were computed for each period. Participants were followed for up to 25 years from the end of each growth period until they developed diabetes. Associations of weight z score mean or weight z score velocity with diabetes incidence were determined with sex-, birth date- and maternal diabetes-adjusted Poisson regression models., Results: Among 2100 participants representing the pre-adolescence growth period, 1558 representing the early adolescence period and 1418 representing the late adolescence period, there were 290, 315 and 380 incident diabetes cases, respectively. During the first 10 years of follow-up, the diabetes incidence rate ratio (95% CI) was 1.72 (1.40, 2.11)/SD of log 10 weight z score mean in pre-adolescence, 2.09 (1.68, 2.60)/SD of log 10 weight z score mean in early adolescence and 1.85 (1.58, 2.17)/SD of log 10 weight z score mean in late adolescence. The diabetes incidence rate ratio (95% CI) was 1.79 (1.49, 2.17)/SD of log 10 weight z score velocity in pre-adolescence, 1.13 (0.91, 1.41)/SD of log 10 weight z score velocity in early adolescence and 1.29 (1.09, 1.51)/SD of log 10 weight z score velocity in late adolescence. There were strong correlations in the weight z score means and weak correlations in the weight z score velocities between successive periods., Conclusions/interpretation: Higher weight and accelerated weight gain in all growth periods associate with increased type 2 diabetes risk. Importantly, higher weight and greater weight velocity during pre-adolescence jointly associate with the highest type 2 diabetes risk. Graphical abstract.

Applying exome sequencing to populations with unique genetic architecture has the potential to reveal novel genes and variants associated with traits and diseases. We sequenced and analyzed the exomes of 6,716 individuals from a Southwestern American Indian (SWAI) population with well-characterized metabolic traits. We found that the SWAI population has distinct allelic architecture compared to populations of European and East Asian ancestry, and there were many predicted loss-of-function (pLOF) and nonsynonymous variants that were highly enriched or private in the SWAI population. We used pLOF and nonsynonymous variants in the SWAI population to evaluate gene-burden associations of candidate genes from European genome-wide association studies (GWASs) for type 2 diabetes, body mass index, and four major plasma lipids. We found 19 significant gene-burden associations for 11 genes, providing additional evidence for prioritizing candidate effector genes of GWAS signals. Interestingly, these associations were mainly driven by pLOF and nonsynonymous variants that are unique or highly enriched in the SWAI population. Particularly, we found four pLOF or nonsynonymous variants in APOB, APOE, PCSK9, and TM6SF2 that are private or enriched in the SWAI population and associated with low-density lipoprotein (LDL) cholesterol levels. Their large estimated effects on LDL cholesterol levels suggest strong impacts on protein function and potential clinical implications of these variants in cardiovascular health. In summary, our study illustrates the utility and potential of exome sequencing in genetically unique populations, such as the SWAI population, to prioritize candidate effector genes within GWAS loci and to find additional variants in known disease genes with potential clinical impact., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)

Objective: Insulinlike growth factor II (IGF-II) regulates metabolism and growth. In humans, both positive and negative relationships have been reported between serum IGF-II levels and obesity. This study assessed the relationship between serum IGF-II levels and BMI and determined whether IGF-II levels predict weight gain., Methods: Serum samples were available from 911 American Indians with a recorded BMI. IGF-II was measured using enzyme-linked immunosorbent assay., Results: Serum IGF-II levels were negatively correlated with BMI (r = -0.17, P = 4.4 × 10 -7 , adjusted for age, sex, and storage time). The strongest correlation was in participants aged ≥ 30 years (r = -0.28, P = 3.4 × 10 -8 , N = 349), a modest correlation was in participants aged 20 to 29 years (r = -0.15, P = 7.6 × 10 -3 , N = 322), and participants aged 15 to 19 years had no correlation (r = 0.05, P = 0.48, N = 240). IGF-II levels did not predict weight gain. However, among individuals who had genotypes for 64 established obesity variants (age ≥ 20 years, N = 671), a genetic risk score for high BMI was associated with lower IGF-II (β = -0.08 SD of IGF-II per SD of the genetic risk score, P = 0.025)., Conclusions: There is a negative relationship between IGF-II levels and BMI, in which the correlation is stronger at older ages. The association between genetic risk for BMI and IGF-II levels suggests that this correlation may be due to an effect of obesity on IGF-II., (Published 2020. This article is a U.S. Government work and is in the public domain in the USA.)

The Pima Indians of the Gila River Indian Community in Arizona have participated in a long-range study of type 2 diabetes mellitus since 1965 and have been the subject of HLA typing and population studies since the early days of serological assays. These data have been in numerous HLA workshops and conferences and have been the source of at least five novel alleles at the classical HLA loci. In recent time nearly the entire study group was subject to next generation sequencing by whole genome or exome technologies, which has allowed us to HLA type over 3000 full heritage persons with recently developed computer algorithms. We present here the results for the classical HLA Loci: HLA-A, B, C, DRA, DRB1, DRB3, DRB4, DRB5, DPA1, DPB1, DQA1, and DQB1 to the third field of resolution for synonymous alleles and type the likely four field resolution alleles from the subset of whole genome sequences. Allele frequencies, and haplotype frequencies at up to five loci, are presented as well as measures of population structure and heterozygosity. We define a core set of HLA variation that approximates the distribution for the Paleo-Indians and impute nine-locus, 4-field haplotypes that are expected to be common in full heritage peoples., (Published by Elsevier Inc.)

Preterm birth (PTB) related health problems take over one million lives each year, and currently, no clinical analysis is available to determine if a fetus is at risk for PTB. Here, we describe the preparation of a key PTB risk biomarker, thrombin-antithrombin (TAT), and characterize it using dot blots, MS, and microchip electrophoresis (µCE). The pH for fluorescently labeling TAT was also optimized using spectrofluorometry and spectrophotometry. The LOD of TAT was measured in µCE. Lastly, TAT was combined with six other PTB risk biomarkers and separated in µCE. The ability to make and characterize TAT is an important step toward the development of an integrated microfluidic diagnostic for PTB risk., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Aims: Type 2 diabetes is a heterogeneous disease and may manifest from multiple disease pathways. We examined insulin secretion and insulin resistance across two ethnicities with particularly high risk for diabetes yet with widely different distributions of weight class., Materials and Methods: In this population-based, cross-sectional study, Pima Indians from Southwestern United States (n = 865) and Asian Indians from Chennai, India (n = 2374) had a 75-g oral glucose tolerance test. We analysed differences in plasma glucose, plasma insulin, insulin resistance (HOMA-IR), and insulin secretion (ΔI 0-30 /ΔG 0-30 ) across categories of body mass index (BMI) and glycemic status per American Diabetes Association criteria., Results: Pima Indians were younger (mean 27.4 ± SD 6.6, Asian: 33.9 ± 6.7 years) and had higher BMI (33.6 ± 8.1, Asian: 25.7 ± 4.9 kg/m 2 ). Among normal weight participants (mean BMI: Pima 22.4 SE 0.2; Asian 22.2 SE 0.06 kg/m 2 ), fasting glucose was higher in Asian Indians (5.2 vs Pima: 4.8 mmol/L, P = .003), adjusted for age and sex. Pima Indians were three times as insulin resistant as Asian Indians (HOMA-IR: 7.7 SE 0.1, Asian: 2.5 SE 0.07), while Asian Indians had three times less insulin secretion (Pima: 2.8 SE 1.0 vs Asian: 0.9 SE 1.0 pmol/mmol), a pattern evident across age, BMI, and glycemic strata., Conclusions: Metabolic differences between Pima and Asian Indians suggest heterogeneous pathways of type 2 diabetes in the early natural history of disease, with emphasis of insulin resistance in Pima Indians and emphasis of poor insulin secretion in Asian Indians., (© 2019 John Wiley & Sons, Ltd.)

Background: In type 2 diabetes (T2DM), the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation for estimated glomerular filtration rate (eGFR) systematically underestimates the measured adjusted glomerular filtration rate (aGFR) when aGFR is high. We studied the extent to which glycemic variables associate with kidney function, and developed equations including these variables that estimate aGFR in people with T2DM., Methods: Diabetic Pima people had aGFR measured from iothalamate clearance divided by body surface area. eGFRs < 60 ml/min/1.73m 2 were excluded. Multivariate linear regression identified variables correlated with kidney function. We constructed equations for approximating aGFR. Correlation analysis and 10-fold cross-validation were used to compare the CKD-EPI equation and the new approximating equations to the measured aGFR. Ability to detect hyperfiltration, defined as aGFR > 120 ml/min/1.73m 2 , was compared by analysis of receiver-operating (ROC) curves., Results: aGFR was measured 2798 times in 269 individuals. HbA1c, fasting plasma glucose (FPG), age, and serum creatinine (SCR) were significantly associated with aGFR. The best equations for approximating aGFR used HbA1c and FPG in addition to age and SCR. They approximate aGFR in this cohort of obese people with T2DM more precisely than the CKD-EPI equation. Analysis of ROC curves show that these equations detect hyperfiltration better than does the CKD-EPI equation., Conclusions: HbA 1c, FPG, age, and SCR yielded the best equations for estimating aGFR in these subjects. The new equations identify hyperfiltration better than the CKD-EPI equation in this cohort and may inform clinical decisions regarding hyperfiltration in individuals with T2DM.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Type 2 diabetes is a common disease worldwide, but its prevalence varies widely by geographical region and by race/ethnicity. This review summarises differences in the frequencies of type 2 diabetes according to race, ethnicity, socioeconomic position, area of residence and environmental toxins. Type 2 diabetes susceptibility often begins early in life, starting with genetic susceptibility at conception and continuing in later life, via in utero, childhood and adult exposures. Early-life factors may lead to overt type 2 diabetes in childhood or in later life, supporting the concept of developmental origins of health and disease. The causes of the racial/ethnic differences in incidence of type 2 diabetes are not well understood. Specifically, the relative contributions of genetic and environmental factors to such differences are largely unknown. With a few exceptions in isolated populations, there is little evidence that differences in frequencies of known type 2 diabetes susceptibility genetic alleles account for racial/ethnic differences, although the search for genetic susceptibility has not been uniform among the world's racial/ethnic groups. In the USA, race/ethnicity is associated with many other risk factors for type 2 diabetes, including being overweight/obese, diet and socioeconomic status. Some studies suggest that some of these factors may account for the race/ethnic differences in prevalence of type 2 diabetes, although there is inadequate research in this area. A better understanding of the impact of these factors on type 2 diabetes risk should lead to more effective prevention and treatment of this disease. This has not yet been achieved but should be a goal for future research.

Aims/hypothesis: Variants in CREBRF (rs12513649 and rs373863828) have been strongly associated with increased BMI and decreased risk of type 2 diabetes in Polynesian populations; the A allele at rs373863828 is common in Polynesians but rare in most other global populations. The aim of the present study was to assess the association of CREBRF variants with obesity and diabetes in Pacific Islander (largely Marianas and Micronesian) populations from Guam and Saipan., Methods: CREBRF rs12513649 and rs373863828 were genotyped in 2022 participants in a community-based cross-sectional study designed to identify determinants of diabetes and end-stage renal disease (ESRD). Associations were analysed with adjustment for age, sex, ESRD and the first four genetic principal components from a genome-wide association study (to account for population stratification); a genomic control procedure was used to account for residual stratification., Results: The G allele at rs12513649 had an overall frequency of 7.7%, which varied from 2.2% to 20.7% across different Marianas and Micronesian populations; overall frequency of the A allele at rs373863828 was 4.2% (range: 1.1-5.4%). The G allele at rs12513649 was associated with higher BMI (β = 1.55 kg/m 2 per copy; p = 0.0026) as was the A allele at rs373863828 (β = 1.48 kg/m 2 , p = 0.033). The same alleles were associated with lower risk of diabetes (OR per copy: 0.63 [p = 0.0063] and 0.49 [p = 0.0022], respectively). Meta-analyses combining the current results with previous results in Polynesians showed a strong association between the A allele at rs373863828 and BMI (β = 1.38 kg/m 2 ; p = 2.5 × 10 -29 ) and diabetes (OR 0.65, p = 1.5 × 10 -13 )., Conclusions/interpretation: These results confirm the associations of CREBRF variants with higher BMI and lower risk of diabetes and, importantly, they suggest that these variants contribute to the risk of obesity and diabetes in Oceanic populations.

Aims/hypothesis: The aim of this work was to estimate the impact of birthweight on early-onset (age <40 years) type 2 diabetes., Methods: A longitudinal study of American Indians, aged ≥5 years, was conducted from 1965 to 2007. Participants who had a recorded birthweight were followed until they developed diabetes or their last examination before the age of 40 years, whichever came first. Age- and sex-adjusted diabetes incidence rates were computed and Poisson regression was used to model the effect of birthweight on diabetes incidence, adjusted for sex, BMI, a type 2 diabetes susceptibility genetic risk score (GRS) and maternal covariates., Results: Among 3039 participants, there were 652 incident diabetes cases over a median follow-up of 14.3 years. Diabetes incidence increased with age and was greater in the lowest and highest quintiles of birthweight. Adjusted for covariates, the effect of birthweight on diabetes varied over time, with a non-linear effect at 10-19 years (p < 0.001) and a negative linear effect at older age intervals (20-29 years, p < 0.001; 30-39 years, p = 0.003). Higher GRS, greater BMI and maternal diabetes had additive but not interactive effects on the association between birthweight and diabetes incidence., Conclusions/interpretation: In this high-risk population, both low and high birthweights were associated with increased type 2 diabetes risk in adolescence (age 10-19 years) but only low birthweight was associated with increased risk in young adulthood (20-39 years). Higher type 2 diabetes GRS, greater BMI and maternal diabetes added to the risk of early-onset diabetes.