AIM Increased placental growth secondary to reduced apoptosis may contribute to the development of macrosomia in GDM pregnancies. We hypothesize that reduced apoptosis in GDM placentas is caused by dysregulation of apoptosis related genes from death receptors or mitochondrial pathway or both to enhance placental growth in GDM pregnancies. METHODS Newborn and placental weights from women with no pregnancy complications (controls; N=5), or with GDM (N=5) were recorded. Placental villi from both groups were either fixed for TUNEL assay, or snap frozen for gene expression analysis by apoptosis PCR microarrays and qPCR. RESULTS Maternal, placental and newborn weights were significantly higher in the GDM group vs. Controls. Apoptotic index of placentas from the GDM group was markedly lower than the Controls. At a significant threshold of 1.5, seven genes (BCL10, BIRC6, BIRC7, CASP5, CASP8P2, CFLAR, and FAS) were down regulated, and 13 genes (BCL2, BCL2L1, BCL2L11, CASP4, DAPK1, IκBκE, MCL1, NFκBIZ, NOD1, PEA15, TNF, TNFRSF25, and XIAP) were unregulated in the GDM placentas. qPCR confirmed the consistency of the PCR microarray. Using Western blotting we found significantly decreased placental pro-apoptotic FAS receptor and FAS ligand (FASL), and increased mitochondrial anti-apoptotic BCL2 post GDM insult. Notably, caspase-3, which plays a central role in the execution-phase of apoptosis, and its substrate poly (ADP-ribose) polymerase (PARP) were significantly down regulated in GDM placentas, as compared to non-diabetic Control placentas. CONCLUSION . Women with gestational diabetes (GDM) are at increased risk for having macrosomic newborns, and larger placentas with reduced apoptosis. Decreased apoptosis subsequent to alterations in apoptotic and inflammatory genes may promote elevated weight in the GDM placentas.

No abstract

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.

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 HbA1c 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. HbA1c). 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. Graphical abstract

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output.

No abstract

There is considerable evidence that birth weight is associated with increased risk of type 2 diabetes (T2D) in adulthood. However, evidence from populations with high prevalence of T2D on the genetic relationships between birth weight and T2D is limited. Data were obtained from a genome-wide association study (GWAS) in an Indigenous population from the Southwest US with high prevalence of T2D in which the relationship of T2D with birth weight is “U-shaped." Weighted polygenic scores (PSs) were constructed using imputed genotypes for genome-wide significant single-nucleotide polymorphisms (SNPs) from GWAS meta-analyses for birth weight (EGG Consortium, 126 SNPs) and T2D (DIAGRAM Consortium, 293 SNPs). Associations of birth weight PS and T2D PS with T2D and birth weight were calculated, accounting for participants’ pairwise relationships, using linear mixed models. Birth weight data (n=3700) were normalized separately by sex and analyzed for associations, adjusted for birth year, gestational age and the first 5 genetic principal components (PCs). T2D (n=7659) data were analyzed for associations, adjusted for age, sex, birth year and the first 5 genetic PCs. Birth weight PS had a significant, positive association with birth weight (β=0.134 SD birth weight per SD PS (95% CI 0.101, 0.168); p=4.1×10-15). The T2D PS was likewise significantly, positively associated with T2D (OR=1.48 per SD (1.38, 1.58); p=8.1×10-31). The birth weight PS was significantly, inversely associated with T2D (OR=0.91 (0.85, 0.97); p=0.0043); we found no evidence for a non-linear relationship between birth weight PS and T2D (p=0.80). The T2D PS was not significantly associated with birth weight (β=-0.005 (-0.040, 0.030); p=0.80). Results indicate that genetic variants that associate with birth weight and T2D from larger European GWAS largely also influence these traits in this Indigenous population. Current findings also support the notion that many variants conferring susceptibility to low birth weight also confer susceptibility to T2D. Disclosure L. E. Wedekind: None. W. Hsueh: None. M. Olaiya: None. S. Kobes: None. L. Baier: None. W. C. Knowler: None. A. Mahajan: Employee; Self; Genentech, Inc. M. Mccarthy: Employee; Self; Genentech, Inc. R. L. Hanson: None.

Genome-wide association studies (GWAS) have identified many variants associated with type 2 diabetes (T2D), but there is little information on their effects in high risk populations such as American Indians. We analyzed 211 primary variants, associated with T2D (P&lt;5.0×10-8) in published GWAS, in 7659 American Indian participants in a population study (33.5% with T2D)- updating our previous study of 63 variants. Genotypes came from a custom Axiom array that captures common variation in American Indians; imputation was performed using whole genome sequence data from 266 Pima Indians. Variants were tested for association with T2D in a mixed model accounting for relatedness with adjustment for age, sex and the 1st 5 genetic principal components to account for population stratification. Heterogeneity was tested by comparing odds ratios (ORs) in American Indians with published ORs. A weighted polygenic risk score across all 211 variants was analyzed. Nominally significant (P&lt;0.05) and directionally consistent replication was observed for 21 of the 211 variants. Notable associations were with rs2237895 in KCNQ1 (OR=1.29, P=2.5×10-8) and rs4929965 in INS/IGF2 (OR=1.28, P=9.8×10-8). Significant heterogeneity was seen for 23 variants- 21 had weaker effects in American Indians than in published values. A summary test over all variants showed effects were generally weaker in American Indians (P=4.0×10-11). The polygenic risk score was strongly associated with T2D (OR=1.38 per SD, P=2.8×10-22). The risk score was also associated with reduced insulin secretion measured by a 25 g intravenous glucose tolerance test (by 10% per SD, P=0.005, n=300 all with normal glucose tolerance), but not insulin sensitivity measured by a hyperinsulinemic-euglycemic “clamp” (P=0.78, n=557 all nondiabetic). These findings suggest that established T2D risk variants generally also affect T2D risk in American Indians (although effects tend to be weaker) and that they act predominantly through diminished insulin secretion. Disclosure R.L. Hanson: None. L.E. Wedekind: None. W. Hsueh: None. S. Kobes: None. L.J. Baier: None. C. Bogardus: None. W.C. Knowler: None.