Publications

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background: Indolepropionate (IPA), a tryptophan metabolite of human gut microbiota origin, is associated with lower risk of type 2 diabetes (T2D) in humans. The complex interplay among tryptophan intake, the gut microbiome, prebiotics, circulating IPA concentrations, and T2D risk has not been investigated. Objectives: We aimed to identify IPA-producing gut microbiota species and investigate potential diet-microbiota interaction on circulating IPA concentrations. Methods: We included 287 men from the Men’s Lifestyle Validation Study, a sub-study of the Health Professionals Follow-Up Study (HPFS), who provided up to two pairs of fecal samples and two blood samples approximately six months apart. Dietary intake was assessed using 7-day diet records. We identified microbial taxonomic features associated with plasma IPA concentrations using generalized linear regression and calculated a rank-based species score to reflect IPA-producing potential. Associations between plasma concentrations of tryptophan metabolites and T2D risk were examined in 13,032 participants from Nurses’ Health Study (NHS), NHSII, and HPFS. Results: Plasma IPA concentrations were associated with overall gut microbial profiles (permutational analysis of variance test, p=0.001). We identified 17 microbial species, such as Eubacterium eligens, Butyrivibrio crossotus , and Faecalibacterium prausnitzii , whose abundance was significantly associated with increased plasma IPA concentrations (false discovery rate < 0.05). A significant association between higher tryptophan intake and higher IPA concentrations was only observed among men who had higher fiber intake and a higher microbial species score consisting of the 17 species (p-interaction < 0.01). Similar modulation was also observed for major tryptophan food contributors including vegetables (p-interaction < 0.01), red/processed meat (p-interaction = 0.02), egg (p-interaction 0.01), dairy (p-interaction = 0.01), and whole grain (p-interaction < 0.01). Moreover, interactions persisted for all fiber subtypes (soluble/insoluble fiber and pectin). We documented 1,744 incident T2D cases during 218,603 person-years of follow-up. Plasma concentrations of tryptophan and three kynurenine-pathway metabolites (kynurenine, xanthurenate, and quinolinate) were positively associated with T2D risk while an inverse association was found for IPA. Conclusions: Specific microbial species and dietary fiber jointly modulate the associations between tryptophan intake and circulating IPA concentrations. In a subsequent analysis, IPA levels were predictive of lower T2D risk. Our findings suggest that the health effects of dietary tryptophan may depend on both gut microbiome composition and prebiotic consumption.

Few studies have examined the association of a wide range of metabolites with total and subtypes of coffee consumption. The aim of this study was to investigate associations of plasma metabolites with total, caffeinated, and decaffeinated coffee consumption. We also assessed the ability of metabolites to discriminate between coffee consumption categories. This is a cross-sectional analysis of 1664 participants from the PREDIMED study. Metabolites were semiquantitatively profiled using a multiplatform approach. Consumption of total coffee, caffeinated coffee and decaffeinated coffee was assessed by using a validated food frequency questionnaire. We assessed associations between 387 metabolite levels with total, caffeinated, or decaffeinated coffee consumption (≥50 mL coffee/day) using elastic net regression analysis. Ten-fold cross-validation analyses were used to estimate the discriminative accuracy of metabolites for total and subtypes of coffee. We identified different sets of metabolites associated with total coffee, caffeinated and decaffeinated coffee consumption. These metabolites consisted of lipid species (e.g., sphingomyelin, phosphatidylethanolamine, and phosphatidylcholine) or were derived from glycolysis (alpha-glycerophosphate) and polyphenol metabolism (hippurate). Other metabolites included caffeine, 5-acetylamino-6-amino-3-methyluracil, cotinine, kynurenic acid, glycocholate, lactate, and allantoin. The area under the curve (AUC) was 0.60 (95% CI 0.56–0.64), 0.78 (95% CI 0.75–0.81) and 0.52 (95% CI 0.49–0.55), in the multimetabolite model, for total, caffeinated, and decaffeinated coffee consumption, respectively. Our comprehensive metabolic analysis did not result in a new, reliable potential set of metabolites for coffee consumption.

OBJECTIVE Low birth weight is associated with an increased risk of type 2 diabetes. The mechanisms underlying this association are unknown and may represent intrauterine programming or two phenotypes of one genotype. The fetal insulin hypothesis proposes that common genetic variants that reduce insulin secretion or action may predispose to type 2 diabetes and also reduce birth weight, since insulin is a key fetal growth factor. We tested whether common genetic variants that predispose to type 2 diabetes also reduce birth weight. RESEARCH DESIGN AND METHODS We genotyped single-nucleotide polymorphisms (SNPs) at five recently identified type 2 diabetes loci (CDKAL1, CDKN2A/B, HHEX-IDE, IGF2BP2, and SLC30A8) in 7,986 mothers and 19,200 offspring from four studies of white Europeans. We tested the association between maternal or fetal genotype at each locus and birth weight of the offspring. RESULTS We found that type 2 diabetes risk alleles at the CDKAL1 and HHEX-IDE loci were associated with reduced birth weight when inherited by the fetus (21 g [95% CI 11–31], P = 2 × 10−5, and 14 g [4–23], P = 0.004, lower birth weight per risk allele, respectively). The 4% of offspring carrying four risk alleles at these two loci were 80 g (95% CI 39–120) lighter at birth than the 8% carrying none (Ptrend = 5 × 10−7). There were no associations between birth weight and fetal genotypes at the three other loci or maternal genotypes at any locus. CONCLUSIONS Our results are in keeping with the fetal insulin hypothesis and provide robust evidence that common disease-associated variants can alter size at birth directly through the fetal genotype.

The fabrication of arrays of Schottky diodes on p-type silicon is described using a representative soft lithographic technique: micromolding in capillaries (MIMIC). It is demonstrated that soft lithography is compatible with multilayer fabrication of electronically functional structures. The characteristics of the diodes were found to be similar to those fabricated by photolithography. The advantages and limitations of MIMIC are outlined, with particular attention being paid to the degree of registration of features that can be achieved.

Abstract Lung function measures are used in the diagnosis of chronic obstructive pulmonary disease. In 38,199 European ancestry individuals, we studied genome-wide association of forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC) and FEV 1 /FVC with 1000 Genomes Project (phase 1)-imputed genotypes and followed up top associations in 54,550 Europeans. We identify 14 novel loci ( P <5 × 10 −8 ) in or near ENSA , RNU5F-1 , KCNS3 , AK097794 , ASTN2 , LHX3 , CCDC91 , TBX3 , TRIP11 , RIN3 , TEKT5 , LTBP4 , MN1 and AP1S2 , and two novel signals at known loci NPNT and GPR126 , providing a basis for new understanding of the genetic determinants of these traits and pulmonary diseases in which they are altered.

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood. We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort. Five common SNPs, defined by showing minor allele frequencies (MAFs) .5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of b= 20.068 g/L per minor allele (P=1.20*10 212 ). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N=410), suggested that AAT serum level is causally determined at this locus by rare (MAF,1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N=8273) was successful (P,0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P=0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N=397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

Background: Prolactin, a multifunctional hormone, is involved in regulating insulin sensitivity and glucose homeostasis in experimental and cross-sectional human studies. However, whether circulating levels of prolactin are associated with risk of type 2 diabetes (T2D) remains unclear. Methods: We analyzed the prospective relationship between circulating prolactin levels and T2D risk in in the Nurses’ Health Study (NHS) and Nurses’ Health Study II (NHSII) with up to 22 years of follow-up. Total plasma prolactin was measured using immunoassay in 8,637 women free of T2D and cardiovascular disease at baseline blood collection (NHSI: 1989-1990; NHSII: 1996-1999) and a subset of 1,017 NHS women who provided a second blood sample in 2000-2002. In addition, baseline bioactive prolactin levels were measured in a subset of 2,658 women using the Nb2 lymphoma cell bioassay. We calculated hazard ratios (HRs) using Cox regressions. Results: A total of 701 incident T2D cases were documented during 159,517 person-years of follow-up. Circulating prolactin levels were inversely associated with T2D risk; the multivariable HR comparing the highest with the lowest quartile of prolactin levels was 0.71 (95% confidence interval, 0.54-0.93; P trend =0.02). The associations were similar by menopausal status and risk factors ( P >0.70 for interaction). Additional adjustment for sex hormones, growth factors, adipokine, and inflammatory markers did not alter the results. The association of bioactive prolactin with T2D risk was suggestively stronger than that of total prolactin (comparable HR=0.56 vs. 0.82 among the 2,658 women). The inverse association of total plasma prolactin with incident T2D waned linearly with time, with a significant association observed during the first 9 years after blood draw. Conclusion: High circulating prolactin level was independently associated with lower risk of T2D in women. Our findings are consistent with experimental evidence, supporting a possible protective role for prolactin in the pathogenesis of T2D.