Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

The Chandra Planetary Nebula Survey (ChanPlaNS). III. X-Ray Emission from the Central Stars of Planetary Nebulae

We present X-ray spectral analysis of 20 point-like X-ray sources detected in Chandra Planetary Nebula Survey observations of 59 planetary nebulae (PNe) in the solar neighborhood. Most of these 20 detections are associated with luminous central stars within relatively young, compact nebulae. The vast majority of these point-like X-ray-emitting sources at PN cores display relatively "hard" (≥0.5 keV) X-ray emission components that are unlikely to be due to photospheric emission from the hot central stars (CSPN). Instead, we demonstrate that these sources are well modeled by optically thin thermal plasmas. From the plasma properties, we identify two classes of CSPN X-ray emission: (1) high-temperature plasmas with X-ray luminosities, LX, that appear uncorrelated with the CSPN bolometric luminosity, Lbol and (2) lower-temperature plasmas with LX/Lbol ~ 10⁻⁷. We suggest these two classes correspond to the physical processes of magnetically active binary companions and self-shocking stellar winds, respectively. In many cases this conclusion is supported by corroborative multiwavelength evidence for the wind and binary properties of the PN central stars. By thus honing in on the origins of X-ray emission from PN central stars, we enhance the ability of CSPN X-ray sources to constrain models of PN shaping that invoke wind interactions and binarity.19 page(s

Research capacity. Enabling the genomic revolution in Africa.

no availabl