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

Sample Preparation and Imaging of Single Adenovirus Particle Using Atomic Force Microscopy in Liquid

Atomic force microscopy (AFM), as a sophisticated imaging tool with nanoscale resolution, is widely used in virus research and the application of functional viral particles. To investigate single viruses by AFM in a physiologically relevant environment (liquid), an appropriate surface treatment to properly adhere the viruses to the substrate is essential. Here we discuss hydrophobic treated glass coverslips as a suitable substrate for the adhesion of single adenovirus particle (Adenovirus type 5 F35, Ad5F35) when studied with AFM in liquid. From the high resolution AFM images, the orientation of the adhered virus particles can be distinguished. Furthermore, the particles exhibit the expected height of -90 nm. This illustrates that the viruses adhere to the substrate firmly without large deformations. Hence, the described method works well on (fragile) viruses. The described experimental approach can be widely used for AFM studies in liquid of virus structure and mechanics as well as for investigating the interaction of viruses with cellular receptors

Scholars in Disguise: The Cheng-Zhu Neo-Confucian Reappraisal of the Merchant Class in Late Ming

10.1080/0147037X.2020.1772556Ming Studies20208223-4