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

A hybrid Eulerian-Lagrangian numerical scheme for solving prognostic equations in fluid dynamics

A new hybrid Eulerian–Lagrangian numerical scheme (HEL) for solving prognostic equations in fluid dynamics is proposed. The basic idea is to use an Eulerian as well as a fully Lagrangian representation of all prognostic variables. The time step in Lagrangian space is obtained as a translation of irregularly spaced Lagrangian parcels along downstream trajectories. Tendencies due to other physical processes than advection are calculated in Eulerian space, interpolated, and added to the Lagrangian parcel values. A directionally biased mixing amongst neighboring Lagrangian parcels is introduced. The rate of mixing is proportional to the local deformation rate of the flow. The time stepping in Eulerian representation is achieved in two steps: first a mass-conserving Eulerian or semi-Lagrangian scheme is used to obtain a provisional forecast. This forecast is then nudged towards target values defined from the irregularly spaced Lagrangian parcel values. The nudging procedure is defined in such a way that mass conservation and shape preservation is ensured in Eulerian space. The HEL scheme has been designed to be accurate, multi-tracer efficient, mass conserving, and shape preserving. In Lagrangian space only physically based mixing takes place; i.e., the problem of artificial numerical mixing is avoided. This property is desirable in atmospheric chemical transport models since spurious numerical mixing can impact chemical concentrations severely. The properties of HEL are here verified in two-dimensional tests. These include deformational passive transport on the sphere, and simulations with a semi-implicit shallow water model including topography