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

Assessment of the key evolutionary traits that prevent extinctions in human-altered habitats using a spatially explicit individual-based model

Identifying key evolutionary strategies that support population persistence remains a challenging task for biodiversity conservation. Here we assess if animal adaptations to cope with low densities (i.e. that facilitate mate-findings or promote spatial aggregation of individuals) can allow species to persist in human-altered habitats. A spatially explicit and individual-based model was developed to assess if, and under what circumstances, such adaptations maintain population viability. The model was parameterised with data from the movement and demography of the spur-thighed tortoise (Testudo graeca) and simulated scenarios with differences in adult survivorships, initial population sizes and habitat alterations. Habitat alterations reduced population viability, and extinction rates were dependent on population characteristics and mate-finding distance. In contrast, philopatry around the birthplace did not prevent extinctions. Our results highlight the importance of considering specific spatial traits of species when assessing their vulnerability to human habitat alterations.Financial support was granted by the Spanish Ministry of Economy, Industry and Competitiveness, and by the European Regional Development Fund (ID: CGL2012-33536-MINECO/FEDER, UE, CGL2015-64144-MINECO/FEDER, UE). E.G. and R.C.R.C were supported by the Regional Valencian Government with a postdoctoral and predoctoral grant respectively (APOSTD/2015/048 and ACIF/2010/133). A.S.A. was supported by a Vicenç Mut contract co-funded by the Regional Government of the Balearic Islands and the European Social Fund (PD/003/2016). A.S.A and J.D.A were supported by a Ramón y Cajal contracts (RYC-2017- 22796 and RYC-2017-22783 respectively) co-funded by the Spanish Ministry of Science, Innovation and Universities, the State Research Agency and the European Social Fund

Key biological traits and genetic consequences of range shifts: simulating early stages of the expansion of the spur-thighed tortoise (Testudo graeca)

Trabajo presentado en el XIV Congreso Luso-Español de Herpetología/ XVIII Congreso Español de Herpetología, celebrado en Lleida (España), del 5 al 8 de octubre de 2016Peer Reviewe

Interferon-alpha-induced TRAIL on natural killer cells is associated with control of hepatitis C virus infection.

BACKGROUND & AIMS: Pegylated interferon-alpha (PEG-IFNalpha), in combination with ribavirin, controls hepatitis C virus (HCV) infection in approximately 50% of patients by mechanisms that are not completely understood. Beside a direct antiviral effect, different immunomodulatory effects have been discussed. Natural killer (NK) cells might be associated with control of HCV infection. We examined the effects of IFNalpha on human NK cells and its relevance to HCV infection. METHODS: We performed gene expression profiling studies of NK cells following stimulation of peripheral blood mononuclear cells with IFNalpha. We evaluated IFNalpha-induced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression using flow cytometry analyses of NK cells isolated from patients with acute or chronic hepatitis C that had received PEG-IFNalpha therapy. RESULTS: TRAIL was among the most up-regulated genes after IFNalpha stimulation of NK cells from healthy controls. After in vitro stimulation with IFNalpha, CD56(dim) NK cells from patients who had responded to PEG-IFNalpha therapy expressed higher levels of TRAIL than cells from patients with chronic hepatitis C. TRAIL expression, ex vivo, was inversely correlated with HCV-RNA levels during the early phase of PEG-IFNalpha therapy. In patients with acute hepatitis C, TRAIL expression on CD56(bright) NK cells increased significantly compared with cells from controls. In in vitro studies, IFNalpha-stimulated NK cells eliminated HCV-replicating hepatoma cells by a TRAIL-mediated mechanism. CONCLUSIONS: IFNalpha-induced expression of TRAIL on NK cells is associated with control of HCV infection; these observations might account for the second-phase decline in HCV-RNA levels during PEG-IFNalpha therapy