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

Classification of bulimic-type eating disorders: from DSM-IV to DSM-5

Proposed changes to the classification of bulimic-type eating disorders in the lead up to the publication of DSM-5 are reviewed. Several of the proposed changes, including according formal diagnostic status to binge eating disorder (BED), removing the separation of bulimia nervosa (BN) into purging and non-purging subtypes, and reducing the binge frequency threshold from twice per week to once per week for both BN and (BED), have considerable empirical evidence to support them and will likely have the effect of facilitating clinical practice, improving access to care, improving public and professional awareness and understanding of these disorders and stimulating the additional research needed to address at least some problematic issues. However, the omission of any reference to variants of BN characterized by subjective, but not objective, binge eating episodes, and to the undue influence of weight or shape on self-evaluation or similar cognitive criterion in relation to the diagnosis of BED, is regrettable, given their potential to inform clinical and research practice and given that there is considerable evidence to support specific reference to these distinctions. Other aspects of the proposed criteria, such as retention of behavioral indicators of impaired control associated with binge eating and the presence of marked distress regarding binge eating among the diagnostic for BED, appear anomalous in that there is little or no evidence to support their validity or clinical utility. It is hoped that these issues will be addressed in final phase of the DSM-5 development process.10 page(s

Eating disorders 'mental health literacy' : an introduction

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Higher BMI, lower self-esteem and more abnormal eating habits are associated with greater body dissatisfaction in adolescents : commentary

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