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

Automating with SIMATIC S7-400 inside TIA Portal: Configuring, Programming and Testing with STEP 7 Professional

This book presents a comprehensive description of the configuration of devices and network for the S7-400 components inside the engineering framework TIA Portal. You learn how to formulate and test a control program with the programming languages LAD, FBD, STL, and SCL. The book is rounded off by configuring the distributed I/O with PROFIBUS DP and PROFINET IO using SIMATIC S7-400 and data exchange via Industrial Ethernet. SIMATIC is the globally established automation system for implementing industrial controllers for machines, production plants and processes. SIMATIC S7-400 is the most powerful automation system within SIMATIC. This process controller is ideal for data-intensive tasks that are especially typical for the process industry. With superb communication capability and integrated interfaces it is optimized for larger tasks such as the coordination of entire systems. Open-loop and closed-loop control tasks are formulated with the STEP 7 Professional V11 engineering software in the field-proven programming languages Ladder Diagram (LAD), Function Block Diagram (FBD), Statement List (STL), and Structured Control Language (SCL). The TIA Portal user interface is tuned to intuitive operation and encompasses all the requirements of automation within its range of functions: from configuring the controller, through programming in the different languages, all the way to the program test. Users of STEP 7 Professional V12 will easily get along with the descriptions based on the V11. With start of V12, the screens of the technology functions might differ slightly from the V11