GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on ‘around the clock’ glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification

Subclinical and clinical hypothyroidism and non-alcoholic fatty liver disease: a cross-sectional study of a random population sample aged 18 to 65 years

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common disorders of the liver worldwide. Recently, a correlation between thyroid dysfunction and NAFLD has been discussed. Objective of the present study was to investigate the association between thyroid dysfunction and hepatic steatosis. Methods: Data from 2,445 subjects (51.7 % females) aged 18 to 65 years participating in a population-based cross-sectional study were assessed based on a standardized questionnaire and documentation of physical, biochemical and ultrasonographic findings. After application of exclusion criteria, a total of 1,276 subjects were included in the study collective. The influence of potential factors on the development of hepatic steatosis was assessed using multivariate logistic regression. Results: The prevalence of hepatic steatosis in the study collective was 27.4 % (n = 349). The serum thyroxin (TT4) concentration in subjects with hepatic steatosis was reduced (p = 0.0004). Adjusting for age, or BMI, there was an increased prevalence of hepatic steatosis in subjects with reduced TT4 concentrations (p = 0.0143; p = <.0001). Conclusions: The findings of the present study confirm an association between both subclinical and clinical hypothyroidism and hepatic steatosis.Published versio

Percutaneous ultrasonographically guided liver punctures: an analysis of 1961 patients over a period of ten years

<p>Abstract</p> <p>Background</p> <p>Ultrasonographically guided punctures of the liver represent a decisive tool in the diagnosis of many diseases of the liver. Objective of the study was to determine the extent to which the complication rate for ultrasonographically guided punctures of the liver is affected by less comprehensively studied risk factors.</p> <p>Methods</p> <p>A total of 2,229 liver biopsies were performed in 1,961 patients (55.5% males; 44.5% females). We recorded actual complications and assessed the following risk factors: needle gauge, puncture technique, examiner experience, coagulation status, puncture target (focal lesion versus parenchyma), lesion size, patient sex and age.</p> <p>Results</p> <p>he rate of complications stood at 1.2% (n = 27), of which 0.5% (n = 12) were major and 0.7% (n = 15) minor complications. A significant increase in complications involving bleeding was observed with larger-gauge needles compared with smaller-gauge needles and for cutting biopsy punctures compared with aspiration biopsies (Menghini technique). In the bivariate analysis complications were 2.7 times more frequent in procedures performed by experienced examiners compared with those with comparatively less experience. Lower values for Quick’s test and higher partial thromboplastin times were associated with a higher rate of bleeding. Neither the puncture target, lesion size or patient sex exerted any measurable influence on the puncture risk. Advanced patient age was associated with a higher rate of complications involving bleeding.</p> <p>Conclusions</p> <p>Our study helps to establish the importance of potential and less comprehensively studied risk factors and may contribute to further reduction in complications rates in routine clinical practice.</p

GWAS of random glucose in 476,326 individuals provide insights into diabetes pathophysiology, complications and treatment stratification.

Conventional measurements of fasting and postprandial blood glucose levels investigated in genome-wide association studies (GWAS) cannot capture the effects of DNA variability on 'around the clock' glucoregulatory processes. Here we show that GWAS meta-analysis of glucose measurements under nonstandardized conditions (random glucose (RG)) in 476,326 individuals of diverse ancestries and without diabetes enables locus discovery and innovative pathophysiological observations. We discovered 120 RG loci represented by 150 distinct signals, including 13 with sex-dimorphic effects, two cross-ancestry and seven rare frequency signals. Of these, 44 loci are new for glycemic traits. Regulatory, glycosylation and metagenomic annotations highlight ileum and colon tissues, indicating an underappreciated role of the gastrointestinal tract in controlling blood glucose. Functional follow-up and molecular dynamics simulations of lower frequency coding variants in glucagon-like peptide-1 receptor (GLP1R), a type 2 diabetes treatment target, reveal that optimal selection of GLP-1R agonist therapy will benefit from tailored genetic stratification. We also provide evidence from Mendelian randomization that lung function is modulated by blood glucose and that pulmonary dysfunction is a diabetes complication. Our investigation yields new insights into the biology of glucose regulation, diabetes complications and pathways for treatment stratification