Graphical Abstract Highlights d Imidazole propionate levels are increased in subjects with type 2 diabetes (T2D) d Imidazole propionate is produced from histidine by T2Dassociated bacteria d Imidazole propionate impairs glucose tolerance and insulin signaling d Imidazole propionate inhibits IRS via activation of p38g/p62/ mTORC1In Brief Imidazole propionate, a metabolite produced by the gut microbiota, is elevated in type 2 diabetes and can directly impair glucose tolerance and insulin signaling. SUMMARYInteractions between the gut microbiota, diet, and the host potentially contribute to the development of metabolic diseases. Here, we identify imidazole propionate as a microbially produced histidinederived metabolite that is present at higher concentrations in subjects with versus without type 2 diabetes. We show that imidazole propionate is produced from histidine in a gut simulator at higher concentrations when using fecal microbiota from subjects with versus without type 2 diabetes and that it impairs glucose tolerance when administered to mice. We further show that imidazole propionate impairs insulin signaling at the level of insulin receptor substrate through the activation of p38g MAPK, which promotes p62 phosphorylation and, subsequently, activation of mechanistic target of rapamycin complex 1 (mTORC1). We also demonstrate increased activation of p62 and mTORC1 in liver from subjects with type 2 diabetes. Our findings indicate that the microbial metabolite imidazole propionate may contribute to the pathogenesis of type 2 diabetes. 948 Cell 175, 947-961, November 1, 2018 (legend continued on next page) 950 Cell 175, 947-961,

Cardiopulmonary diseases are major causes of death worldwide, but currently recommended strategies for diagnosis and prevention may be outdated because of recent changes in risk factor patterns. The Swedish CArdioPulmonarybioImage Study (SCAPIS) combines the use of new imaging technologies, advances in large‐scale ‘omics’ and epidemiological analyses to extensively characterize a Swedish cohort of 30 000 men and women aged between 50 and 64 years. The information obtained will be used to improve risk prediction of cardiopulmonary diseases and optimize the ability to study disease mechanisms. A comprehensive pilot study in 1111 individuals, which was completed in 2012, demonstrated the feasibility and financial and ethical consequences of SCAPIS. Recruitment to the national, multicentre study has recently started.

Highlights d The overall gut microbiota shifts in parallel with glycemic status in humans d The shifts are observed in the absence of diabetes treatment d The variations strongly associate with insulin resistance, but not fasting glucose d Butyrate-producing bacteria are reduced in prediabetes and type 2 diabetes

Background: To quantify the association between effects of interventions on carotid intimamedia thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. Methods: We systematically collated data from randomized controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were utilized. The primary outcome was a combined CVD endpoint defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the two using a Bayesian meta-regression approach. Results: We analyzed data of 119 randomized controlled trials involving 100,667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12,038 patients developed the combined CVD endpoint. Across all interventions, each 10 μm/year reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% credible interval 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 μm/year would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74). Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary vs. secondary prevention trials, type of cIMT measurement, and proportion of female patients. Conclusions: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

This pilot study suggests that arterio-arterial embolism from complicated, nonstenosing carotid atherosclerotic plaques may play a role in a subgroup of patients previously diagnosed with cryptogenic stroke. To further evaluate the significance of AHA type VI plaques in cryptogenic stroke, future studies will have to analyze both clinical and imaging follow-up data, including event rates for secondary strokes.

A critical component in scientific studies of most biological variables is the variation or error in measurements which leads to non-identical results of repeated measurements from the same subject. The aim of this study was to investigate whether the interobserver error (s) in measurement of intima-media thickness (IMT) in carotid and femoral arteries could be decreased if the mean value obtained using two ultrasound images from each of the right and left arteries was used in the analyses instead of the mean value obtained using images from only the right artery. In addition, we wished to evaluate two different reading procedures, one based on manual tracing of echo interfaces and the other on automated edge detection. In a methodological study, 50 subjects were examined with ultrasound twice in the same day by two independent laboratory technologists. The ultrasound images were analysed in two ways: using a computerized manual tracing analysing system and an automated analysing system. When both right and left carotid arteries were examined (manual reading), the interobserver error was smaller than that determined for the examination of only the right artery, for IMTmean in both the common carotid artery (P = 0.06) and the carotid artery bulb (P < 0.05). The interobserver error was also significantly smaller for double-sided vs. one-sided examination with automated reading of IMTmean in the common carotid artery (P < 0.01) and in the carotid artery bulb (P < 0.01). The coefficient of variation (CV) for measurement in the common carotid artery decreased from 8.6% (one-sided, manual reading) to 5.3% (double-sided, automated reading). The interobserver error in measurement of IMT in the common femoral artery did not improve by examination of both right and left arteries. The results from this study show that the interobserver errors in measurement of IMT can be decreased by using ultrasound images from both the right and the left carotid arteries, and that the use of an automated analysing system greatly simplifies the reading of ultrasound images with sustained low variability.

NCT00435734.

Background and Purpose-␤-Adrenergic blockade has in several studies been shown to improve survival after myocardial infarction. In animal experiments ␤-blockers have also shown an antiatherosclerotic effect. The aim of this study was to test the hypothesis that the ␤-blocker metoprolol succinate controlled release/extended release (CR/XL), when given to patients with hypercholesterolemia on concomitant lipid-lowering therapy, provides an additional antiatherosclerotic effect to that provided by the statins, measured as carotid intima-media thickness (IMT). Methods-We conducted a randomized, double-blind, placebo-controlled, single center trial to compare the effect of metoprolol CR/XL (100 mg once daily) and placebo on the progression of carotid IMT during 36 months of treatment in patients with hypercholesterolemia and signs of early atherosclerosis in the carotid artery. Most patients were prescribed lipid-lowering treatment with statins. Results-A highly significant difference in the progression rate of the composite variable of carotid bulb IMTϩcommon carotid IMT was observed between the metoprolol CR/XL and placebo groups after 1 year of treatment (Ϫ0.08 versus Ϫ0.01 mm; Pϭ0.004), an effect that was sustained after 3 years of follow-up (Ϫ0.06 versus ϩ0.03 mm; Pϭ0.011). The patients had high levels of total cholesterol at randomization: 9.4 mmol/L in the metoprolol CR/XL group and 8.6 mmol/L in the placebo group. During the study the 2 randomization groups were treated with lipid-lowering drugs, mainly statins, to a similar extent, and total cholesterol was reduced to 6.4 mmol/L at end of follow-up in both groups. Conclusions-The