Associations of coagulation parameters and thrombin generation potential with the incidence of type 2 diabetes: mediating role of glycoprotein acetylation.

Hypercoagulability is characterized by abnormal elevations of coagulation factor levels and increased thrombin generation potential. Prior studies demonstrated links between impaired glucose metabolism, endothelial dysfunction, and hypercoagulability. However, the associations between hypercoagulability and incident type 2 diabetes as well as its underlying mechanism remain unclear. We aimed to assess the associations between coagulation parameters including coagulation factor (F) VIII, FIX, FXI, fibrinogen, thrombin generation potential (lag time, endogenous thrombin potential [ETP], peak, time-to-peak, velocity) and incident type 2 diabetes, and to study the underlying mechanism by examining the mediating role of glycoprotein acetylation (GlycA). In the Netherlands Epidemiology of Obesity study, we applied a Cox Proportional-Hazards Model in 5718 participants after adjustment for confounders. We further conducted a mediation analysis investigating the mediation effect of GlycA on the observed associations. During a median follow-up of 6.7 years, 281 incident type 2 diabetes diagnoses were reported. Compared with the lowest quartile, hazard ratio (95% confidence interval) of the highest quartile was 2.47 (1.48-4.14) for FIX, 1.37 (0.85-2.20) for FVIII, 1.11 (0.76-1.63) for FXI, 0.98 (0.65-1.48) for fibrinogen, 1.56 (1.07-2.28) for ETP, 1.84 (1.23-2.74) for peak, 1.59 (1.08-2.33) for velocity, 0.92 (0.62-1.38) for lag time, and 1.21 (0.86-1.70) for time-to-peak. GlycA mediated only a small proportion of all observed associations. In conclusion, elevated levels of coagulation factor and thrombin generation potential are associated with incident type 2 diabetes, suggesting the involvement of hypercoagulability in the pathogenesis of type 2 diabetes.

Timing of physical activity in relation to liver fat content and insulin resistance.

AIMS/HYPOTHESIS: We hypothesised that the insulin-sensitising effect of physical activity depends on the timing of the activity. Here, we examined cross-sectional associations of breaks in sedentary time and timing of physical activity with liver fat content and insulin resistance in a Dutch cohort. METHODS: In 775 participants of the Netherlands Epidemiology of Obesity (NEO) study, we assessed sedentary time, breaks in sedentary time and different intensities of physical activity using activity sensors, and liver fat content by magnetic resonance spectroscopy (n=256). Participants were categorised as being most active in the morning (06:00-12:00 hours), afternoon (12:00-18:00 hours) or evening (18:00-00:00 hours) or as engaging in moderate-to-vigorous-physical activity (MVPA) evenly distributed throughout the day. Most active in a certain time block was defined as spending the majority (%) of total daily MVPA in that block. We examined associations between sedentary time, breaks and timing of MVPA with liver fat content and HOMA-IR using linear regression analyses, adjusted for demographic and lifestyle factors including total body fat. Associations of timing of MVPA were additionally adjusted for total MVPA. RESULTS: The participants (42% men) had a mean (SD) age of 56 (4) years and a mean (SD) BMI of 26.2 (4.1) kg/m2. Total sedentary time was not associated with liver fat content or insulin resistance, whereas the amount of breaks in sedentary time was associated with higher liver fat content. Total MVPA (-5%/h [95% CI -10%/h, 0%/h]) and timing of MVPA were associated with reduced insulin resistance but not with liver fat content. Compared with participants who had an even distribution of MVPA throughout the day, insulin resistance was similar (-3% [95% CI -25%, 16%]) in those most active in morning, whereas it was reduced in participants who were most active in the afternoon (-18% [95% CI -33%, -2%]) or evening (-25% [95% CI -49%, -4%]). CONCLUSIONS/INTERPRETATION: The number of daily breaks in sedentary time was not associated with lower liver fat content or reduced insulin resistance. Moderate-to-vigorous activity in the afternoon or evening was associated with a reduction of up to 25% in insulin resistance. Further studies should assess whether timing of physical activity is also important for the occurrence of type 2 diabetes.

Association Between Low Sex Hormone-Binding Globulin and Increased Risk of Type 2 Diabetes Is Mediated by Increased Visceral and Liver Fat: Results From Observational and Mendelian Randomization Analyses.

The aim of this study was to investigate the associations among sex hormone-binding globulin (SHBG), visceral adipose tissue (VAT), liver fat content, and risk of type 2 diabetes (T2D). In the Netherlands Epidemiology of Obesity study, 5,690 women (53%) and men (47%) without preexisting diabetes were included and followed for incident T2D. SHBG concentrations were measured in all participants, VAT was measured using MRI, and liver fat content was measured using proton magnetic resonance spectroscopy in a random subset of 1,822 participants. We examined associations between SHBG and liver fat using linear regression and bidirectional Mendelian randomization analyses and between SHBG and T2D using Cox regression adjusted for confounding and additionally for VAT and liver fat to examine mediation. Mean age was 56 (SD 6) years, mean BMI was 30 (SD 4) kg/m2, median SHBG was 47 (interquartile range [IQR] 34-65) nmol/L in women and 34 (26-43) nmol/L in men, and median liver fat was 3.4% (IQR 1.6-8.2%) in women and 6.0% (2.9-13.5%) in men. Compared with the highest SHBG quartile, liver fat was 2.9-fold (95% CI 2.4, 3.4) increased in women and 1.6-fold (95% CI 1.3, 1.8) increased in men, and the hazard ratio of T2D was 4.9 (95% CI 2.4, 9.9) in women and 1.8 (1.1, 2.9) in men. Genetically predicted SHBG was associated with liver fat content (women: SD -0.45 [95% CI -0.55, -0.35]; men: natural logarithm, -0.25 [95% CI -0.34, -0.16]). VAT and liver fat together mediated 43% (women) and 60% (men) of the SHBG-T2D association. To conclude, in a middle-aged population with overweight, the association between low SHBG and increased risk of T2D was, for a large part, mediated by increased VAT and liver fat.

Objectively Measured Physical Activity and Body Fatness: Associations with Total Body Fat, Visceral Fat, and Liver Fat.

PURPOSE: It remains unclear to what extent habitual physical activity and sedentary time (ST) are associated with visceral fat and liver fat. We studied the substitution of ST with time spent physically active and total body fat (TBF), visceral adipose tissue (VAT), and hepatic triglyceride content (HTGC) in middle-age men and women. DESIGN: In this cross-sectional analysis of the Netherlands Epidemiology of Obesity study, physical activity was assessed in 228 participants using a combined accelerometer and heart rate monitor. TBF was assessed by the Tanita bioelectrical impedance, VAT by magnetic resonance imaging, and HTGC by proton-MR spectroscopy. Behavioral intensity distribution was categorized as ST, time spent in light physical activity (LPA), and moderate to vigorous physical activity (MVPA). To estimate the effect of replacing 30 min·d-1 of ST with 30 min·d-1 LPA or MVPA, we performed isotemporal substitution analyses, adjusted for sex, age, ethnicity, education, the Dutch Healthy Diet index, and smoking. RESULTS: Included participants (41% men) had a mean ± SD age of 56 ± 6 yr and spent 88 ± 56 min in MVPA and 9.0 ± 2.1 h of ST. Replacing 30 min·d-1 of ST with 30 min of MVPA was associated with 1.3% less TBF (95% confidence interval = -2.0 to -0.7), 7.8 cm2 less VAT (-11.6 to -4.0), and 0.89 times HTGC (0.82-0.97). Replacement with LPA was not associated with TBF (-0.03%; -0.5 to 0.4), VAT (-1.7 cm2; -4.4 to 0.9), or HTGC (0.98 times; 0.92-1.04). CONCLUSIONS: Reallocation of time spent sedentary with time spent in MVPA, but not LPA, was associated with less TBF, visceral fat, and liver fat. These findings contribute to the development of more specified guidelines on ST and physical activity.

Effects of dietary macronutrients on liver fat content in adults: a systematic review and meta-analysis of randomized controlled trials.

Dietary macronutrient composition may affect hepatic liver content and its associated diseases, but the results from human intervention trials have been equivocal or underpowered. We aimed to assess the effects of dietary macronutrient composition on liver fat content by conducting a systematic review and meta-analysis of randomized controlled trials in adults. Four databases (PubMed, Embase, Web of Science, and COCHRANE Library) were systematically searched for trials with isocaloric diets evaluating the effect of dietary macronutrient composition (energy percentages of fat, carbohydrates, and protein, and their specific types) on liver fat content as assessed by magnetic resonance techniques, computed tomography or liver biopsy. Data on change in liver fat content were pooled by random or fixed-effects meta-analyses and expressed as standardized mean difference (SMD). We included 26 randomized controlled trials providing data for 32 comparisons on dietary macronutrient composition. Replacing dietary fat with carbohydrates did not result in changes in liver fat (12 comparisons, SMD 0.01 (95% CI -0.36; 0.37)). Unsaturated fat as compared with saturated fat reduced liver fat content (4 comparisons, SMD -0.80 (95% CI -1.09; -0.51)). Replacing carbohydrates with protein reduced liver fat content (5 comparisons, SMD -0.33 (95% CI -0.54; -0.12)). Our meta-analyses showed that replacing carbohydrates with total fat on liver fat content was not effective, while replacing carbohydrates with proteins and saturated fat with unsaturated fat was. More well-performed and well-described studies on the effect of types of carbohydrates and proteins on liver fat content are needed, especially studies comparing proteins with fats.