Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

<b>Objective:</b> Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. <p> </p> <p><b>Research design and methods:</b> We used genetic variants associated (p < 5×10⁻⁸) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n=32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. </p> <p> </p> <p><b>Results:</b> Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio (OR) per one standard deviation (SD) higher exposure 2.16 [2.02 - 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume on risk of type 2 diabetes (1.27 [1.08,1.49] or 27% increased risk and 0.76 [0.62,0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes.</p> <p> </p> <p><b>Conclusions:</b> Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.</p> <p> </p>

Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

<b>Objective:</b> Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. <p> </p> <p><b>Research design and methods:</b> We used genetic variants associated (p < 5×10⁻⁸) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n=32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse-variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. </p> <p> </p> <p><b>Results:</b> Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio (OR) per one standard deviation (SD) higher exposure 2.16 [2.02 - 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume on risk of type 2 diabetes (1.27 [1.08,1.49] or 27% increased risk and 0.76 [0.62,0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes.</p> <p> </p> <p><b>Conclusions:</b> Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.</p> <p> </p>

Deep learning-based pancreas volume assessment in individuals with type 1 diabetes

Pancreas volume is reduced in individuals with diabetes and in autoantibody positive individuals at high risk for developing type 1 diabetes (T1D). Studies investigating pancreas volume are underway to assess pancreas volume in large clinical databases and studies, but manual pancreas annotation is time-consuming and subjective, preventing extension to large studies and databases. This study develops deep learning for automated pancreas volume measurement in individuals with diabetes. A convolutional neural network was trained using manual pancreas annotation on 160 abdominal magnetic resonance imaging (MRI) scans from individuals with T1D, controls, or a combination thereof. Models trained using each cohort were then tested on scans of 25 individuals with T1D. Deep learning and manual segmentations of the pancreas displayed high overlap (Dice coefficient = 0.81) and excellent correlation of pancreas volume measurements (R2 = 0.94). Correlation was highest when training data included individuals both with and without T1D. The pancreas of individuals with T1D can be automatically segmented to measure pancreas volume. This algorithm can be applied to large imaging datasets to quantify the spectrum of human pancreas volume.

Estimating the Effect of Liver and Pancreas Volume and Fat Content on Risk of Diabetes: A Mendelian Randomization Study

OBJECTIVE Fat content and volume of liver and pancreas are associated with risk of diabetes in observational studies; whether these associations are causal is unknown. We conducted a Mendelian randomization (MR) study to examine causality of such associations. RESEARCH DESIGN AND METHODS We used genetic variants associated (P &lt; 5 × 10−8) with the exposures (liver and pancreas volume and fat content) using MRI scans of UK Biobank participants (n = 32,859). We obtained summary-level data for risk of type 1 (9,358 cases) and type 2 (55,005 cases) diabetes from the largest available genome-wide association studies. We performed inverse–variance weighted MR as main analysis and several sensitivity analyses to assess pleiotropy and to exclude variants with potential pleiotropic effects. RESULTS Observationally, liver fat and volume were associated with type 2 diabetes (odds ratio per 1 SD higher exposure 2.16 [2.02, 2.31] and 2.11 [1.96, 2.27], respectively). Pancreatic fat was associated with type 2 diabetes (1.42 [1.34, 1.51]) but not type 1 diabetes, and pancreas volume was negatively associated with type 1 diabetes (0.42 [0.36, 0.48]) and type 2 diabetes (0.73 [0.68, 0.78]). MR analysis provided evidence only for a causal role of liver fat and pancreas volume in risk of type 2 diabetes (1.27 [1.08, 1.49] or 27% increased risk and 0.76 [0.62, 0.94] or 24% decreased risk per 1SD, respectively) and no causal associations with type 1 diabetes. CONCLUSIONS Our findings assist in understanding the causal role of ectopic fat in the liver and pancreas and of organ volume in the pathophysiology of type 1 and 2 diabetes.

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and prior to disease onset. We hypothesized that three pancreas enzymes (amylase, lipase and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody positive (1AAb+) and multiple-AAb+ (≥2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb negative (AAb-) first-degree relatives, and AAb- controls. Lipase and trypsinogen were significantly reduced in ≥2AAb+, recent-onset, and established type 1 diabetes subjects versus controls and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (AUROC=81.4%) performed equivalently to all three enzymes (AUROC=81.4%) in categorizing ≥2AAb+ versus 1AAb+ subjects. For Cohort 2 (n=246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPV_BMI, <i>P</i><0.001), previously measured by magnetic resonance imaging. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPV_BMI and may improve disease staging in pre-type 1 diabetes.

Relationship of Pancreatic Volumes Using CT Scan in Indonesian Adults with Age, Sex, and Body Mass Index

The volume of internal organs, including pancreas, show potential health problems. Several medical conditions are associated with the volume of the pancreas. The study aimed to determine the pancreatic volumes using a computed tomography (CT) scan in normal Indonesian adults and to determine whether the age, sex, and body mass index (BMI) influence the measurement of pancreatic volumes. The study was conducted by 119 people aged between 20-77 years old. Pancreatic volume measurement was performed using the summation of area technique. Statistical analyzes used independent t-test and Pearson correlation test. The study showed a significant difference of pancreatic volumes between normoweight and overweight individuals with p=0.041 (p<0.05). The results showed a significant difference of pancreatic volumes between male and female with p=0.020 (p<0.05). The results showed a significant correlation between pancreatic volumes and age p=0.004 (p<0.05). These findings suggest that the change in pancreas volume with age, sex, and BMI is comparable among different ethnicities, which is also in line with other studies.

Exocrine Pancreatic Enzymes Are a Serological Biomarker for Type 1 Diabetes Staging and Pancreas Size

Exocrine pancreas abnormalities are increasingly recognized as features of type 1 diabetes. We previously reported reduced serum trypsinogen levels and in a separate study, smaller pancreata at and prior to disease onset. We hypothesized that three pancreas enzymes (amylase, lipase and trypsinogen) might serve as serological biomarkers of pancreas volume and risk for type 1 diabetes. Amylase, lipase, and trypsinogen were measured from two independent cohorts, together comprising 800 serum samples from single-autoantibody positive (1AAb+) and multiple-AAb+ (≥2AAb+) subjects, individuals with recent-onset or established type 1 diabetes, their AAb negative (AAb-) first-degree relatives, and AAb- controls. Lipase and trypsinogen were significantly reduced in ≥2AAb+, recent-onset, and established type 1 diabetes subjects versus controls and 1AAb+, while amylase was reduced only in established type 1 diabetes. Logistic regression models demonstrated trypsinogen plus lipase (AUROC=81.4%) performed equivalently to all three enzymes (AUROC=81.4%) in categorizing ≥2AAb+ versus 1AAb+ subjects. For Cohort 2 (n=246), linear regression demonstrated lipase and trypsinogen levels could individually and collectively serve as indicators of BMI-normalized relative pancreas volume (RPV_BMI, <i>P</i><0.001), previously measured by magnetic resonance imaging. Serum lipase and trypsinogen levels together provide the most sensitive serological biomarker of RPV_BMI and may improve disease staging in pre-type 1 diabetes.