Hepatic and pancreatic extracellular volume fraction analysis using contrast-enhanced CT in patients with diabetes mellitus and pre-diabetes.

PURPOSE: Liver and pancreatic fibrosis is associated with diabetes mellitus (DM), and liver fibrosis is associated with pancreatic fibrosis. This study aimed to investigate the relationship between the hepatic and pancreatic extracellular volume fractions (fECVs), which correlate with tissue fibrosis, and their relationships with DM and pre-DM (pDM). MATERIAL AND METHODS: We included 100 consecutive patients with known or suspected liver and/or pancreatic diseases who underwent contrast-enhanced CT. Patients were classified as nondiabetes, pDM, and DM with hemoglobin A1c (HbA1c) levels of < 5.7%, 5.7%-6.5%, and ≥ 6.5% or fasting plasma glucose (FPG) levels of < 100, 100-125 mg/dL, and ≥ 126 mg/dL, respectively. Subtraction images between unenhanced and equilibrium-phase images were prepared. The liver and the pancreas were automatically extracted using a high-speed, three-dimensional image analysis system, and their respective mean CT values were calculated. The enhancement degree of the aorta (Δaorta) was measured. fECV was calculated using the following equation: fECV = (100 - hematocrit) * Δliver or pancreas/Δaorta. Differences were investigated in hepatic and pancreatic fECVs among the three groups, and the correlation between each two in hepatic fECV, pancreatic fECV, and HbA1c was determined. RESULTS: The pancreatic fECV, which was positively correlated with the hepatic fECV and HbA1c (r = 0.51, P < 0.001, and r = 0.51, P < 0.001, respectively), significantly differed among the three groups (P < 0.001) and was significantly greater in DM than in pDM or nondiabetes and in pDM with nondiabetes (P < 0.001). Hepatic fECV was significantly greater in DM than in nondiabetes (P < 0.05). CONCLUSION: The pancreatic fECV and pDM/DM are closely related.

Androgen receptor polyglutamine expansion drives age-dependent quality control defects and muscle dysfunction.

Skeletal muscle has emerged as a critical, disease-relevant target tissue in spinal and bulbar muscular atrophy, a degenerative disorder of the neuromuscular system caused by a CAG/polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. Here, we used RNA-sequencing (RNA-Seq) to identify pathways that are disrupted in diseased muscle using AR113Q knockin mice. This analysis unexpectedly identified substantially diminished expression of numerous ubiquitin/proteasome pathway genes in AR113Q muscle, encoding approximately 30% of proteasome subunits and 20% of E2 ubiquitin conjugases. These changes were age, hormone, and glutamine length dependent and arose due to a toxic gain of function conferred by the mutation. Moreover, altered gene expression was associated with decreased levels of the proteasome transcription factor NRF1 and its activator DDI2 and resulted in diminished proteasome activity. Ubiquitinated ADRM1 was detected in AR113Q muscle, indicating the occurrence of stalled proteasomes in mutant mice. Finally, diminished expression of Drosophila orthologues of NRF1 or ADRM1 promoted the accumulation of polyQ AR protein and increased toxicity. Collectively, these data indicate that AR113Q muscle develops progressive proteasome dysfunction that leads to the impairment of quality control and the accumulation of polyQ AR protein, key features that contribute to the age-dependent onset and progression of this disorder.