Sheng-Chiang Su1,2, Yi-Jen Hung2,3, Fu-Huang Lin4, Chang-Hsun Hsieh2, Chieh-Hua Lu2, Chu-Yen Chien1, Ying-Chen Chen2, Peng-Fei Li2, Feng-Chih Kuo2, Jhih-Syuan Liu2, Nain-Feng Chu2, Chien-Hsing Lee5,6,7. 1. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC. 2. Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd, Neihu District, Taipei City, 114, Taiwan, ROC. 3. Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC. 4. School of Public Health, National Defense Medical Center, Taipei, Taiwan, ROC. 5. Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, ROC. doc10383@gmail.com. 6. Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Chenggong Rd, Neihu District, Taipei City, 114, Taiwan, ROC. doc10383@gmail.com. 7. Department and Graduate Institute of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC. doc10383@gmail.com.
Abstract
AIMS: Endoplasmic reticulum (ER) stress is associated with obesity and type 2 diabetes mellitus (T2DM) and increasing evidence demonstrates that some ER stress markers can represent the severity of metabolic dysfunction in either cellular or animal models. However, no appropriate molecule has been identified to demonstrate these relationships in clinical practice. METHODS: To determine whether the serum level of the ER chaperone, protein disulfide isomerase family A, member 4 (PDIA4), is associated with type 2 diabetes mellitus, obesity, and insulin sensitivity, we conducted a cross-sectional study for which a total of 553 adults, including 159 with normal glucose tolerance (NGT), 169 with prediabetes (Pre-DM), and 225 with newly diagnosed T2DM, were recruited. RESULTS: Serum PDIA4 levels were significantly higher in patients with T2DM than in those with NGT (P < 0.001), even after adjustment for potential confounders. These levels correlated positively with fasting plasma glucose, BMI, waist circumference as well as high-sensitivity C-reactive protein levels, and negatively and strongly correlated with insulin sensitivity. In a multivariate logistic regression analysis, higher serum PDIA4 concentration was observed to be significantly associated with an increased risk of T2DM. CONCLUSIONS: Our findings provide new mechanistic insights linking ER stress, T2DM, insulin sensitivity, and obesity, which may, in part, account for the ER chaperone properties associated with PDIA4. The results suggest that PDIA4 may serve as a potential instigator of and a putative therapeutic target for T2DM.
AIMS: Endoplasmic reticulum (ER) stress is associated with obesity and type 2 diabetes mellitus (T2DM) and increasing evidence demonstrates that some ER stress markers can represent the severity of metabolic dysfunction in either cellular or animal models. However, no appropriate molecule has been identified to demonstrate these relationships in clinical practice. METHODS: To determine whether the serum level of the ER chaperone, protein disulfide isomerase family A, member 4 (PDIA4), is associated with type 2 diabetes mellitus, obesity, and insulin sensitivity, we conducted a cross-sectional study for which a total of 553 adults, including 159 with normal glucose tolerance (NGT), 169 with prediabetes (Pre-DM), and 225 with newly diagnosed T2DM, were recruited. RESULTS: Serum PDIA4 levels were significantly higher in patients with T2DM than in those with NGT (P < 0.001), even after adjustment for potential confounders. These levels correlated positively with fasting plasma glucose, BMI, waist circumference as well as high-sensitivity C-reactive protein levels, and negatively and strongly correlated with insulin sensitivity. In a multivariate logistic regression analysis, higher serum PDIA4 concentration was observed to be significantly associated with an increased risk of T2DM. CONCLUSIONS: Our findings provide new mechanistic insights linking ER stress, T2DM, insulin sensitivity, and obesity, which may, in part, account for the ER chaperone properties associated with PDIA4. The results suggest that PDIA4 may serve as a potential instigator of and a putative therapeutic target for T2DM.
Authors: G Tufo; A W E Jones; Z Wang; J Hamelin; N Tajeddine; D D Esposti; C Martel; C Boursier; C Gallerne; C Migdal; C Lemaire; G Szabadkai; A Lemoine; G Kroemer; C Brenner Journal: Cell Death Differ Date: 2014-01-24 Impact factor: 15.828