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Ming Zhu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Bingxin Xu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Meng Wang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Shangyun Liu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Yue Zhang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Chao Zhang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Melanocortin receptors (MCRs) and their accessory proteins (MRAPs) evolutionarily first appear in the genome of sea lamprey. The most ancient melanocortin system consists of only two melanocortin receptors (slMCa and slMCb) and one MRAP2 (slMRAP2) protein, but the physiological roles have not been fully explored in this primitive species. Here, we synthesize and characterize the pharmacological features of slMRAP2 protein on two slMCRs. Our results show that the slMRAP2 protein lacks the long carboxyl terminus; it directly interacts and decreases the surface expression but enhances the α-MSH-induced agonism of slMCa and slMCb. In comparison with higher organisms such as elephant shark and zebrafish, we also demonstrate the constantly evolving regulatory function of the carboxyl terminus of MRAP2 protein, the unique antiparallel topology of slMRAP2 dimer and the homo- and hetero-dimerization of two slMCRs. This study elucidates the presence and modulation of melanocortin receptor by the accessory protein of the agnathans for the first time, which provides a better insight of the melanocortin system in ancient species of chordates.

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Qiuyu Huang Department of Cardiovascular Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, Fujian Province, China

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Hanshen Chen Department of Anesthesiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian Province, China

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Fan Xu Department of Cardiovascular Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, Fujian Province, China

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Chao Liu Department of Cardiothoracic Surgery, Affiliated People’s Hospital of Jiangsu University, Zhenjiang, Jiangsu Province, China

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Yafeng Wang Department of Cardiology, The People’s Hospital of Xishuangbanna Dai Autonomous Prefecture, Jinghong, Yunnan Province, China

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Weifeng Tang Department of Cardiothoracic Surgery, Nanjing Drum Tower Hospital, Nanjing University Medical School, Jiangsu Province, China

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Liangwan Chen Department of Cardiovascular Surgery, Union Hospital, Fujian Medical University, Fuzhou, Fujian Province, China
Key Laboratory of Cardio-Thoracic Surgery (Fujian Medical University), Fujian Province University, Fuzhou, Fujian Province, China

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Type 2 diabetes mellitus (T2DM) is considered as a metabolic disease with hyperglycemia. Accumulating investigations have explored the important role of hereditary factors for T2DM occurrence. Some functional microRNA (miR) polymorphisms may affect their interactions with target mRNAs and result in an aberrant expression. Thus, miR variants might be considered as a biomarker of the susceptibility of T2DM. In this study, we recruited 502 T2DM cases and 782 healthy subjects. We selected miR-146a rs2910164 C>G, miR-196a2 rs11614913 T>C and miR-499 rs3746444 A>G loci and carried out an investigation to identify whether these miR loci could influence T2DM occurrence. In this investigation, a Bonferroni correction was harnessed. After adjustment, we found that rs2910164 SNP was a protective factor for T2DM (GG vs CC/CG: adjusted P = 0.010), especially in never drinking (GG vs CC/CG: adjusted P = 0.001) and BMI ≥24 kg/m2 (GG vs CC/CG: adjusted P = 0.002) subgroups. We also identified that rs11614913 SNP was a protective factor for T2DM in smoking subjects (CC/TC vs TT: adjusted P = 0.002). When we analyzed an interaction of SNP–SNP with the susceptibility tof T2DM, rs11614913/rs3746444, rs2910164/rs3746444 and rs11614913/rs2910164 combinations were not associated with the risk of T2DM. In summary, this study highlights that rs2910164 SNP decreases the susceptibility of T2DM, especially in BMI ≥24 kg/m2 and never drinking subgroups. In addition, we also identify that rs11614913 C allele decreases the susceptibility of T2DM significantly in smoking subgroup.

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Chao Xu Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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Xiang-Fei Li Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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Hong-Yan Tian Department of Ocean Technology, College of Marine and Biology Engineering, Yancheng Institute of Technology, Yancheng, Province Jiangsu, China

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Hua-Juan Shi Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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Ding-Dong Zhang Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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Kenneth Prudence Abasubong Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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Wen-Bin Liu Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, China

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After a 12-week feeding trial, the glucose tolerance test was performed in Megalobrama amblycephala to evaluate the effects of metformin on the metabolic responses of glycolipids. Plasma insulin peaked at 2 h, then decreased to the basal value at 8–12 h post-injection. Plasma triglyceride levels and liver glycogen contents of the control group was decreased significantly during the first 2 and 1 h, respectively. Then, they returned to basal values at 12 h. During the whole sampling period, the high-carbohydrate groups had significantly higher levels of plasma metabolites and liver glycogen than those of the control group, and metformin supplementation enhanced these changes (except insulin levels). Glucose administration lowered the transcriptions of ampk α1, ampk α2, pepck, g6pase, fbpase, cpt IA and aco, the phosphorylation of Ampk α and the activities of the gluconeogenic enzymes during the first 2–4 h, while the opposite was true of glut 2, gs, gk, pk, accα and fas. High-carbohydrate diets significantly increased the transcriptions of ampk α1, ampk α2, glut 2, gs, gk, pk, accα and fas, the phosphorylation of Ampk α and the activities of the glycolytic enzymes during the whole sampling period, while the opposite was true for the remaining indicators. Furthermore, metformin significantly upregulated the aforementioned indicators (except accα and fas) and the transcriptions of cpt IA and aco. Overall, metformin benefits the glucose homeostasis of Megalobrama amblycephala fed high-carbohydrate diets through the activation of Ampk and the stimulation of glycolysis, glycogenesis and fatty acid oxidation, while depressing gluconeogenesis and lipogenesis.

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Ya Zhang Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Xiaoqiu Chu Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Yuling Liu Department of Endocrinology, Zaozhuang Municipal Hospital, Zaozhuang, China

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Yueting Zhao Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Xue Han Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Xin Hu Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Pingping Xiang Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
Key Laboratory of TCM Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Guofang Chen Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
Key Laboratory of TCM Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Chao Liu Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
Key Laboratory of TCM Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Shuhang Xu Endocrine and Diabetes Center, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Objective

To compare the efficacy and safety of ethanol ablation (EA) and microwave ablation (MWA) in the treatment of cystic or predominantly cystic thyroid nodules.

Methods

Patients with cystic or predominantly cystic thyroid nodules intervened with EA or MWA were retrospectively enrolled and divided into EA group (n  = 30) and MWA group (n  = 31). The volume and volume reduction rate (VRR) of thyroid nodules before ablation, and at 3 and 12 months after ablation were compared between the two groups. The effective rate (ER) and incidence of adverse events in both groups were recorded.

Results

The median VRR and ER at 3 months after ablation were significantly higher in EA group than in MWA group (81.30% vs 75.76%, P = 0.011; 76.67% (23/30) vs 51.61% (16/31), P = 0.040), while no significant difference was detected at 12 months (93.39% vs 88.78%, P = 0.141; 86.67% (26/30) vs 87.10% (27/31), P = 0.960). The median VRR of small nodules in EA group was significantly higher than that in MWA group (81.30% vs 71.18%, P = 0.006; 93.40% vs 83.14%, P = 0.032). There was no significant difference of median VRR in medium nodules at final follow-up between MWA and EA group (93.01% vs 89.68%, P = 0.482). Serious adverse events were not reported in both groups.

Conclusion

EA and MWA are both effective and safe in the treatment of cystic or predominantly cystic thyroid nodules. EA is more cost-effective and effective than MWA for small nodules, but it requires more cycles of treatment and may pose a higher risk of postoperative pain compared with MWA.

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Yujie Ren Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Xue Han Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Yujiang Li Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Guofang Chen Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
Key Laboratory of TCM Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Lin Jiang Department of Endocrinology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China

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Chao Liu Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China
Key Laboratory of TCM Syndrome and Treatment of Yingbing (Thyroid Disease) of State Administration of Traditional Chinese Medicine, Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Shuhang Xu Endocrine and Diabetes Center, The Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, China
Jiangsu Province Academy of Traditional Chinese Medicine, Nanjing, China

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Objective

To assess the long-term efficacy and safety of microwave ablation (MWA) in treating low-risk papillary thyroid microcarcinomas (PTMC) and to identify predictive factors for the postoperative local tumor progression of PTMC.

Methods

A total of 154 low-risk PTMC patients treated with MWA who were followed up for at least 3 months were retrospectively recruited. Ultrasonography was performed after MWA to assess the local tumor progression. Adverse events associated with MWA were recorded. The ablated volume (Va) and initial ablation ratio (IAR) were measured to assess their influences on the recurrence risk of PTMC.

Results

The mean tumor volume of PTMC before MWA was 0.071 (0.039, 0.121) cm3, with a maximum diameter of 0.60 ± 0.18 cm. All PTMC patients were followed up for 6 (3, 18) months. Va increased immediately after MWA, then gradually decreased over time, till significantly smaller at 12 months than that before MWA (P < 0.05). The median volume reduction ratio at 24 months reached 100%, which was maintained during a 60-month follow-up. A total of 7 (4.55%) cases of local tumor progression were recorded during the follow-up. Kaplan–Meier survival analysis revealed that the rate of local tumor progression was significantly lower in PTMC patients with a maximum tumor diameter < 0.70 cm than in those with ≥0.70 cm (P = 0.031). A significant better prognosis was achieved in PTMC patients with IAR ≥ 15 than in those with IAR < 15 (P = 0.015). Sex, age (<55 years) and preoperative thyroid-stimulating hormone (>2.0 mU/L) of PTMC patients were not correlated with local tumor progression.

Conclusion

MWA is an effective therapeutic strategy for low-risk PTMC with high safety. The maximum tumor diameter and IAR are predictive factors for the local tumor progression of PTMC after MWA.

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Ying Xu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Lei Li Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Jihong Zheng Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Meng Wang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Bopei Jiang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Yue Zhai Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Liumei Lu Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Cong Zhang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Zhe Kuang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Xiaomei Yang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Li-Na Jin Department of Hematology, Changzheng Hospital, Naval Medical University, Shanghai, China

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Gufa Lin Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China
Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Orthopaedic Department of Tongji Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, China

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Chao Zhang Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, China

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As a member of the seven-transmembrane rhodopsin-like G protein-coupled receptor superfamily, the melanocortin-3 receptor (MC3R) is vital for the regulation of energy homeostasis and rhythms synchronizing in mammals, and its pharmacological effect could be directly influenced by the presence of melanocortin receptor accessory proteins (MRAPs), MRAP1 and MRAP2. The tetrapod amphibian Xenopus laevis (xl) retains higher duplicated genome than extant teleosts and serves as an ideal model system for embryonic development and physiological studies. However, the melanocortin system of the Xenopus laevis has not yet been thoroughly evaluated. In this work, we performed sequence alignment, phylogenetic tree, and synteny analysis of two xlMC3Rs. Co-immunoprecipitation and immunofluorescence assay further confirmed the co-localization and in vitro interaction of xlMC3Rs with xlMRAPs on the plasma membrane. Our results demonstrated that xlMRAP2.L/S could improve α-MSH-stimulated xlMC3Rs signaling and suppress their surface expression. Moreover, xlMC3R.L showed a similar profile on the ligands and surface expression in the presence of xlMRAP1.L. Overall, the distinct pharmacological modulation of xlMC3R.L and xlMC3R.S by dual MRAP2 proteins elucidated the functional consistency of melanocortin system during genomic duplication of tetrapod vertebrates.

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Hui-qing Yuan Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Jia-xi Miao Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Jia-ping Xu Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Su-xiang Zhu Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Feng Xu Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Xiao-hua Wang Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Chun-hua Wang Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Chao Yu Department of Clinical Laboratory, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Xue-qin Wang Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Jian-bin Su Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Dong-mei Zhang Medical Research Center, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, Nantong, China

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Background

Increased serum cystatin C (CysC) can predict the onset of type 2 diabetes (T2D). Meanwhile, impaired pancreatic α- and β-cell functions get involved in the pathophysiological processes of T2D. So this study was to explore the relationships between serum CysC levels and pancreatic α- and β-cell functions in T2D.

Methods

In this cross-sectional observational study, a total of 2634 patients with T2D were consecutively recruited. Each recruited patient received a serum CysC test and oral glucose tolerance test for synchronous detection of serum C-peptide and plasma glucagon. As components of pancreatic β-cell function, insulin secretion and sensitivity indices were evaluated by C-peptide area under the curve (AUC-CP) and C-peptide-substituted Matsuda’s index (Matsuda-CP), respectively. Fasting glucagon (F-GLA) and post-challenge glucagon calculated by glucagon area under the curve (AUC-GLA) were used to assess pancreatic α-cell function. These skewed indices and were further natural log-transformed (ln).

Results

With quartiles of serum CysC levels ascending, AUC-CP, F-GLA and AUC-GLA were increased, while Matsuda-CP was decreased (P for trend <0.001). Moreover, serum CysC levels were positively related to lnAUC-CP, lnF-GLA and lnAUC-GLA (r= 0.241, 0.131 and 0.208, respectively, P < 0.001), and inversely related to lnMatsuda-CP (r= –0.195, P  < 0.001). Furthermore, after controlling for other relevant variables via multivariable linear regression analysis, serum CysC levels were identified to account for lnAUC-CP (β= 0.178, t= 10.518, P  < 0.001), lnMatsuda-CP (β= –0.137, t= –7.118, P  < 0.001), lnF-GLA (β= 0.049, t= 2.263, P = 0.024) and lnAUC-GLA (β= 0.121, t= 5.730, P  < 0.001).

Conclusions

Increased serum CysC levels may be partly responsible for increased insulin secretion from β-cells, decreased systemic insulin sensitivity, and elevated fasting and postprandial glucagon secretion from α-cells in T2D.

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Chengnan Guo Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yixi Xu Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yange Ma Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Xin Xu Wenzhou Medical University, Wenzhou, Zhejiang, China

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Fang Peng Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Hui-hui Li Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Dongzhen Jin Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Shu-zhen Zhao Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Zhezheng Xia Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Mengyuan Lai Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Mingzhu Che Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Ruogu Huang Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Yanan Wang Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China

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Depeng Jiang Department of Community Health Sciences, College of Medicine, University of Manitoba, Winnipeg, Canada

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Chao Zheng The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

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Guangyun Mao Division of Epidemiology and Health Statistics, Department of Preventive Medicine, School of Public Health & Management, Wenzhou Medical University, Wenzhou, Zhejiang, China
Eye Hospital and School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China
National Clinical Research Center for Ocular Diseases, Wenzhou, Zhejiang, China

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Although previous studies demonstrate that trehalose can help maintain glucose homeostasis in healthy humans, its role and joint effect with glutamate on diabetic retinopathy (DR) remain unclear. We aimed to comprehensively quantify the associations of trehalose and glutamate with DR. This study included 69 pairs of DR and matched type 2 diabetic (T2D) patients. Serum trehalose and glutamate were determined via ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry system. Covariates were collected by a standardized questionnaire, clinical examinations and laboratory assessments. Individual and joint association of trehalose and glutamate with DR were quantified by multiple conditional logistic regression models. The adjusted odds of DR averagely decreased by 86% (odds ratio (OR): 0.14; 95% CI: 0.06, 0.33) with per interquartile range increase of trehalose. Comparing with the lowest quartile, adjusted OR (95% CI) were 0.20 (0.05, 0.83), 0.14 (0.03, 0.63) and 0.01 (<0.01, 0.05) for participants in the second, third and fourth quartiles of trehalose, respectively. In addition, as compared to their counterparts, T2D patients with lower trehalose (<median) and higher glutamate (≥median) had the highest odds of DR (OR: 36.81; 95% CI: 6.75, 200.61). An apparent super-multiplicative effect of trehalose and glutamate on DR was observed, whereas relative excess risk due to interaction was not significant. The study suggests that trehalose is beneficial to inhibit the occurrence of DR and synergistically decreases the risk of DR with reduced glutamate. Our findings also provide new insights into the mechanisms of DR and further longitudinal studies are required to confirm these findings.

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Peng Fan Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Chao-Xia Lu McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Di Zhang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Kun-Qi Yang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Pei-Pei Lu Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Ying Zhang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Xu Meng Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Su-Fang Hao Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Fang Luo Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Ya-Xin Liu Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Hui-Min Zhang Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Lei Song Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Jun Cai Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Xue Zhang McKusick-Zhang Center for Genetic Medicine, State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Xian-Liang Zhou Department of Cardiology, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

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Liddle syndrome (LS), a monogenetic autosomal dominant disorder, is mainly characterized by early-onset hypertension and hypokalemia. Clinically, misdiagnosis or missing diagnosis is common, since clinical phenotypes of LS are variable and nonspecific. We report a family with misdiagnosis of primary aldosteronism (PA), but identify as LS with a pathogenic frameshift mutation of the epithelial sodium channel (ENaC) β subunit. DNA samples were collected from a 32-year-old proband and 31 other relatives in the same family. A designed panel including 41 genes associated with monogenic hypertension was screened using next-generation sequencing. The best candidate disease-causing variants were verified by Sanger sequencing. Genetic analysis of the proband revealed a novel frameshift mutation c.1838delC (p.Pro613Glnfs*675) in exon 13 of SCNN1B. This heterozygous mutation involved the deletion of a cytosine from a string of three consecutive cytosines located at codons 612 to 613 and resulted in deletion of the crucial PY motif and elongation of the β-ENaC protein. The identical mutation was also found in 12 affected family members. Amiloride was effective in alleviating LS for patients. There were no SCNN1A or SCNN1G mutations in this family. Our study emphasizes the importance of considering LS in the differential diagnosis of early-onset hypertension. The identification of a novel frameshift mutation of SCNN1B enriches the genetic spectrum of LS and has allowed treatment of this affected family to prevent severe complications.

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