Diabetes & Metabolism Journal

Original Articles

Basic and Translational Research
Construction of a Novel Secreted Protein Database and Identification of a New Adipokine CRELD2: Shu-Na Wang, Zhi-Yong Li, Qi-Sheng Ling, Peng-Fei Jing, Wen-Yu Liu, Yi-Jie Zhang, Xiu-Ping Zhang, Xi-Yuan Wang, Fu-Qiang Chang, Zhu-Wei Miao, Jing-Xin Zhao, Jin Chen, Chao-Yu Miao; Diabetes Metab J. 2025;49(5):1006-1023. Published online July 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0211

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Abstract PDF Supplementary Material PubReader ePub: Background
Secreted proteins may become therapeutic targets, drugs and biomarkers for aging and disease. This study aimed to establish a novel secreted protein database for adipose tissue under access to food ad libitum (AL) and caloric restriction (CR), and verify a novel adipokine.
Methods
Twelve rat chips were used for whole-genome expression in various adipose tissues from AL and CR rats, followed by bioinformatics analysis and experiments in mice, rats, and humans as well as in obesity and diabetes models.
Results
Adipose tissue expression profiles in rat different locations exhibited unique features, and enrichment analysis of differentially expressed genes between CR and AL groups showed CR effects on different adipose tissues. The 1,472 putative secreted proteins were identified, in which 200 genes were highly expressed, constructing a potential adipokines library. Cysteine rich with EGF like domains 2 (CRELD2, also named MESFATIN), whose gene was mesenteric adipose tissue specifically expressed and upregulated by CR in rat chips, was selected and verified as novel adipokine with proving its expression and secretion in in vivo mouse, rat and human and in vitro adipose tissue and adipocyte. CRELD2 secretion increased during adipocyte differentiation, and CRELD2 recombinant protein promoted adipogenesis. Although CRELD2 serum concentration showed no difference between wild-type mice and genetic ob/ob obesity mice or high fat diet induced obesity mice, CRELD2 expression decreased in white adipose tissues of ob/ob mice.
Conclusion
CRELD2 is a new adipokine involved in adipocyte differentiation and adipogenesis. A novel secreted protein database created from multiple adipose depots with CR intervention is helpful for future discovery and research of more secreted proteins.

Basic and Translational Research
Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage: Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao; Diabetes Metab J. 2025;49(2):210-224. Published online November 6, 2024; DOI: https://doi.org/10.4093/dmj.2024.0099

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Background
Diabetes-induced testicular damage (DITD) is a common complication of diabetes. We investigated underlying mechanism of retinoblastoma-binding protein 6 (Rbbp6)-mediated brain and muscle ARNT-like 1 (Bmal1) ubiquitination in modulating ferroptosis in DITD.
Methods
Spermatogenic cell apoptosis and viability were measured by flow cytometry and cell counting kit 8 (CCK-8), respectively. The impact of Rbbp6 and Bmal1 on ferroptosis was assessed by determining expression of ferroptosis markers glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11), and levels of malondialdehyde (MDA), glutathione (GSH), iron, and lipid peroxidation. Co-immunoprecipitation was performed to determine the interaction between Rbbp6 and Bmal1, as well as the ubiquitination level of Bmal1. The expression levels of Rbbp6, Bmal1, Yes-associated protein 1 (YAP1), ferroptosis markers, and testicular steroidogenic enzymes were tested by Western blot.
Results
Bmal1 protein expression was significantly downregulated, while Rbbp6 was upregulated in DITD mouse model and high glucose (HG)-induced GC-1 spg cells. Overexpression of Bmal1 improved testicular injury in diabetic mice, reduced 4-hydroxynonenal (4-HNE), MDA, iron levels, and increased expression levels of GPX4, SLC7A11, GSH, as well as testicular steroidogenic enzymes. Rbbp6 decreased Bmal1 level through promoting its ubiquitination. Meanwhile, Rbbp6 knockdown inhibited the ferroptosis of HG-induced GC-1 spg cells, which were abolished by silencing Bmal1. In addition, knockdown of YAP1 or treatment with ferroptosis inducer erastin blocked the above effects caused by Bmal1 overexpression.
Conclusion
Rbbp6-mediated Bmal1 ubiquitination suppressed YAP1 pathway, promoting ferroptosis in DITD. This study highlighted Rbbp6/Bmal1/YAP1 axis as a potential therapeutic target for mitigating DITD.

Citations

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Melatonin‐engineered MSCs‐exosomes deliver USP4 to stabilise ARNTL and inhibit clock rhythmic ferroptosis for enhanced flap survival
Xiaoqiong Jiang, Yu Wang, Xuanlong Zhang, Huiming Deng, Liangyu Fang, Chaire Tafadzwa, Jiangnan Yao, Hao Chen, Anqi Ye, Kailiang Zhou, Xiangwei Ling, Jian Xiao
Clinical and Translational Medicine.2026;[Epub] CrossRef
GALNT3-mediated AKT1 glycosylation activates the AKT1/CREB signaling pathway to inhibit high glucose-induced spermatogenic cell apoptosis and mitochondrial dysfunction
Yong Zhao, Jia Luo, Lu Wu
Biochemical and Biophysical Research Communications.2026; 802: 153329. CrossRef
Resveratrol attenuates high-fat diet-induced testicular injury via the NRF2/GPX4 pathway: an integrated metabolomics and network pharmacology study
Yating Lai, Yuanyuan Wang, Wei Zeng, Jiayu Zhang, Jiamin Cao, Mengjia Sun, Hongxue Liang, Zhongxiang Zhao, Jing Jin
Food & Function.2026;[Epub] CrossRef
METTL14 Aggravates Sepsis‐Induced Acute Kidney Injury by Promoting Ferroptosis Through m6A Modification of BMAL1
Yishu Wang, Yang Li, Na Wu, Xinyue Xu, Xiaoxuan Fan, Haifeng Wang
Clinical and Experimental Pharmacology and Physiology.2026;[Epub] CrossRef
Guilu Erxian glue mitigates spermatogenesis dysfunction through HIF-1α/SLC7A11-mediated ferroptosis inhibition: An integrated metabolomics and network pharmacology study
Chuying Tang, Wen Sheng, Xianrui Li, Wei Fu, Meixin Lin, Zheng Wen, Wei Luo, Zezheng Zhang, Qingxia Zheng, Xing Zhou, Jin Ding
Phytomedicine.2025; 148: 157321. CrossRef

Basic Research
PDZD8 Augments Endoplasmic Reticulum-Mitochondria Contact and Regulates Ca²⁺ Dynamics and Cypd Expression to Induce Pancreatic β-Cell Death during Diabetes: Yongxin Liu, Yongqing Wei, Xiaolong Jin, Hongyu Cai, Qianqian Chen, Xiujuan Zhang; Diabetes Metab J. 2024;48(6):1058-1072. Published online July 29, 2024; DOI: https://doi.org/10.4093/dmj.2023.0275

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Background
Diabetes mellitus (DM) is a chronic metabolic disease that poses serious threats to human physical and mental health worldwide. The PDZ domain-containing 8 (PDZD8) protein mediates mitochondria-associated endoplasmic reticulum (ER) membrane (MAM) formation in mammals. We explored the role of PDZD8 in DM and investigated its potential mechanism of action.
Methods
High-fat diet (HFD)- and streptozotocin-induced mouse DM and palmitic acid (PA)-induced insulin 1 (INS-1) cell models were constructed. PDZD8 expression was detected using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting. MAM formation, interactions between voltage-dependent anion-selective channel 1 (VDAC1) and inositol 1,4,5-triphosphate receptor type 1 (IP3R1), pancreatic β-cell apoptosis and proliferation were detected using transmission electron microscopy (TEM), proximity ligation assay (PLA), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunofluorescence staining, and Western blotting. The mitochondrial membrane potential, cell apoptosis, cytotoxicity, and subcellular Ca²⁺ localization in INS-1 cells were detected using a JC-1 probe, flow cytometry, and an lactate dehydrogenase kit.
Results
PDZD8 expression was up-regulated in the islets of HFD mice and PA-treated pancreatic β-cells. PDZD8 knockdown markedly shortened MAM perimeter, suppressed the expression of MAM-related proteins IP3R1, glucose-regulated protein 75 (GRP75), and VDAC1, inhibited the interaction between VDAC1 and IP3R1, alleviated mitochondrial dysfunction and ER stress, reduced the expression of ER stress-related proteins, and decreased apoptosis while increased proliferation of pancreatic β-cells. Additionally, PDZD8 knockdown alleviated Ca²⁺ flow into the mitochondria and decreased cyclophilin D (Cypd) expression. Cypd overexpression alleviated the promoting effect of PDZD8 knockdown on the apoptosis of β-cells.
Conclusion
PDZD8 knockdown inhibited pancreatic β-cell death in DM by alleviated ER-mitochondria contact and the flow of Ca²⁺ into the mitochondria.

Citations

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Aerobic Training Modulates the Expression of Components of the mPTP Through the Reduction of Oxidative Stress in the Soleus Muscle of Streptozotocin-Induced Diabetic Rats
Luis Alberto Sánchez-Briones, Sarai Sánchez-Duarte, Sergio Márquez-Gamiño, Karla Susana Vera-Delgado, Montserrat Guadalupe Vera-Delgado, Rocío Montoya-Pérez, Cipriana Caudillo-Cisneros, Elizabeth Sánchez-Duarte
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Cornuside as a promising therapeutic agent for diabetic kidney disease: Targeting regulation of Ca2+ disorder-mediated renal tubular epithelial cells apoptosis
Gai Gao, Xuan Su, Shuyan Liu, Pan Wang, Jenny Jie Chen, Tongxiang Liu, Jiangyan Xu, Zhenqiang Zhang, Xiaowei Zhang, Zhishen Xie
International Immunopharmacology.2025; 149: 114190. CrossRef
Autistic behavior is a common outcome of biallelic disruption of PDZD8 in humans and mice
Andreea D. Pantiru, Stijn Van de Sompele, Clemence Ligneul, Camille Chatelain, Christophe Barrea, Jason P. Lerch, Beatrice M. Filippi, Serpil Alkan, Elfride De Baere, Jamie Johnston, Steven J. Clapcote
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Mitochondrial complexity is regulated at ER-mitochondria contact sites via PDZD8-FKBP8 tethering
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Nature Communications.2025;[Epub] CrossRef
Mitochondria‐Associated Endoplasmic Reticulum Membranes in Human Health and Diseases
Yong Liu, Zi‐Hui Mao, Junwen Huang, Hui Wang, Xiao Zhang, Xin Zhou, Yue Xu, Shaokang Pan, Dongwei Liu, Zhangsuo Liu, Qi Feng
MedComm.2025;[Epub] CrossRef
Inhibition of STING-induced mitochondrial Drp1/N-GSDMD-mediated MtDNA release alleviates Sepsis-induced lung injury
Shishi Zou, Yifan Zuo, Yukai Chen, Tianyu Zhang, Tinglv Fu, Guorui Li, Rui Xiong, Bohao Liu, Yong Hu, Zhaoyu Hu, Chunguang Miao, Xiaojing Wu, Ning Li, Qing Geng
Cellular and Molecular Life Sciences.2025;[Epub] CrossRef
Tanshinone IIA ameliorates pancreatic injury in type 2 diabetic mice by modulating inflammation and endoplasmic reticulum stress via the IL-6/JAK2/STAT3 pathway
Yingfeng Li, Desheng Wang, Yuhang Liu, Chenyang Liu, Meixi Chen, Jingqi Li, Zunqiu Wu, Ning Wu
Functional & Integrative Genomics.2025;[Epub] CrossRef
Mitochondrial integrations in pancreatic acinar cells: inter-organelle interaction as a key factor in the pathogenesis of acute pancreatitis
S.M. Chooklin, S.S. Chuklin, R.V. Barylyak
GASTROENTEROLOGY.2025; 59(4): 289. CrossRef

Basic Research
Role of SUMO-Specific Protease 2 in Leptin-Induced Fatty Acid Metabolism in White Adipocytes: Praise Chanmee Kim, Ji Seon Lee, Sung Soo Chung, Kyong Soo Park; Diabetes Metab J. 2023;47(3):382-393. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0156

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Background
Leptin is a 16-kDa fat-derived hormone with a primary role in controlling adipose tissue levels. Leptin increases fatty acid oxidation (FAO) acutely through adenosine monophosphate-activated protein kinase (AMPK) and on delay through the SUMO-specific protease 2 (SENP2)–peroxisome proliferator-activated receptor δ/γ (PPARδ/γ) pathway in skeletal muscle. Leptin also directly increases FAO and decreases lipogenesis in adipocytes; however, the mechanism behind these effects remains unknown. Here, we investigated the role of SENP2 in the regulation of fatty acid metabolism by leptin in adipocytes and white adipose tissues.
Methods
The effects of leptin mediated by SENP2 on fatty acid metabolism were tested by siRNA-mediated knockdown in 3T3-L1 adipocytes. The role of SENP2 was confirmed in vivo using adipocyte-specific Senp2 knockout (Senp2-aKO) mice. We revealed the molecular mechanism involved in the leptin-induced transcriptional regulation of carnitine palmitoyl transferase 1b (Cpt1b) and long-chain acyl-coenzyme A synthetase 1 (Acsl1) using transfection/reporter assays and chromatin immunoprecipitation.
Results
SENP2 mediated the increased expression of FAO-associated enzymes, CPT1b and ACSL1, which peaked 24 hours after leptin treatment in adipocytes. In contrast, leptin stimulated FAO through AMPK during the initial several hours after treatment. In white adipose tissues, FAO and mRNA levels of Cpt1b and Acsl1 were increased by 2-fold 24 hours after leptin injection in control mice but not in Senp2-aKO mice. Leptin increased PPARα binding to the Cpt1b and Acsl1 promoters in adipocytes through SENP2.
Conclusion
These results suggest that the SENP2-PPARα pathway plays an important role in leptin-induced FAO in white adipocytes.

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Intermittent cold stimulation affects energy metabolism and improves stress resistance in broiler heart
Tingting Li, Haidong Wei, Shijie Zhang, Xiaotao Liu, Lu Xing, Yuanyuan Liu, Rixin Gong, Jianhong Li
Poultry Science.2024; 103(1): 103190. CrossRef

Review

Basic Research
Role of CRTC2 in Metabolic Homeostasis: Key Regulator of Whole-Body Energy Metabolism?: Hye-Sook Han, Yongmin Kwon, Seung-Hoi Koo; Diabetes Metab J. 2020;44(4):498-508. Published online March 5, 2020; DOI: https://doi.org/10.4093/dmj.2019.0200

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Cyclic adenosine monophosphate (cAMP) signaling is critical for regulating metabolic homeostasis in mammals. In particular, transcriptional regulation by cAMP response element-binding protein (CREB) and its coactivator, CREB-regulated transcription coactivator (CRTC), is essential for controlling the expression of critical enzymes in the metabolic process, leading to more chronic changes in metabolic flux. Among the CRTC isoforms, CRTC2 is predominantly expressed in peripheral tissues and has been shown to be associated with various metabolic pathways in tissue-specific manners. While initial reports showed the physiological role of CRTC2 in regulating gluconeogenesis in the liver, recent studies have further delineated the role of this transcriptional coactivator in the regulation of glucose and lipid metabolism in various tissues, including the liver, pancreatic islets, endocrine tissues of the small intestines, and adipose tissues. In this review, we discuss recent studies that have utilized knockout mouse models to delineate the role of CRTC2 in the regulation of metabolic homeostasis.

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Original Article

Pathophysiology
Essential Role of Protein Arginine Methyltransferase 1 in Pancreas Development by Regulating Protein Stability of Neurogenin 3: Kanghoon Lee, Hyunki Kim, Joonyub Lee, Chang-Myung Oh, Heein Song, Hyeongseok Kim, Seung-Hoi Koo, Junguee Lee, Ajin Lim, Hail Kim; Diabetes Metab J. 2019;43(5):649-658. Published online April 8, 2019; DOI: https://doi.org/10.4093/dmj.2018.0232

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Background

Protein arginine methyltransferase 1 (PRMT1) is a major enzyme responsible for the formation of methylarginine in mammalian cells. Recent studies have revealed that PRMT1 plays important roles in the development of various tissues. However, its role in pancreas development has not yet been elucidated.

Methods

Pancreatic progenitor cell-specific Prmt1 knock-out (Prmt1 PKO) mice were generated and characterized for their metabolic and histological phenotypes and their levels of Neurog3 gene expression and neurogenin 3 (NGN3) protein expression. Protein degradation assays were performed in mPAC cells.

Results

Prmt1 PKO mice showed growth retardation and a severely diabetic phenotype. The pancreatic size and β-cell mass were significantly reduced in Prmt1 PKO mice. Proliferation of progenitor cells during the secondary transition was decreased and endocrine cell differentiation was impaired. These defects in pancreas development could be attributed to the sustained expression of NGN3 in progenitor cells. Protein degradation assays in mPAC cells revealed that PRMT1 was required for the rapid degradation of NGN3.

Conclusion

PRMT1 critically contributes to pancreas development by destabilizing the NGN3 protein.

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Arginine 65 methylation of Neurogenin 3 by PRMT1 is required for pancreatic endocrine development of hESCs
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Arginine 65 Methylation of Neurogenin 3 by PRMT1 Is Required for Pancreatic Endocrine Development of hESCs
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Sahar Waseem, Sudeep Kumar, Kanghoon Lee, Byoung-Ha Yoon, Mirang Kim, Hail Kim, Keesook Lee
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Review

Glycosphingolipid Modification: Structural Diversity, Functional and Mechanistic Integration of Diabetes: Tadashi Yamashita; Diabetes Metab J. 2011;35(4):309-316. Published online August 31, 2011; DOI: https://doi.org/10.4093/dmj.2011.35.4.309

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Glycosphingolipids (GSLs) are present in all mammalian cell plasma membranes and intracellular membrane structures. They are especially concentrated in plasma membrane lipid domains that are specialized for cell signaling. Plasma membranes have typical structures called rafts and caveola domain structures, with large amounts of sphingolipids, cholesterol, and sphingomyelin. GSLs are usually observed in many organs ubiquitously. However, GSLs, including over 400 derivatives, participate in diverse cellular functions. Several studies indicate that GSLs might have an effect on signal transduction related to insulin receptors and epidermal growth factor receptors. GSLs may modulate immune responses by transmitting signals from the exterior to the interior of the cell. Guillain-Barré syndrome is one of the autoimmune disorders characterized by symmetrical weakness in the muscles of the legs. The targets of the immune response are thought to be gangliosides, which are one group of GSLs. Other GSLs may serve as second messengers in several signaling pathways that are important to cell survival or programmed cell death. In the search for clear evidence that GSLs may play critical roles in various biological functions, many researchers have made genetically engineered mice. Before the era of gene manipulation, spontaneous animal models or chemical-induced disease models were used.

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Original Articles

Effect of Mouse Type and Human Type of CpG Oligonucleotide Vaccination on Development of Diabetes in NOD Mice.: Byong Jun Lee, Soo Kie Kim, Eon Sub Park, Hyun Jin Jang, Hyun Chul Cho, Myung Sook Shim, Mi Jin Kim, Young Goo Shin, Choon Hee Chung; Korean Diabetes J. 2002;26(6):451-459. Published online December 1, 2002

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Abstract PDF: BACKGROUND
Type 1 diabetes is autoimmune disease and the modulation of immune system could offer breakthrough to the disease. Unmethylated CpG motifs and their oligoneucleotide are potent immunostimulators that can rebalance autoimmune mechanism. To explore DNA based immunotherapy in type 1 diabetes, we vaccinated different types (mouse and human) of CpG ODN to NOD mice. METHODS: Forty 5 week-old female NOD mice were injected with 100 L (10 g) of mouse type CpG ODN or human type CpG ODN or 0.9% normal saline on inguinal area subcutaneously. Seven, 14, and 28 days later we injected to mice same dose of mouse type CpG ODN or human type CpG ODN or normal saline. Blood glucose was measured and mice were sacrificed when they were diabetic. Pancreata and serum were earned from sacrificed NOD mice to evaluate insulitis and insulin immunoassay. RESULTS: Though the final cumulative incidences of diabetes were not significantly different among groups, the tendency of delaying and suppressing the development of diabetes was observed in the early period of vaccination group of CpG ODN. Especially, mouse type CpG ODN was more effective for rodent species than human type CpG ODN. CONCLUSION: This result suggests that immunomodulation therapy using species- specific CpG motif may have a potential to control autoimmune process as well as dissecting T cell milieu in NOD mice.

Distinct Pattern of GAD65 and GAD67 Gene Expression in the Pancreas of NOD Mouse.: In Young Ko, Yup Kang; Korean Diabetes J. 1997;21(3):243-253. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Glutamic acid decarboxylase(GAD; EC 4.1.1.15), one of the major B-cell autoantigens in IDDM, is an enzyme which catalyzes the synthesis of major inhibitory neurotransmitter, r-aminobutyric acid (GARA), in the mammalian brain, pancreas and other organs. Two isoforms of GAD, GAD65 and GAD67, have been identified which differ in their intracellular localization. Autoantibodies to GAD have been detected several years before the clinical onset of IDDM, implicating GAD as a leading autoantigen which somehow correlated with the pathogenesis of IDDM. We have determined the characteristics of GAD isoform expression in the pancreas of NOD mouse, an animal model extensively employed in IDDM study, using RT-PCR and Southern blot methods. METHODS: Pancreas was obtained from female NOD mouse(neonate, 4, 8, 12, 16, 20 week-old) and age-matched female ICR mouse. Total cellular RNA was I.solated by acid guanidinium thiocyanate method and employed in the RT-PCR amplification using GAD65- and GAD67-specific primer designed in our laboratory. The PCR product was blotted onto the nylon membrane and subjected to Southern analysis using 32P-ATP labelled hybridization probe. RESULTS: In NOD pancreas, GAD67 was expressed six times higher than GAD65 at neonatal stage. Then, the expression was dramatically decreased from 4 weeks when the pancreatic insulitis begins to occur. After 12 weeks of age, both GAD67 and GAD65 expression was almost undetectable. However, in control ICR mouse, there were no significant differenees between GAD65 and GAD67 expression throughout the ages. And, the expression of both GAD65 and OAD67 was not decreased with ages in contrast to NOD mouse. CONCLUSION: In this experiment, we found that the expression of GAD isoforms in NOD mouse shows distinct pattern in comparison to that of control ICR mouse. The expression of GAD67 was significantly higher than GAD65 in neonatal NOD mouse while, in control ICR mouse, same level of GAD isoforrns expression was observed. This finding clearly suggested the possibility that the expression of GAD isoforms in diabetic NOD mouse is quite distinct and may somehow play a role in the pathogenesis of diabetes although the precise mechanism remains to be unveiled. In addition, our data also supported the hypothesis that expressional pattern, and, if possible, ' the etiophysiological function of GAD isoforms in NOD mouse pancreas may be quite different from that in human pancreas.

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