丝胶调控胰腺INS/NPY/FDX1表达改善T2DM小鼠糖代谢紊乱

Sericin regulates pancreatic INS/NPY/FDX1 expression to improve glucose metabolic disorder in mice with T2DM

摘要

目的 探讨丝胶是否通过调控胰腺INS/NPY/FDX1表达改善2型糖尿病（T2DM）模型小鼠糖代谢紊乱。方法 雄性C57BL/6小鼠随机分为对照组、T2DM模型组、低剂量丝胶用药组、高剂量丝胶用药组、二甲双胍用药组,每组5只小鼠。采用高脂饲料联合链脲佐菌素（STZ）腹腔注射建立T2DM小鼠模型,以空腹血糖≥11.1 mmol·L^-1作为成模标准。成模后,低剂量丝胶用药组、高剂量丝胶用药组小鼠分别给予2 700 mg·kg^-1、3 500 mg·kg^-1的丝胶灌胃,二甲双胍用药组小鼠给予216 mg·kg^-1的二甲双胍灌胃,均连续35 d。检测空腹血糖（取尾静脉血）;行口服葡萄糖耐量试验（OGTT）及胰岛素耐量实验（ITT）,并计算曲线下面积（AUC）;免疫组织化学染色检测胰岛细胞胰岛素（INS）和神经肽Y（NPY）蛋白的表达;Western blot检测胰腺组织铁氧化还原蛋白1（FDX1）的表达。结果 与对照组相比,模型组小鼠空腹血糖、OGTT和ITT的AUC、胰岛细胞NPY表达、胰腺组织FDX1表达显著升高（P<0.01）,胰腺组织INS表达显著降低（P<0.05）。高剂量丝胶能显著降低小鼠空腹血糖,OGTT和ITT的AUC（P<0.01）;有效增加INS蛋白表达,减少NPY蛋白、FDX1蛋白表达（P<0.01）;效果与低剂量丝胶、二甲双胍相当或更优。结论 丝胶可明显改善T2DM模型小鼠糖代谢紊乱,其机制可能与下调FDX1、NPY蛋白表达,上调INS-1蛋白表达,保护胰岛β细胞有关。

Abstract

Objective To explore whether sericin can improve glucose metabolism disorder in type 2 diabetes mellitus (T2DM) model mice by regulating the expression of insulin (INS), neuropeptide Y (NPY), and ferredoxin 1 (FDX1) in the pancreas. Methods Male C57BL/6 mice were randomly divided into 5 groups with 5 mice in each group: control group, T2DM model group, low-dose sericin medication group, high-dose sericin medication group, and metformin medication group. T2DM mice models were established by feeding male C57BL/6 mice with high-fat diet combined with intraperitoneal injections of STZ, and fasting blood glucose≥11.1 mmol·L^-1 was used as the criterion for successfully establishing the model. After successfully establishing the model, the mice in low-dose and high-dose sericin groups received 2 700 mg·kg^-1 and 3 500 mg·kg^-1 of sericin respectively, and the mice in metformin group received 216 mg·kg^-1 of metformin. All treatments were given by gavage once daily for 35 consecutive days. fasting blood glucose (from tail vein blood)was measured; area under the curve (AUC) was calculated from oral glucose tolerance tests (OGTT) and insulin tolerance tests (ITT); immunohistochemical staining to detect INS and NPY protein expression in pancreatic islet cells; Western blot to detect FDX1 expression in the pancreas. Results Compared with the control group, the model group showed a significant increase in fasting blood glucose, AUC values for OGTT and ITT, NPY expression in pancreatic islet cells, and FDX1 expression in the pancreas (P<0.01); while the model group showed a significant decrease in INS expression in pancreatic islet cells (P<0.05). High-dose sericin could significantly reduce fasting blood glucose in mice, as well as the AUC values for OGTT and ITT (P<0.01). It also could effectively increase INS expression in pancreatic islet cells, decrease NPY expression in pancreatic islet cells, and FDX1 expression in the pancreas (P<0.01). Its efficacy was comparable to or superior to that of low-dose sericin and metformin. The effects of high-dose sericin were comparable to or superior to those of low-dose sericin and metformin. Conclusion Sericin can improve glucose metabolism disorder in T2DM mice obviously, and the mechanisms may be related to protecting pancreatic islet β cells by down-regulating FDX1 and NPY protein, and up-regulating INS protein.

关键词

丝胶 / 2型糖尿病 / 胰岛素蛋白 / 神经肽Y / 铁氧化还原蛋白1

Key words

sericin / type 2 diabetes mellitus / insulin protein / neuropeptide Y / ferredoxin 1

[1] Liu J, Liu M, Chai Z, et al.Projected rapid growth in diabetes disease burden and economic burden in China: a spatio-temporal study from 2020 to 2030[J]. Lancet Reg Health West Pac, 2023, 33: 100700.
[2] Navigator Study Group, Holman R R, Haffner S M, et al.Effect of nateglinide on the incidence of diabetes and cardiovascular events[J]. N Engl J Med, 2010, 362(16): 1463-1476.
[3] Maedler K, Carr R D, Bosco D, et al.Sulfonylurea Induced β-Cell Apoptosis in Cultured Human Islets[J]. J Clin Endocrino Metab, 2005, 90(1): 501-506.
[4] Liu J, Shi L, Deng Y, et al.Silk sericin-based materials for biomedical applications[J]. Biomaterials, 2022, 287: 121638.
[5] Nadeem Butt E, Ali S, Summer M, et al.Exploring the mechanistic role of silk sericin biological and chemical conjugates for effective acute and chronic wound repair and related complications[J]. 2024, 50(7): 577-592.
[6] 付秀美,马宝君,赵立军,等. 丝胶对2型糖尿病大鼠血糖的影响[J]. 承德医学院学报,2008,25(4):351-353.
[7] 张恩柏,刘云,吴志强,等. 南极磷虾油对2型糖尿病小鼠降血糖功效及其机制研究[J]. 食品研究与开发,2023,44(6):1-6.
[8] Zhao Q, Yu M, Du X, et al.The Role of Cuproptosis Key Factor FDX1 in Gastric Cancer[J]. Curr Pharm Biotechnol, 2024, 26(1): 132-142.
[9] Hsiao J C, Warui D M, Kwon J J, et al.Deep Mutational Scanning of FDX1 Identifies Key Structural Determinants of Lipoylation and Cuproptosis[J]. Nat Commun, 2025, 17(1): 1112.
[10] Li Z P, Zhou H X, Zhai X Y, et al.MELK promotes HCC carcinogenesis through modulating cuproptosis-related gene DLAT-mediated mitochondrial function[J]. Cell Death Dis, 2023, 14(11): 733.
[11] Norton L, Shannon C, Gastaldelli A, et al.Insulin: The master regulator of glucose metabolism[J]. Metabolism, 2022, 129: 155142.
[12] Parker J, Briden L, Gersh F L.Recognizing the Role of Insulin Resistance in Polycystic Ovary Syndrome: A Paradigm Shift from a Glucose-Centric Approach to an Insulin-Centric Model[J]. J Clin Med, 2025, 14(12): 4021.
[13] Młynarska E, Czarnik W, Dzieża N, et al.Type 2 Diabetes Mellitus:New Pathogenetic Mechanisms, Treatment and the Most Important Complications[J]. Int J Mol Sci, 2025, 26(3): 1094.
[14] Serbis A, Giapros V, Tsamis K, et al.Beta Cell Dysfunction in Youth-and Adult-Onset Type 2 Diabetes: An Extensive Narrative Review with a Special Focus on the Role of Nutrients[J]. Nutrients, 2023, 15(9): 2217.
[15] Hirano K, Isogawa A, Tada M, et al.Long-term prognosis of autoimmune pancreatitis in terms of glucose tolerance[J]. Pancreas, 2012, 41(5): 691-695.
[16] Whim M D.Pancreatic beta cells synthesize neuropeptide Y and can rapidly release peptide co-transmitters[J]. PLoS One, 2011, 6(4): e19478.
[17] Yang C H, Ann-Onda D, Lin X, et al.Neuropeptide Y1 receptor antagonism protects β-cells and improves glycemic control in type 2 diabetes[J]. Mol Metab, 2022, 55: 101413.
[18] Imai Y, Patel H R, Hawkins E J, et al.Insulin secretion is increased in pancreatic islets of neuropeptide Y-deficient mice[J]. Endocrinology, 2007, 148(12): 5716-5723.

基金资助

国家自然科学基金项目(81441133)