高剂量糖皮质激素对大鼠糖代谢的影响
收稿日期: 2020-07-28
网络出版日期: 2022-07-25
基金资助
国家自然科学基金项目(81471688);国家自然科学基金项目(81671720);国家自然科学基金项目(81971644)
Effect of high-dose glucocorticoid on glucose metabolism in rats
Received date: 2020-07-28
Online published: 2022-07-25
目的：探讨高剂量糖皮质激素（glucocorticoid,GC）对大鼠葡萄糖糖代谢的影响。方法：采用不同剂量（0~10 mg/kg）的地塞米松干预,选择合适的给药剂量。给予Wistar大鼠高剂量（10 mg/kg）地塞米松,观察高剂量GC对大鼠体重、空腹血糖、空腹胰岛素、糖耐量试验、胰岛素抵抗试验的影响。采用18F-氟代脱氧葡萄糖（fluorodeoxyglucose,FDG）正电子发射体层成像（positron emission tomography,PET）/CT显像,观察高剂量GC对大鼠骨骼肌、肝脏葡萄糖代谢的影响。结果：不同剂量的地塞米松均会引起糖代谢改变,其中10 mg/kg 给药剂量适用于该研究。10 mg/kg地塞米松干预后,大鼠体重明显降低[第0、3、7、11、15 天为（261±8）（226±8）（192±10）（172±10）（156±10） g,均P<0.000 1],空腹血糖[第0、3、7、11、15 天为（4.3±0.8）（14.4±5.2）（8.3±2.6）（9.8±4.4）（9.8±4.9） mmol/L,均P<0.05]和空腹胰岛素水平[第0、3、7、11、15天为（0.8±0.2）（11.6±1.1）（9.2±1.0）（9.2±2.4）（13.5±2.1） μg/L,均P<0.05]升高,血糖曲线下面积增加（第0、3、7、11、15天为858±26、2 350±345、1 680±331、1 352±166、1 553±217,均P<0.05）,胰岛素敏感性降低（第0、3、7、11、15 天为1.26±0.18、0.51±0.09、0.91±0.18、0.77±0.16、0.50±0.16,均P<0.05）。骨骼肌FDG摄取增加（第0、3、7、11、15 天为0.10±0.01、0.15±0.03、0.20±0.02、0.28±0.02、0.27±0.03,均P<0.05）,肝脏FDG摄取增加不明显,骨骼肌和肝脏糖原含量增加。结论：高剂量GC会引起明显的高血糖及高胰岛素血症。高胰岛素血症补偿了GC引起的骨骼肌胰岛素抵抗,不能完全补偿肝脏葡萄糖代谢缺陷。
关键词： 糖皮质激素; 葡萄糖代谢; 胰岛素抵抗; 正电子发射体层成像/CT
赵晴晴, 周金鑫, 潘昱, 琚卉君, 朱丽颖, 刘瑒, 张一帆 . 高剂量糖皮质激素对大鼠糖代谢的影响[J]. 内科理论与实践, 2021 , 16(06) : 397 -403 . DOI: 10.16138/j.1673-6087.2021.06.006
Objective To explore the effect of high-dose glucocorticoid(GC) on glucose metabolism in rats. Methods Choose appropriate dose in dexamethasone treatment through using different doses. By administering high-dose dexamethasone to Wistar rats, the effects of high-dose GC on rat body weight, fasting blood glucose, fasting insulin, glucose tolerance test, and insulin resistance test were observed. 18F-fluorodeoxyglucose(FDG) positron emission tomography (PET)/CT imaging was used to detect the effect of high-dose GC on glucose metabolism in skeletal muscle and liver of rats. Results Different doses of dexamethasone can cause changes in glucose metabolism, of which a dose of 10 mg/kg was suitable for this study. After high-dose dexamethasone treatment, the body weight of rats decreased[days 0,3,7,11,15 were (261±8)(226±8)(192±10)(172±10)(156±10) g, all P<0.000 1], fasting blood glucose [days 0,3,7,11,15 were(4.3±0.8)(14.4±5.2)(8.3±2.6)(9.8±4.4)(9.8±4.9) mmol/L, all P<0.05] and insulin levels increased[days 0,3,7,11,15 were (0.8±0.2)(11.6±1.1)(9.2±1.0)(9.2±2.4)(13.5±2.1) μg/L, all P<0.05], the area under the curve of glucose increased(days 0,3,7,11,15 were 858±26,2 350±345,1 680±331,1 352±166,1 553±217, all P<0.05), and insulin sensitivity decreased(days 0,3,7,11,15 were 1.26±0.18,0.51±0.09,0.91±0.18,0.77±0.16,0.50±0.16, all P<0.05). FDG uptake in skeletal muscle increased (days 0,3,7,11,15 were 0.10±0.01,0.15±0.03,0.20±0.02,0.28±0.02,0.27±0.03, all P<0.05), FDG uptake in liver didn’t change significantly, glycogen content in skeletal muscle and liver increased. Conclusions High-dose GC could cause significant hyperglycemia and hyperinsulinemia. Hyperinsulinemia compensated the insulin resistance of skeletal muscle caused by GC, however it could not completely compensate the deficiency of glucose metabolism in the liver.
| [1] | Vandewalle J, Luypaert A, De Bosscher K, et al. Therapeutic mechanisms of glucocorticoids[J]. Trends Endocrinol Metab, 2018, 29(1): 42-54. |
| [2] | Oray M, Abu Samra K, et al. Long-term side effects of glucocorticoids[J]. Expert Opin Drug Saf, 2016, 15(4): 457-465. |
| [3] | Liu XX, Zhu XM, Miao Q, et al. Hyperglycemia induced by glucocorticoids in nondiabetic patients[J]. Ann Nutr Metab, 2014, 65(4): 324-332. |
| [4] | Pivonello R, Isidori AM, De Martino MC, et al. Complications of Cushing’s syndrome: state of the art[J]. Lancet Diabetes Endocrinol, 2016, 4(7): 611-629. |
| [5] | Ruzzin J, Wagman AS, Jensen J. Glucocorticoid-induced insulin resistance in skeletal muscles: defects in insulin signalling and the effects of a selective glycogen synthase kinase-3 inhibitor[J]. Diabetologia, 2005, 48(10): 2119-2130. |
| [6] | Ogawa A, Johnson JH, Ohneda M, et al. Roles of insulin resistance and beta-cell dysfunction in dexamethasone-induced diabetes[J]. J Clin Invest, 1992, 90(2): 497-504. |
| [7] | Buscombe J. Guidelines for the use of 18F-FDG in infection and inflammation: a new step in cooperation between the EANM and SNMMI[J]. Eur J Nucl Med Mol Imaging, 2013, 40(7): 1120-1121. |
| [8] | Yang Y, Ma D, Wang Y, et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes[J]. J Alzheimers Dis, 2013, 33(2): 329-338. |
| [9] | Mohamad Asri SF, Mohd Ramli ES, Soelaiman IN, et al. Piper sarmentosum effects on 11β-hydroxysteroid dehydrogenase type 1 enzyme in serum and bone in rat model of glucocorticoid-induced osteoporosis[J]. Molecules, 2016, 21(11): 1523. |
| [10] | Cao DS, Zhong L, Hsieh TH, et al. Expression of transient receptor potential ankyrin 1 (TRPA1) and its role in insulin release from rat pancreatic beta cells[J]. PLoS One, 2012, 7(5): e38005. |
| [11] | Protzek AO, Costa-Júnior JM, Rezende LF, et al. Augmented β-cell function and mass in glucocorticoid-treated rodents are associated with increased islet ir-β/AKT/mTOR and decreased AMPK/ACC and AS160 signaling[J]. Int J Endocrinol, 2014, 2014: 983453. |
| [12] | Pataky MW, Wang H, Yu CS, et al. High-fat diet-induced insulin resistance in single skeletal muscle fibers is fiber type selective[J]. Sci Rep, 2017, 7(1): 13642. |
| [13] | Sun Y, Yu M, Liang S, et al. Fluorine-18 labeled rare-earth nanoparticles for positron emission tomography (PET) imaging of sentinel lymph node[J]. Biomaterials, 2011, 32(11): 2999-3007. |
| [14] | Martínez BB, Pereira AC, Muzetti JH, et al. Experimental model of glucocorticoid-induced insulin resistance[J]. Acta Cir Bras, 2016, 31(10): 645-649. |
| [15] | Thomas CR, Turner SL, Jefferson WH, et al. Prevention of dexamethasone-induced insulin resistance by metformin[J]. Biochem Pharmacol, 1998, 56(9): 1145-1150. |
| [16] | Kuo T, McQueen A, Chen TC, et al. Regulation of glucose homeostasis by glucocorticoids[J]. Adv Exp Med Biol, 2015, 872: 99-126. |
| [17] | Pasieka AM, Rafacho A. Impact of glucocorticoid excess on glucose tolerance: clinical and preclinical evidence[J]. Metabolites, 2016, 6(3): 24. |
| [18] | Wang LX, Wang YP, Chen Z, et al. Exendin-4 protects murine pancreatic β-cells from dexamethasone-induced apoptosis through PKA and PI-3K signaling[J]. Diabetes Res Clin Pract, 2010, 90(3): 297-304. |
| [19] | van Raalte DH, Ouwens DM, Diamant M. Novel insights into glucocorticoid-mediated diabetogenic effects: towards expansion of therapeutic options?[J]. Eur J Clin Invest, 2009, 39(2): 81-93. |
| [20] | Courty E, Besseiche A, Do TTH, et al. Adaptive β-cell neogenesis in the adult mouse in response to glucocorticoid-induced insulin resistance[J]. Diabetes, 2019, 68(1): 95-108. |
| [21] | Fine NHF, Doig CL, Elhassan YS, et al. Glucocorticoids reprogram β-cell signaling to preserve insulin secretion[J]. Diabetes, 2018, 67(2): 278-290. |
| [22] | Rafacho A, Abrantes JL, Ribeiro DL, et al. Morphofunctional alterations in endocrine pancreas of short- and long-term dexamethasone-treated rats[J]. Horm Metab Res, 2011, 43(4): 275-281. |
| [23] | Rafacho A, Cestari TM, Taboga SR, et al. High doses of dexamethasone induce increased beta-cell proliferation in pancreatic rat islets[J]. Am J Physiol Endocrinol Metab, 2009, 296(4): E681-E689. |
| [24] | Barbot M, Ceccato F, Scaroni C. Diabetes mellitus secondary to Cushing’s disease front endocrinol[J]. Front Endocrinol (Lausanne), 2018, 9: 284. |
| [25] | Magomedova L, Cummins CL. Glucocorticoids and metabolic control[J]. Handb Exp Pharmacol, 2016, 233: 73-93. |
| [26] | Perez A, Jansen-Chaparro S, Saigi I, et al. Glucocorticoid-induced hyperglycemia[J]. J Diabetes, 2014, 6(1): 9-20. |
| [27] | Nicod N, Giusti V, Besse C, et al. Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers[J]. Obes Res, 2003, 11(5): 625-631. |
| [28] | Burén J, Lai YC, Lundgren M, et al. Insulin action and signalling in fat and muscle from dexamethasone-treated rats[J]. Arch Biochem Biophys, 2008, 474(1): 91-101. |
| [29] | Viglianti BL, Wong KK, Wimer SM, et al. Effect of hyperglycemia on brain and liver 18F-FDG standardized uptake value (FDG SUV) measured by quantitative positron emission tomography (PET) imaging[J]. Biomed Pharmacother, 2017, 88: 1038-1045. |
| [30] | Sprinz C, Altmayer S, Zanon M, et al. Effects of blood glucose level on 18F-FDG uptake for PET/CT in normal organs[J]. PLoS One, 2018, 13(2): e0193140. |
| [31] | Scaroni C, Zilio M, Foti M, et al. Glucose metabolism abnormalities in cushing syndrome: from molecular basis to clinical management[J]. Endocr Rev, 2017, 38(3): 189-219. |
| [32] | Kubota K, Watanabe H, Murata Y, et al. Effects of blood glucose level on FDG uptake by liver[J]. Nucl Med Biol, 2011, 38(3): 347-351. |
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