Protective effect of exogenous insulin on relative adrenal insufficiency in rats with severe acute pancreatitis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHAO Liang ^1,2 , MEI Fangchao ^1,2 , ZHOU Yu ^1,2 , LI Man ^1,3 , WANG Weixing ^1,2 , YU Jia ¹ ,  DENG Wenhong ^1,2,3

1. Department of General Surgery, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;
2. Hubei Key Laboratory of Digestive System Disease, Wuhan 430060, P. R. China;
3. Central Laboratory, Renmin Hospital of Wuhan University, Wuhan 430060, P. R. China;

Corresponding author：

DENG Wenhong, Email: dwh19841020@163.com

Keywords：

severe acute pancreatitis; relative adrenal insufficiency; insulin; corticosterone

DOI：

10.7507/1007-9424.202010087

Video：

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Objective To investigate the protective effect of exogenous insulin on relative adrenal insufficiency (RAI) in rats with severe acute pancreatitis (SAP).Methods Eighty SPF SD rats were randomly divided into 5 groups (n=16): sham operation (SO) group, SAP group, low-dose insulin intervention (low-dose) group (0.05 U/100 g body weight), medium-dose insulin intervention (medium-dose) group (0.1 U/100 g body weight), and high-dose insulin intervention (high-dose) group (0.2 U/100 g body weight). The five groups were randomly divided into two subgroups: cosyntropin stimulation test (CST) subgroup and non-CST subgroup. SAP model was established by retrograde injection of 5% sodium taurocholate into biliopancreatic duct. The rats were sacrificed 3 hours after the establishment of SAP model. The levels of amylase (AMY), alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea (Ur) and creatinine (Cr) were detected by automatic biochemical analyzer. The serum levels of tumor necrosis factor-α (TNF-α) and corticosterone (Cor) were detected by ELISA kit. The pathological changes of pancreas and adrenal gland were observed under light microscope. The lipid content of adrenal gland was observed by oil red O staining.Results Compared with the SO group, the serum levels of Amy, ALT, AST, Ur, Cr, TNF-α and Cor in the SAP group were significantly increased (P<0.05), typical pathological damages occurred in pancreas and adrenal gland, and pathological scores were significantly increased (P<0.05). Compared with the SAP group, the levels of AMY, ALT, AST, Ur, Cr, TNF-α and Cor in the low-dose group were not significantly changed (P>0.05); the levels of AMY, ALT, AST, Ur, Cr and TNF-α in the medium-dose group and the high-dose group were significantly decreased (P<0.05), and Cor levels were significantly increased (P<0.05). Compared with the low-dose group, AMY, ALT, AST, Cr, TNF-α in the medium-dose group and the high-dose group were significantly decreased (P<0.05), Cor level were significantly increased (P<0.05), Ur level had no significant change. There were no significant difference in AMY, ALT, AST, Ur, Cr, TNF-α and Cor levels between the medium-dose group and the high-dose group (P>0.05). After CST intervention, there were no significant change in serum Cor levels in the SAP group and the low-dose group (P>0.05), but the serum Cor levels in the SO group, the medium-dose group and the high-dose group were significantly increased (P<0.05).Conclusion Appropriate dose of exogenous insulin can improve SAP related adrenal injury and RAI, but the specific mechanism still needs further study.

Citation： ZHAO Liang, MEI Fangchao, ZHOU Yu, LI Man, WANG Weixing, YU Jia, DENG Wenhong. Protective effect of exogenous insulin on relative adrenal insufficiency in rats with severe acute pancreatitis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(6): 721-726. doi: 10.7507/1007-9424.202010087 Copy

1.	Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut, 2013, 62(1): 102-111.
2.	中华医学会消化病学分会胰腺疾病学组, 中华胰腺病杂志编辑委员会, 中华消化杂志编辑委员会. 中国急性胰腺炎诊治指南(2019, 沈阳). 中华胰腺病杂志, 2019, 19(5): 321-331.
3.	Boxhoorn L, Voermans RP, Bouwense SA, et al. Acute pancreatitis. Lancet, 2020, 396(10252): 726-734.
4.	Piano S, Favaretto E, Tonon M, et al. Including relative adrenal insufficiency in definition and classification of acute-on-chronic liver failure. Clin Gastroenterol Hepatol, 2020, 18(5): 1188-1196.
5.	Bagate F, Razazi K, Boissier F, et al. Association between relative adrenal insufficiency and septic cardiomyopathy: a preliminary report. Intensive Care Med, 2017, 43(12): 1924-1926.
6.	Bagate F, Lellouche N, Lim P, et al. Prognostic value of relative adrenal insufficiency during cardiogenic shock: a prospective cohort study with long-term follow-up. Shock, 2017, 47(1): 86-92.
7.	De Waele JJ, Hoste EA, Baert D, et al. Relative adrenal insufficiency in patients with severe acute pancreatitis. Intensive Care Med, 2007, 33(10): 1754-1760.
8.	Deng W, Hui Y, Yu J, et al. A new pathological scoring method for adrenal injury in rats with severe acute pancreatitis. Pathol Res Pract, 2014, 210(12): 1011-1017.
9.	Yu J, Zuo T, Deng W, et al. Poly(ADP-ribose) polymerase inhibition suppresses inflammation and promotes recovery from adrenal injury in a rat model of acute necrotizing pancreatitis. BMC Gastroenterol, 2016, 16(1): 81.
10.	Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev, 2018, 98(4): 2133-2223.
11.	DU JD, Zheng X, Huang ZQ, et al. Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis. Exp Ther Med, 2014, 8(1): 141-146.
12.	Yu B, He W, He C, et al. Low-molecular-weight heparin combined with insulin versus insulin alone in the treatment of hypertriglyceridemic pancreatitis (LIHTGP Trial): study protocol for a multicenter, prospective, single-blind, randomized controlled trial. Pancreas, 2020, 49(10): 1383-1387.
13.	Xu LL, Zhao B, Sun SL, et al. High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis. Ann Transl Med, 2020, 8(14): 852.
14.	Hong YP, Yu J, Su YR, et al. High-fat diet aggravates acute pancreatitis via TLR4-mediated necroptosis and inflammation in rats. Oxid Med Cell Longev, 2020, 2020: 8172714.
15.	Muller CA, McArthur N, Belyaev O, et al. The effect of synacthen on acute necrotizing pancreatitis in rats. Pancreas, 2008, 37(3): 316-320.
16.	Schmidt J, Rattner DW, Lewandrowski K, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg, 1992, 215(1): 44-56.
17.	Annetta M, Maviglia R, Proietti R, et al. Use of corticosteroids in critically ill septic patients: a review of mechanisms of adrenal insufficiency in sepsis and treatment. Curr Drug Targets, 2009, 10(9): 887-894.
18.	Yu J, Xu S, Wang WX, et al. Changes of inflammation and apoptosis in adrenal gland after experimental injury in rats with acute necrotizing pancreatitis. Inflammation, 2012, 35(1): 11-22.
19.	狄茂军, 惠远见, 王卫星, 等. 急性出血坏死性胰腺炎大鼠肾上腺病理及功能的变化. 中华实验外科杂志, 2012, 29(6): 1124-1126.
20.	London E, Wassif CA, Horvath A, et al. Cholesterol biosynthesis and trafficking in cortisol-producing lesions of the adrenal cortex. J Clin Endocrinol Metab, 2015, 100(10): 3660-3667.
21.	van der Sluis RJ, Depuydt MAC, Van Eck M, et al. VLDL/LDL serves as the primary source of cholesterol in the adrenal glucocorticoid response to food deprivation. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(7): 158682.
22.	Sandhu J, Li S, Fairall L, et al. Aster proteins facilitate nonvesicular plasma membrane to er cholesterol transport in mammalian cells. Cell, 2018, 175(2): 514-529.
23.	Yellaturu CR, Deng X, Park EA, et al. Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of Insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP). SREBP-1c complex. J Biol Chem, 2009, 284(46): 31726-31734.
24.	Kinyua AW, Doan KV, Yang DJ, et al. Insulin regulates adrenal steroidogenesis by stabilizing SF-1 activity. Sci Rep, 2018, 8(1): 5025.
25.	Hong YP, Guo WY, Wang WX, et al. 4-Phenylbutyric acid attenuates pancreatic beta-cell injury in rats with experimental severe acute pancreatitis. Int J Endocrinol, 2016, 2016: 4592346.
26.	Shi Q, Hong YP, Zhang XY, et al. β cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice. Biochem Biophys Res Commun, 2018, 496(1): 114-119.

1. Banks PA, Bollen TL, Dervenis C, et al. Classification of acute pancreatitis—2012: revision of the Atlanta classification and definitions by international consensus. Gut, 2013, 62(1): 102-111.
2. 中华医学会消化病学分会胰腺疾病学组, 中华胰腺病杂志编辑委员会, 中华消化杂志编辑委员会. 中国急性胰腺炎诊治指南(2019, 沈阳). 中华胰腺病杂志, 2019, 19(5): 321-331.
3. Boxhoorn L, Voermans RP, Bouwense SA, et al. Acute pancreatitis. Lancet, 2020, 396(10252): 726-734.
4. Piano S, Favaretto E, Tonon M, et al. Including relative adrenal insufficiency in definition and classification of acute-on-chronic liver failure. Clin Gastroenterol Hepatol, 2020, 18(5): 1188-1196.
5. Bagate F, Razazi K, Boissier F, et al. Association between relative adrenal insufficiency and septic cardiomyopathy: a preliminary report. Intensive Care Med, 2017, 43(12): 1924-1926.
6. Bagate F, Lellouche N, Lim P, et al. Prognostic value of relative adrenal insufficiency during cardiogenic shock: a prospective cohort study with long-term follow-up. Shock, 2017, 47(1): 86-92.
7. De Waele JJ, Hoste EA, Baert D, et al. Relative adrenal insufficiency in patients with severe acute pancreatitis. Intensive Care Med, 2007, 33(10): 1754-1760.
8. Deng W, Hui Y, Yu J, et al. A new pathological scoring method for adrenal injury in rats with severe acute pancreatitis. Pathol Res Pract, 2014, 210(12): 1011-1017.
9. Yu J, Zuo T, Deng W, et al. Poly(ADP-ribose) polymerase inhibition suppresses inflammation and promotes recovery from adrenal injury in a rat model of acute necrotizing pancreatitis. BMC Gastroenterol, 2016, 16(1): 81.
10. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev, 2018, 98(4): 2133-2223.
11. DU JD, Zheng X, Huang ZQ, et al. Effects of intensive insulin therapy combined with low molecular weight heparin anticoagulant therapy on severe pancreatitis. Exp Ther Med, 2014, 8(1): 141-146.
12. Yu B, He W, He C, et al. Low-molecular-weight heparin combined with insulin versus insulin alone in the treatment of hypertriglyceridemic pancreatitis (LIHTGP Trial): study protocol for a multicenter, prospective, single-blind, randomized controlled trial. Pancreas, 2020, 49(10): 1383-1387.
13. Xu LL, Zhao B, Sun SL, et al. High-dose vitamin C alleviates pancreatic injury via the NRF2/NQO1/HO-1 pathway in a rat model of severe acute pancreatitis. Ann Transl Med, 2020, 8(14): 852.
14. Hong YP, Yu J, Su YR, et al. High-fat diet aggravates acute pancreatitis via TLR4-mediated necroptosis and inflammation in rats. Oxid Med Cell Longev, 2020, 2020: 8172714.
15. Muller CA, McArthur N, Belyaev O, et al. The effect of synacthen on acute necrotizing pancreatitis in rats. Pancreas, 2008, 37(3): 316-320.
16. Schmidt J, Rattner DW, Lewandrowski K, et al. A better model of acute pancreatitis for evaluating therapy. Ann Surg, 1992, 215(1): 44-56.
17. Annetta M, Maviglia R, Proietti R, et al. Use of corticosteroids in critically ill septic patients: a review of mechanisms of adrenal insufficiency in sepsis and treatment. Curr Drug Targets, 2009, 10(9): 887-894.
18. Yu J, Xu S, Wang WX, et al. Changes of inflammation and apoptosis in adrenal gland after experimental injury in rats with acute necrotizing pancreatitis. Inflammation, 2012, 35(1): 11-22.
19. 狄茂军, 惠远见, 王卫星, 等. 急性出血坏死性胰腺炎大鼠肾上腺病理及功能的变化. 中华实验外科杂志, 2012, 29(6): 1124-1126.
20. London E, Wassif CA, Horvath A, et al. Cholesterol biosynthesis and trafficking in cortisol-producing lesions of the adrenal cortex. J Clin Endocrinol Metab, 2015, 100(10): 3660-3667.
21. van der Sluis RJ, Depuydt MAC, Van Eck M, et al. VLDL/LDL serves as the primary source of cholesterol in the adrenal glucocorticoid response to food deprivation. Biochim Biophys Acta Mol Cell Biol Lipids, 2020, 1865(7): 158682.
22. Sandhu J, Li S, Fairall L, et al. Aster proteins facilitate nonvesicular plasma membrane to er cholesterol transport in mammalian cells. Cell, 2018, 175(2): 514-529.
23. Yellaturu CR, Deng X, Park EA, et al. Insulin enhances the biogenesis of nuclear sterol regulatory element-binding protein (SREBP)-1c by posttranscriptional down-regulation of Insig-2A and its dissociation from SREBP cleavage-activating protein (SCAP). SREBP-1c complex. J Biol Chem, 2009, 284(46): 31726-31734.
24. Kinyua AW, Doan KV, Yang DJ, et al. Insulin regulates adrenal steroidogenesis by stabilizing SF-1 activity. Sci Rep, 2018, 8(1): 5025.
25. Hong YP, Guo WY, Wang WX, et al. 4-Phenylbutyric acid attenuates pancreatic beta-cell injury in rats with experimental severe acute pancreatitis. Int J Endocrinol, 2016, 2016: 4592346.
26. Shi Q, Hong YP, Zhang XY, et al. β cells can be generated from cytokeratin 5-positive cells after cerulein-induced pancreatitis in adult mice. Biochem Biophys Res Commun, 2018, 496(1): 114-119.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Protective effect of exogenous insulin on relative adrenal insufficiency in rats with severe acute pancreatitis

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