Relationship between gastric bypass for type 2 diabetes mellitus and JNK signaling pathway_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

ZHANG Qiang ,  CHEN Xuan ,  XU Liang

Department of Gastrointestinal Surgery, The First Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan 646000, P. R. China;

Corresponding author：

XU Liang, Email: 751734194@qq.com

Keywords：

gastric bypass; type 2 diabetes mellitus; JNK signaling pathway

DOI：

10.7507/1007-9424.201803023

Video：

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Objective To explore mechanism of gastric bypass in treating obesity with type 2 diabetes mellitus (T2DM) and its relationship with c-Jun N-terminal kinase (JNK) signaling pathway. Methods The INS-1 cells were divided into 4 groups according to the different treatment: control group (complete medium), high glucose group (30 mmol/L glucose medium), exendin-4 group (high glucose+100 nmol/L exendin-4), and JNK agonist group (high glucose+100 nmol/L exendin-4+JNK agonist). When these cells were cultured on day 7, the cell activity was assessed by the MTT staining. The cell apoptosis was determined by the fluorescence microscopy analysis after the Hoechst/PI staining and flow cytometric assay after the Annexin V-FITC/PI staining. The expressions of the human immunoglobulin binding protein (Bip), CCAAT/enhancer-binding protein homologous protein (CHOP), P-SAPK/JNK, and caspase-3 protein were detected by the Western blot. Results Compared with the control group, the cell activities were significantly decreased (P<0.05), the cell apoptosis rates and the P-SAPK/JNK and caspase-3 protein expression levels were significantly increased (P<0.01) in the high glucose group and the JNK agonist group, but the Bip and CHOP protein expression levels were significantly increased (P<0.01) in the high glucose group. Compared with the high glucose group, the cell activity was significantly increased (P<0.05), the cell apoptosis rate and the Bip, CHOP, P-SAPK/JNK, and caspase-3 protein expression levels were significantly decreased (P<0.01) in the exendin-4 group, the Bip and CHOP protein expression levels were significantly decreased (P<0.01) in the JNK agonist group. Compared with the exendin-4 group, the cell activity was significantly decreased (P<0.05), the cell apoptosis rate and the P-SAPK/JNK and caspase-3 protein expression levels were significantly increased (P<0.01) in the JNK agonist group. Conclusion Gastric bypass can inhibit endoplasmic reticulum stress of pancreatic islet β-cells by regulating secretion of glucagon like peptide-1, thereby inhibiting JNK signaling pathway, protecting pancreatic islet β-cells and inhibiting apoptosis, so as to achieve effect of treating T2DM.

Citation： ZHANG Qiang, CHEN Xuan, XU Liang. Relationship between gastric bypass for type 2 diabetes mellitus and JNK signaling pathway. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2018, 25(9): 1055-1059. doi: 10.7507/1007-9424.201803023 Copy

1.	Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA, 2012, 308(11): 1122-1131.
2.	Stano S, Alam F, Wu L, et al. Effect of meal size and texture on gastric pouch emptying and glucagon-like peptide 1 after gastric bypass surgery. Surg Obes Relat Dis, 2017, 13(12): 1975-1983.
3.	Mingrone G, Nolfe G, Gissey G C, et al. Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion. Diabetologia, 2009, 52(5): 873-881.
4.	Chen WJ, Wang LX, Wang YP, et al. Exendin-4 protects MIN6 cells from t-BHP-induced apoptosis via IRE1-JNK-caspase-3 signaling. Int J Endocrinol, 2012, 2012: 549081.
5.	Xiong SW, Cao J, Liu XM, et al. Effect of modified Roux-en-Y gastric bypass surgery on GLP-1, GIP in patients with type 2 diabetes mellitus. Gastroenterol Res Pract, 2015, 2015: 625196.
6.	Liu XY, Liu SP, Jiang J, et al. Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein. Eur Rev Med Pharmacol Sci, 2016, 20(6): 1098-1108.
7.	Nance K, Eagon JC, Klein S, et al. Effects of sleeve gastrectomy vs. Roux-en-Y gastric bypass on eating behavior and sweet taste perception in subjects with obesity. Nutrients, 2017, 10(1): pii: E18.
8.	Williams DL. Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology, 2009, 150(7): 2997-3001.
9.	Hotamisligil GS. Inflammation and metabolic disorders. Nature, 2006, 444(7121): 860-867.
10.	Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med, 2012, 366(17): 1577-1585.
11.	Isbell JM, Tamboli RA, Hansen EN, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery. Diabetes Care, 2010, 33(7): 1438-1442.
12.	Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic beta-cells and diabetes mellitus. Exp Biol Med (Maywood), 2003, 228(10): 1213-1217.
13.	Wang H, Kouri G, Wollheim CB. ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. J Cell Sci, 2005, 118(Pt 17): 3905-3915.
14.	Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med, 2007, 357(8): 753-761.
15.	Clements RH, Gonzalez QH, Long CI, et al. Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-Ⅱ diabetes mellitus. Am Surg, 2004, 70(1): 1-4.
16.	Pournaras DJ, Osborne A, Hawkins SC, et al. Remission of type 2 diabetes after gastric bypass and banding: mechanisms and 2 year outcomes. Ann Surg, 2010, 252(6): 966-971.
17.	Laferrère B. Do we really know why diabetes remits after gastric bypass surgery? Endocrine, 2011, 40(2): 162-167.
18.	Rubino F. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis. Diabetes Care, 2008, 31(Suppl 2): S290-S296.
19.	Allen RE, Hughes TD, Ng JL, et al. Mechanisms behind the immediate effects of Roux-en-Y gastric bypass surgery on type 2 diabetes. Theor Biol Med Model, 2013, 10: 45.
20.	Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 2004, 306(5695): 457-461.
21.	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. Diabetes Res Clin Pract, 2010, 90(3): 297-304.
22.	Lee WJ, Chong K, Aung L, et al. Metabolic surgery for diabetes treatment: sleeve gastrectomy or gastric bypass? World J Surg, 2017, 41(1): 216-223.
23.	Alamuddin N, Vetter ML, Ahima RS, et al. Changes in fasting and prandial gut and adiposity hormones following vertical sleeve gastrectomy or Roux-en-Y gastric bypass: an 18-month prospective study. Obes Surg, 2017, 27(6): 1563-1572.
24.	Verheij M, Bose R, Lin XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature, 1996, 380(6569): 75-79.
25.	Nakagawa A, Satake H, Nakabayashi H, et al. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci, 2004, 110(1): 36-43.

1. Adams TD, Davidson LE, Litwin SE, et al. Health benefits of gastric bypass surgery after 6 years. JAMA, 2012, 308(11): 1122-1131.
2. Stano S, Alam F, Wu L, et al. Effect of meal size and texture on gastric pouch emptying and glucagon-like peptide 1 after gastric bypass surgery. Surg Obes Relat Dis, 2017, 13(12): 1975-1983.
3. Mingrone G, Nolfe G, Gissey G C, et al. Circadian rhythms of GIP and GLP1 in glucose-tolerant and in type 2 diabetic patients after biliopancreatic diversion. Diabetologia, 2009, 52(5): 873-881.
4. Chen WJ, Wang LX, Wang YP, et al. Exendin-4 protects MIN6 cells from t-BHP-induced apoptosis via IRE1-JNK-caspase-3 signaling. Int J Endocrinol, 2012, 2012: 549081.
5. Xiong SW, Cao J, Liu XM, et al. Effect of modified Roux-en-Y gastric bypass surgery on GLP-1, GIP in patients with type 2 diabetes mellitus. Gastroenterol Res Pract, 2015, 2015: 625196.
6. Liu XY, Liu SP, Jiang J, et al. Inhibition of the JNK signaling pathway increases sensitivity of hepatocellular carcinoma cells to cisplatin by down-regulating expression of P-glycoprotein. Eur Rev Med Pharmacol Sci, 2016, 20(6): 1098-1108.
7. Nance K, Eagon JC, Klein S, et al. Effects of sleeve gastrectomy vs. Roux-en-Y gastric bypass on eating behavior and sweet taste perception in subjects with obesity. Nutrients, 2017, 10(1): pii: E18.
8. Williams DL. Minireview: finding the sweet spot: peripheral versus central glucagon-like peptide 1 action in feeding and glucose homeostasis. Endocrinology, 2009, 150(7): 2997-3001.
9. Hotamisligil GS. Inflammation and metabolic disorders. Nature, 2006, 444(7121): 860-867.
10. Mingrone G, Panunzi S, De Gaetano A, et al. Bariatric surgery versus conventional medical therapy for type 2 diabetes. N Engl J Med, 2012, 366(17): 1577-1585.
11. Isbell JM, Tamboli RA, Hansen EN, et al. The importance of caloric restriction in the early improvements in insulin sensitivity after Roux-en-Y gastric bypass surgery. Diabetes Care, 2010, 33(7): 1438-1442.
12. Araki E, Oyadomari S, Mori M. Impact of endoplasmic reticulum stress pathway on pancreatic beta-cells and diabetes mellitus. Exp Biol Med (Maywood), 2003, 228(10): 1213-1217.
13. Wang H, Kouri G, Wollheim CB. ER stress and SREBP-1 activation are implicated in beta-cell glucolipotoxicity. J Cell Sci, 2005, 118(Pt 17): 3905-3915.
14. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med, 2007, 357(8): 753-761.
15. Clements RH, Gonzalez QH, Long CI, et al. Hormonal changes after Roux-en Y gastric bypass for morbid obesity and the control of type-Ⅱ diabetes mellitus. Am Surg, 2004, 70(1): 1-4.
16. Pournaras DJ, Osborne A, Hawkins SC, et al. Remission of type 2 diabetes after gastric bypass and banding: mechanisms and 2 year outcomes. Ann Surg, 2010, 252(6): 966-971.
17. Laferrère B. Do we really know why diabetes remits after gastric bypass surgery? Endocrine, 2011, 40(2): 162-167.
18. Rubino F. Is type 2 diabetes an operable intestinal disease? A provocative yet reasonable hypothesis. Diabetes Care, 2008, 31(Suppl 2): S290-S296.
19. Allen RE, Hughes TD, Ng JL, et al. Mechanisms behind the immediate effects of Roux-en-Y gastric bypass surgery on type 2 diabetes. Theor Biol Med Model, 2013, 10: 45.
20. Ozcan U, Cao Q, Yilmaz E, et al. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science, 2004, 306(5695): 457-461.
21. 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. Diabetes Res Clin Pract, 2010, 90(3): 297-304.
22. Lee WJ, Chong K, Aung L, et al. Metabolic surgery for diabetes treatment: sleeve gastrectomy or gastric bypass? World J Surg, 2017, 41(1): 216-223.
23. Alamuddin N, Vetter ML, Ahima RS, et al. Changes in fasting and prandial gut and adiposity hormones following vertical sleeve gastrectomy or Roux-en-Y gastric bypass: an 18-month prospective study. Obes Surg, 2017, 27(6): 1563-1572.
24. Verheij M, Bose R, Lin XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis. Nature, 1996, 380(6569): 75-79.
25. Nakagawa A, Satake H, Nakabayashi H, et al. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci, 2004, 110(1): 36-43.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Relationship between gastric bypass for type 2 diabetes mellitus and JNK signaling pathway

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