Effects of glucoxicity and lipotoxicity on ketone production and the skeletal muscle ultrastructure in high-fat-fed obese rats_West China Medical Journal

Authors：

TAN Huiwen ^1,2 , PAN Hua ¹ ,  YU Yerong ¹ , LONG Yang ² , ZHANG Xiangxun ²

1. Department of Endocrinology & Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Laboratory of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

YU Yerong, Email: yerongyu@scu.edu.cn

Keywords：

Glucoxicity; Lipotoxicity; Skeletal muscle; Mitochondria; Obese rat

DOI：

10.7507/1002-0179.201611042

Video：

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Objective To analyze the glucolipotoxicity effects of glucose combined with free fatty acid (FFA) on ketone production and ultrastructure of skeletal muscle, by exogenous elevating circulating glucose and FFA concentration. Methods Fifty Wistar rats were divided into high-fat-feed induced obesity group (OB group, n=40) and ordinary feed as normal control group (NC group, n=10). Circulating glucose and FFA levels were increased by infusion in high-fat-fed obese rats. The levels of serum lipid, plasma FFA and beta-hydroxybutyric acid were detected by the horizontal colorimetry, and the microstructure of skeletal muscle was observed by transmission electron microscopy, especially the changes of the mitochondrial structure. Euglycemic-hyperinsulinemic clamp with tracer infusion was performed to assess peripheral insulin sensitivity. Results The average weight and body fat ratio in the OB group was higher than that in the NC group (P<0.05). Insulin clamp test to assess peripheral insulin sensitivity showed that the steady-state glucose Infusion rate in the OB group during clamp test was significantly lower than that in the NC group [OB: (19.26±1.84) mg/(kg·min)vs. NC: (28.82±1.69) mg/(kg·min), P<0.05]. The mitochondrial denaturation of skeletal muscle in the OB group of rats was observed, and the swelling and crest permutation, the accumulation of lipid droplets and cavitation were formed, and hypertrophy of mitochondria were also seen after intralipid and glucose infusion, which was obvious in the combined infusion group. Conclusions By exogenous elevating circulating glucose and FFA concentration, the products of ketone body increases. The mitochondrial damage of skeletal muscle suggests that mitochondrial may be the potential target of glucoxicity and lipotocicity.

Citation： TAN Huiwen, PAN Hua, YU Yerong, LONG Yang, ZHANG Xiangxun. Effects of glucoxicity and lipotoxicity on ketone production and the skeletal muscle ultrastructure in high-fat-fed obese rats. West China Medical Journal, 2017, 32(12): 1841-1845. doi: 10.7507/1002-0179.201611042 Copy

1.	Vulesevic B, Mcneill B, Geoffrion MA, et al. Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice. Cardiovasc Res, 2014, 101(2): 306-316.
2.	Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature, 2001, 409(6818): 307-312.
3.	Corcoran MP, Lamon-Fava S, Fielding RA. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. AM J Clin Nutr, 2007, 85(3): 662-677.
4.	Doliba NM, Liu Q, Li C, et al. Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: protection by casein kinase 2 inhibitor. Mol Metab, 2017, 6(10): 1240-1253.
5.	Alves TC, Befroy DE, Kibbey RG, et al. Regulation of hepatic fat and glucose oxidation in rats with Lipid-Induced hepatic insulin resistance. Hepatology, 2011, 53(4): 1175-1181.
6.	谭惠文, 赵乃倩, 余叶蓉, 等. 糖脂毒性对肥胖大鼠β细胞功能和凋亡的影响研究. 四川大学学报: 医学版, 2017, 48(1): 71-75.
7.	Kraegen EW, James DE, Bennett SP, et al. In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol, 1983, 245(1): E1-E7.
8.	谭惠文, 余叶蓉, 李秀钧. 正常血糖-高胰岛素钳夹技术在胰岛素制剂药物代谢动力学研究中的应用进展. 华西医学, 2017, 32(11): 1801-1804.
9.	Karbaschi R, Sadeghimahalli F, Zardooz H. Maternal high-fat diet inversely affects insulin sensitivity in dams and young adult male rat offspring. J Zhejiang Univ Sci B, 2016, 17(9): 728-732.
10.	Randle PJ, GARLAND PB, HALES CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet, 1963, 1(7285): 785-789.
11.	赵乃倩, 余叶蓉, 谭惠文, 等. 糖脂联合毒性导致胰岛β细胞功能障碍. 中华内分泌代谢杂志, 2009, 25(1): 28-29.
12.	Muniyappa R, Lee S, Chen H, et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab, 2008, 294(1): E15-E26.
13.	Krebs M, Roden M. Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculature. Diabetes Obes Metab, 2005, 7(6): 621-632.
14.	Borkman M, Storlien LH, Pan DA, et al. The relation between insulin sensitivity and fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med, 1993, 328(4): 238-244.
15.	Kelly DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resisitence: a reexamination. Diabetes, 2000, 49(5): 677-683.
16.	Hu Y, Xu XH, He K, et al. Genome-wide analysis of DNA methylation variations caused by chronic glucolipotoxicity in beta-cells. Exp Clin Endocrinol Diabetes, 2014, 122(2): 71-78.
17.	Teodoro JS, Duarte FV, Gomes AP, et al. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: A possible role for SirT3 activation. Mitochondrion, 2013, 13(6): 637-646.
18.	Jain SS, Paglialunga S, Vigna C, et al. High-Fat Diet-Induced mitochondrial biogenesis is regulated by Mitochondrial-Derived reactive Oxygen species activation of CaMKII. Diabetes, 2014, 63(6): 1907-1913.
19.	Han van der Kolk JH, Gross JJ, Gerber V, et al. Disturbed bovine mitochondrial lipid metabolism: a review.Vet Q. 2017, 37(1):262-273.

1. Vulesevic B, Mcneill B, Geoffrion MA, et al. Glyoxalase-1 overexpression in bone marrow cells reverses defective neovascularization in STZ-induced diabetic mice. Cardiovasc Res, 2014, 101(2): 306-316.
2. Steppan CM, Bailey ST, Bhat S, et al. The hormone resistin links obesity to diabetes. Nature, 2001, 409(6818): 307-312.
3. Corcoran MP, Lamon-Fava S, Fielding RA. Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise. AM J Clin Nutr, 2007, 85(3): 662-677.
4. Doliba NM, Liu Q, Li C, et al. Inhibition of cholinergic potentiation of insulin secretion from pancreatic islets by chronic elevation of glucose and fatty acids: protection by casein kinase 2 inhibitor. Mol Metab, 2017, 6(10): 1240-1253.
5. Alves TC, Befroy DE, Kibbey RG, et al. Regulation of hepatic fat and glucose oxidation in rats with Lipid-Induced hepatic insulin resistance. Hepatology, 2011, 53(4): 1175-1181.
6. 谭惠文, 赵乃倩, 余叶蓉, 等. 糖脂毒性对肥胖大鼠β细胞功能和凋亡的影响研究. 四川大学学报: 医学版, 2017, 48(1): 71-75.
7. Kraegen EW, James DE, Bennett SP, et al. In vivo insulin sensitivity in the rat determined by euglycemic clamp. Am J Physiol, 1983, 245(1): E1-E7.
8. 谭惠文, 余叶蓉, 李秀钧. 正常血糖-高胰岛素钳夹技术在胰岛素制剂药物代谢动力学研究中的应用进展. 华西医学, 2017, 32(11): 1801-1804.
9. Karbaschi R, Sadeghimahalli F, Zardooz H. Maternal high-fat diet inversely affects insulin sensitivity in dams and young adult male rat offspring. J Zhejiang Univ Sci B, 2016, 17(9): 728-732.
10. Randle PJ, GARLAND PB, HALES CN, et al. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet, 1963, 1(7285): 785-789.
11. 赵乃倩, 余叶蓉, 谭惠文, 等. 糖脂联合毒性导致胰岛β细胞功能障碍. 中华内分泌代谢杂志, 2009, 25(1): 28-29.
12. Muniyappa R, Lee S, Chen H, et al. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage. Am J Physiol Endocrinol Metab, 2008, 294(1): E15-E26.
13. Krebs M, Roden M. Molecular mechanisms of lipid-induced insulin resistance in muscle, liver and vasculature. Diabetes Obes Metab, 2005, 7(6): 621-632.
14. Borkman M, Storlien LH, Pan DA, et al. The relation between insulin sensitivity and fatty-acid composition of skeletal-muscle phospholipids. N Engl J Med, 1993, 328(4): 238-244.
15. Kelly DE, Mandarino LJ. Fuel selection in human skeletal muscle in insulin resisitence: a reexamination. Diabetes, 2000, 49(5): 677-683.
16. Hu Y, Xu XH, He K, et al. Genome-wide analysis of DNA methylation variations caused by chronic glucolipotoxicity in beta-cells. Exp Clin Endocrinol Diabetes, 2014, 122(2): 71-78.
17. Teodoro JS, Duarte FV, Gomes AP, et al. Berberine reverts hepatic mitochondrial dysfunction in high-fat fed rats: A possible role for SirT3 activation. Mitochondrion, 2013, 13(6): 637-646.
18. Jain SS, Paglialunga S, Vigna C, et al. High-Fat Diet-Induced mitochondrial biogenesis is regulated by Mitochondrial-Derived reactive Oxygen species activation of CaMKII. Diabetes, 2014, 63(6): 1907-1913.
19. Han van der Kolk JH, Gross JJ, Gerber V, et al. Disturbed bovine mitochondrial lipid metabolism: a review.Vet Q. 2017, 37(1):262-273.

West China Medical Journal

Effects of glucoxicity and lipotoxicity on ketone production and the skeletal muscle ultrastructure in high-fat-fed obese rats

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