Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome
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There is a growing interest in identifying putative insulin sensitizers from the herbal sources.
Aim of the study
The present study explores the effects of naringenin, a bioflavonoid, in the high fructose-induced model of insulin resistance.
Adult male Wistar rats were divided into two groups and were fed either a starch-based control diet or a high fructose diet (60 g/100 g) for 60 days. From the 16th day, rats in each group were divided into two, one of which was administered naringenin (50 mg/kg b.w.) and the other was untreated for the next 45 days. Oral glucose tolerance test (OGTT) was done on day 59. On day 60, the levels of glucose, insulin, triglycerides (TG), free fatty acids (FFA) in blood, and the activities of insulin-inducible and suppressible enzymes in the cytosolic and mitochondrial fractions of liver and skeletal muscle were assayed. The extent of protein tyrosine phosphorylation in response to insulin was determined by assaying protein tyrosine kinase (PTK) and protein tyrosine phosphatase (PTP) in liver. Liver histology with periodic acid-Schiff (PAS) staining was done to detect glycogen.
Fructose administration increased the plasma levels of glucose, insulin, TG, and FFA as compared to control rats. Insulin resistance was indicated by alterations in insulin sensitivity indices. Alterations in enzyme activities and reduced glycogen content were observed in fructose-fed rats. PTP activity was higher, while PTK activity was lower suggesting reduced tyrosine phosphorylation status. Administration of naringenin improved insulin sensitivity and enhanced tyrosine phosphorylation in fructose-fed animals, while it did not affect the parameters in control diet-fed rats.
Naringenin improves insulin signaling and sensitivity and thereby promotes the cellular actions of insulin in this model.
KeywordsFructose Insulin resistance Rats Naringenin Tyrosine phosphorylation
Homeostatic model assessment
Free fatty acids
Insulin sensitivity index
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide reduced
Oral glucose tolerance test
Protein tyrosine phosphatase
Protein tyrosine kinase
Quantitative insulin sensitivity check index
The authors thank Dr. R. Sundarapandiyan, Lecturer, Department of Pathology, Government Medical College, Theni, Tamil Nadu, India for his help in histopathological studies and the Indian Council of Medical Research, New Delhi, India, for providing financial support.
- 1.Ali MM, El Kader MA (2004) The influence of naringin on the oxidative state of rats with streptozotocin-induced acute hyperglycaemia. Z Naturforsch C 59:726–733Google Scholar
- 4.Bezerra RM, Ueno M, Silva MS, Tavares DQ, Carvalho CR, Saad MJ (2000) A high fructose diet affects the early steps of insulin action in muscle and liver of rats. J Nutr 30:1531–1535Google Scholar
- 5.Bizeau ME, Thresher JS, Pagliassotti MJ (2001) A high-sucrose diet increases gluconeogenic capacity in isolated periportal and perivenous rat hepatocytes. Am J Physiol Endocrinol Metab 280:E695–E702Google Scholar
- 7.Brandstrup N, Kirk JE, Bruni C (1957) The hexokinase and phosphoglucoisomerase activities of aortic and pulmonary artery tissue in individuals of various ages. J Gerontol 12:166–171Google Scholar
- 9.Cornblath M, Randle PJ, Parmeggiani A, Morgan HE (1963) Effects of glucagon and anoxia on lactate production, glycogen content and phosphorylase activity in the perfused isolated rat heart. J Biol Chem 235:1592–1597Google Scholar
- 11.Foster LB, Dunn RT (1973) Stable reagents for determination of serum triglycerides by a colorimetric Hantzsch condensation method. Clin Chem 19:338–340Google Scholar
- 12.Felgines C, Texier O, Morand C, Manach C, Scalbert A, Régerat F, Rémésy C (2000) Bioavailability of the flavanone naringenin and its glycosides in rats. Am J Physiol Gastrointest Liver Physiol 279:G1148–G1154Google Scholar
- 13.Fuhr U, Klittich K, Staib AH (1993) Inhibitory effect of grapefruit juice and its bitter principal naringenin on CYP1A2 dependent metabolism of caffeine in man. Br J Clin Pharmacol 35:431–436Google Scholar
- 17.Hannan JM, Ali L, Rokeya B, Khaleque J, Akhter M, Flatt PR, Abdel-Wahab YH (2007) Soluble dietary fibre fraction of Trigonella foenum-graecum (fenugreek) seed improves glucose homeostasis in animal models of type 1 and type 2 diabetes by delaying carbohydrate digestion and absorption, and enhancing insulin action. Br J Nutr 97:514–521CrossRefGoogle Scholar
- 20.Jung UJ, Lee MK, Jeong KS, Choi MS (2004) The hypoglycemic effect of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KSJ-db/db mice. J Nutr 134:2499–2503Google Scholar
- 22.King J (1965) The dehydrogenases or oxidoreductases-lactate dehydrogenase. In: Van D (ed) Practical clinical enzymology. Nostrand Company Ltd, London, pp 83–93Google Scholar
- 25.Lam TK, Van de Werve G, Giacca A (2003) Free fatty acids increase basal hepatic glucose production and induce hepatic insulin resistance at different sites. Am J Physiol Endocrinol Metab 284:E281–E290Google Scholar
- 27.Lee CH, Jeong TS, Choi YK, Hyun BW, Oh GT, Kim EH, Kim JR, Han JI, Bok SH (2001) Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem Biophys Res Commun 284:681–688CrossRefGoogle Scholar
- 30.Lim SL, Soh KP, Kuppusamy UR (2008) Effects of naringenin on lipogenesis, lipolysis and glucose uptake in rat adipocyte primary culture: a natural antidiabetic agent. Internet J Altern Med 5:1–10Google Scholar
- 32.Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275Google Scholar
- 34.Martinez FJ, Rizza RA, Romero JC (1994) High-fructose feeding elicits insulin resistance, hyperinsulinism, and hypertension in normal mongrel dogs. Hypertension 23:456–463Google Scholar
- 38.Morales MA, Jabaggy AJ, Terenzyl HP (1973) Mutations affecting accumulation of glycogen. Neurospora News lett 20:24–25Google Scholar
- 39.Obrosova I, Oates P, Nakano T, Petrash JM (1996) Glycolytic pathway, redox state of NAD-couples and energy metabolism in lens in rats with short-term streptozotocin diabetes (Abstract). Diabetes 45(suppl 2):195AGoogle Scholar
- 40.Ortiz-Andrade RR, Sánchez-Salgado JC, Navarrete-Vázquez G, Webster SP, Binnie M, García-Jiménez S, León-Rivera I, Cigarroa-Vázquez P, Villalobos-Molina R, Estrada-Soto S (2008) Antidiabetic and toxicological evaluations of naringenin in normoglycaemic and NIDDM rat models and its implications on extra-pancreatic glucose regulation. Diabetes Obes Metab 10:1097–1104CrossRefGoogle Scholar
- 46.Shang M, Cai S, Han J, Li J, Zhao Y, Zheng J, Namba T, Kadota S, Tezuka Y, Fan W (1998) Studies on flavonoids from fenugreek (Trigonella foenum graecum L). Zhongguo Zhong Yao Za Zhi 23:614–616Google Scholar
- 48.Slater EC, Bonner WD (1952) Effect of fluoride on succinate oxidase system. J Biochem 52:185–196Google Scholar
- 50.Southgate DA (1995) Digestion and metabolism of sugars. Am J Clin Nutr 62:203S–211SGoogle Scholar
- 51.Suga A, Hirano T, Kageyama H, Osaka T, Namba Y, Tsuji M, Miura M, Adachi M, Inoue S (2000) Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats. Am J Physiol Endocrinol Metab 278:E677–E683Google Scholar
- 54.Thresher JS, Podolin DA, Wei Y, Mazzeo RS, Pagliassotti MJ (2000) Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance. Am J Physiol Regul Integr Comp Physiol 279:R1334–R1340Google Scholar
- 57.White MF, Kahn CR (1994) The insulin signaling system. J Biol Chem 269:1–4Google Scholar