High Fat and Highly Thermolyzed Fat Diets Promote Insulin Resistance and Increase DNA Damage in Rats

Abstract

Many studies have demonstrated that DNA damage may be associated with type 2 diabetes mellitus (T2DM) and its complications. The goal of this study was to evaluate the effects of the potential relationship between fat (thermolyzed) intake, glucose dyshomeostasis and DNA injury in rats. Biochemical parameters related to glucose metabolism (i.e., blood glucose levels, insulin tolerance tests, glucose tolerance tests and fat cell glucose oxidation) and general health parameters (i.e., body weight, retroperitoneal and epididymal adipose tissue) were evaluated in rats after a 12-month treatment with either a high fat or a high thermolyzed fat diet. The high fat diet (HFD) and high fat thermolyzed diet (HFTD) showed increased body weight and impaired insulin sensitivity at the studied time-points in insulin tolerance test (ITT) and glucose tolerance test (GTT). Interestingly, only animals subjected to the HFTD diet showed decreased epididymal fat cell glucose oxidation. We show which high fat diets have the capacity to reduce glycogen synthesis by direct and indirect pathways. HFTD promoted an increase in lipid peroxidation in the liver, demonstrating significant damage in lipids in relation to other groups. Blood and hippocampus DNA damage was significantly higher in animals subjected to HFDs, and the highest damage was observed in animals from the HFTD group. Striatum DNA damage was significantly higher in animals subjected to HFDs, compared with the control group. These results show a positive correlation between high fat diet, glucose dyshomeostasis, oxidative stress and DNA damage.

Get full access to this article

View all access options for this article.

References

Smyth S, Heron A. Diabetes and obesity: the twin epidemics. Nat Med 12:75–80, 2006.

McGarry JD. Dysregulation of fatty acid metabolism in etiology of type 2 diabetes. Diabetes 51:7–18, 2002.

Lazar MA. How obesity causes diabetes: not a tall tale. Science 307:373–375, 2005.

Sandu O, Song K, Cai W, Zheng F, Uribarri J, Vlassara H. Insulin resistance and type 2 diabetes in high-fat-fed mice are linked to high glycotoxin intake. Diabetes 54:2314–2319, 2005.

Diamanti-Kandarakis E, Piperi C, Korkolopoulou P, Kandaraki E, Levidou G, Papalois A, Patsouris E, Papavassiliou AG. Accumulation of dietary glycotoxins in the reproductive system of normal female rats. J Mol Med 85:1413–1420, 2007.

Cerf ME. High fat diet modulation of glucose sensing in the beta-cell. Med Sci Monit 13:RA12–7, 2007.

Slim RM, Toborek M, Watkins BA, Boissonneault GA, Hennig B. Susceptibility to hepatic oxidative stress in rabbits fed different animal and plant fats. J Am Coll Nutr 15:289–294, 1996.

Hamelet J, Demuth K, Paul JL, Delabar JM, Janel N. Hyperhomocysteinemia due to cystathionine beta synthase deficiency induces dysregulation of genes involved in hepatic lipid homeostasis in mice. J Hepatol 46:151–159, 2007.

Raval J, Lyman S, Nitta T, Mohuczy D, Lemasters JJ, Kim JS, et al. Basal reactive oxygen species determine the susceptibility to apoptosis in cirrhotic hepatocytes. Free Radic Biol Med 41:1645–1654, 2006.

10.

Kohen R, Nyska A. Oxidation of biological systems: oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicol Pathol 30:620–650, 2002.

11.

Blasiak J, Arabski M, Krupa R, Wozniak K, Zadrozny M, Kasznicki J, Zurawska M, Drzewoski J. DNA damage and repair in type 2 diabetes mellitus. Mutat Res 554:297–304, 2004.

12.

Lean ME, Noroozi M, Kelly I, Burns J, Talwar D, Sattar N, Crozier A. Dietary flavonols protect diabetic human lymphocytes against oxidative damage to DNA. Diabetes 48:176–181, 1999.

13.

Kubow S. Routes of formation and toxic consequences of lipid oxidation products in foods. Free Rad Biol Med 12:63–81, 1992.

14.

Lam KTT, Guiterrez-Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309:943–947, 2005.

15.

Pierre K, Parent A, Jayet P-Y, Halestrap AP, Scherrer U, Pellerin L. Enhanced expression of three monocarboxylate transporter isoforms in the brain of obese mice. J Physiol 583:469–486, 2007.

16.

Teixeira AM, Reckziegel P, Müller Liz, Pereira RP, Roos DH, Rocha JB, Bürger ME. Intense exercise potentiates oxidative stress in striatum of reserpine-treated animals. Pharmacol Biochem Behav 92:231–235, 2009.

17.

Dolnikoff M, Martin-Hidalgo A, Machado UF, Lima FB, Herrera E. Decreased lipolysis and enhanced glycerol and glucose utilization by adipose tissue prior to development of obesity in monosodium glutamate (MSG) treated-rats. Int J Obes Rel Metab Dis 25:426–433, 2001.

18.

Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Meth Enzymol 186:421–431, 1990.

19.

Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, et al. Determination of carbonyl content in oxidatively modified proteins. Meth Enzymol 186:464–478, 1990.

20.

Gedik CM, Grant G, Morrice PC, Wood SG, Collins AR. Effects of age and dietary restriction on oxidative DNA damage, antioxidant protection and DNA repair in rats. Eur J Nutr 44:263–272, 2005.

21.

Tice RR, Agurell E, Anderson D, Burlinson B, Hartmann A, Kobayashi H, Miyamae Y, Rojas E, Ryu JC, Sasaki YF. Single cell gel/comet assay: guidelines for in vitro and in vivo genetic toxicology testing. Environ Mol Mutagen 35:206–221, 2000.

22.

Collins AR, Dobson VL, Dusinska M, Kennedy G, Stetina R. The comet assay: what can it really tell us? Mutat Res 29:183–193, 1997.

23.

Albers JW, Herman WH, Pop-Busui R, Martin CL, Cleary P, Waberski B. Subclinical neuropathy among Diabetes Control and Complications Trial participants without diagnosable neuropathy at trial completion: possible predictors of incident neuropathy? Diabetes Care 30:2613–2618, 2007.

24.

Tesfaye S, Kempler P. Painful diabetic neuropathy. Diabetologia 48:805–807, 2005.

25.

Kodl CT, Seaquist ER. Cognitive dysfunction and diabetes mellitus. Endocr Rev 29:494–511, 2008.

26.

Tiehuis AM, Vincken KL, van den Berg E, Hendrikse J, Manschot SM, Mali WP, Kappelle LJ, Biessels GJ. Cerebral perfusion in relation to cognitive function and type 2 diabetes. Diabetologia 51:1321–1326, 2008.

27.

Hirosumi J, Tuncman G, Chang L, Görgün CZ, Uysal KT, Maeda K, Karin M, Hotamisligil GS. A central role for JNK in obesity and insulin resistance. Nature 420:333–336, 2002.

28.

Matsuzawa-Nagata N, Takamura T, Ando H, Nakamura S, Kurita S, Misu H, Ota T, Yokoyama M, Honda M, Miyamoto K, Kaneko S. Increased oxidative stress precedes the onset of high-fat diet-induced insulin resistance and obesity. Metabolism 57:1071–1077, 2008.

29.

Defronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4):773–795, 2009.

30.

Marshall JA, Hamman RF, Baxter J. High-fat, low-carbohydrate diet and the etiology of non-insulin-dependent diabetes mellitus: the San Luis Valley Diabetes Study. Am J Epidemiol 134:590–603, 1991.

31.

Winzell MS, Ahren B. The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes. Diabetes 53:S215–219, 2004.

32.

Velho G, Petersen KF, Perseghin G, Hwang JH, Rothman DL, Pueyo ME, Cline GW, Froguel P, Shulman GI. Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects. J Clin Invest 98:1755–1761, 1996.

33.

Newgard CB, Hirsch LJ, Foster DW, McGarry JD. Studies on the mechanism by which exogenous glucose is converted into liver glycogen in the rat. A direct or an indirect pathway? J Biol Chem 258:8046–8052, 1983.

34.

Hofmann SM, Dong HJ, Li Z, Cai W, Altomonte J, Thung SN, Zeng F, Fisher EA, Vlassara H. Improved insulin sensitivity is associated with restricted intake of dietary glycoxidation products in the db/db mouse. Diabetes 51:2082–2089, 2002.

35.

Sauter NS, Schulthess FT, Galasso R, Castellani LW, Maedler K. The antiinflammatory cytokine interleukin-1 receptor antagonist protects from high-fat diet-induced hyperglycemia. Endocrinology 149:2208–2218, 2008.

36.

Stitt AW, Bhaduri T, McMullen CBT, Gardiner TA, Archer DB. Advanced glycation end products induce blood-retinal barrier dysfunction in normoglycemic rats. Mol Cell Biol Res Commun 3:380–388, 2000.

37.

Vlassara H, Fuh H, Makita Z, Krungkrai S, Cerami A, Bucala R. Exogenous advanced glycosylation end products induce complex vascular dysfunction in normal animals: a model for diabetes and aging complication. Proc Natl Acad Sci U S A 88:12043–12047, 1992.