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Diabetes/ Insulin Resistance

Brief Scientific Literature Review- October 2008
High Fructose/Sucrose Diets for inducing Hypertriglyceridemia
and Insulin Resistance in Rodents
Vikas V. Surve, Ph.D., Consulting Scientist, Research Diets, Inc.

Consumption of sucrose and more recently of High Fructose Corn Syrup (HFCS) has increased dramatically through processed foods such as beverages, jams, jellies, baked goods and dairy products. HFCS is inexpensive and sweeter than sucrose which increases its palatability and hence is rapidly replacing sucrose in processed foods; this has been suggested to induce overeating in humans (1, 2).

In the past few decades, we have learned that an increased intake of refined carbohydrates such as HFCS and the disaccharide sucrose (which is composed of fructose + glucose), is associated with hypertension, obesity, diabetes, kidney disease and cardiovascular diseases, both in humans and rodents (3-6, 7, 8-14). These detrimental effects of fructose on health can be attributed to how fructose is metabolized after its dietary intake. After absorption in the gastrointestinal tract, fructose is transported via the portal circulation to the liver, where it enters hepatocytes via the glucose transporter GLUT5-independently of insulin - and is rapidly metabolized (15, 16). Also, phosphofructokinase, a hepatic enzyme that governs glycolysis in

liver, negatively regulates glucose breakdown while fructose can evade this rate-limiting control mechanism and is metabolized into glycerol- 3-phosphate and acetyl–coenzyme A. These two intermediate metabolites are then used as substrates for glyceride synthesis, contributing to very low-density lipoprotein (VLDL) triglyceride production in the liver (3, 7).

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Furthermore, due to the lack of GLUT5 expression in β-cells, fructose unlike glucose does not directly stimulate pancreatic insulin release (16). The exposure of the liver to such large quantities of fructose leads to rapid stimulation of lipogenesis and triglyceride accumulation, which in turn contributes to reduced insulin sensitivity and hepatic insulin resistance/glucose intolerance (3). A recent finding that dietary fructose fails to stimulate both insulin and leptin secretion and attenuates postprandial ghrelin suppression has led to suggestion that prolonged consumption of diets high in fructose could lead to increased caloric intake and contribute to weight gain and obesity (17).

Rat Models
Amongst rodents, high fructose diets induce hypertriglyceridemia, insulin resistance and hypertension in Sprague-Dawley (SD) rats (8-10), Wistar rats (11, 12) and hamsters (13, 14). The SD (18) and Wistar rat (19) are established models of sucrose-induced insulin resistance and hypertriglyceridemia. Both of these phenotypes can develop within two weeks when these animals are fed a diet containing 65% sucrose (by weight) relative to one with 65% corn starch (18, 19). It has been shown that, as in humans, the active ingredient from the high sucrose diet is fructose rather than glucose which results in the metabolic syndrome; whereas equivalent amounts of glucose or starch do not induce these indications (20-22). Unless fed for a prolonged period of time, these high fructose/sucrose diets do not appear to lead to excessive weight gain (11).

In addition to inducing the metabolic syndrome, administering a high fructose diet to SD rats results in the development of renal hypertrophy, afferent arteriolar thickening, glomerular hypertension, and cortical vasoconstriction (23). When SD rats were fed a 60% fructose diet for 10 weeks, it induced hypertriglyceridemia, hyperinsulinemia and more importantly hyperuricemia (20). Uric acid has been implicated to play a role in the metabolic syndrome by inhibiting nitric oxide bioavailability which is required by insulin to stimulate glucose uptake. Lowering uric acid in these high fructose fed animals was able to prevent or reverse features of metabolic syndrome such as hyperinsulinemia, systolic hypertension, hypertriglyceridemia and weight gain (20). Also, Shapiro et al have recently shown that chronic fructose consumption induces leptin resistance in SD rats and accelerates high fat induced obesity (24). Similar to SD rats, Wistar rats fed with a 66% fructose diet over a period of 10 weeks had increased systolic and diastolic blood pressure and increased pulse pressure, an index of vascular stiffness (12). When the high fructose diet was supplemented with long-chain (n-3) polyunsaturated fatty acids the metabolic and vascular disorders were prevented (12).

Hamster Models
The Syrian Golden hamster (Mesocricetus auratus) is a widely used model for lipoprotein research since the main plasma cholesterol carrier in the hamster is LDL and unlike rats, its lipoprotein metabolism appears to closely resemble that of humans (25). Hamsters can be made hyperinsulinemic, hypertriglyceridemic, and insulin-resistant by feeding them with high fructose diets (13). Similar to rats, hamsters fed high fructose diets (~60% of energy) may develop insulin resistance and elevations in triglycerides after only two weeks compared to diets low in fructose (13, 14). The fructose fed hamster model is characterized by high plasma levels of VLDL and apolipoprotein B due to hepatic lipoprotein overproduction (14). Interestingly, hamsters fed high sucrose diets do not have elevated triglycerides levels and develop only mild insulin resistance relative to those fed diets high in fructose (13). Since sucrose is one-half fructose, it appears that the level of dietary fructose is quite important in the rapid development of insulin resistance and elevated triglycerides in hamsters.

Mouse Models
In contrast to rats and hamsters, the mouse is used less frequently as a model for sucrose/fructose- induced insulin resistance and hypertriglyceridemia. The response to high fructose/sucrose diets is very strain-dependent in the mouse (26) and commonly used strains like the C57Bl/6 mice either do not develop insulin resistance or develop slowly (27). When C57Bl/6 mice and Wistar rats were gavaged with high fructose for three weeks, C57Bl/6 mice in contrast to Wistar rats responded with lowered plasma triglycerides and total cholesterol thus presenting a biochemical profile that could be considered to be healthier for the cardiovascular system (28). On the other hand, when C57/Bl6 mice were fed a high fructose diet for eight weeks, they developed increased mean arterial pressure, reduced glucose tolerance and increased plasma cholesterol which was attributed to the activation of the sympathetic and angiotensin systems (29). Also, Cunha et al showed that twelve weeks of high fructose feeding of C57/Bl6 mice resulted in impairment of renal function documented by increase in urinary protein excretion and increase in urinary volume (30). However, the mouse genome is easier to manipulate than that of the rat and several knockout models (that are prone to develop atherosclerosis) also show elevated triglyceride responses to high dietary fructose (31).

Thus, depending on the rodent model chosen, high fructose/sucrose diets can replicate several aspects of the human metabolic syndrome such as hypertriglyceridemia, hypertension and hyperinsulinemia.

References:
1. Yudkin J. Evolutionary and historical changes in dietary carbohydrates. Am J Clin Nutr 20:108-115, 1967.
2. Bray GA, Nielsen SJ, and Popkin BM. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 79: 537-543, 2004.
3. Basciano H, Federico L, and Adeli K. Fructose, insulin resistance, and metabolic dyslipidemia. Nutr Metab (Lond) 2: 5, 2005.
4. Havel PJ. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 63: 133-157, 2005.
5. Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, and Sanchez-Lozada LG. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 86:899-906, 2007.
6. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr 76:911-922, 2002.
7. Qu S, Su D, Altomonte J, Kamagate A, He J, Perdomo G, Tse T, Jiang Y, Dong HH. PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1. Am J Physiol Endocrinol Metab 2007;292:421-434.
8. Zavaroni I, Sander S, Scott S, Reaven GM. Effect of fructose feeding on insulin secretion and insulin action in the rat. Metabolism 29(10):970-973,1980.
9. Hwang IS, Ho H, Hoffman BB, Reaven GM. Fructose-induced insulin resistance and hypertension in rats. Hypertension 10:512–516, 1987.
10. Sleder J, Chen,YD, Cully MD, Reaven GM. Hyperinsulinemia in fructose-induced hypertriglyceridemia in the rat. Metabolism 29:303-305, 1980.
11. Chicco A, D'Alessandro ME, Karabatas L, Pastorale C, Basabe JC, Lombardo YB. Muscle lipid metabolism and insulin secretion are altered in insulin-resistant rats fed a high sucrose diet. J Nutr. 133:127-133, 2003.
12. Robbez Masson V, Lucas A, Gueugneau AM, Macaire JP, Paul JL, Grynberg A, Rousseau D. Long-chain (n-3) polyunsaturated fatty acids prevent metabolic and vascular disorders in fructose-fed rats. J Nutr 138(10):1915-1922, 2008.
13. Kasim-Karakas SE, Vriend H, Almario R, Chow LC, Goodman MN. Effects of dietary carbohydrates on glucose and lipid metabolism in golden Syrian hamsters J Lab Clin Med 128: 208–213, 1996.
14. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, Lewis GF, Adeli K. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem 275:8416-8425, 2000.
15. Smith Jr LH, Ettinger RH, Seligson D. A comparison of the metabolism of fructose and glucose in hepatic disease and diabetes mellitus. J Clin Invest 32:273-282, 1953.
16. Sato Y, Ito T, Udaka N, Kanisawa M, Noguchi Y, Cushman SW, Satoh S. Immunohistochemical localization of facilitated-diffusion glucose transporters in rat pancreatic islets. Tissue Cell 28:637-643, 1996.
17. Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D'Alessio D, and Havel PJ. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 89: 2963-2972, 2004.
18. Pagliassotti MJ, Prach PA, Koppenhafer TA, Pan DA. Changes in insulin action, triglycerides, and lipid composition during sucrose feeding in rats. Am J Physiol 271:1319-1326, 1996.
19. Pagliassotti MJ, Gayles EC, Podolin DA, Wei Y, Morin CL. Developmental stage modifies diet-induced peripheral insulin resistance in rats. Am J Physiol Regul Integr Comp Physiol 278: 66- 73, 2000.
20. Nakagawa T, Hu H, Zharikov S, Tuttle KR, Short RA, Glushakova O, Ouyang X, Feig DI, Block ER, Herrera-Acosta J, Patel JM, Johnson RJ. A causal role for uric acid in fructose-induced metabolic syndrome. Am J Physiol Renal Physiol 290:625–631, 2006.
21. Thorburn AW, Storlien LH, Jenkins AB, Khouri S, Kraegen EW. Fructose-induced in vivo insulin resistance and elevated plasma triglyceride levels in rats. Am J Clin Nutr 49:1155-1163, 1989.
22. Thresher JS, Podolin DA, Wei Y, Mazzeo RS, Pagliassotti MJ. Comparison of the effects of sucrose and fructose on insulin action and glucose tolerance. Am J Physiol Regul Integr Comp Physiol 279:R1334-R1340, 2000.
23. Sánchez-Lozada LG, Tapia E, Jiménez A, Bautista P, Cristóbal M, Nepomuceno T, Soto V, Avila-Casado C, Nakagawa T, Johnson RJ, Herrera-Acosta J, Franco M. Fructose-induced metabolic syndrome is associated with glomerular hypertension and renal microvascular damage in rats. Am J Physiol Renal Physiol 292:423–429, 2007.
24. Shapiro A, Mu W, Roncal CA, Cheng KY, Johnson RJ, Scarpace PJ. Fructose-Induced Leptin Resistance Exacerbates Weight Gain in Response to Subsequent High Fat Feeding. Am J Physiol Regul Integr Comp Physiol 2008.
25. Sullivan MP, Cerda JJ, Robbins FL, Burgi, CW, Beatty RJ. The gerbil, hamster, and guinea pig as rodent models for hyperlipidemia. Lab Anim Sci 43: 575–578, 1993.
26. Nagata R, Nishio Y, Sekine O, Nagai Y, Maeno Y, Ugi S, Maegawa H, Kashiwagi A. Single nucleotide polymorphism (- 468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis [corrected]. J Biol Chem 279:29031-29042, 2004.
27. Sumiyoshi M, Sakanaka M, Kimura Y. Chronic intake of high fat and high-sucrose diets differentially affects glucose intolerance in mice. J Nutr 136:582-587, 2006.
28. Barbosa CR, Albuquerque EM, Faria EC, Oliveira HC, Castilho LN. Opposite lipemic response of Wistar rats and C57BL/6 mice to dietary glucose or fructose supplementation. Braz J Med Biol Res 40(3):323-31, 2007.
29. Farah V, Elased KM, Chen Y, Key MP,Cunha TS, Irigoyen MC, Morris M. Nocturnal hypertension in mice consuming a high fructose diet. Auton Neurosci 30;130(1-2):41-50, 2006.
30. Cunha TS, Farah V, Paulini J, Pazzine M, Elased KM, Marcondes FK, Cláudia Irigoyen M, De Angelis K, Mirkin LD, Morris M. Relationship between renal and cardiovascular changes in a murine model of glucose intolerance. Regul Pept Mar 1;139(1-3):1-4, 2007.
31. Merat S, Casanada F, Sutphin M, Palinski W, Reaven PD. Western-type diets induce insulin resistance and hyperinsulinemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis compared with normoinsulinemic mice in which similar plasma cholesterol levels are achieved by a fructose-rich diet. Arterioscler Thromb Vasc Biol 19:1223-1230, 1999.

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