Diabetes/ Insulin Resistance
280

Effect of High Fructose/Sucrose Diets on Plasma
Lipid Levels and Insulin Resistance in Rodents

High Fructose Diets
Refined carbohydrate sources such as high fructose corn syrup(HFCS) are used in many processed foods and surveys in the U.S.
have suggested that the intake of this sweetener has increased
dramatically since the 1970s (3). As we have learned over the past few
decades, an excess intake of refined carbohydrates is associated withincreased weight gain, hypertriglyceridemia (hyper-TG), and insulin
resistance (IR) in humans and animal models (5, 1). In order tounderstand more about the impact of refined carbohydrates on healthand therapies to reduce these metabolic syndrome (MS) phenotypes,
certain rodent models have been useful. Purified diets containing
around 60% - 70% (by energy) fructose or sucrose (which is a 50:50
molar mixture of fructose and glucose) are capable of elevating TG
and glucose production in the liver, ultimately leading to IR andhyper-TG relative to diets containing mainly glucose carbohydrate
sources (i.e. dextrose, corn starch) (5, 1). Typically, rodent chow diets
contain only 4% sucrose and < 0.5% free fructose with mostcarbohydrate as both digestible starch and non-digestible fiber fromgrain sources (i.e. wheat, corn, soy). In contrast, low-fat purified diets
can contain higher levels of sucrose and this will depend heavily on
the formula being used. If desired, it is easy to modify purified dietsby manipulating the carbohydrate sources to promote MS while
maintaining essential nutrients at recommended levels. However,each rodent model responds differently to high levels of sucrose andfructose.

Rat Models
Sprague-Dawley and Wistar rats are both established models ofsucrose-induced IR and hyper-TG (12,10). Both of these phenotypes
can develop as quickly as 2 weeks when these animals are fed a dietcontaining 68% sucrose (by energy) relative to one with the samelevel of carbohydrate as corn starch (12). It appears that the fructose
component of sucrose is largely responsible for the hyper-TG and IR
produced by high sucrose diets (13, 17, 16). While a very high concentration of sucrose or fructose induces this phenotype quickly in malerats, a lower level of sucrose (17% of energy) can also allow for IR
when fed to rats for 30 weeks relative to a diet containing mainly
corn starch (11). Furthermore, gender is important in the development of sucrose induced IR and hyper-TG in rats as females (unlikemales) are typically not responsive to elevations in dietary sucrose (6).
Other than IR and hyper-TG, high sucrose or fructose diets canpromote marginal weight gain in rats, but this typically requires a
prolonged period of time and a significantly greater energy intake (4).

Glucose (mg/dl)

by Matthew R. Ricci, Ph.D. VP, Science Director, Research Diets, Inc. andMichael A. Pellizzon, Ph. D., Senior Scientist, Research Diets, Inc.

260

STSU

240

F/G
F/ST

220
200
180

Glucose Area Under Curve(mg/dl - 80 min)

ReportRepeat

4000

*

3500

Revise

*

3000
4500

*

ST
SU
F/G
F/ST

2000
1500
1000
500
0

160
140
120
100
020

40

60

80

100

Time (min)Plot of plasma glucose (mg/dl) across time for starch (St)-sucrose (SU)-, fructose/glucose (F/G)-, and F/ST-fed rats in response to a glucose bolus of 0.4 g/kg body
wt injected intravenously. Values are means + SE for 10 rats/group. Inset: glucose
incremental area under the curve. Values are means + SE for 10 rats/group.
*Significantly different from ST-fed animals (P< 0.05).
Graphic respresention - for detail see reference (17).

Hamster Models
Similar to rats, hamsters fed high fructose diets (~60% of energy) may
develop IR and elevations in circulating TG levels after only 2 weeks
compared to those fed low fructose (7, 15). However, unlike rats,
hamsters fed high-sucrose diets (60% by energy) may not elevate TG
and develop only mild IR (7). Since sucrose is one-half fructose, itappears that the level of dietary fructose is quite important in therapid development of IR and hyper-TG in hamsters. Other factors,
including the addition of cholesterol (0.25%) may also allow theresearcher to induce a combination of hypercholesterolemia, greaterIR, and hyper-TG in this model compared to fructose alone (2) further
improving the fructose-fed hamster’s use as a model of dyslipidemia.

Mouse Models
In contrast to rats and hamsters, the mouse is used less frequently
as a model for sucrose/fructose-induced IR and hyper-TG as thecommonly used C57BL/6 mouse either does not develop IR ordevelops the phenotype more slowly (9, 14). Despite not developing IR,
glucose tolerance can be induced in C57BL/6 mice fed a high sucrose
diet (50% sucrose) relative to those fed a similar diet high in corn
starch from 10 – 55 weeks, which has been attributed to a reduced
pancreatic insulin secretion (14). However, the mouse genome is mucheasier to manipulate than that of the rat allowing for several knockout
models, including the LDLr KO mouse, to show responses (i.e.
hyper-TG) to high dietary fructose (8).

Diabetes/ Insulin Resistance
References

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1. Basciano, H., Federico, L. & Adeli, Khosrow, 2005. Fructose, insulin resistance, andmetabolic dyslipidemia. Nutrition & Metabolism, 2(1), p.5.
2. Basciano, H. et al., 2009. Metabolic effects of dietary cholesterol in an animal modelof insulin resistance and hepatic steatosis. American Journal of Physiology.
Endocrinology and Metabolism, 297(2), pp.E462-73.
3. Bray, G.A., Nielsen, S.J. & Popkin, B.M., 2004. Consumption of high-fructose cornsyrup in beverages may play a role in the epidemic of obesity. The American Journalof Clinical Nutrition, 79(4), pp.537-43.
4. Chicco, A. et al., 2003. Muscle lipid metabolism and insulin secretion are altered ininsulin-resistant rats fed a high sucrose diet. The Journal of Nutrition, 133(1),pp.127-33.
5. Daly, M.E. et al., 1997. Dietary carbohydrates and insulin sensitivity: a review of theevidence and Clinical implications. The American Journal of Clinical Nutrition,66(5), pp.1072-85.
6. Horton, T.J. et al., 1997. Female rats do not develop sucrose-induced insulinresistance. The American Journal of Physiology, 272(5 Pt 2), pp.R1571-6.
7. Kasim-Karakas, S.E. et al., 1996. Effects of dietary carbohydrates on glucose and lipid
metabolism in golden Syrian hamsters. The Journal of Laboratory and Clinical
Medicine, 128(2), pp.208-13.
8. Merat, S. et al., 1999. Western-type diets induce insulin resistance and hyperinsu
linemia in LDL receptor-deficient mice but do not increase aortic atherosclerosis
compared with normoinsulinemic mice in which similar plasma cholesterol levels areachieved by a fructose-rich diet. Arteriosclerosis, Thrombosis, and Vascular Biology,
9(5), pp.1223-30.
9. Nagata, R. et al., 2004. Single nucleotide polymorphism (-468 Gly to A) at thepromoter region of SREBP-1c associates with genetic defect of fructose-induced
hepatic lipogenesis [corrected]. The Journal of Biological Chemistry, 279(28),pp.29031-42.
10. Pagliassotti, M.J. et al., 2000. Developmental stage modifies diet-induced peripheral
insulin resistance in rats. American Journal of Physiology. Regulatory, Integrativeand comparative Physiology, 278(1), pp.R66-73.
11. Pagliassotti, M.J. & Prach, P.A., 1995. Quantity of sucrose alters the tissue pattern andtime course of insulin resistance in young rats. The American Journal of Physiology,269(3 Pt 2), pp.R641-6.
12. Pagliassotti, M.J. et al., 1996. Changes in insulin action, triglycerides, and lipid
composition during sucrose feeding in rats. The American Journal of Physiology,271(5 Pt 2), pp.R1319-26.
13. Sleder, J. et al., 1980. Hyperinsulinemia in fructose-induced hypertriglyceridemia inthe rat. Metabolism: Clinical and Experimental, 29(4), pp.303-5.
14. Sumiyoshi, M., Sakanaka, M. & Kimura, Y., 2006. Chronic intake of high-fat andhigh-sucrose diets differentially affects glucose intolerance in mice. The Journal ofNutrition, 136(3), pp.582-7.
15. Taghibiglou, C. et al., 2000. 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 m. The Journal of Biological Chemistry, 275(12),pp.8416-25.
16. Thorburn, A.W. et al., 1989. Fructose-induced in vivo insulin resistance and elevatedplasma triglyceride levels in rats. The American Journal of Clinical Nutrition, 49(6),pp.1155-63.
17. Thresher, J.S. et al., 2000. Comparison of the effects of sucrose and fructose on insulin
action and glucose tolerance. American Journal of Physiology. Regulatory, Integrativeand Comparative Physiology, 279(4), pp.R1334-40.

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