Health Implications of Fructose Consumption: A Review of Recent Data

A Review of Recent Data

Salwa W Rizkalla

Disclosures

Nutr Metab. 2010;7 

In This Article

Fructose and Insulin Resistance

Evidence from Experimental Studies in Animals

There is much evidence in animal models supporting the notion that fructose when consumed in high amounts contributes to hepatic and peripheral insulin resistance.[70,71,119,120] In rats fed a fructose- rich diet Thorburn et al,[120] using the hyperinsulinemic euglycemic clamp method, demonstrated lower insulin stimulated glucose uptake in hindlimb muscles and adipose tissues than in rats fed a dextrose rich diet. A decrease in skeletal and hepatic insulin receptor number, determined by an in situ autoradiography technique, as well as a decrease in their gene expression was found by 66% fructose feeding for 2 weeks in rats.[121] Moreover, decreased insulin-induced insulin receptor phosphorylation was demonstrated in the liver of fructose fed rats[122] A 57% fructose diet induced, similarly, a decrease in insulin stimulated glucose incorporation into lipids but increased the antilipolytic action of insulin in isolated adipocytes of normal rats.[13,69]

Three weeks of a 10% fructose-rich diet[123] induced adaptive changes in islets of rats: decreased β-cell mass with increasing apoptotic cells, increased glucose-induced insulin release and islet glucose metabolism, increased glucokinase, but not hexokinase activity. These modifications resulted in an increase of insulin release in spite of marked β-cell mass reduction leading to hyper insulinemia, impaired glucose tolerance and insulin resistance.

Here again, the high fructose fed rats used as a model of insulin resistance to evaluate the islet adaptive changes in such situations (peoples at risk of developing type 2 diabetes). Recently, the group of Havel[124] has demonstrated that 4 months of sustained fructose consumption (20% of energy) accelerate the onset of type 2 diabetes in a model of pylogenic obese type 2 diabetic rats. The presence of an antioxidant with insulin sensitizing activity ameliorates the effect of fructose by improving glucose homeostasis, which is likely due to preserving β-cell function.

Moreover, fructose-fed rats demonstrated a defect in neural insulin signaling pathway in the brain. Decreased insulin stimulated-tyrosine phosphorylation of insulin receptors and insulin receptor substrate 1 (IRS-1) were demonstrated in the fructose-fed hamsters.[125] Also insulin-mediated phosphorylation of residues necessary for activation of another key effector of insulin signalling was markedly decreased.

Nevertheless, high fructose-fed rat model is often used in many studies as a dietary model of insulin resistance.[15,126,127] In rodents, therefore, there is no doubt that high-fructose feeding cause insulin resistance.

Acute Studies in Humans

In humans, hardly any evidence exists to confirm directly the negative effects of fructose on insulin sensitivity. Fructose has been considered as a therapeutic tool in the diet of diabetic patients due to its low glycemic index[128] and because it's initial metabolic steps do not need insulin.[79] It elicits an increase in energy expenditure that has been suggested to be beneficial for obese subjects with or without diabetes.[97,129] The effect of fructose infusion on hepatic insulin sensitivity in conditions of moderate hyperglycaemia has been studied during hyperglycaemic clamp study with or without infusion of 16.7 μmol/kg/min fructose.[130] The acute fructose infusion induced both extra hepatic and hepatic insulin resistance, which has been suggested to be secondary to an increased intrahepatic glucose 6-phosphate synthesis. These results raise questions as to whether ingested fructose as part of the diet may have the same effects.

Chronic Studies in Humans

Consuming an extra 1000 Kcal as fructose, which is a high amount, for one week induced a reduction in both insulin binding and insulin sensitivity when compared to effects after the same amount of glucose in young healthy subjects.[131] In a special case, the presence of fructose as the unique source of carbohydrate in a very low calorie diet (600 Kcal) postponed by two weeks the expected amelioration of a low calorie diet for plasma glucose and insulin levels as well as insulin binding.[132]

Moderate fructose intake (1/3 carbohydrate intake), however, in healthy subjects for 2 weeks has no deleterious effect on insulin sensitivity compared to the same amount of sucrose.[133,134]

In healthy subjects, consuming up to1.5 g fructose/kg body weight per day for 4 weeks increased plasma triglycerides but without inducing insulin resistance.[135] The authors of the latter study were able, however, to detect early molecular alterations in only two skeletal muscle genes. They suggested, therefore, that these alterations could induce later whole body insulin resistance.[135] The same group showed that fructose overfeeding (3.5 g fructose/kg fat-free mass/day, again a high dose) for 6 days produces hepatic insulin resistance in men, whereas these effects are markedly blunted in healthy young men.[136]

In diabetic subjects, other chronic studies could not detect any deleterious effects of moderate fructose intakes: 30 g fructose/day compared to starch as a part of 1400 - 1600 Kcal for 8 weeks,[112] or one year[137] or 60g fructose/day for 12 weeks,[138] or 6 months.[139]

Using high amount of fructose, however, as fructose-sweetened beverages at 25% of energy requirements for 10 weeks, led to an increase in fasting plasma glucose and insulin levels and decreased insulin sensitivity compared to the same amount of glucose sweetened beverages.[23]

Epidemiological Studies

In a prospective large cross-sectional study -Nurses Healthy Study I and II- an association was found between high intake of fructose and the high C-peptide concentrations.[140] Due to this association, the authors suggested that fructose intake may play a role in the development of insulin resistance and type 2 diabetes. However, causal relationship could not be identified from this study design.

In a longitudinal study, Janket et al[141] evaluated the relationship between risk of type 2 diabetes and intakes of total caloric sweeteners, sucrose, fructose, glucose and lactose in a cohort of 38,480 female health professionals. Neither fructose, glucose nor sucrose was related to the risk of developing type 2 diabetes. Therefore, no difference could be detected between the different sugars.

While some investigators are able to detect deleterious effects with high doses or could not detect with moderate doses, others found beneficial effects. Koivisto et al[113] demonstrated that the substitution of moderate amounts of fructose (45–65 g/day: 20% of carbohydrate calories) for complex carbohydrates for 4 weeks improves insulin sensitivity in type 2 diabetic patients. Similarly Reiser et al[102] found that patients adapted to 20% of energy as fructose for 5 weeks had improved plasma glucose responses to a glucose charge compared to a group adapted to starch diet. In a group of children with diabetes 1g fructose/kg/day (30g/day maximum) with guar gum for three weeks was found to decrease HBA1c but with increased glucoseuria.[142]

In small doses, however, dietary fructose appears to be beneficial in enhancing glucose tolerance.[143,144] The addition of small doses of fructose to a glucose meal can enhance hepatic glucose disposal. Moreover, the addition of small amounts of fructose to orally ingested glucose increases hepatic glycogen synthesis and reduces glycemic responses in subjects with type 2 diabetes.[145] This effect was found to be due to a rise in Fructose-1-P which has an important indirect effect on hepatic glucose metabolism by modulating glucokinase activity which is a key regulatory enzyme required for the formation of glucose -6-P. Glucokinase also is involved in the inhibition of hepatic glucose release by portal hyperglycemia.[146] Fructose-1-P, at low levels antagonizes a glucokinase regulatory protein, enhancing, then, glucokinase activity. Stimulation of hepatic glycogen synthesis by this mechanism may be of potential therapeutic value. However, high doses could be deleterious.

Recently, a meta-analysis[40] demonstrated that fructose intakes from 0 to ≥ 90g/d have a beneficial effect on HbA1c. This meta-analysis was done on a group of studies in healthy, glucose intolerant and type-2 diabetes. The authors, however, are aware that 50 to 100g is a high fructose intake that could affect postprandial triglycerides. Whether a lowering or maintaining of low HbA1c with these doses of fructose would persist is unknown. We could conclude that moderate fructose consumption (<50 g/d, or >10%ME) appears acceptable and potentially beneficial.

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