Fructose, insulin resistance, and metabolic dyslipidemia

Abstract

Obesity and type 2 diabetes are occurring at epidemic rates in the United States and many parts of the world. The "obesity epidemic" appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in the amount of dietary fructose consumption from high intake of sucrose and high fructose corn syrup, a common sweetener used in the food industry. A high flux of fructose to the liver, the main organ capable of metabolizing this simple carbohydrate, perturbs glucose metabolism and glucose uptake pathways, and leads to a significantly enhanced rate of de novo lipogenesis and triglyceride (TG) synthesis, driven by the high flux of glycerol and acyl portions of TG molecules from fructose catabolism. These metabolic disturbances appear to underlie the induction of insulin resistance commonly observed with high fructose feeding in both humans and animal models. Fructose-induced insulin resistant states are commonly characterized by a profound metabolic dyslipidemia, which appears to result from hepatic and intestinal overproduction of atherogenic lipoprotein particles. Thus, emerging evidence from recent epidemiological and biochemical studies clearly suggests that the high dietary intake of fructose has rapidly become an important causative factor in the development of the metabolic syndrome. There is an urgent need for increased public awareness of the risks associated with high fructose consumption and greater efforts should be made to curb the supplementation of packaged foods with high fructose additives. The present review will discuss the trends in fructose consumption, the metabolic consequences of increased fructose intake, and the molecular mechanisms leading to fructose-induced lipogenesis, insulin resistance and metabolic dyslipidemia.

Figure 1

Fructose-induced insulin resistance: evidence from euglycemic hyperinsulinemic clamp studies. Mean glucose levels (A) were slightly but significantly higher in fructose-fed vs. control animals during the last 30 mins of the clamp period (p < 0.01). Mean insulin levels (B) were slightly but not significantly higher in the fructose-fed vs. control hamsters during the clamp period. The glucose infusion rate (Ginf) (C) during the clamp period was significantly lower in fructose-fed vs. control animals (p < 0.01). The calculated insulin sensitivity index (S_I – see methods) (D) was also significantly lower in the fructose-fed vs. control hamsters (p = 0.03). Fructose-fed (n = 9), control hamsters (n = 10). (adapted from Taghibiglou et al. [100]).

Figure 2

Hepatic fructose metabolism: A highly lipogenic pathway. Fructose is readily absorbed from the diet and rapidly metabolized principally in the liver. Fructose can provide carbon atoms for both the glycerol and the acyl portions of triglyceride. Fructose is thus a highly efficient inducer of de novo lipogenesis. High concentrations of fructose can serve as a relatively unregulated source of acetyl CoA. In contrast to glucose, dietary fructose does NOT stimulate insulin or leptin (which are both important regulators of energy intake and body adiposity). Stimulated triglyceride synthesis is likely to lead to hepatic accumulation of triglyceride, which has been shown to reduce hepatic insulin sensitivity, as well as increased formation of VLDL particles due to higher substrate availability, increased apoB stability, and higher MTP, the critical factor in VLDL assembly.