Fructose and hepatic insulin resistance

Abstract

Excessive caloric intake in a form of high-fat diet (HFD) was long thought to be the major risk factor for development of obesity and its complications, such as fatty liver disease and insulin resistance. Recently, there has been a paradigm shift and more attention is attributed to the effects of sugar-sweetened beverages (SSBs) as one of the culprits of the obesity epidemic. In this review, we present the data invoking fructose intake with development of hepatic insulin resistance in human studies and discuss the pathways by which fructose impairs hepatic insulin action in experimental animal models. First, we described well-characterized pathways by which fructose metabolism indirectly leads to hepatic insulin resistance. These include unequivocal effects of fructose to promote de novo lipogenesis (DNL), impair fatty acid oxidation (FAO), induce endoplasmic reticulum (ER) stress and trigger hepatic inflammation. Additionally, we entertained the hypothesis that fructose can directly impede insulin signaling in the liver. This appears to be mediated by reduced insulin receptor and insulin receptor substrate 2 (IRS2) expression, increased protein-tyrosine phosphatase 1B (PTP1b) activity, whereas knockdown of ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, increased insulin sensitivity. In summary, dietary fructose intake strongly promotes hepatic insulin resistance via complex interplay of several metabolic pathways, at least some of which are independent of increased weight gain and caloric intake. The current evidence shows that the fructose, but not glucose, component of dietary sugar drives metabolic complications and contradicts the notion that fructose is merely a source of palatable calories that leads to increased weight gain and insulin resistance.

Keywords: NAFLD; Sugar; fructose; insulin resistance; obesity; sugar-sweetened beverages.

Figure 1.

Clinical Studies of Fructose and Hepatic Insulin Resistance The top right side of the figure depicts short-term (~1–2 weeks) clinical studies in humans on a regular diet supplemented with additional 3–4g/kg of fructose. The top left side of the figure lists long-term (3–12 weeks) studies of fructose supplementation in human subjects on a regular diet, but with much lower amount of fructose. These short- and long-term studies document that hypercaloric fructose supplementation is associated with development of hepatic insulin resistance. The bottom panel depicts crossover studies of isocaloric short- (bottom right) and long-term (bottom left) consumption of dietary fructose. These studies demonstrate that weight maintaining diet supplemented with fructose is associated with hepatic insulin resistance. Lastly, epidemiologic evidence indicates that increased fructose intake, in sugar-sweetened beverages (SSB) on a population level, leads to outcomes suggestive of insulin resistance, even when adjusted for BMI or energy intake.

Figure 2.

Fructose Activated Pathways That Lead to Insulin Resistance Fructose is metabolized in hepatocytes by ketohexokinase (KHK). This leads to decreased adenosine triphosphate (ATP) levels and increased uric acid production. Uric acid further stimulates KHK expression in a feed forward loop. Fructose strongly increases hepatic de novo lipogenesis (DNL). This is mediated through sterol regulatory element-binding protein 1c (SREBP1c) and carbohydrate-responsive element-binding protein (ChREBP) transcription factors that are at least in part regulated through peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1b). They upregulate enzymes involved in free fatty acid (FFA) synthesis, such as ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1). Accumulation of FFA in hepatocyte leads to insulin resistance, either directly or through buildup of more complex lipids and intermediates of lipid oxidation. In addition to DNL, fructose decreases mitochondrial fatty acid oxidation (FAO). This leads to a further decrease in ATP, decreased mitochondrial size and attenuated mitochondrial proteome, whereas mitochondrial fission, protein acetylation and reactive oxygen species (ROS) are increased. Decreased FAO is signaled through upregulation of ChREBP and a decrease in peroxisome proliferator activated receptor alpha (PPARα). Mitochondrial dysfunction and decreased FAO have been strongly linked with the development of hepatic insulin resistance. Fructose also strongly induces ER stress and hepatic inflammation, both of which can lead to hepatic insulin resistance.

Figure 3.

Effects of Fructose on Insulin Signaling Pathway Insulin binds to the insulin receptor (IR), which leads to autophosphorylation of IR and triggers the insulin signaling cascade. Insulin receptor substrates (IRS) dock to IR to further propagate insulin signaling by interacting with phosphoinositol 3 kinase. PI3K phosphorylates phosphoinositol diphosphate to phosphoinositol triphosphate (PIP₃), which activates 3-phosphoinositide-dependent protein kinase 1 (PDPK1) that subsequently phosphorylates Akt, one of the critical nodes in the insulin-signaling network. Fructose intake has been associated with a decrease in IR and IRS2 expression, with no change in IRS1 levels, leading to decreased Akt phosphorylation. Additionally, fructose may increase protein-tyrosine phosphatase 1b (PTP1b) activity, which results in dephosphorylation of IR and IRS2, further leading to decreased Akt phosphorylation. This process may not be entirely independent of lipogenesis as fructose through PTP1b induces protein phosphatase 2A (PP2A), which increases SREBP1. Whereas dietary fructose decreases insulin signaling, knockdown of ketohexokinase (KHK) reduces fructose metabolism and increases phosphorylation of Akt.