Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans
Kimber L. Stanhope ... Lars Berglund, Peter J. Havel
Kimber L. Stanhope ... Lars Berglund, Peter J. Havel
Published May 1, 2009
Citation Information: J Clin Invest. 2009;119(5):1322-1334. doi:10.1172/JCI37385.
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Categories: Research Article Cardiology

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Abstract

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle–triglyceride and –cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Authors

Kimber L. Stanhope, Jean Marc Schwarz, Nancy L. Keim, Steven C. Griffen, Andrew A. Bremer, James L. Graham, Bonnie Hatcher, Chad L. Cox, Artem Dyachenko, Wei Zhang, John P. McGahan, Anthony Seibert, Ronald M. Krauss, Sally Chiu, Ernst J. Schaefer, Masumi Ai, Seiko Otokozawa, Katsuyuki Nakajima, Takamitsu Nakano, Carine Beysen, Marc K. Hellerstein, Lars Berglund, Peter J. Havel

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Proposed mechanisms underlying the differential effects of fructose and ...

Figure 6

Proposed mechanisms underlying the differential effects of fructose and glucose consumption.

Hepatic glucose metabolism is regulated by phosphofructokinase, which is inhibited by ATP and citrate when energy status is high, thus limiting hepatic uptake of dietary glucose and production of DNL substrates. The hepatic metabolism of dietary fructose is independent of energy status, resulting in unregulated hepatic fructose uptake and increased lipogenesis. The resulting increased hepatic lipid decreases apoB degradation and increases production/secretion of VLDL-TG, mainly as TG-rich VLDL1 (29). This, along with chylomicron competition for LPL-mediated TG hydrolysis and reduced LPL activation by insulin, results in longer VLDL residence time, allowing for augmented cholesteryl ester transfer protein–mediated (CETP-mediated) lipid exchanges with LDL and increased LDL-TG and RLP levels. Hydrolysis of LDL-TG by hepatic lipase increases plasma sdLDL concentrations. After an overnight fast, DNL is no longer elevated and VLDL and chylomicrons remnants have been cleared; thus, plasma TG levels are normal. Postprandially, the increment of plasma apoB levels is associated with VLDL particles; in the fasting state, it is presumably associated with sdLDL, which turns over more slowly. As SAT is more sensitive to insulin activation of LPL activity than VAT, reduced postmeal insulin exposure may lead to less TG uptake in SAT and thus increased TG uptake/accumulation in VAT. Increased hepatic lipid supply may also induce hepatic insulin resistance, possibly through increased levels of diacylglycerol, which activates novel PKC (85). Novel PKC decreases tyrosine phosphorylation of the insulin receptor/insulin receptor substrate 1, resulting in increased hepatic glucose production, impaired glucose tolerance, and increased fasting glucose and insulin concentrations. oxLDL, oxidized LDL.