Insulin Resistance in Metabolic Syndrome – Obesity-associated mechanisms

Stanhope and Havel, in a study published in 2008 [6, p.16], for instance elucidate the mechanisms via which consumption of a diet rich in fructose, but not glucose, contributes to the onset of visceral adiposity, dyslipidemia and insulin resistance – three features that are associated with metabolic syndrome. In this study, development of insulin resistance in the liver cells is attributed, primarily, to development of such resistance in adipose tissue, which, in turn, is associated with increased visceral adiposity that arises with increased production of very low-density lipoproteins (VLDL) induced by enhanced levels of fructose [6]. The authors for instance suggest that “10 weeks of fructose consumption markedly increases postprandial triglyceride concentrations in older adults”, with such increases noted to occur within 24 hours in younger adults following fructose consumption [6, p. 17]. Such hypertriglyceridemia is associated with increases in de-novo lipogenesis, whose products are involved in feedback regulation in the production and secretion of VLDL. Increased triglycerides are also associated with increased deposition of lipids in the visceral adipose tissue [6]. The identification of visceral adiposity as a causative factor in insulin resistance is suggested to result from increased “portal delivery of free fatty acids to the liver” from the visceral fat [6, p. 16]. Apart from the resistance developed due to visceral adiposity, it has also been suggested that fructose could independently lead to insulin resistance in the hepatocytes, through its provision of substrates for lipogenesis, which leads to a lipid overload associated with activation of protein kinase C and accumulation of triglycerides [6].

Rendering support to the suggestion that insulin resistance in fructose intake arises out of lipogenesis-promoting activity of fructose, Huang et al. [7, p. 20] argue out such effects to result from “impaired glucose and lipid metabolism and increased proinflammatory cytokine expression.” Using human hepatoma (HepG2) cells, the study evaluated how fructose affects hepatic metabolism of triglycerides in vitro, by incubating the cells in a medium that contained either glucose or a combination of glucose and fructose [7]. The study quantified the level of triglycerides by evaluating intra-cellular and extracellular concentrations of palmitate and oleate by GC-mass spectroscopy [7, p. 23]. The study results indicated that triglyceride generation was significantly higher in fructose-treated cells as compared to glucose-treated ones, with palmitate levels in cells treated with fructose at diabetic-range glucose concentrations being as high as two folds those in cells treated with glucose alone. Extracellular concentrations of oleate were also found to be as high as four folds in fructose-treated cells as compared to cells treated with glucose only. Following such evidence of increased synthesis of triglycerides in fructose-treated cells, the study’s second assay concerned the exploration of mechanism(s) via which fructose led to increased synthesis of triglycerides. Go to lipogenesis.

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