The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 12 No. 2 • April 2009

Upregulation of Aldose Reductase During Foam Cell Formation: Possible Link Among Diabetes, Hyperlipidemia, and Atherosclerosis

The enzyme aldose reductase is the rate-limiting enzyme in the polyol pathway, whereby aldehydes as well as sugars such as glucose and galactose are metabolized to produce sorbitol. Sorbitol is then metabolized by the enzyme sorbitol dehydrogenase to fructose. Increased fructose is a source of AGE production and oxidative stress. Various pathological conditions have been found to be improved by inhibitors of aldose reductase, including impaired nerve conduction velocity and symptoms of neuropathy, as are found in diabetes. Recent research using LDL receptor-deficient diabetic mice was reported to find increased atherosclerotic lesions in the transgenic animals overexpressing human aldose reductase.1

A study1 using gene chips to identify differences in gene expression during foam cell formation reported that there was “a significant increase of aldose reductase mRNA expression after treatment of primary human blood monocyte-derived macrophages with oxidized low-density lipoprotein (oxLDL).” The authors therefore hypothesized that increased aldose reductase expression in human foam cell formation may represent a novel proinflammatory pathway leading to increased oxidative stress and to an increased risk of atherosclerosis.

The authors report in their new study2 that there was a significant increase of aldose reductase expression in human macrophages under hyperglycemic as compared to normoglycemic conditions. Moreover, “[e]xposure of macrophages to oxLDL resulted in a 10-fold increase of AR [aldose reductase] activity under hyperglycemic, but not normoglycemic conditions.” Pretreatment of macrophages with an aldose reductase inhibitor (the drug epalrestat) before and throughout exposure to oxLDL resulted in a significantly reduced formation of reactive oxygen species (ROS) under hyperglycemic conditions. The authors interpret their findings to suggest that “under hyperglycemic conditions ~20% to 30% of the oxidative stress in macrophage foam cells is attributable to AR activity.”

Interestingly, there are a number of readily available, relatively inexpensive natural products that inhibit aldose reductase. For example, a recent paper3 reports that a hot water extract of Matricaria chamomilla (chamomile tea) showed potent inhibition against aldose reductase and that its components umbelliferone, esculetin, luteolin, and quercetin “could significantly inhibit the accumulation of sorbitol in human erythrocytes.” The authors report that the major flavonoid components of chamomile are apigenin, luteolin, and quercetin, which comprise 16.8%, 1.9%, and 9.9%, respectively, of total flavonoids. The authors conclude: “These results clearly suggested that daily consumption of chamomile tea with meals could contribute to the prevention of the progress of hyperglycemia and diabetic complications.”


  1. Cho et al. “Induction of dendritic cell-like phenotype in macrophages during foam cell formation,” Physiol Genomics 29:149-160 (2007).
  2. Gleissner et al. “Upregulation of aldose reductase during foam cell formation as possible link among diabetes, hyperlipidemia, and atherosclerosis,” Arterioscler Thromb Vasc Biol 28:1137-43 (2008).
  3. Kato et al. “Protective effects of dietary chamomile tea on diabetic complications,” J Agric Food Chem 56:8206-11 (2008).

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