Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

Abstract

Aldose reductase (AR), an enzyme widely believed to be involved in the aberrant metabolism of glucose and development of diabetic complications, is expressed at low levels in the mouse. We studied whether expression of human AR (hAR), its inhibition with lidorestat, which is an AR inhibitor (ARI), and the presence of streptozotocin (STZ)-induced diabetes altered plasma fructose, mortality, and/or vascular lesions in low-density lipoprotein (LDL) receptor-deficient [Ldlr(Ϫ/Ϫ)] mice. Mice were made diabetic at 12 weeks of age with low-dose STZ treatment. Four weeks later, the diabetic animals (glucose Ͼ 20 mM) were blindly assigned to a 0.15% cholesterol diet with or without ARI. After 4 and 6 weeks, there were no significant differences in body weights or plasma cholesterol, triglyceride, and glucose levels between the groups. Diabetic Ldlr(Ϫ/Ϫ) mice receiving ARI had plasma fructose levels of 5.2 Ϯ 2.3 g/ml; placebo-treated mice had plasma fructose levels of 12.08 Ϯ 7.4 g/ml, p Ͻ 0.01, despite the induction of fructosemetabolizing enzymes, fructose kinase and adolase B. After 6 weeks, hAR/Ldlr(Ϫ/Ϫ) mice on the placebo-containing diet had greater mortality (31%, n ϭ 9/26 versus 6%, n ϭ 1/21, p Ͻ 0.05). The mortality rate in the ARI-treated group was similar to that in non-hAR-expressing mice. Therefore, diabetic hAR-expressing mice had increased fructose and greater mortality that was corrected by inclusion of lidorestat, an ARI, in the diet. If similar effects are found in humans, such treatment could improve clinical outcome in diabetic patients.Although the relationship between hyperglycemia and a number of vascular disorders is well established, responsible pathways are still unclear. Methods to define these pathways have been hindered by the difficulty of reproducing human diabetic complications in animal models. This has especially been the case for macrovascular disease (Goldberg and Dansky, 2006). In part, this is because of the difficulty of controlling other risk factors in diabetic setting; many atherosclerosisprone diabetic mice become severely hyperlipidemic. Thus, severe hypercholesterolemia in the mouse might obscure the vascular-toxic effects of hyperglycemia (Kanter et al., 2007).Several pathways have been implicated in glucose-induced cellular toxicity (Reusch, 2003). One of these, the polyol pathway, is mediated by the enzyme aldose reductase (AR), an enzyme whose activity is markedly lower in mice than in humans (Hwang et al., 2002;Vikramadithyan et al., 2005). Perhaps, for this reason, by expressing human AR (hAR) in mice, atherosclerosis was increased in the presence of streptozotocin (STZ)-induced diabetes (Vikramadithyan et al., 2005).To determine whether pharmacologic inhibition of AR altered complications in diabetic hAR-expressing LDL receptor knockout [Ldlr(Ϫ/Ϫ)] mice, a blinded study was performed. We first showed that hAR expression and its inhibition alter plasma levels of fructose, a product of the polyol pathway. Lidorestat, a potent AR inhibitor (ARI), reduced mortality r...

Human Aldose Reductase Expression Accelerates Atherosclerosis in Diabetic Apolipoprotein E−/− Mice

“…But critically, the ARI lidorestat did not increase lesion size. 28 The absence of atheroprotection in AR knockout mice in the apoE−/− background warrants investigation of potential compensation from other genes that may have adversely affected the phenotype. Or this suggests that a minimal amount of AR activity is necessary for optimal arterial health, while greater amounts can be toxic.…”

Intestinal Absorption of Fructose

“…Fructose is synthesized in the kidney and other organ systems from glucose by the polyol pathway, which then exports endogenous fructose into the blood. Systemically inhibiting the polyol pathway with the aldose reductase inhibitor lidorestat reduces plasma fructose concentrations (97). In humans, the cerebrospinal fluid has almost 20-fold greater fructose concentrations (~0.18 mM by GCMS) than those in plasma and cord venous blood, suggesting that endogenous production is likely responsible for virtually all fructose found in the brain (55).…”

Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

“…Thus, it appears that hyperglycemia is needed and might need to be sufficiently increased to provide substrate for AR. In contrast, in the presence of higher cholesterol levels, AR effects were “swamped” 100, and AR inhibitors (ARIs) also did not alter lesion extent. Others have found increased AR expression in activated macrophages and suggested that this enzyme is inflammatory because AR inhibition led to reduced oxidative stress 101, 102.…”