Polymorphisms of the Aldose Reductase Gene and Susceptibility to Diabetic Microvascular Complications

Abstract

Diabetes is a major cause of mortality and morbidity due to the long term microvascular complications of this disease. There is now convincing evidence to show that genetic factors together with elevated blood glucose play an important role in the susceptibility to diabetic nephropathy as well as retinopathy. The polyol pathway is thought to play an important role in the pathogenesis of diabetic microvascular complications. Aldose reductase is the first and rate-limiting enzyme of the polyol pathway. Polymorphisms in the promoter region as well as elsewhere in the gene have been associated with susceptibility to nephropathy, retinopathy as well as diabetic neuropathy. These associations have been replicated in patients with either type 1 or type 2 diabetes mellitus as well as across ethnic groups. These polymorphisms in the promoter region are also associated with expression of the gene. Although clinical trials using inhibitors of aldose reductase to treat diabetic microvascular complications have largely been unsuccessful, the identification of the susceptibility genes may help in the design of future drug regimens.

A Selective Aldose Reductase Inhibitor of a New Structural Class Prevents or Reverses Early Retinal Abnormalities in Experimental Diabetic Retinopathy

“…These results confirm and extend our previous findings with sorbinil (1,9), an ARI of a different structural class and a less selective inhibitor of aldose reductase. The data are also consistent with recent evidence that deletion of the gene for aldose reductase prevents retinal abnormalities triggered by diabetes in db/db mice (2), and they are supportive of the genetic data linking aldose reductase alleles associated with elevated expression of the protein to higher risk for development of diabetic retinopathy in humans (19). Although each of these different types of data has potential limitations when taken individually (e.g., unsuspected off-target effects in the drug studies, unknown but functionally meaningful consequences of gene deletion, and incomplete definition of the functional effects of gene polymorphisms), when taken together they make a compelling case that aldose reductase plays a critical role in the development of diabetic retinopathy.…”

The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification

“…Mice overexpressing AKR1B1 in the lens or Schwann cells show greater susceptibility to diabetic cataractogenesis or neuropathy, supporting the idea that AKR1B1 is involved in the development of some diabetic complications (Lee et al, 1995;Song et al, 2003). Nevertheless, the role of AKR1B1 in diabetes remains controversial and the reader is directed to several extensive reviews on this topic (Demaine, 2003;Chung and Chung, 2003;Srivastava et al, 2005b;Oates, 2002). Numerous clinical studies have been conducted to test the effect of AKR1B1 inhibition on diabetic complications.…”

Mechanisms by which diabetes increases cardiovascular disease

“…However, ARI were not successful for treatment of other microvascular diabetic complications, but different AR inhibitors were used in different trials, which complicates interpretation [14]. Furthermore, AR polymorphisms in different individuals may be responsible for different susceptibility for ARI therapy [15]. Hyperglycemia is known to alter AR activity [16], thus the dosage of ARI may not have been equally efficient in all individuals tested.…”