Aldose reductase inhibitors in the prevention of diabetic complications
- Eli A Friedman, MD
Eli A Friedman, MD
- Distinguished Teaching Professor of Medicine
- Downstate Medical Center, Brooklyn, New York
- Section Editors
- Gary C Curhan, MD, ScD
Gary C Curhan, MD, ScD
- Section Editor — Chronic Kidney Disease
- Professor of Medicine
- Harvard Medical School
- David M Nathan, MD
David M Nathan, MD
- Editor-in-Chief — Endocrinology
- Section Editor — Diabetes Mellitus
- Professor of Medicine
- Harvard Medical School
The Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study (UKPDS) , and other studies have demonstrated the central role of hyperglycemia in the pathogenesis of diabetic microvascular complications such as retinopathy, nephropathy, and neuropathy. In addition to degree of hyperglycemia as a risk factor, mounting evidence suggests that both the incidence and severity of diabetic microvasculopathy are modulated by individual genotypes . Although the molecular basis of how hyperglycemia causes tissue injury is still being defined, two proposed mechanisms, both linked to what has been termed "oxidative stress," are the downstream impact of accumulation of sorbitol and advanced glycosylation end products. (See "Glycemic control and vascular complications in type 1 diabetes mellitus".)
Oxidative stress is strongly implicated as a mediator of multiple diabetes-induced microvascular complications, including nephropathy, retinopathy, and distal symmetric polyneuropathy. Key mediators of glucose-induced oxidative injury are superoxide anions and nitric oxide (NO). One proposed sequence of how hyperglycemia leads to oxidative stress is that high ambient glucose levels increase mitochondrial synthesis of reactive oxygen species, activate protein kinase C (PKC), and overexpress sorbitol. Superoxides are believed to underlie many of the oxidative changes in hyperglycemic conditions, including increases in aldose reductase and protein kinase C activity.
Clinical trials of agents that quench the effects of formed reactive oxygen species in rodents, including vitamin E, C, and alpha-lipoic acid have had limited success in improving cardiovascular outcomes. Statins, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and thiazolidinediones may improve cardiovascular outcomes among patients with diabetes by reducing production of reactive oxygen species at a more proximal part of the cascade, thereby more effectively decreasing the oxidative stress burden. Statins and ACE inhibitors/ARBs appear synergistic in reducing oxidative stress and vascular disease .
However, despite strong evidence that oxidative stress is associated with diabetic complications including nephropathy, retinopathy, and neuropathy, clinical trials of several antioxidants (such as aldose reductase inhibitors, alpha-lipoic acid, vitamins C and E, and growth factors) in diabetic neuropathy and retinopathy, although strongly positive in rodents (with several exceptions ), have not established therapeutic efficacy .
The possible role of the sorbitol pathway in this process remains controversial [6-8]. Glucose that enters cells is metabolized in part to sorbitol via the enzyme aldose reductase. Aldose reductase has a low affinity for glucose, and little substrate is processed under physiologic conditions. However, glucose conversion to sorbitol is more pronounced with chronic hyperglycemia. The accumulation of sorbitol within the cells results in a rise in cell osmolality and a decrease in intracellular myoinositol; these changes in turn lead to a decrease in Na-K-ATPase activity and a possible shift in the redox potential within cells. Hyperglycemia may also contribute directly to the decline in cell myoinositol levels by competitively interfering with myoinositol uptake from the extracellular fluid via a sodium-myoinositol cotransporter .
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