Aldose Reductase Inhibitors

Aldose Reductase Inhibitors

Also called: ARIs

Summary

Aldose reductase inhibitors (ARIs) are an experimental class of medications that inhibit an enzyme (protein that produces chemical reactions in the body) called aldose reductase. This enzyme normally increases the rate at which aldoses (types of sugars) are reduced to sorbitol, a sugar alcohol. Sorbitol can cause problems for people with diabetes, who are vulnerable to high glucose (blood sugar).

When too much sorbitol becomes trapped in the eye or nerve cells, it can cause cataracts (clouding of the eye lens) or damage nerve cells in the eyes of people with diabetes. This can cause an eye disorder known as diabetic retinopathy. Excess sorbitol may also be involved in a common nerve disease known as diabetic neuropathy and a common kidney disease called diabetic nephropathy.

Aldose reductase inhibitors are being studied as a potential treatment to prevent or control damage to the eyes, nerves and kidneys in people with diabetes.

About aldose reductase inhibitors

Aldose reductase inhibitors are medications that inhibit the actions of aldose reductase, an enzyme (protein that produces chemical reactions in the body) that can potentially increase the level of glucose (blood sugar) in a person’s bloodstream.

Aldose reductase normally increases the rate at which aldoses (types of simple sugars) are reduced to sorbitol, a type of sugar alcohol. The body uses sorbitol slowly and, if diabetes is present, has trouble absorbing it. This contributes to cellular damage.

The reduction of sorbitol is a chemical reaction that happens in three parts:

  • A compound (substance made by combining two or more elements) loses oxygen.
  • A compound or element gains hydrogen (a gas that occurs naturally in many compounds).
  • An atom or ion gains electrons. Atoms are the smallest part of a substance containing all the properties of that substance. Ions are atoms that gain an electric charge by gaining or losing one or more electrons (negatively charged particles).

People with diabetes have problems related to insulin (a hormone that transports sugars from the bloodstream to the cells) that sometimes allow the amount of sorbitol in a person’s eye to build up excessively. This can lead to cataracts, a clouding of the eye lens that impairs vision. Aldose reductase can also damage the nerve cells of the eyes. This can cause a disorder of the eyes’ blood vessels known as diabetic retinopathy.

Excess sorbitol may also cause a form of damage to nerves throughout the body that is known as diabetic neuropathy. However, experts are not sure of the exact cause of this disease.

In addition, the accumulation of sorbitol or other polyols may play a role in the development or progression of the kidney disease diabetic nephropathy, according to the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK). Studies on animals have indicated that suppression of aldose reductase might promote kidney function, and research on people with insulin-dependent diabetes have shown that ARIs lower the glomerular filtration rate and benefit those with proteinuria.

Polyols are found in naturally in some nutritious vegetables, fruits and grains. Manufacturers also process polyols to make reduced-calorie sugar substitutes, such as sorbitol, maltitol and xylitol. However, dietary sorbitol is poorly absorbed and is not believed to cause diabetic complications. People with diabetes may safely consume polyols and artificial sweeteners in moderation, according to the American Diabetes Association, which also encourages a diet adequate in high-fiber, vitamin-rich vegetables, fruits and whole grains.

Aldose reductase inhibitors are being studied as a potential treatment to prevent eye, nerve and kidney damage in people with diabetes. In the early 1990s, experts were hopeful that aldose reductase inhibitors would be an effective treatment for diabetic neuropathy. Experts have speculated that high sorbitol levels are a likely cause of neuropathy. However, results of studies have been mixed.

Research is continuing. For example:

  • Scientists in 2004 found that an experimental aldose reductase inhibitor called ranirestat (AS-3201) showed improvements in diabetic volunteers’ nerve conduction velocity. According to a follow-up study published in 2006, a Phase III clinical trial showed that patients with diabetic sensorimotor polyneuropathy who were treated with ranirestat at 60 weeks still had the improved sensory nerve function that was noted at 12 weeks and also had improved motor nerve function.
  • Research on people with diabetic neuropathy has suggested that the experimental ARI fidarestat may enhance nerve conduction and relieve pain and other symptoms. Fidarestat is also being investigation in the treatment of diabetic retinopathy.
  • Studies have found the ARI epalrestat may be useful in restoring impaired endothelial (vascular) function and in treating diabetic complications such as gastroparesis, a type of autonomic neuropathy that affects the stomach.
  • A class of ARIs called pyridazinones, including ARI-809, may be more promising in fighting complications such as cataracts and diabetic retinopathy that older, less-selective ARIs, scientists reported in 2006.
  • Scientists have found that some thiazolidinediones, a class of antidiabetic agents that is already in wide use, may inhibit aldose reductase in addition to lowering glucose.
  • Researchers reported in 2006 that PMI 5011, an extract from a type of tarragon (Artemisia dracunculus), may inhibit aldose reductase and have uses in treating diabetic complications.
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