Diabetic Retinopathy Mechanism ProbedDiabetic Retinopathy Mechanism Probed

An international team of researchers has resurrected a once-discarded theory to explain the mechanism underlying how chronic hyperglycemia in diabetes causes the microvascular complications that lead to diabetic retinopathy and other tissue problems. The findings, they say, may point to new avenues of research into novel therapies to treat such conditions.

Scientists from the United States and Denmark report that studies in laboratory rats bolster the idea that a primary cause of microvascular complications is chemically reactive, tissue-damaging free radicals and other chemical changes resulting from the increased transfer of electrons and protons from glucose to nicotinamide adenine dinucleotide (NAD) by a sequence of chemical reactions known as the sorbitol pathway (Diabetes. 2004;53:2931-2938).

Joseph R. Williamson, MD, lead investigator and retired pathology faculty member at Washington University School of Medicine in St Louis, originally proposed this theory 11 years ago (Diabetes. 1993;42:801-813). He said the idea had not found many backers because the number of electrons transferred to NAD by this pathway was thought to be insufficient to produce enough free radicals to result in microvascular complications. In addition, a 1990 publication of a large randomized trial that found that a drug acting on the sorbitol pathway to treat diabetic retinopathy was ineffective (Arch Ophthalmol. 1990;108:1234-1244).

With the sorbitol pathway theory largely ignored, diabetes researchers turned their attention to other proposed mechanisms for the complications of diabetes, which can be divided into two camps. One focuses on the toxic effects of hyperglycemia directly on tissues. The other holds that glucose metabolism creates sustained alterations in cell signaling pathways, producing disruptions in the healthy function of tissues (JAMA. 2002;288:2579-2588).

But Williamson and colleagues suggest that their new findings indicate that the sorbitol pathway deserves another look as a potential target for intervention. He and colleagues specifically focused on the pathway’s role with respect to a coenzyme in cells, NAD. During glycolysis, NAD enables cells to release glucose’s stored energy by acting as a carrier of electrons and protons, a process that converts glucose and NAD into pyruvate and reduced NAD (NADH).

Williamson said cells need high levels of NAD available for this energy transfer, and that various healthy tissues typically have an NAD:NADH ratio of between 500:1 to 2000:1. In patients with diabetes, however, an overabundance of NADH can lower that ratio to as low as 200:1. As the NAD:NADH ratio falls, he explained, it increasingly curbs the transfer of energy from glucose to the cell and creates metabolic imbalances that damage vessels and nerves.

In studies of rat retinas in vitro, Williamson’s team showed that hyperglycemia and hypoxia decreased the NAD:NADH ratio in different ways. Hyperglycemia does it by increasing the rate of transformation of NAD to NADH, and hypoxia does it by making it difficult for cells to convert NADH back to NAD. In both conditions, the increased NADH is recycled back to NAD by processes that produce free radicals and other metabolic changes.

It is the long-term effects of these processes that causes the damage seen in diabetes, the researchers suggested. “The consequences of increased redox cycling of NADH by these processes are additive—they have the potential to produce much more damage than you might expect if you looked at either one independently,” Williamson said.

Adding to the mix is that diabetes increases the transformation of NAD to NADH by hiking a cell’s consumption of glucose through the sorbitol pathway. But because this transfer occurs at a low rate compared with glycolysis, some researchers have dismissed the sorbitol pathway as a potential generator of enough free radicals to play a significant role in causing diabetic complications.

But Williamson counters that the pyruvate generated during glycolysis also transforms NADH back to NAD. In contrast, because the sorbitol pathway does not make pyruvate, the NADH generated by the sorbitol pathway must be recycled by other processes that also create free radicals.

“If you make a normal animal hyperglycemic by infusing glucose into it for 5 hours or so, you’ll see some of the same changes in the blood vessels that you see very early on in diabetics,” Williamson said. “However, we have shown that if you infuse pyruvate at the same time you infuse the glucose, you completely block those changes.”

The new work bolstering the sorbitol pathway’s role in diabetic complications is “biochemically sound” but leaves some unanswered questions, said Mara Lorenzi, MD, a professor of ophthalmology at Harvard Medical School, in Boston. “While these changes may occur, the research does not say whether, and how, these transfers inflict the damage in the retina,” she said. “Also, some cells in the retina are more sensitive to [the sorbitol] pathway than others, so what it means for the whole retina is unclear.”

Still, Lorenzi is an advocate for further research studying the role of the sorbitol pathway in human diabetic retinopathy (Diabetes. 2004;53:2404-2411). She added that the Williamson team’s work is important because it will help move a possible solution to the diabetic microvascular complications debate back into the forefront with other theories.

To provide additional evidence supporting their theory, the Williamson team has answered questions raised by critics in the past in a 47-page appendix to the Diabetes article available on the Internet at http://diabetes.diabetesjournals.org/cgi/content/full/53/11/2931/DC1.

Williamson said the group’s findings have therapeutic implications. The work, he said, suggests two interventions may be needed for optimal results in preventing diabetic microvascular complications: keeping patients’ blood glucose levels as close to normal as possible and treatment with sorbitol pathway inhibitors.