A Root Cause of Vision Loss in Diabetes?


Diabetes-related vision loss, one of the most feared complications of the disease, is caused by a progressive pathogenic process known as diabetic retinopathy, or DR. High blood sugar is the predominant risk factor for DR, so many people believe that glucose toxicity is the main contributor to the development of this disease. Yet, to date, no pharmaceutical product specifically targeting glucose-dependent pathways exists for DR.

Diabetic retinopathy, shown here, causes vision loss in diabetic patients.

Diabetes is a disease characterized by a largely disrupted metabolism that affects the way cells manage lipids, amino acids, and signaling networks that regulate growth and proliferation, in addition to its impact on glucose. As a result, abnormalities in lipid metabolism are common in diabetes. For example, diabetic patients often suffer from non-alcoholic fatty liver disease, which is characterized by a chronic positive energy balance causing increased lipid synthesis and elevated hepatic triglyceride levels. Thus, we thought that the retina might change its lipid metabolic programming in response to an abundance of fuel in diabetes.

To test this possibility, our group investigated the pathways that govern retinal lipid biogenesis (the process of fatty acid synthesis from small precursors) during experimental diabetes in mice. In several models of diabetes, we observed an increase of about 70% over controls in the synthesis of retinal palmitate, a ubiquitous saturated fatty acid that forms a building block for many lipids. This change in lipid production was likely due to high glucose alone, as isolated retinal tissue exposed to high glucose showed the same increase in palmitate production.


Courtesy of Rithwick Rajagopal

Mechanically, elevated glucose levels increased the enzymatic activity of two regulatory enzymes: acetyl Co-A carboxylase and fatty acid synthase, or FAS. Mice with partial loss of function of FAS in rod photoreceptors – the predominant cell type in the retina – were spared vision loss from diabetes, even though they developed comparable severe systemic metabolic disease to that of the control mice. Conversely, mice with a gain in FAS function developed vision loss twice as fast as wild-type mice after induction of diabetes. Taken together, our findings imply increased retinal FAS activity and increased palmitate as root causes of vision loss in diabetes.

The mechanisms of palmitate toxicity in the retina remain elusive. Unlike the liver, the diabetic retina does not develop intracellular lipid droplets and does not have significant stores of triglycerides. Additionally, in comprehensive investigations of retinal membrane lipids, we found only modest changes associated with the disease. Instead, palmitate could trigger pathological signaling either through lipid second messengers or through the lipidation of protein messengers. Our group is actively exploring these possibilities.

Our results shed light on a puzzling feature of human DR: Although glucose is the primary risk factor for vision loss in diabetes, it only explains a fraction of the variability in disease progression. The differences between individuals in terms of the biosynthetic flux of retinal lipids may explain part of the variance in the response to glucose.

Future drug therapy to refine retinal lipid biogenesis in DR may offer a new approach for the treatment of an increasingly common cause of visual impairment.

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