Basic research targets complications of diabetes

Take-home

Trends highlight the urgency of developing new medical therapies for the management of diabetes and ensuring that such therapies will be safe for young patients.

Eye on Research By J. Mark Petrash, PhD

Recent trends highlight the urgency of developing new medical therapies for the management of diabetes and of ensuring that such therapies will be safe enough for young patients to take them during their developmental and reproductive years.

Diabetes mellitus (DM) is among the most common systemic diseases in the United States, affecting nearly 26 million Americans.¹ The prevalence of diabetes among adults 20 years and older has been increasing, contributing to a 21% increase in the prevalence of nonrefractive visual impairment (Figure 1).²

Diabetic retinopathy (DR) is a frequent complication of diabetes. It is estimated that 28.5% of people with diabetes aged 40 years or older have DR, and it is the leading cause of new cases of blindness among adults aged 20 to 74 years.¹

Even more alarming, however, is the increase in type 2 diabetes and related complications in children. The SEARCH for Diabetes in Youth Study Group recently reported the prevalence of DR among youth diagnosed with diabetes for at least 5 years to be 17% for those with type 1 DM and 42% for those with type 2 (Figure 2).³

Laying the foundation

New drug development in diabetic eye care has been based in part on earlier ocular tissue research. By studying the differences in the molecular profile of donor tissue from diseased and healthy eyes, researchers have been able to identify critical biomarkers of disease. For example, the enzymatic products of aldose reductase (AKR1B1) are significantly higher levels in the diabetic eye tissues as compared with age-matched nondiabetics.⁴

AKR1B1 is the key enzyme in the polyol metabolic pathway and likely one of the primary mediators of many diabetic complications, including diabetic cataract and retinopathy. The polyol pathway is activated by an increased flux of glucose within cells and contributes to increased osmotic and oxidative stresses, which, in turn, trigger a sequence of metabolic changes in the lens, retina, and other ocular tissues.⁵

In our lab, we have done extensive work to add to the understanding of this metabolic pathway by grafting it onto a mouse lens. The “humanized” mice carry cloned genes responsible for human crystalline lens proteins and can thereby serve as a test platform for discovering drugs to inhibit aldose reductase.

Drug discovery, delivery

We know that overexpression of AKR1B1 in the lens of transgenic mice accelerates lens abnormalities (Figure 3) and retinal vasculature changes, validating the connection between this pathway and diabetic eye disease.^6-8

Moreover, we have shown that a number of different compounds are able to inhibit aldose reductase and prevent or slow the progression of cataract in the humanized mouse lens.^9-12 This indicates that the orally-delivered drugs we are discovering are able to penetrate into the target ocular tissues.

This research is exciting not only for its potential effect on diabetic cataract, but also on the much more sight-threatening condition of DR. We believe that successful interference with the polyol will have downstream effects on all the ocular sequellae of diabetes. Indeed, inhibitors with antioxidant and anti-inflammatory action could be useful in a broad range of settings even beyond diabetes and the eye.

In addition to the new drug discovery work, we are also investigating sustained-release formulations of biotherapeutic proteins. Current treatments for retinal disease, such as bevacizumab and ranibizumab, have been successful. However, the requirement for frequent injection increases the risk of complications and imposes a significant burden on patients, physicians, and the health-care system.

By packaging therapeutic proteins into slow-release nanoparticles, it may be possible to sustain therapeutic levels over a much longer period between injections. Nanotechnology also opens the door for modifying systemic anti-inflammatory drugs for safe use in the eye.

True validation of the extensive ongoing work in AKR1B1 inhibition and other potential treatments for DR must rely on testing carried out with human-derived cells and tissues.

The Lion’s Eye Institute for Transplant and Research (see “About this series”) is uniquely positioned to support the kinds of research on donor tissue that will be essential for translating findings from experimental animal models into therapeutic strategies in humans. It is critically important that diabetes researchers continue to have access to freshly procured, high-quality human tissue, both diseased and not.

Access to such tissue, coupled with associated clinical history, would enable scientists to conduct studies aimed at identifying important biomarkers of disease onset and progression. Ideally, biomarker profiles can be established to link the ophthalmic presentation (phenotype) of individuals with their biochemical and genetic profiles.

In this way, it may be possible to identify individuals at high risk for onset of DR, providing ophthalmologists and their patients with information they can use when deciding how to intervene as early as possible in the disease process.

References

Centers for Disease Control and Prevention. National Diabetes Fact Sheet, 2011. http//www.cdc.gov/diabetes/pubs/factsheet11.htm.

Ko F, Vitale S, Chou CF, et al. Prevalence of nonrefractive visual impairment in U.S. adults and associated risk factors, 1999-2002 and 2005-2008. JAMA. 2012;308:2361-2368.

Mayer-Davis EJ, Saadine J, D’Agostino RB Jr., et al. Diabetic retinopathy in the SEARCH for Diabetes in Youth Cohort: a pilot study. Diabet Med. 2012;29:1148-1152.

Kinoshita JH, Nishimura C. The involvement of aldose reductase in diabetic complications. Diabetes Metab Rev. 1988;4:323-337.

Srivastava SK, Yadav UC, Reddy AB, et al. Aldose reductase inhibition suppresses oxideative stress-induced inflammatory disorders. Chem Biol Interact. 2011;191:330-338.

Lee AY, Chung SK, Chung SS. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci USA. 1995;92:2780-2784.

Yamaoka T, Nishimura C, Yamashita K, et al. Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA. Diabetologia. 1995;38:255-261.

Zablocki GJ, Ruzycki PA, Overturf MA, et al. Aldose reductase-mediated induction of epithelium-to-mesenchymal transition (EMT) in lens. Chem Biol Interact. 2011;191:351-356.

Puppala M, Ponder J, Suryanarayana P, et al. The isolation and characterization of b-glucogallin as a novel aldose reductase inhibitor from emblica officinalis. PLoS ONE. 2012;7:e31399.

Muthenna P, Suryanarayana P, Gunda SK, et al. Inhibition of aldose reductase by dietary antioxidant curcumin: mechanism of inhibition, specificity and significance. FEBS Lett. 2009;583:3637-3642.

Puppala M, Palla S, Reddy PY, et al. Mechanism, specificity, and significance of aldose reductase inhibition by curcumin. ARVO Meeting Abstracts April 11, 2010;51:3819.

Palla S, Saraswat M, Reddy PY, et al. Inhibition of aldose reductase, protein glycation and delay of diabetic cataract in rats by rutin. ARVO Meeting Abstracts April 11, 2008; 49:1467.

J. Mark Petrash, PhD, is vice chairman for research in the Department of Ophthalmology, University of Colorado-Denver, past president of the Association for Research and Vision in Ophthalmology and a member of the LEITR Research Advisory Board. Readers may contact him at Mark.Petrash@ucdenver.edu.

About this series

Eye on Research is a quarterly series of articles highlighting cutting-edge ophthalmic research with the potential to have a significant effect on vision and ocular health worldwide. The series is supported by the Lions Eye Institute for Transplant and Research, Inc. (LEITR), a nonprofit organization dedicated to the recovery, evaluation, and distribution of eye tissue for transplantation, research, and education. Located in Tampa, FL, LEITR is the only combined eye bank and ocular research center in the world. LEITR provides fresh donor globes, corneas, lenses, trabecular meshwork, and other tissues from diseased and healthy human eyes, often within 4 to 6 hours of death, to researchers for immediate use in their own labs or in its onsite research facility. For more information, contact info@LionsEyeInstitute.org or visit LionsEyeInstitute.org.

(Figure 1) Data from two 5-year periods in the National Health and Nutrition Examination Survey (NHANES) suggest an alarming increase in nonrefractive visual impairment (vision worse than 20/40 aided by autorefractor) that closely mirrors the corresponding increase in the prevalence of diabetes diagnosed 10 or more years previously, the only risk factor that changed between the two time periods. Adapted from Ko F, et al. JAMA. 2012;308:2361-2368

(Figure 2) A recent pilot analysis of youth diagnosed with diabetes for at least 5 years demonstrates alarmingly high prevalence of diabetic retinopathy, particularly among minority youth with type 2 diabetes. Adapted from Mayer-Davis EJ, et al. Diabet Med. 2012;29:1148-1152.

Histological section taken from a mouse lens that has been humanized by inserting the gene for human aldose reductase (AKR1B1). Acceleration of the polyol pathway in this animal model demonstrates histopathology typical of diabetic cataract: (arrows) swollen vacuoles in the lens cortex associated with accumulation of excess sorbitol produced by the polyol pathway. (Figures courtesy of J. Mark Petrash, PhD)