Researchers Identify a Mechanism that May Explain Why Some People Experience Accelerated Diabetic Retinopathy and Vision Loss

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New diabetes and diabetic retinopathy research from Harvard Medical School, via Investigative Ophthalmology & Visual Science, the official journal of the Association for Research in Vision and Ophthalmology (ARVO), has demonstrated an association between a defective myogenic response – the increase or decrease in blood pressure that serves to regulate a consistent blood flow within the vessels of the retina – and early, accelerated development of diabetic retinopathy (explained below) in people with type 1 [i.e., insulin-dependent] diabetes.

Although the study included a small number of subjects and addressed only type 1 diabetes, the research serves to identify a mechanism that may explain why some people develop diabetic retinopathy sooner than others. In addition, the authors state that these findings “provide a target for future study, which may lead to therapies to delay or prevent the development of accelerated diabetic retinopathy.”

From Investigative Ophthalmology & Visual Science

This new diabetes research, entitled Defective Myogenic Response of Retinal Vessels Is Associated with Accelerated Onset of Retinopathy in Type 1 Diabetic Individuals, has been published as an open-source article in the April 2016 edition of Investigative Ophthalmology & Visual Science, the official journal of the Association for Research in Vision and Ophthalmology (ARVO). ARVO is an international organization that encourages and assists research, training, publication, and dissemination of knowledge in vision and ophthalmology, including low vision.

The authors are Francesco Tecilazich; Gilbert T. Feke; Sara Mazzantini; Lucia Sobrin; and Mara Lorenzi, who represent the following institutions: Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary at Harvard Medical School, Boston, Massachusetts.

About the Research

Excerpted from Researchers identify candidate biomarker of accelerated onset diabetic retinopathy at Science Codex:

Researchers … have shown an association between a defective myogenic response – the regulatory increase or decrease in blood pressure to keep blood flow within the vessels of the retina constant – and early, accelerated development of retinopathy in patients with type 1 diabetes. These findings identify one mechanism to explain why some patients develop diabetic retinopathy sooner than others. Furthermore, the findings provide a target for future study, which may lead to therapies to delay or prevent the development of accelerated onset diabetic retinopathy.

“In patients with a normal myogenic response, the retinal vessels constrict [i.e., become smaller] when increased pressure arrives, to maintain constant blood flow and avoid damage to the smaller vessels in the retina,” said [study co-author] Mara Lorenzi, M.D. “But we saw that, in about half of the diabetic patients in our study, the vessels did not constrict. In fact, paradoxically, some patients’ vessels dilated [i.e., opened up or became larger], and the blood flow to the retina was increased. This becomes a mechanism of damage for the small vessels, because these tiny, delicate capillaries are exposed to a big flow of pressure that can lead to the little hemorrhages and fluid leakage that are characteristic of diabetic retinopathy.”

The study included a small prospective study, in which the researchers closely followed 17 patients with type 1 diabetes whose myogenic responses had been measured four years prior. In approximately half of those patients, the researchers had observed defective myogenic responses. Five out of seven patients with defective myogenic responses developed accelerated diabetic retinopathy.

[Editor’s note: A prospective study measures a group of individuals over time and follows up with the study subjects in the future. A cross-sectional study, on the other hand, analyzes a population of subjects at one specific point in time.]

The study also included a different group of patients with type 1 diabetes who had just developed retinopathy. Among these patients, the defective myogenic response was found only in those in whom retinopathy had appeared after a short duration of diabetes (fewer than 15 years of diabetes).

With the knowledge gained from the new studies, the researchers hope to target the defective myogenic response and develop therapies to prevent the development of accelerated diabetic retinopathy in this population. A larger study is needed to test the predictive capability of this abnormality. “Now, we have a target to be investigated for the development of drugs or interventions to halt or stall the onset of clinical retinopathy,” Dr. Lorenzi said.

About Diabetic Eye Disease

Diabetic Retinopathy

Although people with diabetes are more likely to develop cataracts at a younger age and are twice as likely to develop glaucoma as people who do not have diabetes, the primary vision problem caused by diabetes is diabetic retinopathy, the leading cause of new cases of blindness and low vision in adults aged 20-65:

NEI example of seeing with diabetic retinopathy: many blind spots and overall blurriness
What a person with diabetic retinopathy sees
  • “Retinopathy” is a general term that describes damage to the retina.
  • The retina is a thin, light-sensitive tissue that lines the inside surface of the eye. Nerve cells in the retina convert incoming light into electrical impulses. These electrical impulses are carried by the optic nerve to the brain, which interprets them as visual images.
  • Diabetic retinopathy occurs when there is damage to the small blood vessels that nourish tissue and nerve cells in the retina.
  • “Proliferative” is a general term that means to grow or increase at a rapid rate by producing new tissue or cells. When the term “proliferative” is used in relation to diabetic retinopathy, it describes the growth, or proliferation, of abnormal new blood vessels in the retina. “Non-proliferative” indicates that this process is not yet occurring.
  • Proliferative diabetic retinopathy affects approximately 1 in 20 individuals with the disease.

Four Stages of Diabetic Retinopathy

According to the National Eye Institute, diabetic retinopathy has four stages:

  • Mild non-proliferative retinopathy: At this early stage, small areas of balloon-like swelling occur in the retina’s tiny blood vessels.
  • Moderate non-proliferative retinopathy: As the disease progresses, some blood vessels that nourish the retina become blocked.
  • Severe non-proliferative retinopathy: Many more blood vessels become blocked, which disrupts the blood supply that nourishes the retina. The damaged retina then signals the body to produce new blood vessels.
  • Proliferative retinopathy: At this advanced stage, signals sent by the retina trigger the development of new blood vessels that grow (or proliferate) in the retina and the vitreous, which is a transparent gel that fills the interior of the eye. Because these new blood vessels are abnormal, they can rupture and bleed, causing hemorrhages in the retina or vitreous. Scar tissue can develop and can tug at the retina, causing further damage or even retinal detachment.

Diabetic Macular Edema

Diabetic macular edema [edema = a swelling or accumulation of fluid] (DME) can occur in people with diabetes when retinal blood vessels begin to leak into the macula, the part of the eye responsible for detailed central vision. These leakages cause the macula to thicken and swell, which, in turn, creates a progressive distortion of central vision.

Although this swelling does not always lead to severe vision loss or blindness, it can cause a significant loss of central, or detail, vision, and is the primary cause of vision loss in people with diabetic retinopathy. DME can occur at any stage of diabetic retinopathy, but it is more likely to occur as the disease progresses.

You can learn more about diabetes and diabetic retinopathy at Introduction to Diabetes and Diabetic Retinopathy at the VisionAware website.

More about the Research from Investigative Ophthalmology & Visual Science

From the article abstract:

Purpose: We seek to identify pathogenic [i.e., causing, or capable of causing, disease] mechanisms for diabetic retinopathy that can become therapeutic targets beyond hyperglycemia and hypertension.

We investigated if a defective myogenic response of retinal arteries to increased perfusion pressure [i.e., the passage of a fluid through the vessels], which exposes capillaries to increased pressure and flow, is associated with the onset of clinical retinopathy.

Methods: We examined prospectively the incidence of retinopathy in type 1 diabetic individuals tested 4 years earlier for the retinal arterial myogenic response, and in a cross-sectional study the prevalence of defective myogenic response in type 1 patients who had diabetic retinopathy. Among these, we contrasted early-onset to late-onset retinopathy. We measured the myogenic response using a laser Doppler blood flowmeter after a change in posture from sitting to reclining, which increases retinal perfusion pressure.

Results: Five of seven participants who 4 years prior had a defective myogenic response had now developed clinical retinopathy; as compared with only one of six participants who 4 years prior had a normal response. In the cross-sectional study, all participants had normal retinal hemodynamics at steady state. In response to the postural change, only the [early-onset diabetic retinopathy] group showed defective myogenic response and abnormally high retinal blood flow.

Conclusions: In type 1 diabetic patients, a defective myogenic response of retinal arteries to pressure is not required for the development of clinical retinopathy, but is prominently associated with an accelerated onset of retinopathy.

The study authors also concluded with the following observations:

The main limitation of this study is the small number of patients tested. Additionally, the study addressed solely patients with type 1 diabetes who did not take vasoactive drugs; thus, it is unknown whether the findings can be extended to the much more common setting of patients with type 2 (non-insulin-dependent) diabetes, often taking drugs for systemic hypertension.

This is, however, not unlikely, because a defective myogenic response of retinal vessels to a pressure stimulus (increased systemic blood pressure induced by isometric exercise) has been noted also in type 2 diabetic patients, some treated with vasoactive drugs, who had retinopathy with or without macular edema.

[Editor’s note: Vasoactive drugs are a class of medications that have the effect of either increasing or decreasing blood pressure and/or heart rate.]

Our new observations that a defective myogenic response to pressure of retinal vessels can be an accelerator of retinopathy, together with the observations that a defective myogenic response to pressure [also] is prevalent in type 2 diabetes, and is present in sight-threatening retinopathy, call for a definitive longitudinal cohort study.

If a fully powered study confirmed that a defective myogenic response predicts an accelerated onset and/or course of diabetic retinopathy, there will be rationale and impetus to developing targeted drugs. In the meantime, our findings renew the emphasis on monitoring and treating aggressively in our patients any increase in systemic blood pressure, because a defective vascular constriction magnifies widely the effects of any increment in blood pressure on retinal vessels.

VisionAware will continue to report the results of this research as they become available.

Additional Information