1 year later, even in patients without any prior retinopathy. It can be utilized to assess the risk of DR development in these patients and may be a valuable outcome measure in evaluation of novel prophylactic therapeutics directed at impeding DR.

Adolescents and Adult Diabetes

Are the mfERG abnormalities we see in adult diabetic subjects also present in adolescent patients with diabetes?

In 2005, the Center for Disease Control (CDC) in the US estimated that there are 206,000 people under the age of 20 that have diabetes, and approximately one in six overweight adolescents have prediabetes (CDC, 2005). Type 2 diabetes now accounts for up to 20% of all newly diagnosed adolescent cases [36].

In 2008, we reported that indeed, adolescents with type 2 diabetes do have abnormal neural function in the retina [37]. We also noted early indications of abnormal dilation of venules and abnormal thinning of the retina. Adolescents with type 2 diabetes often present with comorbidities such as obesity, hyperinsulinemia, hypertension, and hyperlipidemia. All of these conditions can impact both the vascular and neurologic health of the patient. Our study was the first of its kind to examine the neural retinal function, structure, and retinal vascular health in adolescents with type 2 diabetes.

Fifteen adolescents diagnosed with type 2 diabetes, aged 13–21 years with a mean diabetes duration of 2.1 ± 1.3 years, were examined. Twenty-six age-matched control subjects were also tested. The mfERGs of the type 2 diabetic patients were significantly delayed ( p = 0.03). The diabetic group also showed significant retinal thinning and significant venular dilation.

Type 1 vs. Type 2: Differences in Retinal Function

In a recent paper, we noted differences in type 1 and type 2 adults with diabetes [25]. Neural function in the retina was distinctly poorer in the type 2 patients. We have noted this same difference when comparing adolescents with type 1 and type 2 diabetes [38]. This raises questions about possible underlying differences in pathophysiology of the retina (and beyond). Type 2 diabetes patients typically have more numerous cardiovascular risk factors and comorbidity factors than type 1 patients. Our current research is looking at this more carefully.

THE HORIZON FOR PATIENT CARE OF DIABETES

RETINA AND RESEARCH AGENDA

The early neural changes in the retina of eye, produced by diabetes well before clinical signs of vascular retinopathy, have quite significant implications for patient care and management of eye complications as we look to the horizon. The mfERG implicit time, measured with clinical instrumentation, clearly identifies almost 20% of the central retina of patients with diabetes as functioning abnormally prior to visible retinopathy. This “neuropathy” is consistent with the changing view of the retinal complications of diabetes that has previously had almost entirely a “vascular” label; it still does with most clinicians. Regardless of the perspective of neural preceding vascular or vice versa—the debate will likely hinge on whichever new technical assessment tools

are most sensitive—it is clear that the identification of functional deficits, early in the disease complication process of the eye, provides new opportunities for the development of new therapies and assessment tools for the staging of retinal changes.

Clinicians have primarily been limited to assessment of visual acuity at one central and tiny location of the retina, and to visual fields with relatively insensitive markers in diabetes. In fact, both visual acuity and visual fields by conventional perimetry are characteristic of fairly late stage vasculopathy of the retina—well after any prophylactic treatments could be applied. The early “warning signals” of the mfERG, coupled with an apparently powerful predictive ability for future retinopathy within a year or two, are an exciting advance in the potential management of the diabetic complications of the retina. New candidate interventions, aimed at preventing or slowing the path of retinopathy progression at early stages, may now be contemplated with biological and objective markers of functional improvement. With visual acuity loss typically occurring only after many years, it becomes a most unattractive outcome measure for any early intervention efficacy studies.

In management, it is conceivable that patient monitoring, based on the progression of neural abnormality, will be a valuable tool in the hands of eye care practitioners. Ophthalmologists and optometrists could have the ability to gauge both the severity of neural dysfunction and the likelihood of incipient local retinopathy and use this information to stage an appropriate and timely intervention.

Looking even further ahead, it is conceivable that as other functional measures of the retina, known to be altered at early stages of the diabetic complications (e.g., alterations in the retinal pigment epithelium function, or systemic serum markers or indices known to be risk factors) that might make the predictive models of incipient damage in the retina even more powerful than they already are. It is important to examine the potential relationships between the mfERG IT delays in diabetes and to look at systemic markers of glycemic control, diabetes-related inflammation, microvascular damage, and dyslipidemia (abnormal concentrations of lipids in the blood). These systemic markers are associated with diabetes and microvascular disease including diabetic retinopathy.

Taken a step further, as research links systemic serum risk factors to particular retinal structure changes, whether neural or vascular, it is conceivable that personalized treatment and management options will evolve for diabetic retinal health. Certainly, the opportunities for research to unveil those relationships and the underlying mechanisms provide an exciting opportunity in clinical research.

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Part III

How Does Diabetes Affect the Eye?