Figure 1. Example of a severe vitreous hemorrhage.
It is well known that diabetes is a major cause of death and disability in the United States. It is also the leading cause of blindness in adults 20-74 years of age.(1)
Over 6% of the general population and 18.3% of persons over age 60 are diabetic.(1) In addition, an estimated 5 million people in the US (3.2% of the population) are diabetic but unaware of it.(1,2)
Although diabetes is not yet considered curable, serious consequences, including blindness, can be significantly reduced by timely diagnosis and proper treatment.
Working in coordination with other health care providers, optometrists can play a major role in the detection and management of diabetes as illustrated by the following case example.
CASE EXAMPLE
C.J., a 59-year-old white female, came into my office reporting "a blanket over her vision in the left eye for the last week." She was monocular due to a gunshot wound to the right eye 12 years previous. C.J. had been diagnosed with diabetes at age 34 and was controlling it with a combination of diet and medication. She reported that she did not know the name of her medication but that the doctor was switching them a lot. She was also taking estrogen along with medications for high cholesterol and hypertension. She reported having laser surgery performed on her left eye twice but could not recall what it was for.
Visual acuity was 20/100 OS, which did not improve with pinhole. Biomicroscopy revealed 1+ arcus and trace nuclear sclerotic cataract in the left eye. A limited view of the left eye's fundus revealed a vitreous hemorrhage as well as multiple dot-blot retinal hemorrhages and exudates. Laser scars were also present in the peripheral retina of the left eye. The view of the macula and disk was inadequate to determine if neovascularization or macular edema were present.
Figure 1. Example of a severe vitreous hemorrhage.
C.J. was referred to a retinal specialist who performed an ultrasound and ruled out retinal detachment.
The findings of C.J.’s vision exam were reported to her primary health care provider who added glipizide (Glucotrol®) to her current regimen of metformin (Glucophage®).
Two months later, C.J. did not eat dinner and forgot that she took her medications, so she took a second dose. Later that night her daughter found her sitting on her bed sweating profusely, drooling, and with her face and hands stiff and contorted. Her daughter thought she was having a stroke. When the paramedics arrived they found that her blood sugar was in the 30’s. Oral glucose revived her within minutes. C.J. was hospitalized for three days while physicians tried to find a medication that would stabilize her blood sugar level.
Several months after this episode, C.J. returned to my office after visiting her retinal specialist. The vitreous hemorrhage was still present, but it had improved dramatically so the specialist chose to follow and observe C.J. rather than perform a vitrectomy. Three months later she saw the retinal specialist again and was told that the hemorrhage was totally cleared. She was referred back to my office for further monitoring. C.J.’s visual acuity at this time was correctable to 20/25 OS, and her sugar level was under control.
The case of C.J. provides a good example of how coordination between an optometrist, a retinal specialist, and the patient's primary care physicians managed her diabetes more effectively and prevented or delayed the development of additional serious ocular consequences.
ETIOLOGY OF DIABETES
In a normal person, blood glucose level rises after a meal but then drops rapidly as islet cells of the pancreas secrete insulin. The insulin facilitates movement of glucose out of the blood into the cells where it can be metabolized. In a diabetic, either the islet cells have lost their ability to secrete sufficient insulin or the insulin is unable to move glucose from the blood into the cells (insulin resistance). Although definitions vary somewhat, these conditions define the two major types of diabetes. In type 1 diabetes, there is an insufficient supply of insulin. In type 2 diabetes the supply of insulin can be normal but cells have become resistant to its activity.
Type 1 Diabetes
Five to ten percent of diabetics are type 1.(1) This condition was previously known as insulin-dependent diabetes mellitus, juvenile-onset diabetes, or Type I diabetes because it usually affects children and young adults and because type 1 patients require an exogenous supply of insulin.
Type 1 diabetes occurs when the body’s immune system destroys the insulin producing islet cells in the pancreas. The majority of type 1 diabetics have an immune-mediated etiology and have been referred to as type 1a. Type 1a patients have autoimmune markers including islet cell auto antibodies (ICAs), insulin autoantibodies (IAAs), glutamic acid decarboxylase autoantibodies (GADAs), and IA-2 autoantibodies (IA-2As).(3, 4) Human leukocyte antigens such as HLA-DR3 and HLA-DR4 are also associated with the development of type 1a diabetes.(3,5)
A minority of type 1 patients do not have any autoimmune markers or HLA associations. In these patients, genetics plays a significant role in development of the condition.(4)
Unfortunately, once the islet cells have been destroyed, there is no currently available method for replacing them (stem cell research offers promise in this area), and the patient will need externally supplied insulin for life.
Type 2 Diabetes
Type 2 diabetes, previously known as non-insulin dependent diabetes mellitus, adult-onset diabetes, or type II diabetes, is the most common type of diabetes accounting for approximately 90% of diabetic cases.(1)
In type 2 diabetes, it is believed that glucose receptors in cell walls that are normally opened by insulin fail to function correctly. The biochemistry of these receptors is complex and not yet well understood.(6)
As a result of receptor failure, glucose level in the blood increases. Islet cells make more insulin in an attempt to lower the glucose level. Increased insulin production can be maintained for many years, but eventually the islet cells "burn out" and the type 2 patient can require exogenous insulin. During what may be a several year period during which glucose levels are elevated but partially compensated for by increased insulin production, the patient might be relatively symptom free. However, occult damage could be occurring in the eyes and other organs during this period if glucose levels are high enough.
Type 2 diabetic patients are typically over 40 years of age, over weight, and often not very physically active. It is unknown whether there is a common cause for the obesity and the diabetes or whether the obesity causes the diabetes, but common biochemical links are being investigated.(7)
The relationship of obesity to type 2 diabetes is a subject of intense study. Possibilities are that obesity increases the probability that diabetes genes will express themselves, that obesity causes diabetes directly, that diabetes causes obesity directly, or that there is a common factor that causes both diseases.
Researchers at the University of Pennsylvania School of Medicine have found a hormone called resistin secreted by fat cells in mice that causes cells to resist the effects of insulin.(8) This suggests that obesity can cause diabetes and is in accord with the common finding that weight loss lowers blood glucose levels in some patients. Other researchers are concentrating on different steps in the glucose metabolism pathway, such as glycogen synthase kinase-3beta that might be responsible for diabetes.(9)
There is a definite genetic and racial association with type 2 diabetes. The disease is more common in people of African, Native American, Latino, and Pacific Island descent. This supports the theory that there is a significant genetic/biochemical anomaly associated with development of type 2 diabetes.
Although the risk of type 2 diabetes in the general population is about five percent, people who have a parent or sibling with the disease have double or triple this risk. If the sibling with diabetes is an identical twin, the risk is almost 100 percent.
Despite the fact that type 2 diabetes clearly runs in families, researchers have not found a single gene mutation that causes the disease. Instead, many genes appear to be involved.(10) No human leukocyte antigen (HLA) markers have been found to be associated with type 2 diabetes.(5)
SYMPTOMS OF DIABETES
Prior to treatment, patients with type 1 diabetes are often quite sick and relatively easy to diagnose if the appropriate tests are conducted. Glucose levels for these patients can be extremely high. The body attempts to lower the glucose levels by excreting sugar in the urine which causes thirst. Poorly controlled type 1 patients drink copious quantities of water in an effort to dilute their blood glucose. They are also often hungry because their cells cannot get enough glucose but can lose weight for no apparent reason.
Blood circulation is compromised in type 1 patients because of changes in vessel walls, and this can result in organ damage along with poor wound healing.
These factors result in the classic symptoms of diabetes: polydipsia (frequent drinking), polyphagia (frequent hunger), polyuria (frequent urination), weight loss, delayed healing of skin wounds, and recurrent infections of the skin or genitalia. Because glucose is not being used effectively for cellular metabolism, patients with high glucose levels also often report significant fatigue.
Type 2 patients are more difficult to diagnose on the basis of symptoms because their bodies attempt to compensate for insulin resistance by making more insulin. However, complaints of polyuria, polydipsia, fatigue, slow wound healing, and frequent infections, along with risk factors such as age, obesity, and family history should cause the health care provider to order tests for determining blood glucose levels.
ASSESSMENT OF GLUCOSE LEVELS
The most obvious sign that a patient has diabetes is an elevated blood glucose level. At any point in time, glucose level is a function of multiple factors including recent dietary intake, insulin level, and the ability of insulin to move glucose out of the blood and into cells. Blood tests can be ordered when a health care provider needs to confirm a diagnosis of diabetes or monitor the efficacy of therapy.
Casual Plasma Glucose Level
The casual plasma glucose test is a way to check for diabetes in which the blood glucose level is tested without regard to the time since the last meal. The patient is not required to go without eating prior to this test. In non-diabetics the casual blood glucose level is typically between 90-130 mg/dl before meals and less than 180 mg/dl two hours after starting a meal. Symptoms of diabetes and a casual plasma glucose of 200 mg/dl indicates a diagnosis of diabetes.
Fasting Glucose Level
Typically, the 8-hour fasting level of blood glucose for a normal person is under 100 mg/dL. According to American Diabetes Association criteria, a consistent fasting blood glucose level between 100 and 125 mg/dL signals pre-diabetes, and a person with a consistent fasting blood glucose level of 126 mg/dL or more is diabetic. (Pre-diabetes is a condition that occurs when a person's blood glucose levels are higher than normal but not high enough for a diagnosis of diabetes. There are an estimated 41 million pre-diabetic Americans.)(11)
Figure 2. The fasting glucose level (or the glucose level at any time during the day) can easily be determined by using a drop of blood and a relatively inexpensive meter. (Image from http://www.diabetesuffolk.com/Managing%20Diabetes/images-meters/AccuCheck%20Advantage/accuChek16a.jpg)
Glucose Tolerance Test
The fasting level provides a snapshot view of a person's glucose level, but more information about glucose utilization can be obtained by providing a glucose load and then monitoring the resulting rise and fall of glucose level in the blood. According to American Diabetes Association criteria, if the level is between 140 and 199 mg/dL two hours after drinking a glucose load, the person has pre-diabetes. If the two-hour blood glucose level is 200 mg/dL or higher, the person has diabetes.
Figure 3. Glucose tolerance test curves for normal and diabetic patients. The glucose load was administered at time zero. (Image from http://cwx.prenhall.com/bookbind/pubbooks/mcmurrygob/ medialib/media_portfolio/text_images/FG23_08-04UN.JPG)
A1c Test
Information about "average" glucose levels over a period of several months can be obtained by using the A1c test, also known as the HbA1c, glycohemoglobin, glycated hemoglobin, or glycosylated hemoglobin test. A1c is formed when glucose in the blood binds to hemoglobin and forms a stable glycated hemoglobin complex. Red blood cells normally live for about 3 months, and A1c values are directly proportional to the average level of glucose over this period.(12)
A healthy person without diabetes will have an A1c between 4% (0.04) and 6% (0.06). For every 1% (0.01) increase in A1c, there has been a corresponding blood glucose increase of about 30 mg/dL over the past several months. Diabetics have a target A1c of 7 or below, and values of 8 or above suggest the need for additional treatment.(13)
The A1c test has previously involved laboratory work, but a single blood drop test device is now available from Metrika. It allows patients to measure their A1c level at home and the unit can also be used in the office to assess the A1c of patients who might have questionable glucose control or unreliable fasting level reports.(14)
Figure 4. Metrika A1c test unit. (Image from http://www.a1cnow.com)
MANAGEMENT OF DIABETES
In some ways diabetes is analogous to glaucoma. In glaucoma, the intraocular pressure (IOP) is too high; in diabetes, the blood glucose level is too high. In both diseases, there is a series of medications and treatments with increasing potency and risk that are designed to reduce the abnormal values. Also in both conditions, it is unlikely that the underlying disease process will "cured." Instead, the goal of management is to reduce the rate at which new signs and symptoms occur and their severity.
Type 1 Diabetes
Type 1 patients have lost the ability to produce insulin and must receive an exogenous supply. Insulin is broken down in the stomach so it cannot be delivered orally. Although some research is being directed toward the use of nasal inhalers, essentially all type 1 patients receive their insulin either by subcutaneous bolus injection or by injection using a metering pump.
Figure 5. Insulin pump designed to deliver a continuous infusion of insulin through a catheter inserted into the abdomen. (Image from http://www.uihealthcare.com/news/news/2001/02/images/12insulinpump02.jpg)
In a person without diabetes, insulin levels rise after a meal to move glucose into the cells and then fall to prevent blood glucose levels from dropping too far, which would result in hypoglycemia. The goal of exogenous insulin injection for the type 1 patient is to simulate this rise and fall of insulin levels in response to blood glucose level changes. This means that the patient must measure his or her glucose level frequently during the day and inject insulin in types and amounts as indicated. Using too little insulin results in hyperglycemia and using too much can produce the symptoms of hypoglycemia, which include diminished physical and mental function, and even death.
To help type 1 patients maintain proper glucose levels, insulin comes in a variety of types. Some is derived from animals and some is of human origin. Some is quick acting for use after meals and some is long acting for background glucose level maintenance.
Table 1. Insulin types and characteristics. (Table from http://www.clevelandclinic.org/health/health-info/docs/3300/3376.asp?index=11452)
|
Insulin Type
|
Brand Name
|
Onset
|
Peak
|
Duration
|
| Rapid Acting | Humalog | 15 to 30 min. | 30 min to 2.5 hours | 3 to 5 hours |
| Rapid Acting | Novolog | 10 to 20 min. | 1 to 3 hours | 3 to 5 hours |
| Short Acting | Regular (R) | 30 min. to 1 hour | 2 to 5 hours | 5 to 8 hours |
| Intermediate Acting | NPH (N) | 1 to 2 hours | 4 to 12 hours | 18 to 24 hours |
| Intermediate Acting | Lente (L) | 1 to 2.5 hours | 3 to 10 hours | 18 to 24 hours |
| Intermediate Acting | Ultralente (U) | 30 min. to 3 hours | 10 to 20 hours | 20 to 36 hours |
| Intermediate Acting | Lantus | 1 to 1.5 hour | No peak time; insulin is delivered at a steady level | 20 to 24 hours |
| Pre-Mixed Premixed insulins are a combination of specific proportions of intermediate-acting and short-acting insulin in one bottle or insulin pen (the numbers following the brand name indicate the percentage of each type of insulin) | Humulin 70/30 | 30 min. | 2 to 4 hours | 14 to 24 hours |
| Pre-Mixed | Novolin 70/30 | 30 min. | 2 to 12 hours | Up to 24 hours |
| Pre-Mixed | Novolog 70/30 | 10-20 min. | 1 to 4 hours | Up to 24 hours |
| Pre-Mixed | Humulin 50/50 | 30 min. | 2-5 hours | 18-24 hours |
| Pre-Mixed | Humalog mix 75/25 | 15 min. | 30 min. to 2.5 hour | 16-20 hours |
The use of insulin is complicated for adult patients, and more so for school age and younger diabetics. Most type 1 patients have misjudged their insulin requirements one or more times in their lives and have required emergency room care for hypoglycemia. For this reason, type 1 patients should carry glucose tablets or candy at all times, and health care providers should always have a supply or fruit juice or glucose available. If a diabetic patient is experiencing problems, they could be associated with either hyper- or hypoglycemia, and sometimes it is hard to tell which is happening. Giving sugar to a patient whose glucose level is already too high does relatively little damage, but giving sugar to a patient with hypoglycemia can be lifesaving.
Type 2 Diabetes
The initial management approach for most newly diagnosed type 2 patients is to reduce blood glucose levels by a combination of diet and exercise. The diet is modified to reduce glucose and fat intake, which should result in weight loss. An exercise program, which will help to "burn off" some of the excess glucose, increase cardiovascular endurance, and develop additional muscle mass will also be recommended. Avoiding smoking and excessive alcohol consumption will not only help to lower glucose levels, it has also been shown to decrease blood pressure and can help with lipid control.(15)
These recommendations are well founded but often difficult for an obese patient to follow; weight loss through dieting is very difficult for many obese patients. It is recommended that a registered dietitian and diabetes educator provide assistance in guiding the patient’s nutritional therapy and life-style changes.
For many patients, diet and exercise do not provide a sufficient reduction in glucose levels, and medications must be used. Analogous to glaucoma medications, there is a range of diabetes medications that affect different aspects of the glucose metabolic cycle. Typically, the physician has a favorite medication to start patients on and then changes dosages or adds other medications until satisfactory control is obtained.
The specific goals of treatment are different for each individual; however, general goals can be specified: an HbA1c of less than 7.0%, a pre-meal plasma glucose level of 90–130 mg/dL, and a post-meal glucose level of less than 180 mg/dL.(15)
Again, as a parallel to glaucoma, eventually the patient's initial medication will become less effective and must be modified. This can happen because the initial medication simply stops working or because the islet cells of the pancreas are burning out and insulin production decreases. Eventually the islet cells may stop producing insulin. At this point the patient will need exogenous insulin injections just as a type 1 patient would.
Table 2. Types of Oral Diabetes Medication. This table shows most of the currently available oral medications divided by type and mode of action. The table is modified from a table presented at http://www.postgradmed.com/issues/2002/03_02/mayerson.htm, which was adapted from the original source: Inzucchi SE. Yale Diabetes Center Diabetes Facts & Guidelines. New Haven, Conn: Yale Diabetes Center, 2001:30-1.
|
Drug Type and Action
|
Name
|
Tablet Sizes
|
Total Daily Dose (mg)
|
Dosing Interval
|
Potential Adverse Effects
|
| Sulfonylureas: Stimulate the beta cells to produce more insulin. | Glyburide (DiaBeta, Micronase) | 2.5, 5 mg | 1.25 to 20 | QD or BID | Weight gain, hypoglycemia |
| Sulfonylurea | Glyburide, micronized (Glynase PresTab) | 1.5, 3, 6 mg | 0.75 to 12 | QD or BID | Weight gain, hypoglycemia |
| Sulfonylurea | Glipizide (Glucotrol) | 5, 10 mg | 2.5 to 40 | QD or BID | Weight gain, hypoglycemia |
| Sulfonylurea | Glipizide, extended-release (Glucotrol XL) | 2.5, 5, 10 mg | 2.5 to 20 | QD | Weight gain, hypoglycemia |
| Sulfonylurea | Glimepiride (Amaryl) | 1, 2, 4 mg | 1 to 8 | QD | Weight gain, hypoglycemia |
| Nonsulfonylurea Secretagogues (Meglitinides): Stimulate the pancreas to release insulin. | Nateglinide (Starlix) | 60, 120 mg | 180 to 360 | TID | Weight gain, hypoglycemia |
| Nonsulfonylurea Secretagogue (Meglitinide) | Repaglinide (Prandin) | 0.5, 1, 2 mg | 1.5 to 16 | TID or QID | Weight gain, hypoglycemia |
| Biguanides: Work by lowering the amount of glucose produced by the liver as well as decreasing the absorption of glucose in the intestinal tract. They also improve the muscle cell sensitivity to insulin. | Metformin HCl (Glucophage) | 500, 850, 1,000 mg | 1,000 to 2,550 | BID or TID | Diarrhea, lactic acidosis |
| Biguanide | Metformin, extended-release (Glucophage XR) | 500 mg | 1,000 to 2,000 | QD or BID | Nausea, diarrhea, abdominal pain, lactic acidosis |
| Alpha-glucosidase Inhibitors: Lower blood glucose levels by decreasing the breakdown of starch and some sugars. | Acarbose (Precose) | 25, 50, 100 mg | 150 to 300 | TID | Gas, abdominal pain, diarrhea |
| Alpha-glucosidase Inhibitor | Miglitol (Glyset) | 25, 50, 100 mg | 150 to 300 | TID | Gas, abdominal pain, diarrhea |
| Thiazolidinediones: Work by making muscle tissue more sensitive to insulin and by lowering the amount of glucose produced by the liver. | Rosiglitazone maleate (Avandia) | 2, 4, 8 mg | 4 to 8 | QD or BID | Weight gain, edema |
| Thiazolidinedione | Pioglitazone HCl (Actos) | 15, 30, 45 mg | 15 to 45 | QD | Weight gain, edema |
| Fixed combinations | Glyburide/metformin (Glucovance) | 1.25/250, 2.5/500, 5/500 mg | 2 to 4 tabs | BID | Nausea, diarrhea, abdominal pain, lactic acidosis, weight gain, hypoglycemia |
SYSTEMIC CONSEQUENCES OF DIABETES
Diabetes can damage essentially every part of the body and can produce cardiovascular disease, nephropathy, neuropathy, and retinopathy.
Even though diabetes can cause wide-spread damage, the Diabetes Control and Complications Trial (DCCT) demonstrated that the risk of diabetic complications can be reduced by keeping glucose levels under control.(16) This study followed 1441 type 1 diabetic patients over a 6.5 year period. Patients were placed on either intensive therapy, keeping their blood glucose levels close to a normal range, or conventional therapy with one or two insulin injection per day. As compared to the group with conventional therapy, the group with intensive therapy had a 76% reduction in the development of retinopathy and a 54% reduction in the progression of retinopathy. The group also had a 54% reduction in occurrence of advanced kidney disease and a 60% reduction in occurrence of neuropathy.
The DCCT considered only type 1 diabetics. The UK Prospective Diabetes Study considered intensive versus conventional therapy for type 2 diabetics and showed that improved control in type 2 patients led to a reduction in microvascular complications including retinopathy by up to 25%.(17)
Acute Consequences of High and Low Glucose Levels
When cells do not have access to sufficient supplies of glucose, they are forced to burn fat for fuel. This might sound just fine to the dieter, and, in fact, the current low carbohydrate diets actually put patients into states of mild ketosis as a result of fat burning. In the diabetic, however, fat burning can go to extremes and result in ketoacidosis, in which blood pH drops and severe symptoms can result in death.
Perhaps the most frequent acute problem faced by diabetics is hypoglycemia in which the glucose level can drop to 40 mg/dL or less. Alcohol, excess insulin, not eating, and drugs including antibiotics, nonselective beta-blockers, and MAO antidepressants can all lower blood glucose to dangerous levels.(18)
When the blood glucose level gets too high, hyperglycemia, with levels of 600 mg/dL or more, can occur. These glucose levels are significantly disruptive to the body and coma can result.
Microvascular Consequences
Many of the problems diabetics experience come from the disease's effects on blood vessels. In fact, some have suggested that diabetes should be regarded as a microvascular disease caused by or associated with increased glucose levels. In turn, these microvascular problems cause retinopathy, nephropathy, and neuropathy.
One of diabetes' effects is increased permeability of small blood vessels. To understand how diabetes might affect blood vessels, a review of vessel anatomy and physiology will be helpful. All blood vessels have an inner layer of endothelial cells. Larger vessels have additional layers outside of the endothelial cells, but capillary walls consist of only the endothelial cells. In most cases, gaps between adjacent endothelial cells are sealed off by tight junctions, which are aggregates of proteins on the cell membranes. One of the proteins, occludin, bridges between cells. This normally prevents leakage of water and large molecules and makes blood vessel walls relatively impermeable.
It has been shown that hyperglycemia can cause an increased level of vascular endothelial growth factor (VEGF) in the blood. VEGF activates the enzyme protein kinase C (beta isomer) that can decrease the amount of occludin. This causes the vessel wall cells to leak large molecules and water, i.e., vascular permeability is increased.
In a study that measured blood VEGF concentrations in poorly controlled diabetic patients, VEGF was elevated as compared to healthy patients. After treatment to bring sugar levels down, VEGF levels also decreased.(19)
When VEGF is injected intravitreally, protein kinase C in the retina is rapidly activated and an increased retinal vasopermeability is observed.(20) This can account for some of retinal damage caused by diabetes.
In the retina, VEGF is also associated with neovascularization in which new blood vessels sprout from capillaries. For these new vessels to grow, the tight capillary wall junctions must be broken, and VEGF could do this by affecting the occludin.
The VEGF-protein kinase C-occludin link is especially interesting due to the pivotal role these molecules play in the microvascular problems associated with diabetes. VEGF and/or protein kinase C represent an exciting target for therapeutic intervention. Clinical trials using a portion of antibody that blocks VEGF activity are currently underway as are clinical trials using ruboxistaurine, a protein kinase C inhibitor.
Some of changes that occur in diabetic retinopathy suggest that inflammation might also be involved. Clinical trials using intravitreal triamcinolone acetonide, a steroid inflammation inhibitor, are underway for the treatment of diabetic retinopathy, especially macular edema.(21)
Cardiovascular/Macrovascular Consequences
In larger vessels, diabetes can exacerbate atherosclerosis and increase the effects of hypertension. For these reasons, it is extremely important for diabetic patients to keep their blood pressure and lipid levels under control. High blood pressure causes damage mainly to the arterioles, and high lipid levels are associated with atherosclerotic damage to the large arteries.
Cardiovascular disease is the cause of death for 86% of people with diabetes.(22) In diabetics, atherosclerosis occurs earlier and with a more malignant course. Lowering LDL levels, raising HDL levels, and lowering triglycerides has also been shown to significantly reduce the incidence of vascular disease and cerebrovascular events in diabetics.(15) LDL should be less than 100 mg/dL, triglycerides less than 150 mg/dL, and HDL should be greater than 40 mg/dL.(15)
Up to 60% of adults with diabetes also have hypertension,(15, 22) which can exacerbate the tendency for blood vessels to leak, and even a mild rise in blood pressure can worsen retinal and kidney disease. A 10 mm Hg reduction in systolic blood pressure can reduce the risk for complications related to diabetes by 12%.(22) For diabetics, blood pressure should be kept below 130/80 mm Hg.
Neuropathy
Neurons in the brain do not use insulin as a mediator for moving glucose across vessel walls and into cells. They take glucose as needed using other mechanisms, but they can be significantly compromised and malfunction during hyper- or hypoglycemia.
Peripheral nerves can be significantly damaged by diabetes. Up to 50% of diabetics have at least some form of nerve damage.(23) Motor, sensory, and autonomic nerves can be affected. The damage often manifests itself as muscular weakness, numbness, and loss of autonomic organ function causing diarrhea, loss of bladder control, and impotence. Symptoms may also include a sensation of prickling, tingling, or sharp needlelike pain.
Although the exact causes of diabetic neuropathy are not totally understood, several factors probably contribute to this complication. Hyperglycemia can cause chemical changes in nerves, which can impair their ability to send action potentials. High blood glucose levels also damage blood vessels that provide metabolic support for the nerve cells. In addition, inherited factors, unrelated to diabetes, may make some people more susceptible to nerve disease than others.
One area of active research involves considering the effects of defective glucose metabolism on the amount of nitric oxide in various tissues. Nitric oxide dilates blood vessels, but, for a person with diabetes, low levels of nitric oxide may lead to constriction of blood vessels supplying the nerves, thus contributing to neuropathy.(18)
Nephropathy
Twenty to forty percent of diabetic patients will eventually develop diabetic nephropathy.(15) Kidney failure is indicated by leakage of protein into the urine. Microalbuminuria occurs when a small amount of protein (30-299 mg per 24 hours) leaks, and macroalbuminuria occurs when larger amounts (>300 mg per 24 hours) are found in the urine.
Progression from microalbuminuria to macroalbuminuria typically predicts a progression to end-stage renal disease within a few years.(15) Strict blood sugar control reduces the risk of microalbuminuria by one third and delays progression from microalbuminuria to macroalbuminuria.(15) Blood pressure control can also slow the progression of nephropathy.
Extremities
Foot ulceration and other infections are common complications of diabetes. These problems can occur due to neuropathy and/or poor blood flow to the feet. Diabetes can lessen the patient’s ability to feel pain causing him or her to not feel damage to the skin and give infections a longer time to develop before care is sought. In addition, poor circulation and high glucose levels make the patient less able to fight infection. Foot infections require care of a podiatrist; amputations can sometimes be required to prevent the spread of infection.
Skin
Diabetic patients are more prone to bacterial and fungal infections than are normal persons and are more likely to get styes, boils, and infections of the hair follicles. The reason for the infection susceptibility is probably related to vascular problems caused by the diabetes, but may also be related to the amount of glucose in the blood itself. Research is ongoing regarding this question.
Harmless light brown, scaly areas on the skin can also occur due to small blood vessel changes in diabetes. These most commonly occur on the fronts of the legs.
In addition, diabetic patients are at increased risk for gum disease and should see a dentist regularly.
OCULAR CONSEQUENCES OF DIABETES
Anterior Segment Consequences
Tear Film and Conjunctiva
Glucose levels in the tears increase in diabetes, and this can change tear osmolarity making them mildly irritating. In addition, tear quality and quantity can be affected in diabetes, and dry eye symptoms can result. Artificial tears, ointment, or punctual occlusion may decrease these symptoms.
Conjunctival microaneurysms also occur in diabetic patients. They typically do not require treatment but should be monitored.
Cornea
Changes in epithelial basement membrane structure make the cornea more susceptible to recurrent corneal erosions and abrasions from even minimal trauma.(24) Basement membrane changes can also cause prolonged healing time.
Neurotrophic corneal ulcers are more common in diabetic patients. As corneal sensation is diminished, the patient becomes more prone to spontaneous ulcers.
Iris
A general evaluation of the iris including a gonioscopic evaluation of the anterior angle should be performed on diabetic patients to determine if rubeosis iridis is present. The growth of new vessels in the iris is probably stimulated by cells that do not receive a sufficient supply of glucose. Typically the new vessels are first seen at the pupil border and in the anterior chamber angle. Peripheral anterior synechiae, which can cause neovascular glaucoma, may form after neovascularization has been present for some time.
The presence of rubeosis iridis typically indicates the existence of retinal ischemia and suggests a retinal specialist referral.
Diabetic patients with poor control can be difficult to dilate because of neuropathy involving the sympathetic iris tissues. For this reason, a combination of tropicamide and phenylephrine should be used for dilation.(18)
Lens
The effects of shifts in blood glucose level on refractive error are well known. Over time, patients become more myopic as glucose and sorbital levels increase in the lens and pull water into its structures. This makes the lens swell and acquire more plus power. The reverse happens as glucose level decreases. Multiple spectacle prescriptions are occasionally necessary for patients who cannot achieve good glucose level control.
Due to cell damage, diabetic patients are more likely than normals to develop premature and rapidly growing cataracts.(24, 25) Cataract types encountered in diabetics include anterior cortical, posterior subcapsular, nuclear, and snowflake.(5) Snowflake cataracts are rare and usually indicate very high blood glucose levels.(26) Early cataract changes are reversible when glucose levels are returned to normal.(24)
Cataract extraction should be considered if visualization of the retina is inadequate or if the patient’s visual acuity is not satisfactory.
Posterior Segment Consequences
Diabetic effects on the anterior segment of the eye can be troublesome, but posterior segment effects can be devastating. Problems typically increase with patient age, duration of the diabetes, and high blood glucose levels.
Vitreous
Vitreous hemorrhage can occur if vessels growing into the vitreous from the retina leak or if blood spreads from retinal hemorrhages. Consultation with a retinal specialist can be helpful in determining the source of bleeding and the prognosis for return of visual acuity. A vitrectomy may be required if the hemorrhage does not resolve in a timely manner.
Optic Nerve
Diabetic papillopathy, which is similar in appearance to papilledema, can cause decreased acuity, visual field defects, and an afferent papillary defect. This condition usually improves without treatment.
Patients with diabetes are at greater risk for anterior ischemic optic neuropathy (AION).(24) Patients with this condition report a sudden decrease in visual acuity or field loss. Altitudinal field loss, afferent pupillary defect, and a pale swelling of the optic nerve head are typically seen.
Diabetic patients are also at greater risk for artery and vein occlusion of the nerve and disc, and, for reasons that are not well understood, they are twice as likely to have open-angle glaucoma.(25)
Extraocular Muscles Consequences
Isolated third, fourth, or sixth cranial nerve palsies can occur with diabetes. The patient will often present with pain in the involved eye, diplopia, and/or ptosis. When the third nerve is involved, pupillary function is usually normal. This pupillary sparing is helpful in distinguishing diabetic third nerve palsy from other causes of third nerve palsy such as a tumor or aneurysm.
Recovery of extraocular muscle function typically occurs after 1 to 4 months.(23) Controlling glucose, blood pressure, and lipid levels may aid in this recovery.(23) Temporary prism or eye patching can be used to relieve the diplopia. A neurology consultation should be requested if more than one oculomotor nerve is involved, if the pupil is involved, or if the condition does not resolve spontaneously within 1 to 4 months.
Retina
Diabetic retinopathy is the leading cause of new blindness in people between 20 and 74 years of age.(24, 27) Factors that influence the development of retinopathy include blood glucose control, blood pressure, length of time since diabetes onset, and genetics, with the best predictor being diabetes duration.
Diabetic retinopathy is typically divided into two main categories: nonproliferative diabetic retinopathy (NPDR) and proliferative diabetic retinopathy (PDR). Macular edema can be present at either level.
Nonproliferative Retinopathy
Microaneurysms, retinal hemorrhages, hard exudates, cotton wool spots, intraretinal microvascular abnormality (IRMA), and venous beading characterize nonproliferative diabetic retinopathy. Unless macular edema is present, early NPDR typically has no effect on vision.
Microaneurysms are the earliest clinical signs of diabetic retinopathy. These capillary outpouchings appear as small red dots and are easily mistaken for dot hemorrhages. However, the microaneurysms are typically smaller and have more discrete edges than dot hemorrhages.
Figure 6. This figure shows the difference between microaneurysms (two thin arrowheads lower on the figure) and dot hemorrhages (two thicker arrowheads higher up on the figure).
The walls of microaneurysms are thin and can rupture causing intraretinal hemorrhages. The appearance of the hemorrhages coincides with the structure of the retinal layer in which they are found. Flame-shaped hemorrhages are located in the nerve fiber layer and follow the flow of nerve fibers. Dot-blot hemorrhages are in the outer plexiform and inner nuclear layers and reflect the more column-shaped anatomy of these layers.
Figure 7. This figure shows two flame hemorrhages (arrows) as well as dot-blot hemorrhages and cotton wool spots.
Lipids are present in the serum that is leaked from weakened retinal blood vessels. The lipid material left in the retina after the fluid is reabsorbed is seen as hard exudates and indicates an area of long-standing edema/leakage. Exudates often form in a circular pattern around a microaneurysm (circinate retinopathy).
Figure 8. Circinate retinopathy (arrow) as well as other exudates and hemorrhages are shown.
The weakened capillaries can collapse causing capillary occlusion and retinal ischemia. The affected nerves swell and lose their transparency causing cotton wool spots, also known as soft exudates. These appear as feathery, white spots and are often near blood vessel bifurcations.
Figure 9. This figure shows multiple cotton wool spots.
As diabetic retinopathy progresses, retinal veins become dilated and tortuous. When the retinal veins become focally dilated, they look like a string of beads. This venous beading is caused by severe retinal hypoxia.
Figure 10. This figure shows venous beading. The beading is subtle and somewhat difficult to see.
Ischemic conditions of the retina also cause intraretinal microvascular abnormality (IRMA). IRMA can resemble neovascularization, but the main differences are that IRMA does not show profuse leakage during fluorescein angiography and it does not cross over major blood vessels. IRMA is often found near cotton wool spots.
Figure 11. This figure shows IRMA as well as venous beading. (Image from http://eyelearn.med.utoronto.ca/Lectures04-05/Retinal/04PrePro.htm#prepro)
Levels of NPDR and Progression
A description of NPDR levels, progression risks and follow-up recommendations is presented in Table 3. The standard photographs of the modified Airlie House classification system referred to in the Table can be viewed at URL http://eyephoto.ophth.wisc.edu/ResearchAreas/Diabetes/DiabStds.htm
Table 3. NPDR levels, progression risks and follow-up recommendations
|
Retinopathy Level
|
Description
|
Risk of Progression to PDR within 1 year
|
Recommended Treatment/ Follow-up
|
| Mild NPDR |
At least one hemorrhage or microaneurysm. (Severity less than that in standard photograph 2A.)
|
5% | Yearly follow-up. No further testing necessary. |
| Moderate NPDR | One to three retinal photographic areas show hemorrhages or microaneurysm worse than that in standard photograph 2A. Cotton wool spots. Mild venous beading. Mild IRMA. | 12 to 27% | Take fundus photos. Reevaluate 6 to 8 months if no macular edema present. Reevaluate in 4 to 6 months if clinically insignificant macular edema is present. Focal laser treatment may be considered with CSME. |
| Severe NPDR | Four retinal quadrants show hemorrhages or microaneurysm worse than that in standard photograph 2A. Venous beading (greater than that in standard photograph 6B) in two quadrants. IRMA (greater than that in standard photograph 8A) in at least one quadrant. | 52% | Take fundus photos. Follow-up every 2 to 3 months. PRP may be necessary. Focal laser treatment should be considered if macular edema is present, even if clinically insignificant. |
| Very Severe NPDR | Two of the features of severe NPDR | 75% | Same as that for Severe NPDR or severe proliferative retinopathy |
Proliferative Diabetic Retinopathy
Patients with proliferative diabetic retinopathy (PDR), the more advanced stage of retinopathy, will show many of the same signs as patients with NPDR. The feature that differentiates NPDR from PDR is the proliferation of new blood vessels, probably caused by retinal ischemia and mediated by VEGF as discussed elsewhere in this course.
The new blood vessel growth, referred to as neovascularization, can be at or within 1 disk diameter of the disk (NVD), neovascularization elsewhere on the retina (NVE), on the iris (rubeosis iridis), and/or in the trabecular meshwork. NVD indicates a more widespread ischemia, and NVE typically indicates a more localized condition.(24)
Neovascularization puts the patient at risk for fibrosis, tractional retinal detachment, preretinal hemorrhage, vitreous hemorrhage, and neovascular glaucoma. Patients with PDR may be asymptomatic or they may complain of visual loss or floaters, often due to vitreal hemorrhage and/or retinal detachment.
PDR is classified as either early or severe. A patient with severe PDR is at an especially high risk for visual loss. A patient with neovascularization that does not meet the characteristics of severe PDR listed below is classified as having early PDR.
Table 4. Characteristics of severe PDR. Retinopathy is classified as severe PDR when a patient has one or more of the following. The standard photographs of the modified Airlie House classification system referred to in the Table can be viewed at URL http://eyephoto.ophth.wisc.edu/ResearchAreas/Diabetes/DiabStds.htm
| NVD larger than one-quarter to one-third disc diameter in size (greater than in the standard photo 10A) |
| NVD smaller than one-quarter disc diameter in size with the presence of a vitreous or preretinal hemorrhage |
| NVE larger than one-half disc diameter in size with the presence of a vitreous or preretinal hemorrhage |
Figure 12. This figure shows the retina of a patient with severe PDR. Neovascularization of the disk and vitreous hemorrhage are present. The hemorrhage makes the retinal view somewhat hazy.
The Diabetic Retinopathy Study demonstrated that panretinal photocoagulation can reduce the risk of severe vision loss due to PDR by as much as 60%.(4, 27, 28) Therefore, patients with PDR should be referred to a retinal specialist within 24 to 48 hours. Pan-retinal photocoagulation is generally indicated even in cases of early PDR.
For patients with PDR, any macular edema should be considered for focal laser photocoagulation treatment, even if the edema is not clinically significant.
Progression from NPDR to PDR
Table 5 shows the incidence of retinopathy and progression of the retinopathy relative to diabetes duration.(4, 25)
Table 5. Incidence of retinopathy relative to duration of type 1 and type 2 diabetes.
|
Diabetes Type
|
Duration of Disease
|
Probability of Retinopathy
|
Probability of Progression
|
| Type 1 | 10-years | 60 to 74% have retinopathy | Unspecified |
| Type 1 | 15-years | 98% have retinopathy | 25% have progressed to proliferative retinopathy |
| Type 1 | 20-years | 100% have retinopathy | 50% have progressed to proliferative retinopathy |
| Type 2 | At diagnosis | 10 to 20% have retinopathy | Unspecified |
| Type 2 | 4-years | 4 to 29% have retinopathy | Unspecified |
| Type 2 | 15-years | 60 to 80% have retinopathy | 5 to 20% have progressed to proliferative retinopathy |
Although the best predictor of diabetic retinopathy is disease duration, strict control of glucose level has been shown to reduce the incidence and severity of diabetic retinopathy as well as slowing its progression.(5, 24) Therapy that keeps blood glucose levels as close to normal as possible can reduce development of retinopathy by up to 76% and progression by 54%.(16, 17, 27)
Non-Clinically Significant Macular Edema
Non-clinically significant macular edema presents as any retinal thickening or hard exudates within one disc diameter of the fovea.
Patients with non-clinically significant macular edema should be re-examined every 3 to 4 months.
Clinically Significant Macular Edema
Clinically significant macular edema (CSME) is the most common cause of decreased visual acuity in diabetic patients. It can occur at any stage of retinopathy when blood vessels begin to leak in the macular region.
CSME presents as cysts, retinal thickening, and hard exudates. (Figure 13) The macular edema, which is best seen with a fundus contact lens, will obscure the normal choroidal and retinal pigment epithelial pattern.
Macular edema is considered clinically significant if one or more of the following is present:(5, 27)
A retinal consult should be obtained within 2-4 weeks for patients with clinically significant macular edema unless the patient also has severe PDR. Then they should be referred within 24-48 hours.
Figure 13. This image shows a retina with clinically significant macular edema.
RECOMMENDED EXAMINATION FOR A DIABETIC PATIENT
The American Diabetes Association recommends a dilated fundus exam at least once per year for diabetic patients. Beyond this baseline, examination frequency should be determined by duration of the diabetes, level of blood glucose control, stage of retinopathy, and other ocular findings. Annual examinations are appropriate if there is no retinopathy or if only mild NPDR is present. The patient should be examined more frequently if significant retinopathy is present.
During the examination, a thorough history should be taken including the following: family history of diabetes: duration and specific diagnoses of the patient's diabetes; blood glucose level test results including HbA1c and fasting levels; medications being taken or other treatment modalities being used; and weight, blood pressure, and serum lipid levels. Smoking and the use of alcohol should also be discussed.
In addition to a dilated stereoscopic examination of the posterior pole and peripheral retina, the following tests should be included in a diabetic examination: visual acuity, pupillary reflexes, ocular motilities, refraction, blood pressure measurement, blood glucose measurement, tonometry, and biomicroscopy including iris examination. Fundus photography is useful for documentation as well as classifying any retinopathy. Gonioscopy, color vision testing, and Amsler grid testing may also be indicated to aid in the diagnosis or evaluation of retinopathy or other conditions associated with the diabetes.
Retinal Thickness Analysis
In the past, diagnosis of macular edema was reliant upon subjective judgments of a doctor. The Heidelberg Retina Tomograph (HRT), Optical Coherence Tomographer (OCT), and Retinal Thickness Analyzer (RTA) can now objectively and noninvasively measure retinal thickness and diagnose edema. This makes earlier detection and treatment of macular edema possible.(29, 30)
Other advantages of objective measurements using the HRT, OCT, and RTA are that subtle thickness changes can be assessed over time and the effectiveness of treatments can be monitored.
Figure 14. This image shows a retina with hemorrhages inferior temporal to the macula and a cotton wool spot superior nasal to the macula. The same eye is shown in Figure 15 with the overlying RTA thickness plot.
Figure 15. This is an RTA image showing retinal thickening near the area of hemorrhages and retinal thinning in the ischemic area next to a cotton wool spot. Red and yellow indicate areas of retinal thickening; green indicates retinal thinning.
TREATMENT OPTIONS FOR DIABETIC RETINOPATHY
Early detection and appropriate laser therapy can greatly reduce the risk for developing severe vision loss in diabetic patients.(4, 27, 28) Referral to a retinal specialist is warranted when any amount of clinically significant macular edema, severe NPDR, or PDR is present. It is important to make patients aware that laser photocoagulation treatment is aimed at reducing the risk of further visual loss. The treatment generally does not reverse loss that is already present.
Pan-retinal Photocoagulation
Argon laser pan-retinal photocoagulation (PRP), also known as scatter laser photocoagulation, is used to reduce the risk of visual loss in patients with PDR. PRP reduces the risk of vitreous hemorrhage and retinal detachment by causing regression of neovascularization.
Rather than targeting new blood vessels, the treatment is delivered over a wide area of the more peripheral retina and attempts to destroy ischemic tissue that is the stimulus for new vessel growth. Although this procedure has value, the nerve fiber layer scarring and destruction caused by PRP can result in extensive visual field loss and possible night blindness.
The Diabetic Retinopathy Study established that the benefits of PRP are greatest for patients who display the high-risk characteristics described previously. The study also showed that severe vision loss can be reduced by 50 to 60% when PRP is performed on high risk patients.(4, 27, 28) For these patients, 26% of untreated eyes progressed to severe vision loss whereas only 11% of treated eyes progressed to this point.(15) Accordingly, high risk patients should be referred to a retinal specialist within as soon as possible to discuss PRP.
Because of the extensive tissue destruction associated with PRP, it is not recommended for patients with mild or moderate nonproliferative diabetic retinopathy.
Focal and Macular Grid Laser Photocoagulation
Patients with clinically significant macular edema should be referred for either focal or macular gird laser photocoagulation. Fluorescein angiography will be used prior to photocoagulation to determine the degree of macular perfusion and to identify the location of blood vessels causing the edema.(27) The laser is then applied in either a grid-pattern (macular grid photocoagulation) or directly to leaking blood vessels (focal laser photocoagulation).
Focal laser treatment is used to treat leaky microaneurysms whereas macular grid photocoagulation is used when specific leaky blood vessels cannot be identified. These treatments do not cure blurry vision, but they can stop acuity from decreasing. Laser photocoagulation to has been shown to reduce the risk of moderate vision loss by 50%.(15, 28)
Vitrectomy
More serious cases of diabetic retinopathy may require a vitrectomy to prevent tractional retinal detachment or to remove a vitreous hemorrhage that has not resolved within 6 months.
Non-surgical Treatment
Surgical treatment is an important option in the treatment of diabetic retinopathy, but non-surgical treatments can be equally important in preserving quality of the patient’s life. In the United States most patients who have been diagnosed as being diabetic within the last decade have received the standard lecture regarding diet and exercise. Many patients will deny ever having heard the lecture, either because it was delivered too quickly by a busy physician or in excruciating (and sometimes frightening) detail by a well-meaning diabetes educator.
Many or most diabetic patients know that they need to have frequent examinations, to monitor their glucose levels, and to take medications on a regular basis - but many do not do these things. It is often very difficult to educate patients and convince them to take personal responsibility for their diabetic care until a toe or two is lost or until visual acuity is reduced. Then the condition becomes frighteningly real and the patient is often in fear for his or her life. At that time, providing literature or making a referral to a support group can be helpful.
Of utmost importance is communicating with the primary care physician, endocrinologist, dietitian, and other caregivers regarding diabetic patients. Caring for diabetes must be a multidisciplinary effort. If you chose to counsel with and educate your diabetic patients, remember that a trim doctor telling an overweight patient to lose weight can be a difficult sell. You must also budget enough time to really make a psychological connection with your patient.
The goal of non-surgical treatment should be to maximize the quality and duration of life for the patient by preventing or reducing diabetic complications. When you discuss diabetes with a patient, remember that you are discussing the disease that will probably be the cause of his or her death - no matter how good glucose control is. This should not be a quick discussion in the hallway on the way from the examining room to the waiting room.
CONCLUSION
Early diagnosis and treatment of diabetes can preserve sight. Optometrists play a significant role in identifying patients with diabetic retinopathy and choosing appropriate treatment in order to prevent or delay severe vision loss. Because retinopathy can occur without any symptoms, patients should be educated regarding the importance of yearly dilated eye exams, and they should understand that the risk of vision loss can be significantly reduced by appropriate treatment. Controlling blood sugar, hypertension, and cholesterol levels should also be emphasized during each diabetic examination.
Working with the patient’s primary care physician or endocrinologist is essential in managing this disease and decreasing its associated complications.
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Denise Goodwin, OD Pacific University College of Optometry 2043 College Way Forest Grove OR 97116Pacific University College of Optometry provides On-Line CE as a service to optometrists. The college does not endorse or recommend any products, equipment, or services that might be discussed in the courses. Courses are prepared by individuals believed to be experts in their areas of specialization who are compensated for their efforts. The College relies on their expertise to produce accurate and timely courses.
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