Diabetes Mellitus: Definition, Types, Effects and Causes

 Diabetes mellitus (DM) is a disease that affects a persons ability to metabolize sugars. A patient with DM will experience numerous symptoms including hyperglycemia, polyuria, polydipsia, polyphagia, and blurry vision. Patients also typically experience yeast infections more often than patients without DM. While patients may experience all or only a few of these symptoms, they will often be unaware of the condition until diagnosed by a physician. If a patients blood glucose level remains high for a long period of time, due to poor compliance with prescribed medications and diet, they can experience complications such as diabetic retinopathy, hypertension, neuropathy, and increased infections of the feet. Thus, its incredibly important for patients to monitor their blood glucose levels at home. This provides patients with key information to adjust their medication levels and restrict their diet based on their most current readings.

DM consists of two main types: type 1 and type 2. Type 1 is caused by destruction of the beta cells in the pancreas, which produce insulin. It accounts for approximately 10% of DM, and it is thought to be an autoimmune process. Type 2 is due to a combination of resistance to insulin and inadequate insulin production by the pancreas. It accounts for approximately 90% of DM. DM is diagnosed if any of the following conditions are met: an HbA1c of 6.5% or higher, a fasting plasma glucose level of 126mg/dl or higher, a 2 hour plasma glucose level of 200mg/dl or higher, or a random plasma glucose reading of 200mg/dl or higher. HbA1c measures a patients blood glucose level by measuring the percent of hemoglobin that binds glucose. Typically glucose doesn’t bind to hemoglobin, but when a patient experiences hyperglycemia, more glucose binds to hemoglobin. This measurement is preferred because it is an average reading over a period of a few months rather than a one time measurement like the other diagnostic tests.

According to the American Diabetes Association, as of 2015, 9.4% (30.3 million) of the United States population had diabetes. Of that 9.4%, roughly 24% (12 million) of patients were undiagnosed. Approximately 25.2% of people over 65 have diabetes while only 0.24% of people under 20 have diabetes. Diabetes is more common in American Indians, blacks, and hispanics in the U.S. On a global scale, approximately 422 million people have diabetes. This equates to almost a 4% increase since 1980. The prevalence of diabetes varies greatly across the globe, but higher rates of type 1 diabetes appear in European countries followed closely by Canada and the United States. Type 2 diabetes shows higher rates among the groups discussed previously in the United States, as well as Fiji, China, and South Africa.

Patients are at a higher risk for developing diabetes if they have any of the following characteristics: they are overweight, over the age of 45, are American Indian, black, hispanic, or Pacific Islander, have hypertension, are not physically active, have a family history of diabetes, etc. Rates of diabetes are increasing rapidly in countries that are adopting a lifestyle similar to that of the United States. More and more people are becoming obese leading to more patients being diagnosed with type 2 diabetes. A persons BMI is used as an indicator to determine if a patient is overweight or obese. BMI stands for body mass index and it is equal to the patients weight in kilograms divided by their height in meters squared. A BMI of 27.3 or higher is considered overweight while 30 or higher is considered obese. While some muscular patients can experience a superficially high BMI, it is still thought of as a good indicator of a persons healthy weight.

One of the biggest concerns in patients who have had diabetes for a long period of time is the development of diabetic retinopathy (DR). Approximately 93 million people across the world have DR. Incidence of DR varies greatly across the globe, but on average 30-40% of patients with DM will develop DR. Many risk factors for developing DR exist including: the length of time the patient has had diabetes, males are at higher risk than females, hypertension, high HbA1c levels, smoking, puberty increases rates in patients with type 1 DM, pregnancy, as well as renal damage can all cause increased risk of developing DR.

DR occurs due to various pathways in the body being impacted by increased glucose levels. The polyol pathway reduces excess glucose in the retina to sorbitol and then into fructose. Converting sorbitol into fructose is slow which leads to sorbitol being trapped in the retinal cells. This creates osmotic damage in the retinal cells as water follows its concentration gradient. This can also produce a myopic shift due to the lens becoming less flexible in young patients, or leading to a higher refractive index in patients with no accommodation. Since water regulation is impacted, patients can often experience dry eye symptoms as well. This pathway has also been linked to increased thickness of the basement membrane of the retinal capilaries. Hyperglycemia also leads to increased protein kinase C activation which results in changes to retinal hemodynamics, and the expression of vascular endothelial growth factor (VEGF), and endothelial permeability. This can lead to oxidative stress as well as macular edema. Macular edema causes photoreceptors to be oriented incorrectly leading to poor vision. Ischemia leads to VEGF recruitment which causes neovascularization in order to get more oxygen to the hypoxic area. Neovascularization leads to leaky, fragile blood vessels being formed. VEGF is also thought to control the actions of insulin growth factor 1 (IGF1); however, IGF1s role in DR isn’t fully understood at this time. When the contents of the vessels leak into the vitreous vision is negatively impacted. Neovascularization of the iris can also lead to open angle glaucoma due to hypoxic conditions created by changes in the vasculature. Hypertension also causes endothelial damage. Thus, many pathways contribute to the development of DR and a cure would be very difficult to obtain.

The two main types of DR are proliferative DR (PDR) and nonproliferative DR (NPDR), which can further be broken down into mild, moderate, and severe categories. In mild NPDR, microaneurysms occur. Microaneurysms are small areas of blood vessels that become weak due to loss of pericytes and balloon outward. In moderate NPDR, microaneurysms, dot hemorrhages, and scattered exudates occur. In severe NPDR, blot and flame hemorrhages, cotton wool spots, hard exudates, and definite venous beading occur, but no signs of PDR are present. Dot and blot hemorrhages are micro aneurysms that have ruptured in the inner and outer plexiform layers. Hard exudates consist of lipids that have leaked from the retinal capillaries once weakened. These exudates appear yellow and are typically found around the macula which can lead to impaired vision. Cotton wool spots are caused by ischemia in the retinal vessels leading to infarction of the nerve fiber layer in the retina. These spots appear white and fluffy when viewing the retina. In PDR retinal ischemia leads to the formation of new, leaky blood vessels. Patients with PDR may have vitreous hemorrhages, neovascularization near the optic disc, and beading and kinking of the vasculature due to the hypoxic conditions of the retina. PDR can lead to tractional retinal detachments and blindness. This occurs when new blood vessels created by VEGF use the vitreous as a scaffold. As the vessels become attached to the vitreous, when the eye moves the retina experiences traction, and retinal detachments can occur. It’s important for a patient with diabetes to receive annual exams to prevent NPDR from developing into PDR for as long as possible.

Many factors of DR cause vision loss some of which include: macular edema which causes photoreceptors to be oriented incorrectly, leaking of vascular contents into the vitreous due to neovascularization, and hard yellow exudates centered around the macula and optic nerve head. The most likely cause of vision loss in both eyes of this patient would be macular edema. This diagnosis could be confirmed using various imaging techniques and tests such as retinal imaging, fundus photography, and optical coherence tomography (OCT). Retinal imaging simply takes a photo of the retina. Fundus photography requires the patient to be dilated, then the retina can be viewed. OCT can provide cross sections of the retina which can provide information on exactly how much edema is present in a given area, where a detachment has occurred, where a retinal hemorrhage is located, etc. Information from OCT allows the doctor to determine how aggressive treatment needs to be for a particular patient.

Fluorescein angiography can also be performed to determine the location of blocked or leaky retinal veins or arteries. First the patient would be dilated and baseline photos of the retina would be taken. Next, NaFl dye is injected into the patients vein. The NaFl dye can have negative side effects such as nausea, vomiting, and warm flush, so its best to inform the patient of these potential side effects before beginning the procedure. Finally, the examiner should begin taking photos. The dye travels from the patients arm where injected to the patients eye where it reaches the choriocapillaris vessels first. Since the choriocapillaris is fenestrated, the dye is visible as a patchy background glow in the choroidal flush phase. This takes only 10-15 seconds to occur. Next, central arteries fill quickly, followed by peripheral arteries, then capillaries, followed by peripheral veins, and finally central veins. Dye should remain within these vessels, but if the vasculature is damaged, like in DR, fluorescein can be seen leaking out of the vessels. Similarly, if a vessel is blocked, filling of the vessels won’t occur as described previously and a block would be easily identified using this technique. Finally, in the late phase, the choriocapillaris, arteries, and veins all drain the dye. The dye causes the optic nerve head to glow as it exits the eye. This phase occurs roughly 10 minutes after the dye is injected.

Several treatment options for DR exist including pan retinal photocoagulation (PRP). In PRP, an argon laser is used to create 1200-1800, 200-500 micron burns across the retina. These burns cause the leaking blood vessels to undergo coagulation necrosis. Since no oxygen is needed in this area of the retina after being burned, the rest of the retina receives better oxygenation. This treatment has been shown to be incredibly effective, but it can also cause complications such as exudative retinal detachments, macular edema, visual field defects, and night vision defects, so patients should be aware of other treatment options as well as PRP. A somewhat similar treatment, focal laser treatment, exists for macular edema. This laser treatment is used to create 50-100 micron burns on leaky blood vessels. This allows the inner retina to better utilize oxygen in a manner similar to PRP. This treatment has been shown to reduce a patients chance of visual acuity loss by 50%.

Other treatment options are also available to patients with DR. One such treatment option is Avastin. Avastin is given via intravitreal injections in the eye, and it binds to the receptor binding domain of VEGF-A, which prevents VEGF-A from interacting with its receptor; thus it doesn’t signal for the formation of new, leaky blood vessels. Similar drugs are also on the market including Lucentis and Eylea. Since VEGF is blocked, macular edema would be reduced leading to better visual acuities for patients. One study found that over the course of 5 years Avastin injections stabilized or improved visual acuities in 70% of cases. PRP should also be considered with the injections as its more likely to provide better long term control of the patients symptoms. While this treatment has been shown to be highly effective, its important to inform the patient of possible risks associated with these injections. The biggest risk is the development of infections, including endopthalmitis, which can lead to the patient losing their eye.

Since the patient in this case has blood in the vitreous, ultrasonography can be used to determine if a retinal detachment or vitreal detachment is present. B-scan ultrasonography is a noninvasive procedure that utilizes a probe and sound waves to produces a 2-D grid of black and white dots. Black dots correspond to areas of low reflective interfaces while white dots correspond to high reflective interfaces. If the results show no retinal detachment, but blood is present in the vitreous it may be necessary to perform a vitrectomy. A vitrectomy removes the vitreous gel which new blood vessels have attached to in DR. Removing this gel will prevent further tractional forces from acting on the retina and decrease the chance of a retinal detachment. Once the vitreal gel is removed, a bubble made of gas or oil is used to keep the retina in place. Eventually the body will produce fluids that replace the bubble and it can be removed with a second surgery.

Overall diabetes is a rather complicated condition that affects many organ systems within the body including the eye. It’s important for patients to manage their blood sugar effectively in order to reduce the damage being done to the vasculature and organs. If diabetes remains uncontrolled, eye health can suffer greatly and result in complications such as macular edema and DR. It’s important for patients to be well educated about the possible repercussions of the disease. While a cure for DR doesn’t currently exist it is possible to manage symptoms and is important for patients to receive annual exams to follow the progression of their symptoms and treatments.

References

1. Lee, R., Wong, T. Y., & Sabanayagam, C. (2015). Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye and vision (London, England), 2, 17. doi:10.1186/s40662-015-0026-2
2. Forouhi, N. G., & Wareham, N. J. (2014). Epidemiology of diabetes. Medicine (Abingdon, England : UK ed.), 42(12), 698–702. doi:10.1016/j.mpmed.2014.09.007
3. Kharroubi, A. T., & Darwish, H. M. (2015). Diabetes mellitus: The epidemic of the century. World journal of diabetes, 6(6), 850–867. doi:10.4239/wjd.v6.i6.850
4. Forouhi, N. G., & Wareham, N. J. (2014). Epidemiology of diabetes. Medicine (Abingdon, England : UK ed.), 42(12), 698–702. doi:10.1016/j.mpmed.2014.09.007
5. Joanna M. Tarr, Kirti Kaul, Mohit Chopra, Eva M. Kohner, and Rakesh Chibber, “Pathophysiology of Diabetic Retinopathy,” ISRN Ophthalmology, vol. 2013, Article ID 343560, 13 pages, 2013. https://doi.org/10.1155/2013/343560.
6. Shivani V. Reddy & Deeba Husain (2018) Panretinal Photocoagulation: A Review of Complications, Seminars in Ophthalmology, 33:1, 83-88, DOI: 10.1080/08820538.2017.1353820
7. Romero-Aroca, P., Reyes-Torres, J., Baget-Bernaldiz, M., & Blasco-Suñe, C. (2014). Laser treatment for diabetic macular edema in the 21st century. Current diabetes reviews, 10(2), 100–112. doi:10.2174/1573399810666140402123026
8. Kernt, M., Cheuteu, R. E., Cserhati, S., Seidensticker, F., Liegl, R. G., Lang, J., … Neubauer, A. S. (2012). Pain and accuracy of focal laser treatment for diabetic macular edema using a retinal navigated laser (Navilas). Clinical ophthalmology (Auckland, N.Z.), 6, 289–296. doi:10.2147/OPTH.S27859
9. Perente, I., Alkin, Z., Ozkaya, A., Dardabounis, D., Ogreden, T. A., Konstantinidis, A., … Yazici, A. T. (2014). Focal laser photocoagulation in non-center involved diabetic macular edema. Medical hypothesis, discovery & innovation ophthalmology journal, 3(1), 9–16.
10. Grisanti, S., & Ziemssen, F. (2007). Bevacizumab: off-label use in ophthalmology. Indian journal of ophthalmology, 55(6), 417–420. doi:10.4103/0301-4738.36474
11. Aironi, V. D., & Gandage, S. G. (2009). Pictorial essay: B-scan ultrasonography in ocular abnormalities. The Indian journal of radiology & imaging, 19(2), 109–115. doi:10.4103/0971-3026.50827
12. World Health Organization. Diabetes. (2018, October 30). Retrieved November 4, 2019, from https://www.who.int/news-room/fact-sheets/detail/diabetes.
13. American Diabetes Association. Statistics About Diabetes. (n.d.). Retrieved November 4, 2019, from https://www.diabetes.org/resources/statistics/statistics-about-diabetes.