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Diabetic Complications

1.00 Contact Hour
A score of 80% correct answers on a test is required to successfully complete any course and attain a certificate of completion.
Author:    Dana Bartlett (BS, MS, MA)


This module will discuss the pathogenesis, clinical presentation, and treatment of three complications of diabetes mellitus: diabetic retinopathy, diabetic nephropathy, and diabetic neuropathies.


When this module has been completed, the learner will be able to:

  1. Identify the basic pathologic process that causes diabetic retinopathy.
  2. Identify five risk factors that contribute to the development of diabetic complications
  3. Identify the most important goal of treating diabetic complications
  4. Identify three specific treatments used for diabetic retinopathy.
  5. Identify three specific treatments used for diabetic nephropathy.
  6. Identify three medications used to treat pain caused by diabetic neuropathies.


Diabetes mellitus is one of the most common chronic diseases. The number of people who will develop diabetes is expected to increase tremendously and with that will come an increasing number of people who will develop diabetic retinopathy, nephropathy, and/or neuropathy. 

These complications are insidious in onset and progression and they are a significant cause of morbidity and mortality. They can be prevented and if they do occur, their onset and progression can be favorably influenced by close attention to glycemic control and life style changes. Unfortunately, it is all too clear that many people who have diabetes find tight glycemic control and losing weight,

Preventing and managing these complication is a life-long process. In order to help detect and treat diabetic retinopathy, nephropathy, and neuropathy, nurses must understand their pathogenesis, know who is at risk, understand the treatments, and be able to educate and support patients with their preventive and self-care efforts. 

Diabetes mellitus is characterized by chronic hyperglycemia and chronic hyperglycemia is the primary cause of diabetic retinopathy, diabetic nephropathy, and diabetic neuropathy. Hyperglycemia initiates many pathological processes that have profound and damaging effects on the eyes, the kidneys and the nervous system. Many organs and tissues can limit the movement of glucose across cell membranes so that even if the blood glucose level is very high, the internal environment of the cells is protected. However, the eyes, the kidneys, and certain parts of the nervous system lack this protection. These organs - and specific cells in the capillaries of the retinas, the renal vasculature, and neurons and Schwann cells in peripheral nerves - cannot reduce glucose transport across their membranes if hyperglycemia is present (Brownlee, 2005)

As mentioned earlier, hyperglycemia initiates pathological processes that cause direct damage to cells and tissue so if the blood glucose is persistently high, ocular, renal, and neurological damage will almost always occur.   

Hypertension, high serum lipids and serum triglycerides, cigarette smoking, obesity, and advanced age can also contribute to the development of diabetic retinopathy, nephropathy, and neuropathy, but the duration and level of hyperglycemia is the most important risk factor for diabetic complications.

Case Study #1

A 55-year-old male with a PMH of type 2 diabetes mellitus is admitted to a hospital for complaints of pain and decreased sensation in both feet and occasional episodes of blurred vision. His medications include metformin and glipizide. His blood pressure is 172/88 mm Hg; his fasting serum glucose is 256 mg/dL; his HbA1c is 9.5%, and his weight is 97 kg. An exam and nerve conduction studies of his lower extremities reveals decreased pain sensation and diminished nerve conduction. An ophthalmologic exam reveals decreased visual acuity and new and extensive retinal vascular growth. The physician increases the dose of metformin, and prescribes insulin and a small dose of an ACE inhibitor. The patient is encouraged to exercise and the dietary department provides him with a weight-reducing diet. At a follow-up nine months after discharge, the patient has lost 7 kg, his blood pressure is 144/76, and his fasting serum glucose is 118 mg/dL, and hid HbA1c is 7.0%. The retinal vascular growth has not diminished, but it has not extended and the patient reports that he has increased sensation and decreased pain in both feet.

Case Study #2

A 77-year-old female with a PMH of HTN and type 2 diabetes is admitted to a hospital for treatment of a non-healing ulcer of her foot. On admission it is noted that her fasting serum glucose is 221 mg/dL; her HbA1c is 10.1%; her blood pressure is 181/82, and; her serum BUN and creatinine are elevated, 52 mg/dL and 4.3 mg/dL, respectively. She is taking metformin, glipizide, enalapril, and HCTZ. Insulin and amlodipine are added to her medication regimen. Intensive therapy directed by the diabetic nurse specialist succeeds in healing the ulcer. But although the new medications succeed in decreasing her blood pressure and blood sugar, her renal function worsens and the patient must undergo twice weekly hemodialysis.

Diabetic Retinopathy

Diabetic retinopathy is the most common ocular complication of diabetes. Diabetic retinopathy is a microangiopathy, a disease that weakens and damages small blood vessels and diabetic retinopathy affects the arterioles, capillaries, and venules in the retina (Seyin, Kara, Pekel, 2015). The pathogenesis of diabetic retinopathy is not completely understood, but persistent and chronic elevations of blood glucose are thought to damage the retinal vasculature by the following processes.

  1. Formation of sorbitol by the polyol pathway: The polyol pathway is a method of glucose breakdown that occurs when normal glucose metabolism cannot occur and blood glucose becomes elevated. Hyperglycemia causes an excessive production of sorbitol by the polyol pathway; sorbitol does not easily cross the membranes of retinal cells; excess amounts of sorbitol accumulate in the retina, and; sorbitol then causes osmotic damage to the retinal vasculature (Seyin, Kara, Pekel, 2015; McCulloch, 2014).
  2. Accumulation of advanced glycation end-products: Glycation is defined as the bonding of a glucose molecule to a protein or a lipid and the formation of advanced glycation end-products (AGEs). Glycation is a normal metabolic process that occurs when the blood glucose level exceeds the body’s need for glucose or its ability to metabolize glucose. In the non-diabetic this process occurs very slowly and it is reversible so AGEs do not cause harm. Patients with diabetes who have chronic hyperglycemia form large amounts of AGEs and AGEs cause direct damage to the retinal vasculature (Seyin, Kara, Pekel, 2015; McCulloch, 2014).  
  3. Inflammation and oxidative stress (Seyin, Kara, Pekel, 2015; Shin, Sorenson, Sheibani, 2014).
  4. Excess production of vascular endothelial growth factor: Vascular endothelial growth factor (VEGF) is a protein that promotes the growth and formation of blood vessels. Chronic hyperglycemia causes an excess production of VEGF. The new blood vessels that are formed are directly damaging to the retina and they are also very fragile and prone to rupture, causing local edema and hypoxia. In addition, high levels of VEGF also damage the existing retinal vasculature (Martinez-Zapata, Martí-Carvajal, Solà, et al; Abcouwer, Gardner, 2014).
  5. Renin-angiotensin-aldosterone system: The renin-angiotensin-aldosterone system (RAAS) plays an important part in the auto-regulation of blood pressure and glucose metabolism. Diabetes increases the activity of  RAAS receptors and RAAS signaling molecules in the retina and this, in turn, is thought to increase the local production of VEGF and increase the activity of protein kinase (Seyin, Kara, Pekel, 2105; Rahimi, Moradi, Nasri, 2014; Tarr, Kaul, Chopra, et al, 2013)
  6. Protein C kinase activation: Protein C kinase (PCK) is an enzyme that regulates many physiological processes. Hyperglycemia activates PKC which in turn; 1) increases the expression of VEGF in the retina; 2) disrupts retinal blood flow, and; 3) damages the structural integrity of the retinal vasculature (Tarr, Kaul, Chopra, et al, 2013)

Diabetic retinopathy is the most common cause of visual impairment and blindness in people 25-74 years of age (Fraser, D’Amico, 2014; Rosberger 2013). The prevalence of diabetic retinopathy and vision-threatening retinopathy among adults in the US has been estimated to be 28.5% and 4.4% (Zhang, Saaddine, Chou, et al, 2010). In adult with diabetes the numbers are much higher (Shin, Sorenson, Sheibani, 2014). Fifteen years after diagnosis of diabetes 75%-95% of patients with type 1 diabetes and 41% of patients with type 2 diabetes will have evidence of diabetic retinopathy (Bhavsar, 2104) and within 15-20 years almost every patient with type 1 diabetes and the great majority of patients who have type 2 diabetes will have diabetic retinopathy (Gilbert, 2015; Fraser, D’Amico, 2014). Young people with type 1 diabetes do not develop retinopathy for at least 3–5 years after the onset of the systemic disease. Patients with type 2 diabetics may have retinopathy at the time of diagnosis, and it may be the first sign of ocular disease in this population.

Diabetic retinopathy causes many pathological changes in the eye, and diabetic macular edema is one of the most common and most serious of these changes (Marozas, Fort, 2014). The macula is an anatomically distinct region of the retina that provides the eye with high-acuity visual ability. Thickening and disruption of the retinal vasculature causes a breakdown of the blood-retina-barrier and subsequently, edema that is localized to the macula (Mavrikakis, 2014). Diabetic macular edema is the leading cause of blindness in patients who have diabetic retinopathy; it can happen to anyone who has the disease at any time (Fraser, D’Amico, 2014; Golan, Loewenstein, 2014; Garg, Davis, 2009). Diabetic macular edema affects almost one-third of patients who have had diabetes for ≥ 20 years and spontaneous recovery seldom happens (Jin, Luo, Bai, et al, 2015).


Diabetic retinopathy is classified as proliferative or non-proliferative. (Fraser, D’Amico, 2014). The non-proliferative form is characterized by micro-aneurysms, retinal ischemia, and intra-retinal hemorrhages. As the disease progresses, excess production of VEGF stimulates the production of new blood vessels and this, along with the other pathologic processes explained previously, moves the disease into the proliferative form, exposing the retina to the possibility of serious, irreversible damage (Garg, Davis, 2009).

The disease is further classified as early, high-risk, or severe (proliferative) or mild, moderate, severe, or very severe (non-proliferative), and proliferative retinopathy may, or may not be preceded by severe non-proliferative disease (Fraser, D’Amico, 2014). Differentiating diabetic retinopathy into sub-types allows practitioners to determine the risk for progression and decide on the best follow-up and treatment strategies.

Patients who have the advanced stages of proliferative diabetic retinopathy have traditionally been considered to be the most at-risk for developing visual abnormalities, but it has become evident that patients with milder forms have visual dysfunction as well (Marozas, Fort, 2014). Not all patients who have non-proliferative retinopathy will progress to proliferative retinopathy, and proliferative retinopathy may develop in patients who have only a mild form of the non-proliferative disease. However, mild or moderate non-proliferative retinopathy increases the risk of developing proliferative retinopathy by approximately 5%-15% and patients who have severe or very severe non-proliferative disease have a risk for developing proliferative retinopathy that has been estimated to be 52%-75% (Fraser, D’Amico, 2014).


The diagnosis of diabetic retinopathy can be made by fundoscopic examination using a slit lamp or an ophthalmoscope. Two other techniques that are increasingly being used to confirm the diagnosis and/or evaluate the progression of the disease are ultrawide field fundus fluorescein angiography (UWFA) and optical coherence tomography (OCT) (Song, Wong, 2014). The technique of UWFA involves injection of fluorescein dye into a peripheral vein and photographic examination of the retina. The UWFA technique visualizes a much greater area of the retina, it can detect pathologies not seen by standard techniques, and its accuracy and operation are less dependent on the skill of the operator. (Kiss, Berenberg, 2014; Wessel, Asker, Parlitsis, et al, 2012; Kaines, Oliver, Reddy, et al, 2009). Optical coherence tomography uses a forced beam of light that provide a three-dimensional image of the retina, and it is particularly useful for detecting macular edema (Virgili, Menchini, Casazza, et al, 2105; Bhavsar, 2014). Fundal cameras and wide-field laser ophthalmoscopy are other useful diagnostic techniques.


Treatment of diabetic retinopathy begins with preventive care and screening. Preventive care largely focuses on modification of risk factors and this will be discussed in a separate section.

Screening for diabetic retinopathy is critically important because the great majority of people who have diabetic retinopathy have no symptoms until the disease is quite advanced and macular edema or proliferative diabetic retinopathy have developed. At that point the patient may report blurred vision, the presence of floaters, progressive loss of visual acuity, and/or visual distortion (Bhavsar, 2014; Fraser, D’Amico, 2014) but the disease is well established, and because therapy can provide symptomatic relief and slow the progression of diabetic, early detection is paramount. An initial screening can be done using an ophthalmoscope and after the eyes have been dilated, or by fundal photography (McCulloch, January, 2014). Patients who have type 1 diabetes that has been diagnosed by age 30 rarely develop diabetic retinopathy within five years of the diagnosis, so screening can begin some time after that point (McCulloch, January, 2104). Many patients who have type 2 diabetes have some evidence of retinopathy when the diabetes is first diagnosed so screening for ocular damage should begin at that point (McCulloch, January, 2014). Optimal screening intervals are less well defined. Commonly cited screening recommendations include:

  1. Every year (initially) and more frequent examinations if abnormalities are noted. Less frequent examinations, every 2 - 3 years may be reasonable if the initial examination is normal (McCulloch, January, 2104). Women who have diabetes and are pregnant should be screened in the first trimester (McCulloch, January 2014).
  2.  An examination every 2 years if there is no evidence of diabetic retinopathy. The examinations should be at ≤ 1 year intervals if the patient has diabetic retinopathy (Echouffo-Tcheugui, Ali, Roglic, et al, 2013).
  3.  A dilated eye examination should be done every year on all patients who have diabetes, starting at the time of diagnosis for patients who have type 2 diabetes and starting five years from the time of diagnosis for patients who have type 1 diabetes (Gilbert, 2015).

 Patients who have diabetes should have an annual eye examination (Garg, Davis, 2009; Fong, Aiello, Gardiner, et al, 2004). Women who have diabetes and are pregnant should have an examination early in the first trimester (Garg, Davis, 2009).

Treatment of diabetic retinopathy should begin with tight glycemic control. Glycemic control and/or attaining normoglycemia has been shown to prevent the onset and slow the progression of diabetic retinopathy (Chew, Davis, Danis, et al, 2014; Gilbert, 2014) and it is the primary mode of treatment.

Reduction and control of risk factors associated with diabetic retinopathy, specifically hypertension and lipid disorders, has been traditionally seen as a valuable way of reducing both the incidence and progression of diabetic retinopathy and they are still recommended. However, the value of this approach is less certain and more controversial than glucose control. There is evidence supporting tight control of blood pressure as an effective preventive measure (Do, Wang, Vedula, et al, 2015; Muir, Grubber, Mruthyunjaya, et al, 2013; UK Prospective Diabetes Study group, 1998) and evidence that suggests it is not effective or may be only partially so (Do, Wang, Vedula, 2015; ACCORD Study Group; ACCORD Eye Study Group, Chew, et al, 2010). The angiotensin converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARB) have been shown to be effective for reducing the progression of diabetic retinopathy (Wang, Wang, Zhang, et al, 2015 n).

The preventive effects of reducing serum lipids in patients at risk for diabetic retinopathy also has adherents (Das, Stroud, Mehta, et al, 2015; Chew, Davis, Danis, et al, 2014; ACCORD Study Group; ACCORD Eye Study Group, Chew, et al, 2010), but there are authors who conclude that there is little evidence for a cause and effect relationship of lipid disorders and diabetic retinopathy or that the evidence for a preventive role of lipid lowering is robust or conclusive (Sacks, Hermann, Fioretto, et al, 2014; Cetin, Bulgu,  Ozdemir, et al, 2013; Chang, Wu, 2013).

Specific therapies for the treatment of diabetic retinopathy include laser therapy, intravitreal medications and surgery.

Laser Therapy

Laser therapy, also commonly called laser photocoagulation, is a commonly used treatment for diabetic macular edema, proliferative diabetic retinopathy, and diabetic macular edema in patients with non-proliferative disease (Chhablani, Sambhana, Mathai, et al, 2015; Bhavsar, 2014; Evans, Michelessi, Virgili, 2014). The technique seals leaking blood vessel or destroys area of neovascularization. Although it is not curative or universally effective, it is simple, it requires only brief office visits and the use of a local anesthetic, and it can greatly reduce the risk of severe vision loss (Bandello, Lattanzio, Zucchiatti, et al, 2013) Complications such as decreased peripheral, color, and night vision are common but are rarely serious and comparatively mild when compared to the risk of blindness (Rosberger, 2103) and macular edema can reoccur (Lee, Chhablani, Chan, et al, 2013).

Intravitreal Medications

Intravitreal medications have been shown to prevent vision loss in patients who have diabetic retinopathy and to increase visual acuity (Seyin, Kara, Pekel, 2015). Steroids such as dexamethasone and triamcinilone have anti-inflammatory and anti-angiogenic properties and intravitreal injections of these drugs can stabilize the blood-retinal barrier, reduce macular edema, and increase visual acuity (Bonnin, Dupas, Sanharawi, et al, 2015; Seyin, Kara, Pekel, 2015; Jeon, Lee, 2014). These effects, however, typically last three months and then the treatment must be repeated (Sayin, Kara, Pekel, 2015; Jeon, Lee, 2104). Complications include increased intraocular pressure and infection (Sayin, Kara, Pekel). VEGF inhibitor drugs are another option.

These medications bind to, and inhibit the activity of VEGF and by doing so they suppress neovascularization and slow vision loss. They have been shown to be superior to laser photocoagulation for the treatment of diabetic macular edema and they are considered the standard therapy for the disease (Manasseh, Shao, Taylor, 2015; The Diabetic Retinopathy Clinical Research Network, 2015). The VEGF-inhibitors have also been successfully used to treat proliferative diabetic retinopathy but the evidence of their efficacy for this is less robust (Martinez-Zapata, Martí-Carvajal, Solà, et al, 2014). The VEGF inhibitor medications commonly used are aflibercept, bavacizumab, pegaptanib, and ranibizumab but only aflibercept and ranibizumab are FDA-approved for the treatment of macular edema. A topical anesthetic, a topical antibiotic, and a local injection of an anesthetic are administered and then the eye is injected with a VEGF. Multiple injections are often needed, and the common side effects include conjunctival hemorrhage, infection, and eye pain.


Surgery is an option for patients who have diabetic macular edema, and the pars plana vitrectomy is the most commonly performed procedure. Pars plana vitrectomy involves removal of vitreous gel through the pars plana, a structure which is part of the ciliary body: this is the basic procedure and there are several ways it can be done. The pars plana vitrectomy can be used for patients who have not responded to laser photocoagulation, intra-vitreal steroids, or VEGF inhibitors (Seyin, Kara, Pekel, 2015) and unlike those therapies pars plana vitrectomy can alleviate retinal hypoxia, the underlying cause of diabetic macular edema (Golan, Lowenstein, 2014; Seyin, Kara, Pekel, 2015). The results of this operation are usually quite good; most patients have complete resolution of macular edema and stabilization and/or improvement of visual acuity (Adelman, Parnes, Michalewska, et al, 2015; Golan, Lowenstein, 2014). The procedure can be done as a day surgery using local anesthesia. Post-operative cataracts are common (Feng, Adelman, 2014). Other common post-operative complications include retinal detachment, bleeding, and infection, the last two seldom occurring (Patel, 2013).

Diabetic Nephropathy

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) (Kowalski, Krikorian, Lerma, 2014). It is more common in patients with type 2 diabetes and more common in African Americans, Asian Americans, and Native Americans (Kowalski, Krikrorina, Lerma, 2014). Approximately 15%-25% of all patients who have type 1 diabetes and 30%-40% of all patients who have type 2 diabetes have diabetic nephropathy (Gilbert, 2015).

The pathogenesis of diabetic nephropathy is very complex and it involves hemodynamic, inflammatory, and metabolic factors that are interdependent and in many cases can initiate, exacerbate, and prolong one another. Hyperglycemia and genetic susceptibility are the basic causes of diabetic nephropathy (MacIsaac, Ekinci, Jerums, 2014) and chronic elevated serum glucose and genetic pre-disposition initiate the pathologic processes that damage the kidneys. These processes include (Kowalski, Krikorian, Lerma, 2014; Lv, Chen, Hu, et al, 2014; MacIsaac, Ekinci, Jerums, 2014; Chen, Tseng, 2013):

  1. Hyperglycemia is the essential element of diabetic nephropathy. Hyperglycemia causes accumulations of AGEs, activation of the polyol pathway, increased protein kinase activity, and increased production of inflammatory cytokines.
  2. Genetic: There is evidence that genetic susceptibility is essential for the development of diabetic nephropathy but causative gens have not been identified.
  3. Hypertension: Activation of the RAAS cause hypertension is both a cause and a consequence of diabetic nephropathy. Shear force causes damage to blood vessels and glomeruli and also stimulates and prolongs inflammation and oxidative stress.
  4. Dyslipidemia and smoking: Dyslipidemia is strongly associated with diabetic nephropathy, but it is unclear how lipid abnormalities contribute to the disease.  
  5. Oxidative stress: Oxidative stress is considered to be a major pathologic process of diabetic nephropathy. Hyperglycemia and hypertension cause an increased production of reactive oxygen species (a.k.a., free radicals) by activation of the polyol pathway and glycation, and oxidative stress causes direct damage to the renal parenchyma and the renal vasculature.
  6. Inflammation: Inflammation is activated by oxidative stress. Inflammation in turn exacerbates and prolongs oxidative stress and causes direct damage to the kidney.
  7. Fibrosis: Fibrosis is caused by hyperglycemia, hypertension, inflammation, and oxidative stress and fibrosis, in turn, stimulates and prolongs these processes.

Diabetic nephropathy is a chronic condition. The disease is characterized by a progressive decline in renal function that begins with transient glomerular hyper-filtration. As the renal vasculature and the renal parenchyma slowly become damaged, increasing amounts of protein in the form of albumin are excreted in the urine; this condition is called albuminuria. Hypertension and fibrosis develop and eventually, to a greater or lesser degree, the functional ability of kidneys is impaired and the glomerular filtration rate (GFR) becomes decreased (Batuman, 2014; Kowalski, Krikorian, Lerma, 2014). When the GFR is <15 mL/min/1.73 m2, the patient has ESRD (Kowalski, Krikorian, Lerma, 2014).

In patients who have type 1 diabetes nephropathy usually begins 15-25 years after the diagnosis of diabetes and it almost always progresses to ESRD (Lim, 2014; Waanders, Visser, Gans, 2013). In contrast many patients who have type 2 diabetes will have some evidence of nephropathy at the time diabetes is diagnosed but approximately 20% of these patients will develop ESRD (Lim, 2014; Waanders, Visser, Gans, 2013).

Patients who have diabetic nephropathy will not have signs or symptoms that are specific to the disease and as mentioned before, patients who have type 2 diabetes will often have evidence of diabetic nephropathy at the time the diabetes is diagnosed. However, complications that are associated with or caused by diabetes such as diabetic retinopathy, peripheral neuropathy, skin ulcers, or hypertension are commonly seen in conjunction with diabetic nephropathy.


Diabetic nephropathy can be divided into five stages that reflect the history of the disease (Batuman, 2014).

  • Stage 1: Hyper-function and hypertrophy - Glomerular hyperfiltration, increased GFR and increased ACR, and normal blood pressure except in patients with type 2 diabetes.
  • Stage 2: Silent stage - Normal GFR, increased ACR in patients with type 2 diabetes/normal ACR in patients with type 1, and normal blood pressure except in patients with type 2 diabetes.
  • Stage 3: Incipient - GFR begins to decline, ACR is between 30 - 300 mg/g, and hypertension is present.
  • Stage 4: Over diabetic nephropathy - GFR is below normal, ACR is > 300 mg/g, and hypertension is present.
  • Stage 5: Uremic – ESRD is present, the GFR is < 10, the ACR is decreasing, and hypertension is present


The diagnosis of diabetic nephropathy is made by: 1) measurement of the urine albumin/creatinine ratio; 2) measurement of GFR, and; 3) measurement of blood pressure. Each of these has diagnostic significance but they cannot stand alone. For example, the GFR may be decreased but albuminuria may be absent (Gilbert, 2014; Kowalski, Krikorian, Lerma, 2014). Other tests such as renal ultrasound or a renal biopsy can be done on a case-by-case basis.  

Urine albumin/creatinine ratio: The gold standard for measuring urine albumin in patients who are being screened for diabetic nephropathy is a 24-hour urine collection but this is cumbersome and prone to error and a urine albumin/creatinine ratio (ACR) is considered the first choice test (Kowalski, Krikorian, Lerma, 2014). A first morning void is collected and if the ACR is > 30 mg/dL the test should be repeated twice over the course of 3 to 6 months. A normal level is < 30 mg/g; 30 - 300 mg/g is considered to indicate a risk for developing nephropathy, and this is commonly called microalbuminuria; > 300 mg/g is considered severe and is commonly called macroalbuminuria. The results of the ACR may be inaccurate if the patient has any conditions that can increase urinary excretion of albumin: CHF, febrile illness, hematuria, menstruation, uncontrolled hypertension, recent vigorous exercise, significant hyperglycemia, uncontrolled hypertension, or a urinary tract infection (Gilbert, 2014; Kowalski, Krikorian, Lerma, 2014). Albuminuria is considered diagnostic for diabetic nephropathy but albuminaria may be absent in patients who have the disease (Kowalski, Krikorian, Lerma, 2014), and it is not considered to be strongly predictive for the development of diabetic nephropathy (MacIsaac, Ekinci, Jerums, 2014).

Glomerular filtration rate: The glomerular filtration rate is the volume of fluid that is filtered through the glomeruli per unit of time, and it is commonly used to assess renal function. A GFR of > 90 mL/min/1.73 m2 is considered normal and a level of < 60 mL/min/1.73 m2 should be considered a possible early warning sign for diabetic nephropathy (Gilbert, 2014). The GFR is patients who have diabetic nephropathy will slowly decline over time.

Hypertension: In patients with type 1 diabetes blood pressure usually becomes elevated only after macroalbuminuria has developed; in patients with type 2 diabetes hypertension is often present at the time of diagnosis and thus may not be related to diabetic nephropathy (MacIsaac, Ekinci, Jerums, 2014).


Screening for diabetic nephropathy should be done at the time of diagnosis for patients who have type 2 diabetes. Patients who have type 1 diabetes should be screened beginning at five years after diagnosis but if a patient has poor glycemic control, hypertension, dyslipidemia, or is non-compliant with therapy she/he should be should be screened before the five year mark (Kowalski, Korina, Lerma, 2014). Yearly screening should be done after the first measurements of ACR, GFR, and blood pressure.  


Treatment can delay the onset and progression of diabetic nephropathy but it requires considerable commitment from clinicians and patients. Life style changes in particular are very well known to be difficult for people to start and maintain.

Glycemic control is the most important treatment for diabetic nephropathy and tight glycemic control (a hemoglobin A1c of 6%-6.5%) has been shown to significantly reduce albuminuria and nephropathy (Perkovic, Heerspink, Chalmers, et al, 2013; Coca, Ismail-Beigi, Haq, et al, 2012; Ismail-Beigi, Craven, Banerji, et al, 2010). Diet, exercise and medications can all be used to attain glycemic control.

Blood pressure control using an ACE inhibitor or an ARB is an effective method for reducing albuminuria and decreasing the progression of kidney damage in patients who have diabetes (Kowlaski, Krikorian, Lerma, 2014; Lim, 2014). The ACE inhibitors appear to be superior to the ARBs (Lim, 2014), and combination therapy with an ACE inhibitor and an ARB is not recommended (Kowlaski, Krikorian, Lerma, 2014; Lim, 2104). Aldosterone antagonists, calcium channel blockers, and diuretics are considered second-line therapies (Lim, 2014). Prophylactic use of anti-hypertensives in diabetic patients who are normotensive and do not have significant albuminuria is not recommended. The optimal blood pressure level is somewhat controversial but most sources recommend a blood pressure of < 140/90 mmHg (Lim, 20140.  

Dyslipidemia control and reduction for patients who have diabetes has been shown to decrease albuminuria (Abe, Maruyama, Okada, et al, 2011; Ansquer, Foucher, Rattier, et al, 2005), and therapy with a statin with or without ezetimibe is recommended for all patients < 50 years who have diabetes and chronic kidney disease and for all patients > 50 years who have chronic kidney disease, whether they do or do not have diabetes (Tonelli, Wanner, et al, 2014).

Life style changes including proper diet (low protein, salt restricted), exercise, smoking cessation, and weight loss can help reduce the onset and progression of diabetic nephropathy (Kowlaski, Krikorian, Lerma, 2014; Lim, 2014; Noborisaka, 2013; Pedersen, Gaede, 2003).

Peritoneal dialysis, hemodialysis, a kidney transplant, or combined kidney-pancreas transplantation can be used in patients who have ESRD. Combined kidney-pancreas transplantation has been reported to decrease the four-year mortality rate in patients with diabetic nephropathy from 40% to10% and improve glycemic control (Wiseman, 2010).

Diabetic Neuropathies

Diabetic neuropathies are common complications of type 1 and type 2 diabetes.  Neuropathy is present at the time of the diagnosis of diabetes in 7.5%-8% of all patients (Gilbert, 2014, Quan, 2014) and depending on the age of the patient, the duration of his/her diabetes, and the severity of the diabetes,  neuropathies are present in up to 70% of all patients with diabetes (Charnogursky, Emanuele,  Emanuele, 2014; Gilbert, 2014).


These disorders can affect autonomic, motor, or sensory nerves. They are quite complex and there are many sub-types. There are several classification schemes used to categorize diabetic neuropathies: by way of their anatomical distribution (eg, proximal versus distal); by the pattern of symptoms (eg, acute, versus chronic), or; by the nature of the symptoms (eg, painful versus non-painful, focal versus non-focal, and autonomic, motor, or sensory (Albers, Pop-Busui, 2104; Tesfaye, Boulton, Dyck, et al, 2010). A discussion of all of the sub-types of diabetic neuropathy would be quite lengthy, and it is most practical to simply divide the diabetic neuropathies into peripheral and autonomic forms. This module will provide information about the most common forms of diabetic neuropathy, chronic distal, symmetric polyneuropathy and autonomic neuropathies.

Chronic, Distal, Symmetrical Polyneuropathy

Chronic, distal, symmetrical polyneuropathy accounts for approximately 75% of all diabetic neuropathies (Albers, Pop-Busui, 2014). The clinical presentation of this form of diabetic neuropathy is variable and some or all of the following signs and symptoms may be present or may develop over time. (Rosenberg, Watson, 2105; Albers, Pop-Busui, 2014; Aslam, Singh, J, Rajbhandari, 2014; Gilbert, 2014; Quan, 2014).

  1. Stocking-glove neuropathy: The patient ahs the sensation that she/he is wearing stockings and gloves.
  2. A feeling of deadness or numbness in the extremities.
  3. Loss of balance.
  4. Aching, allodynia (pain caused by a stimulus which would not normally produce pain) burning, hypersensitivity to touch, prickling, tingling.
  5. Impaired coordination and/or motor weaknesses.
  6. Approximately 15%-25% of patients develop painful diabetic neuropathy. The symptoms of painful diabetic neuropathy can be intense and debilitating: patients may be unable to work and may suffer from depression and social withdrawal. Painful diabetic neuropathy is more frequent in patients who have poor glycemic control and who are elderly, obese, or have peripheral vascular disease (Ziegler, Fonesca, 2015).
  7. Abnormal nerve conduction study and EMG study results.
  8. Diabetic neuropathy is the primary cause of diabetic skin ulcers and ulcers, and it is the leading cause of non-traumatic limb amputations.

This disorder represents an imbalance between nerve damage and repair (Charnogursky, Emanuele, Emanuele, 2014) and as with most diabetic complications the pathogenesis is complex but hyperglycemia is the primary cause. The pathologic processes responsible for this disorder include (but are not limited to) many of the ones discussed in previous sections of the module: accumulation of AGEs; activation of the polyol pathway; direct damage to nerves and local vasculature; inflammation; ischemia; oxidative stress, and; protein kinase C activity (Albers, Pop-Busui, 2014; Charnogursky, Emanuele, Emanuele, 2014; Gilbert, 2014; Singh, Kishore, Kaur, 2014).

Risk factors for the development of chronic, distal, symmetrical polyneuropathy include the level and severity of the patient’s diabetes; advanced age; alcohol abuse; dyslipidemia; poor glycemic control, hypertension; obesity, and; smoking (Charnogursky, Emanuele, Emanuele, 2014; Quan, 2014).


Diagnosing chronic, distal, symmetrical polyneuropathy begins with excluding systemic illnesses or trauma as possible causes and having a high index of suspicion, ie, the patient has diabetes mellitus or another diabetic complication. A physical examination and nerve conduction studies are the cornerstones of the diagnostic process, but both can be misleading; several studies have shown that physicians’ examinations and performance and interpretation of nerve conduction studies can at times be unreliable and that there are inter-observer variations (Albers, Pop-Busui, 2104). There are no universally agreed upon diagnostic criteria for the diabetic neuropathies (Jin, Park, 2015), but the following are considered to be typical of the disease (Jin, Park, 2015; Gilbert, 2104; Quan, 2104)

  • The onset of sign and symptoms is insidious and they usually begin in the feet.
  • The signs and symptoms are typically worse at night.
  • There is a decrease or loss of the ability in the feet to detect vibrations and to detect a pinprick sensation so an examination should be done with a tuning fork and with a standard 10 gauge monofilament that is used to check for pinprick sensation.
  • Ankle reflexes are absent or reduced.
  • Nerve conduction study abnormalities may precede the clinical signs and symptoms.
  • Questionnaires have been developed to help practitioners diagnose chronic, distal, symmetrical polyneuropathy (and other peripheral neuropathies). These can be useful as screening tools and some, such as the DN4, have good sensitivity and specificity (Hartemann, Attal, Bouhassira, et al, 2011). But even the DN4 may fail to recognize 10%-20% of patients who have a peripheral neuropathy so a questionnaire by itself in insufficient for diagnosis (Deli, Bosnyak, Pusch, et al, 2013).


Treatment of chronic, distal, symmetrical polyneuropathy - or any diabetic neuropathy - begins with glycemic control. Several large studies and reviews have shown that good glycemic control can reduce both the onset and slow the progression of this disorder (Fullerton, Jeitler, Seitz, et al, 2014; Martin, Albers, Pop-Busui, et al, 2014; Callaghan, Little, Feldman, et al, 2012). However, good glycemic control cannot completely diminish or reverse pain once it has begun (Rosenberg, Watson, 2015; Feldman, McCulloch, 2015). Concurrently with efforts to maintain good glycemic control patients should be encouraged (if needed) to lose weight, exercise, stop smoking, and eat properly as these behavioral/life style interventions, when combined with aggressive glycemic control, can slow the progression of diabetic neuropathy (Gaede, Vedel, Larsen, 2003). Patients who have diabetic neuropathy (and all patients who have diabetes) should be thoroughly educated on the topic of diabetic foot care; this is a vital part of self-care for diabetic patients who have peripheral neuropathy.


Medications are rarely able to completely alleviate pain caused by diabetic peripheral neuropathy. However, medications can diminish pain, give patients symptomatic relief, and improve quality of life and fortunately for some patients, spontaneous remission of diabetic peripheral neuropathies does occur (Feldman, McCulloch, 2015). There is a wide variety of medications that can be used and there is no one drug that is considered to be superior or preferred to the others. The decision as to which medication to use to treat painful diabetic neuropathy should be based on: 1) the patient’s level of pain; 2) his/her co-morbidities; 3) other medications that are being used, and; 4) the known side effects of each drug.

The level of pain relief that a medication provides will vary from patient to patient. If a medication has been determined to be at least somewhat successful but the desired level of pain relief or functional ability has not been reached, it is preferable to add another medication rather than stopping the drug: using medications from several different classes has been shown to be an effective approach. (Rosenberg, Watson, 2015; Zeigler, Fonesca, 2015). The following medications are commonly used to treat painful diabetic neuropathy.

Tricyclic anti-depressants: These drugs affect the actions of many neurotransmitters but their primary mechanism of action is norepinephrine and serotonin re-uptake inhibition. There is good evidence that the tricyclic antidepressants (TCAs) such as amitriptyline and nortriptyline are effective for treating painful diabetic neuropathy and they are often the first-choice drug for this purpose (Finnerup, Attal, Haroutounian, 2015). Drowsiness, dry mouth, orthostatic hypotension are common side effects.

Serotonin-norepinephrine inhibitors: The serotonin-norepinephrine inhibitors (SNRIs) block the re-uptake of serotonin as do the TCAs but these drugs tend to cause fewer anti-adrenergic, anticholinergic, and muscarinic side effects. Duloxetine is the only SNRI that is FDA-approved for painful diabetic neuropathy. It has been shown to be effective for this purpose (Finnerup, Attal, Haroutounian, 2015; Lunn, Hughes, Wiffen, 2014) and several studies have found that duloxetine works as well as the TCAs but it has fewer and more tolerable side effects. Common side effects include drowsiness, headache, and nausea. Venlafaxine is another SNRI that has been used to treat diabetic neuropathy but it is considered to be less effective than duloxetine (Finnerup, Attal, Haroutounian, 2015).

Anti-convulsants: Carbamazepine, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topirimate, valproic acid, and zonisamide have all been used to treat diabetic neuropathic pain. The evidence is most supportive of gabapentin and pregabalin, and they are considered first-line drugs for this application (Finnerup, Attal, Haroutounian, 2015; Rosenberg, Watson, 2015). Both gabapentin and pregabalin work by inhibiting the movement of calcium through calcium ion channels in the central nervous system and decreasing the activity of excitatory neurotransmitters. Common side effects of gabapentin and pregabalin are ataxia, dizziness, drowsiness, and weight gain.

Opioids and opioid-like drugs: Opioids and the opioid-like drugs tapentadol tramadol are commonly used analgesics that work by acting as µ receptor agonists  and also (tapentadol and tramadol) by inhibiting reuptake of norepinephrine and serotonin. These drugs have been proven to be effective for treating painful diabetic neuropathy. However, because of their side effect profile and issues of addiction, dependency, tolerance, and misuse the opioids - particularly strong opioids - are considered to be second or even third-choice medications for treating painful diabetic neuropathy (Finnerup, Attal,  Haroutounian, 2015; Rosenberg, Watson, 2015; Ziegler, Fonesca, 2015). Common side effects of these drugs include constipation, nausea, pruritus, and sedation. 

Capsaicin patches: Capsaicin is oil that is derived from chili peppers. The analgesic action of capsaicin is complicated and not completely understood, but it has long been used as a topical analgesic and some studies have demonstrated it its efficacy in treating painful diabetic neuropathy (Finnerup, Attal, Haroutounian, 2015; Rosenberg, Watson, 2015; Charnogursky, Emanuele, Emanuele, 2014). The patches must be applied several times and the cream can be very irritating to the skin.

Lidocaine patches: Lidocaine blocks nerve impulse conduction by inhibiting the movement of sodium through sodium ion channels and preventing cells from depolarizing. Lidocaine is widely used as a topical anesthetic and there are studies supporting its use for the treatment of painful diabetic neuropathy (Finnerup, Sindrup, Jensen, 2010; Baron, Mayoral, Leijon, et al, 2009), but a recent review article noted that the evidence for the efficacy of lidocaine is limited and that much of the research is of short duration (Finnerup, Attal, Hartounian, 2015).

Botulinum toxin injection:  Botulinum toxin prevents the release of acetylcholine at the neuro-muscular junction. It has shown some effectiveness a treatment for painful diabetic neuropathy (Finnerup, Attal, Hartounian; Ghasemi, Ansari, Basiri, et al, 2014). Common side effects include blurred vision, injection site pain, and weakness.

Alpha lipoic acid, baclofen, cannabinoids, topical clonidine, isosrbide, lacosamide, levetiracetam, topical menthol, mexiletine, NDMA inhibitors, selective serotonin re-uptake inhibitors, and other medications have also been used to treat painful diabetic neuropathy, as have non-medicinal treatments such as acupuncture and psychotherapy, but the evidence for the effectiveness of these drugs and modalities is considered weak, inconclusive, or scant (Finnerup, Attal, Hartounian, 2015; Rosenberg, Watson, 2015). Recent reviews indicate that the preferential order of medication use for the treatment of painful diabetic neuropathy is: (Finnerup, Attal, Hartounian, 2015; Rosenberg, Watson, 2015; Zeigler, Fonesca, 2015)

  • First-line: TCAs, duloxetine, gabapentin, or pregablin.
  • Second-line: Capsaicin cream, lidocaine cream, or tramadol.
  • Third-line: Opioids, botulinum injection.

Diabetic Autonomic Neuropathies

Diabetic autonomic neuropathies can affect any organ that has autonomic innervation. These neuropathies most often accompany a peripheral neuropathy; they rarely occur alone (Albers, Pop-Busui, 2014). The initial signs and symptoms of a diabetic autonomic neuropathy are usually mild and may be overlooked but the disease is progressive and eventually serious effects will be noted. Subclinical evidence of these neuropathy sub-types has been seen within one year of the diagnosis of type 2 diabetes and within 2 years of the diagnosis of type 1 diabetes (Verotti, Prezioso, Sacttoni, et al, 2014).

As with all diabetic complications hyperglycemia is the initiating cause of autonomic diabetic neuropathies, and chronically elevated serum glucose initiates and sustains the (previously discussed) pathologic processes that are the basis of the signs and symptoms of the disease (Verotti, Prezioso, Sacttoni, et al, 2014).  

The incidence of diabetic autonomic neuropathies varies considerably depending on the organ system affected and the diagnostic criteria used, but the autonomic neuropathies are not uncommon: cardiovascular autonomic neuropathy has been noted in 7% of all diabetic patients at the time of diagnosis of diabetes and a 16%- 20% prevalence of this sub-type has been confirmed in several studies (Verotti, Prezioso, Sactonni, et al, 2104).

Cardiovascular autonomic neuropathy: This sub-type of diabetic neuropathy is caused by impaired autonomic control of the cardiovascular system, and it is the most common of the diabetic autonomic neuropathies. Signs and symptoms of this sub-type include arrhythmias, exercise intolerance, myocardial ischemia and (occasionally) infarction, orthostatic hypotension, prolongation of the QT interval, and resting tachycardia. Cardiovascular autonomic neuropathy has been associated with an increased risk of mortality (Maser, Mitchell, Vinik, et al, 2003), a significant risk of both silent myocardial ischemia and myocardial infarction (Vinik, Herbas, 2013; Vinik, Maser, Mitchell, et al, 2003), and worse outcome after myocardial infarction (Vujosevic, Zamaklar Belada, et al, 2012). Orthostatic hypotension is considered to be a very severe sign

Gastrointestinal autonomic neuropathy: The signs and symptoms of this sub-type will vary depending on what part of the gastrointestinal tract has been affected. Patients may experience abdominal pain, anorexia, decreased bowel motility, decreased esophageal transit time, diarrhea, constipation, gastroparesis, and pre-mature satiety (Stevens, 2014).

Bladder autonomic neuropathy: Patients with this disorder experience incontinence, frequency, urgency, nocturia, and retention Stevens, 2104).

Sexual autonomic neuropathy: Sexual autonomic neuropathy can cause erectile dysfunction, decreased libido, and vaginal dryness (Stevens, 2014).  

Peripheral autonomic dysfunction: Peripheral autonomic dysfunction is characterized by cramps, edema, excessive sweating, itching, and skin and nail changes (Stevens, 2014).


Diagnosis of the diabetic autonomic neuropathies relies on a careful physical examination, a detailed patient history, and specialized testing.

There are no universally agreed upon diagnostic criteria for cardiovascular autonomic neuropathy (Dimitropoulos, Tahrani, Stevens, 2014; Spallone, Ziegler, Freeman, et al, 2001). The test most commonly used to diagnose cardiovascular autonomic neuropathy are the cardiovascular autonomic reflex tests (CARTs) (Stevens, 2014; Spallone, Ziegler, Freeman, et al, 2011). There are a variety of CARTs than can be used (eg, the patient’s heart rate response to deep breathing or a vagal maneuver), they are easy to perform and non-invasive, and they have good sensitivity and specificity (Stevens, 2104; Spallone, Ziegler, Freeman, et al, 2011). However, there are many variables that can affect the reliability and outcomes of the tests so careful performance of the CARTs is crucial. Clinicians are encouraged to perform several CARTs and some sources state that a diagnosis of cardiovascular autonomic neuropathy requires abnormal results of at least two CARTs (Vinik, Erbas, Casellini, 2013; Spallone, Ziegler, Freeman, et al, 2011), but other sources (Stevens, 2014) disagree.

Diagnosis of gastrointestinal autonomic neuropathy, sexual, and peripheral autonomic neuropathy is often made using a clinical assessment and with a detailed patient interview. Urodynamic test can be done for bladder neuropathy, and ultrasonography, magnetic resonance scinitigraphy, and stable isoptope breath tests cane be used to measure gastric emptying (Frieling, 2014).


Treatment of the autonomic neuropathies always begins with tight glycemic control. Tight glycemic control cannot reverse or cure diabetic autonomic neuropathy, but it has been proven to prevent or delay the development of the disease (Ang, Jaiswal, Martin, et al, 2014; Dimitropoulos, Tahrani, Stevens, 2014). Lifestyle changes, i.e. weight loss, proper diet, and an exercise program should also be started.  Behavioral interventions such as dietary changes, maintaining a strict urination schedule, and close attention to postural shifts can be used for patients who have gastrointestinal, bladder, or cardiovascular autonomic neuropathy, respectively. Drug therapy can be used to provide symptomatic relief for patients who have an autonomic neuropathy, but there is little evidence for the effectiveness of any of the medications that have been used. (Dimitropoulos, Tahrani, Stevens; Spallone, Ziegler, Freeman, 2011


The diabetic complications of nephropathy, neuropathy, and retinopathy cause significant morbidity and as the incidence of diabetes - particularly type 2 diabetes - is steadily increasing, these complications will become increasingly common.

The available treatments can delay the onset and slow the progression of diabetic complications but the most important mode of treatment and prevention is tight glycemic control. There is clear evidence that strict control of serum glucose (along with blood pressure, control, weight loss, and diet) can prevent the development of these complications and can decrease their progression if they are present. Because these diabetic complications have an insidious onset and often do not respond to therapy, it is vital that at-risk patients: 1) be educated about diabetic complications; 2) have access to resources that will help them initiate and sustain tight glycemic control and life style changes, and; 3) be closely monitored and supported


ACCORD Study Group; ACCORD Eye Study Group, Chew, E.Y., Ambrosius, W.T., Davis, M.D., Danis, R.P, et al. (2010. Effects of medical therapies on retinopathy progression in type 2 diabetes. N Engl J Med; 363(3):233-44

Abcouwer, S.F., Gardner,T.W. (2104). Diabetic retinopathy: loss of neuroretinal adaptation to the diabetic metabolic environment. Ann NY Acad Sci, 1311:174-90.

Abe, M., Maruyama, N., Okada, K., Matsumoto, S., Matsumoto, K., Soma, M. (2011). Effects of lipid-lowering therapy with rosuvastatin on kidney function and oxidative stress in patients with diabetic nephropathy. J Atheroscler Thromb,18(11):1018-28.

Adelman, R., Parnes, A., Michalewska, Z., Parolini, B., Boscher, C., Ducournau D. (2015). Strategy for the management of diabetic macular edema: the European vitreo-retinal society macular edema study. Biomed Res Int,;2015:352487. doi: 10.1155/2015/352487. Epub 2015 Jan 28.

Albers, J.W. Pop-Busui, R. (2014). Diabetic neuropathy: mechanisms, emerging treatments, and subtypes. Curr Neurol Neurosci Rep, 14(8): 473. doi: 10.1007/s11910-014-0473-5.

Ang, L., Jaiswal, M., Martin, C., Pop-Busui, R. (2014). Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):528. doi: 10.1007/s11892-014-0528-7.

Ansquer, J.C., Foucher. C., Rattier, S., Taskinen, M.R., Steiner, G; DAIS Investigators. (2005). Fenofibrate reduces progression to microalbuminuria over 3 years in a placebo-controlled study in type 2 diabetes: results from the Diabetes Atherosclerosis Intervention Study (DAIS). Am J Kidney Dis, 45(3): 485-93.

Aslam, A., Singh, J., Rajbhandari, S. (2014). Pathogenesis of painful diabetic neuropathy. Pain Res Treat 2014;2014:412041. doi: 10.1155/2014/412041. Epub 2014 May 6.

Bandello, F., Lattanzio, R., Zucchiatti, I., Del Turco, C. (2013). Pathophysiology and treatment of diabetic retinopathy. Acta Diabetol, 50(1):1-20.

Baron, R., Mayoral, V., Leijon, G., Binder, A., Steigerwald, I., Serpell, M. (2009). Efficacy and safety of combination therapy with 5% lidocaine medicated plaster and pregabalin in post-herpetic neuralgia and diabetic polyneuropathy, 25(7):1677-87.

Batuman, V. (2104). Diabetic nephropathy. eMedicine. May 28, 2104. Retrieved March 1, 2015 from Medscape.

Bhavsar AR (2014). Diabetic retinopathy. eMedicine.

April 10, 2014. Retrieved February 25, 2015 from Medscape.

Bonnin, S., Dupas, B., Sanharawi, M.E., Perol. J., Erginay, A., Tadayoni, R., et al. (2105). Efficacy of dexamethasone intravitreal implant for the treatment of diabetic macular edema. Eur J Ophthalmol.,Feb 10:0. doi: 10.5301/ejo.5000581. [Epub ahead of print]

Brownlee, M. (2005).The pathobiology of diabetic complications. Diabetes, 54(6), 1615-1625.

Callaghan, B.C., Little, A.A., Feldman, E.L., Hughes, R.A. (2012). Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012 Jun 13;6:CD007543. doi: 10.1002/14651858.CD007543.pub2.

Cetin, E.N., Bulgu, Y., Ozdemir, S., Topsakal, S., Akin, F., Aybek, H., et al. (2013). Association of serum lipids with diabetic retinopathy. Int J Ophthalmol, 18;6(3):346-9.

Chen, S.C., Tseng, C.H. (2013). Dyslipidemia, kidney disease, and cardiovascular disease in diabetic patients. Rev Diabet Stud, Summer-Fall;10(2-3):88-100.

Charnogursky, G.A., Emanuele, N.V, Emanuele, M.A. (2014). Neurologic complications of diabetes. Curr Neurol Neurosci Rep, 14:457

Chang, Y.C., Wu, W.C. (2013) Dyslipidemia and diabetic retinopathy. Rev Diabet Stud, Summer-Fall;10(2-3): 121-32.

Chhablani, J., Sambhana, S., Mathai, A., Gupta, V., Arevalo, J.F., Kozak, I. (2015). Clinical efficacy of navigated panretinal photocoagulation in proliferative diabetic retinopathy. Am J Ophthalmol. 2015 Feb 19. pii: S0002-9394(15)00092-6. doi: 10.1016/j.ajo.2015.02.006. [Epub ahead of print]

Chew, E.Y., Davis, M.D., Danis, R.P., Lovato, J.F., Perdue, L.H., Greven, C, et al (2014). The effects of medical management on the progression of diabetic retinopathy in persons with type 2 diabetes: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye Study. Ophthalmology,121(12):2443-51.

Coca, S.G., Ismail-Beigi, F., Haq, N., Krumholz, H.M., Parikh, C.R. (2012). Role of intensive glucose control in development of renal end points in type 2 diabetes mellitus. Arch Intern Med, 172(10):761-9.

Das, A., Stroud,S., Mehta, A., Rangasamy, S. (2015). New treatments for diabetic retinopathy. Diabetes Obes Metab,17(3):219-30.

Deli, G., Bosnyak, E., Pusch, G., Komoly, S., Feher, G. (2013). Diabetic neuropathies: diagnosis and management. Neuroendocrinology, 98(4): 267-80.

Dimitropoulos, G., Tahrani, A.A., Stevens, M.J. (2014). Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes, 15(5):17-39.

Do, D.V, Wang, X., Vedula, S.S., Marrone, M., Sleilati, G., Hawkins, B.S., et al (2015). Blood pressure control for diabetic retinopathy. Cochrane Database Syst Rev. 2015 Jan 31;1:CD006127. doi: 10.1002/14651858.CD006127.pub2.

Dworkin, R.H., O’Connor, A.B., Audette, J., Baron, R., Gourlay, G.K., Haanpää, M.L. et al. (2010). Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. MayoClin Proc, 85: S3-14.

Echouffo-Tcheugui, J.B., Ali, M.K., Roglic, G., Hayward, R.A., Narayan, K.M. (2013). Screening intervals for diabetic retinopathy and incidence of visual loss: a systematic review. Diabet Med, 30(11):1272-92.

Evans, J.R., Michelessi, M., Virgili, G. (2014). Laser photocoagulation for proliferative diabetic retinopathy. Cochrane Database Syst Rev, Nov 24;11:CD011234. doi: 10.1002/14651858.CD011234.pub2.

Feng, H., Adelman. R.A. (2014). Cataract formation following vitreoretinal procedures. Clin Ophthalmol, 23;8:1957-65.

Finnerup, N.B., Sindrup, S.H., Jensen, T.S. (2010). The evidence for pharmacological treatment of neuropathic pain. Pain, 150(3): 573–81.

Finnerup, N.B., Attal, N., Haroutounian, S., McNicol, E., Baron, R., Dworkin, R.H., et al. (2015). Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015 Jan 6. pii: S1474-4422(14)70251-0. doi: 10.1016/S1474-4422(14)70251-0. [Epub ahead of print]

Fong, D.S., Aiello, L., Gardner, T.W., King, G.L., Blankenship, G., Cavallerano, J.D, et al; American Diabetes Association. (2004). Retinopathy in diabetes, Diabet Care, 27 suppl 1;S84-7.

Fraser, C.E. D’Amcio, D.J. (2014). Diabetic retinopathy: Classification and clinical features. UpToDate. September 24, 2014. Retrieved February 24, 2015 from

Frieling T. (2014). Diabetic autonomic neuropathy of the gastrointestinal tract. UpToDate. May 14, 2104. Retrieved March 5, 2015 from

Fullerton, B., Jeitler, K., Seitz, M., Horvath, K., Berghold, A., Siebenhofer, A. (2014). Intensive glucose control versus conventional glucose control for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2014 Feb 14;2:CD009122. doi: 10.1002/14651858.CD009122.pub2.

Gaede, P., Vedel, P., Larsen, N., Jensen, G.V., Parving, H.H., Pedersen, O. (2003). Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N Engl J Med, 348(5):383-93.

Garg, S., Davis, R.M. (2009). Diabetic retinopathy screening update.  Clin Diabet, 27(4):140-5.

Ghasemi, M., Ansari, M., Basiri. K., Shaigannejad V. (2014). The effects of intradermal botulinum toxin type a injections on pain symptoms of patients with diabetic neuropathy. J Res Med Sci,19(2):106-11.

Gibbons, C.H., Freeman, R., Veves, A. (2010). Diabetic neuropathy: a cross-sectional study of the relationship among tests of neurophysiology. Diabet Care, 33(12), 2629-34.

Gilbert, M.P. (2015). Screening and treatment by the primary care provider of the common complications of diabetes mellitus. Med Clin North Am, 99(1): 201-19.

Golan, S., Loewenstein, A. (2014). Surgical treatment for macular edema. Semin Ophthalmol, 29(4):242-56.

Hartemann, A., Attal, N., Bouhassira, D., Dumont, I., Gin, H., Jeanne, S., et al. Painful diabetic neuropathy: diagnosis and management. Diabetes Metab, 37:377-88.

Ismail-Beigi. F., Craven, T., Banerji, M.A., Basile, J., Calles, J., Cohen, R.M., et al; ACCORD trial group. (2010). Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet, 376(9739):419-430.

Jeon, S., Lee, W.K. (2014). Effect of intravitreal triamcinolone in diabetic macular edema unresponsive to intravitreal bevacizumab. Retina, 34(8):1606-11.

Jin, E., Luo, L., Bai, Y., Zhao M (2015). Comparative effectiveness of intravitreal bevacizumab with or without triamcinolone acetonide for treatment of diabetic macular edema. Ann Pharmacother. 2015 Jan 26. pii: 1060028014568006. [Epub ahead of print]

Jin, H.Y., Park, T.S. (2015). Can nerve conduction studies detect earlier and predict clinical diabetic neuropathy? J Diabetes Investig, 6(1):18-20.

Kaines, A., Reddy, S., Schwartz, S.D. (2009). Ultrawide angle angiography for the detection and management of diabetic retinopathy. Int Ophthamol Clin, 49:53-9.

Kiss, S., Berenberg, T.L. (2014). Ultra widefield fundus imaging for diabetic retinopathy. Curr Diab Rep. 2014 Aug;14(8):514. doi: 10.1007/s11892-014-0514-0.

Klein, B.E., Myers, C.E., Howard, K.P., Klein, R. (2014). Serum lipids and proliferative diabetic retinopathy and macular edema in persons with long-term type 1 diabetes mellitus: The Wisconsin Epidemiologic Study of Diabetic Retinopathy. JAMA Ophthalmol, Dec 11. doi: 10.1001/jamaophthalmol.2014.5108. [Epub ahead of print]

Kowalski, A., Krikorian, A., Lerma, E.V. (2014). Diabetic nephropathy for the primary care provider: new understandings on early detection and treatment. Ochsner, 14(3):369-79.

Lee, S.N., Chhablani, J., Chan, C.K., Wang, H., Barteselli, G., El-Emam, S, et al. (2013). Characterization of microaneurysm closure after focal laser photocoagulation in diabetic macular edema. Am J Ophthalmol, 155(5):905-12.

Lim, A.Kh. (2014). Diabetic nephropathy - complications and treatment. Int J Nephrol Renovasc Dis, 15;7:361-81

Lunn, M.P., Hughes, R.A, Wiffen, P.J. (2014). Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014 Jan 3;1:CD007115. doi: 10.1002/14651858.CD007115.pub3.

Lv, M., Chen, Z., Hu, G., Li, Q. (2014). Therapeutic strategies of diabetic nephropathy: recent progress and future perspectives. Drug Discov Today. 2014 Oct 31. pii: S1359-6446(14)00412-7. doi: 10.1016/j.drudis.2014.10.007. [Epub ahead of print]

MacIsaac, R.J., Ekinci, E.I., Jerums, G. (2014). Markers of and risk factors for the development and progression of diabetic kidney disease. Am J Kidney Dis, 63(2 Suppl 2):S39-62

Manasseh, G.S., Shao, E.H., Taylor, S.R. (2015). Treatment of diabetic retinopathy.  Br J Hosp Med (Lond), 76(1):35-40.

Maser, R.E., Mitchell, B.D., Vinik, A.I., Freeman, R. (2003). The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes: a meta-analysis.Diabet Care, 26(6):1895-901.

Marozas, L.M., Fort, P.E (2014) Diabetic retinopathy - Update on prevention techniques, present therapies, and new leads. US Ophthalmic Rev, 7(1):54-58.

Martin, C.L., Albers J.W., Pop-Busui, R, DCCT/EDIC Research Group. (2014). Neuropathy and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study. (2014). Diabet Care, 37(1):31-8.

Martinez-Zapata M.J., Martí-Carvajal A.J., Solà, I., Pijoán, J.I., Buil-Calvo, J.A., Cordero, J.A., et al. (2014). Anti-vascular endothelial growth factor for proliferative diabetic retinopathy. Cochrane Database Syst Rev. 2014 Nov 24;11:CD008721. doi: 10.1002/14651858.CD008721.pub2.

Mavrikakis, E. (2014). Diabetic macular edema. eMedicine. October 14, 2104. Retrieved February 27, 2015 from Medscape.

McCulloch, D.K. (2014). Diabetic retinopathy: Screening. UpToDate. January 22, 2014. Retrieved February 24, 2015 from

McCulloch D.K. (2014). Diabetic retinopathy: pathogenesis. UpToDate, December 10, 2104. Retrieved February 21, 2105 from

Muir, K.W., Grubber, J., Mruthyunjaya, P., McCant, F., Bosworth, H.B. (2013). Progression of diabetic retinopathy in the hypertension intervention nurse telemedicine study. JAMA Ophthalmol,131(7):957-8.

Noborisaka, Y. (2013). Smoking and chronic kidney disease in healthy populations. Nephrourol Mon, 5(1):655-67.

Patel, C.C. (2013. Pars plana vitrectomy. eMedicine. August 1, 2013. Retrieved February 28, 2015 from Medscape.

Pedersen, O., Gaede, P. (2003). Intensified multifactorial intervention and car­diovascular outcome in type 2 diabetes: the Steno-2 study. Metabolism, 52(8 Suppl 1):19-23.

Perkovic, V., Heerspink, H.L., Chalmers, J., Woodward, M., Jun, M., Li, Q., et al. (2013). Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Kidney Int, 83(3):517-23.

Pop-Busui R, Evans GW, Gerstein HC, et al. (2010). Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabet Care. 33(7), 1578-1584.

Porta, M., Curletto, G., Cipullo, D., Rigault de la Longrais, R., Trento, M., Passera, P., et al (2014). Estimating the delay between onset and diagnosis of type 2 diabetes from the time course of retinopathy prevalence. Diabet Care. 37(6):1668-74.

Quan, D. (2014). Diabetic neuropathy. eMedicine. May 29, 2014. Retrieved March 2, 2015 from  Medscape.

Rahimi, Z., Moradi, M., Nasri, H. (2014). A systematic review of the role of renin angiotensin aldosterone system genes in diabetes mellitus, diabetic retinopathy and diabetic neuropathy. J Res Med Sci,19(11):1090-8.

Rosenberg, C.J., Watson, J.C. (2015). Treatment of painful diabetic peripheral neuropathy. Prosthet Ortht Int, 39(1): 17-28

Rosberger, D.F. (2013). Diabetic retinopathy: current concepts and emerging therapy. Endocrinol Metab Clin North Am, 42(4):721-45.

Sacks, F.M., Hermans, M.P., Fioretto, P., Valensi, P., Davis, T., Horton E., et al. (2014). Association between plasma triglycerides and high-density lipoprotein cholesterol and microvascular kidney disease and retinopathy in type 2 diabetes mellitus: a global case-control study in 13 countries. Circulation,129(9):999-1008.

Seyin, N., Kara, N., Pekel, G. (2015). Ocular complications of diabetes. World J Diabetes, 6(1), 92-108.

Shin, E.S., Sorenson, C.M., Sheibani, N. (2014). Diabetes and retinal vascular dysfunction. J Ophthalmic Vis Res, 9(3):362-73.

Singh, R., Kishore, L., Kaur, N. (2014). Diabetic peripheral neuropathy: current perspective and future directions. Pharmacol Res, 80:21-35.

Song S.J., Wong T.Y. (2014). Currents concepts in diabetic retinopathy. Diabetes  Metab J, 38:416-25.

Spallone, V,, Ziegler, D., Freeman, R,, Bernardi, L., Frontoni, S., Pop-Busui R, et al. (2011). Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev, 27(7):639-53.

Stevens, M.J. (2014). Diabetic autonomic neuropathy. UpToDate. February 21, 2014. Retrieved March 4, 2015 from

Tarr, J.M., Kaul, K., Chopra, M., Kohner, E.M., Chibber. R. (2013). Pathophysiology of diabetic retinopathy. ISRN Ophthalmol. Jan 15;2013:343560. doi: 10.1155/2013/343560. eCollection 2013.

Tesfaye, S., Boulton, A.J.M., Dyck, P.J., et al. (2010). Diabetic neuropathies: Update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabet Care, 33(10),2285-2293.

The Accord Study Group and the Accord Eye Study Group. (2010). Effects of medical therapies on retinopathy progression in type 2 diabetes. N Eng J Med, 363(3), 233-244.

The Diabetic Retinopathy Clinical Research Network. (2015). Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med, 2015 Feb 18. [Epub ahead of print]

Tonelli, M., Wanner, C.; Kidney Disease: Improving Global Outcomes Lipid Guideline Development Work Group Members. (2014). Lipid management in chronic kidney disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2013 clinical practice guideline. Ann Intern Med, 60(3):182.

UK Prospective Diabetes Study Group. (1998). Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ, 317(7160):703–13.

Verotti, A., Prezioso, G., Sacttoni, R., Chiarelli, F. (2014). Autonomic neuropathy in diabetes mellitus. Front Endocrin (Lasusanne). 2014; 5: 205. Published online 2014 Dec 1. doi:  10.3389/fendo.2014.00205

Vinik, A.I., Erbas, T. (2013). Diabetic autonomic neuropathy. Hand Clin Neurol, 117:279-94.

Vinik, A.I., Erbas, T., Casellini, C.M. (2013). Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Investig, 4(1):4-18.

Virgili, G. Menchini, F. Casazza,G. Hogg, R. Das, R.R., Wang, X., et al (2015). Optical coherence tomography (OCT) for detection of macular oedema in patients with diabetic retinopathy. Cochrane Database Syst Rev. 2015 Jan 7;1:CD008081. doi: 10.1002/14651858.CD008081.pub3.

Vujosevic, S., Zamaklar, M., Belada, N., Stamatovic, S. (2012). Mortality after acute myocardial infarction: significance of cardiovascular diabetic autonomic neuropathy (CDAN). (2012). Med Arch, 66(5):296-9.

Waanders, F., Visser, F.W., Gans. R.O. (2013). Current concepts in the management of diabetic nephropathy. Neth J Med, 71(9):448-58.

Wang, B., Wang, F., Zhang, Y., Zhao S.H., Zhao, W.J., Yan, S.L., et al. (2015). Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis. Lancet Diabetes Endocrinol, Feb 5. pii: S2213-8587(14)70256-6. doi: 10.1016/S2213-8587(14)70256-6. [Epub ahead of print]

Wessel, M.M., Aaker, G.D,, Parlitsis, G., Cho, M,, D'Amico, D.J., Kiss S. (2012). Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina, 32(4):785-91

Wiseman, A.C. (2010). The role of kidney-pancreas transplantation in diabetic kidney disease. Curr Diab Rep, 10(5):385-91.

Zhang, X., Saaddine, J.B., Chou, C.F., Cotch, M.F., Cheng, Y.J., Geiss, L.S., et al. (2010). Prevalence of diabetic retinopathy in the United States, 2005-2008. ,JAMA, 304(6):649-56.

Ziegler, D., Fonseca, V. (2015). From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications, 29(1):146-56.

This course is applicable for the following professions:

Advanced Registered Nurse Practitioner (ARNP), Clinical Nurse Specialist (CNS), Dietitian/Nutritionalist (RDN), Licensed Practical Nurse (LPN), Licensed Vocational Nurses (LVN), Registered Nurse (RN)


CPD: Practice Effectively, Diabetes, Medical Surgical

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