Complications of Diabetes Mellitus
Diabetes mellitus (DM), both type 1 and type 2, affects many organ systems, particularly the heart, eyes, kidneys, and the peripheral and autonomic nervous systems. Pregnant women with poorly controlled diabetes are more likely to experience birth complications and give birth to newborns with macrosomia than are women with well controlled or no diabetes.
Prevention of macrovascular and microvascular complications of diabetes depends on control of the major modifiable risk factors such as smoking, sedentary lifestyle, diet, blood pressure, blood lipid concentrations, and albuminuria. These last 3 are amenable to dietary interventions, as described below. Blood glucose control has always been touted as beneficial for prevention of complications, but tight control achieved with combinations of medication or multiple daily injections of insulin in type 2 diabetes is less effective than previously thought and comes with other risks, such as severe hypoglycemia, increased cardiac mortality, and weight gain.
1. Cardiovascular Complications
Atherosclerotic cardiovascular disease (ASCVD), defined as acute coronary syndromes (ACSs), a history of myocardial infarction (MI), stable or unstable angina, coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origin, is the leading cause of morbidity and mortality and is the largest contributor to direct and indirect costs for individuals with diabetes. Control of cardiac risk factors is therefore critical, particularly smoking, hypertension, and dyslipidemias (see CHD, Hypertension, and Dyslipidemias chapters).
Gender. Women with diabetes have a greater risk of developing diabetes-related cardiovascular disease, compared with men with diabetes.
Patients with diabetes may have atypical presentations for CVD. Screening with electrocardiogram or cardiac stress tests may be appropriate in some patients.
Blood pressure control is particularly important for individuals with diabetes. Goal blood pressure should be less than 140/90 mm Hg, and further lowering may be beneficial and appropriate for some patients (see Hypertension chapter).
Until recently, goals for blood lipid concentrations for people with diabetes were to keep LDL cholesterol below 100 mg/dL (or below 70 mg/dL in patients with known CVD), triglycerides below 150 mg/dL, and HDL greater than 40 mg/dL for men and greater than 50 mg/dL for women. However, the American College of Cardiology and American Heart Association currently recommend using the ACC/AHA calculator to gauge patients’ 10-year risk of heart disease and plan appropriate diet and pharmacologic therapies, rather than using specific lipid values for treatment planning (see Dyslipidemias chapter).
Dietary and behavioral modifications, including smoking cessation, regular exercise, and loss of excess weight, are critical for the prevention and management of cardiac complications in patient with diabetes.
When further therapy is needed, specific medications can be helpful.
Aspirin (75-162 mg/day) can be used as a primary prevention tool in most women over age 60 and most men over age 50, if they have at least one of the above listed CVD risk factors. Potential side effects, including bleeding, must be considered.
Patients with diabetes and a blood pressure of > 120/80 mmHg should be counseled on implementation of lifestyle changes, and those with a blood pressure of > 140/90 mmHg should be treated with both lifestyle modification and pharmacological intervention. Lifestyle changes include weight loss, diet modifications including the reduction of sodium, limitation of alcohol, and participation in physical activity. Plant-based diets are particularly effective, because they not only reduce blood pressure, but also improve body weight, lipids, and glycemic control.
Hypertension in diabetes should be treated with an a ngiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Additional blood-pressure-lowering may be required. These include diuretics, beta-blockers, and calcium channel blockers (see Hypertension chapter).
The American College of Cardiology and American Heart Association currently recommend using the ACC/AHA calculator to gauge patients’ 10-year risk of heart disease and plan appropriate diet and pharmacologic therapies, rather than using specific lipid values for treatment planning.
In addition to lifestyle changes, all patients with diabetes aged 40 and older may benefit from moderate-intensity statin therapy. A high-dose statin may be required for patients who have ASCVD or ASCVD risk factors (see Risk Factors). The American Diabetes Association (ADA) provides additional recommendations for individuals < 40 or > 70 years of age. For those who do not tolerate high-dose statins, moderate statin therapy plus ezetimibe may be indicated. With each additional medication, the option of dietary intervention should be offered. Periodic monitoring of LDL cholesterol and liver function is recommended to check the efficacy and safety of statin therapy (see Hyperlipidemia chapter).
To reduce the risk of cardiac complications, the appropriate dietary changes are those that improve plasma lipid concentrations, reduce blood pressure, and control glycemia. These steps are discussed in detail in the chapters on coronary heart disease, hyperlipidemia, hypertension, and diabetes. More recent evidence indicates that diet-derived advanced glycation end products (AGEs) contribute to diabetic complications, including cardiovascular disease, and that these should be avoided as well. Although controlling blood sugar helps to inhibit the formation of AGEs, a significant amount come from diets high in animal protein and fat. These have numerous harmful effects on the vasculature, including induction of aortic atherosclerotic lesions, cross-linking of arterial wall connective tissue protein, and neointimal formation after arterial injury, increasing vascular permeability, and markedly impairing the vascular vasodilatory response.
A systematic review and meta-analysis concluded that vegetarian diets were associated with a significant reduction in HbA1c compared with nonvegetarian diets. These diets also significantly lower other cardiovascular risk factors, including weight, blood pressure, and lipids. A systematic review of “Mediterranean diets” concluded similar findings. Both types of diets draw their nutrition primarily or exclusively from plant sources and are high in antioxidant nutrients.
2. Ophthalmic Complications
Glaucoma and Cataracts
Glaucoma and cataracts may develop earlier in diabetes patients, compared with those without diabetes (see Glaucoma and Cataract chapters).
In diabetes, pathologic changes in the retinal vasculature pose a major long-term threat to vision. In nonproliferative diabetic retinopathy, microaneurysms, small “dot and blot” hemorrhages, hard exudates (lipid material that can be toxic to the retina), and retinal infarcts known as “cotton wool spots” appear. These changes tend to concentrate in the macula, where they can blur and distort central vision.
In proliferative retinopathy (neovascularization), fragile, abnormal vessels grow into the vitreous, presumably in response to ischemia. Vitreous hemorrhage causes symptoms ranging from “floaters” to complete visual obscuration. Ultimately, tractional retinal detachment can result. Retinopathy is not painful, so the condition can progress undetected by the patient.
Good blood glucose control, as indicated by a low HbA1c, can reduce the risk of ophthalmic involvement and slow its progression. , , , , Similarly, blood pressure control is important, as poorly controlled hypertension increases the severity of retinopathy. , ,
Poor blood glucose control.
Duration of diabetes.
Type of diabetes. Retinopathy is more common in type 1 than type 2.
Retinopathy can be diagnosed by ophthalmoscopy with dilated pupils.
Use of a fundus lens at the slit lamp allows a stereoscopic view and facilitates diagnosis of macular edema.
In fluorescein angiography, an intravenous injection of fluorescein followed by serial photography of the fundus reveals leakage from microaneurysms, nonperfusion, and other useful information to guide therapy.
For proliferative retinopathy where vitreous hemorrhage appears likely, panretinal laser photocoagulation often stabilizes neovascularization or even causes it to regress.
When diabetic retinopathy causes clinically significant macular edema (defined by severity of leakage and proximity to the central macula), photocoagulation can slow progression. Individual microaneurysms can be obliterated, or a broader grid photocoagulated, if the leakage pattern is diffuse. Intravitreal steroids and vascular endothelial growth factor inhibitors may also play a role in treatment.
Individuals with type 2 diabetes should have a dilated eye exam soon after diagnosis, and those with type 1 diabetes should be examined within 5 years of diagnosis. If eye exams are normal and the patient is in good glycemic control, exams every 2 years may be considered.
Nutritional interventions that improve control of blood glucose, blood pressure, and lipid concentrations may help prevent or slow ophthalmic complications. AGEs have been linked with diabetic complications, including retinopathy, in participants in the Diabetes Control and Complications Trial (DCCT), and were highly correlated with its progression. Avoidance of dietary sources of AGEs may be important for preventing diabetic eye diseases and other complications of diabetes.
Most individuals with diabetes are insulin resistant, and evidence indicates that 85% of persons with type 2 diabetes also have metabolic syndrome. Both of these conditions are associated with elevated intraocular pressure, a well-known risk factor for glaucoma. Control of high blood pressure (a component of the metabolic syndrome) is also important in the care of glaucoma (see Glaucoma chapter). Several studies have suggested a lower risk for glaucoma in persons eating higher amounts of vitamin A-containing vegetables; however, none of these has been specific to the diabetic population. Physical activity is a fundamental part of control of diabetes in general and for the control of certain diabetic complications; however, individuals with diabetes should be advised to mainly participate in aerobic exercise, which lowers intraocular pressure (IOP) rather than weight lifting, which increases IOP.
Individuals with diabetes are at increased risk for cataract. However, no controlled clinical trials using nutrition therapies indicate that diet changes reduce this risk among individuals with diabetes. In the general population, a number of dietary factors are associated with lower cataract risk, including maintenance of ideal weight and normal lipid levels, high intake of antioxidant-containing foods, avoidance of alcohol, and avoidance of sources of galactose (i.e., dairy products) (see Cataract chapter).
Evidence indicates that control of blood glucose, blood pressure,  and blood cholesterol reduces the onset and progression of diabetic retinopathy. ,  A specific diet therapy suitable for prevention of retinopathy has not yet been established. However, evidence from the Diabetes Complications and Control Trial (DCCT) associated diets high in fat and low in fiber with progression of retinopathy,  suggesting that low-fat, high-fiber diets may have promise for reducing retinopathy risk. In addition, AGEs have been associated with the presence and progression of diabetic retinopathy,  and low AGE diets have been found in studies of diabetic subjects to improve microvascular function when compared with high AGE diets. 
Diabetic nephropathy, also known as diabetic kidney disease (DKD, involves pathologic changes to the kidney vasculature that is identified as a decrease in kidney function and/or evidence of kidney damage. Evidence of reduced kidney function is measured by estimated glomerular filtration rate (eGRF) < 60 mL/min/1.73 m 2. Kidney damage is measured by albuminuria (ratio of albumin to creatinine > 30 mg/g). Albumin in the urine is also a sign of cardiovascular disease and hypertension and can also be a marker for endothelial dysfunction. Globally, diabetic kidney disease is a serious and rising global health problem and is the leading cause of chronic kidney disease and end stage renal failure. Pathogenesis involves hypertension, ischemia, hyperglycemia, and advanced glycosylation end products. Persistently elevated blood glucose, blood pressure, and cholesterol and triglyceride concentrations are associated with microalbuminuria.
Pima Indians with type 2 diabetes have a particularly high susceptibility to nephropathy, with prevalence of up to 50% after 20 years. However, Pimas living in the US are at much higher risk, compared with Pimas in Mexico, suggesting that the risk may be partly mediated by diet and lifestyle rather than genetic factors.
Risk factors include:
Family history of diabetic nephropathy.
Duration of diabetes.
Poor blood glucose control.
Elevated glomerular filtration rate.
Dietary factors (see Nutritional Considerations below).
Other possible risk factors include obesity, increasing age, and smoking.
Microalbuminuria, sometimes referred to as “moderately increased albuminuria,” is defined as a persistent loss of albumin in the urine of 30-300 mg/day, and is the first indication of nephropathy. A urine albumin-creatinine ratio with a value of 30 mg/g or greater also suggests microalbuminuria. Macroalbuminuria, or “severely increased albuminuria,” is diagnosed when urinary albumin losses are > 300 mg/day (> 300 mg/g creatinine)
Transient microalbuminuria may occur with hyperglycemia, exercise, heart failure, and febrile illness.
Annual screening, using urine albumin-to-creatinine ratio testing and estimated glomerular filtration rate calculation, is recommended for all patients with diabetes. When the results suggest microalbuminuria, repeat specimens (albumin-creatinine ratio) should be obtained 2-3 times over the following 3-6 months. If at least 2 samples are abnormal, a diagnosis of albuminuria is appropriate.  24-hour urine samples are not required to make this diagnosis.
Treatment recommendations for nephropathy are similar in type 1 and type 2 diabetes.
Glycemic control with dietary intervention is recommended. No significant improvement in the risk of end stage renal disease was found in a recent meta-analysis of studies using multiple medications to reduce A1c. 
Treatment with ACE inhibitors or ARBs helps prevent or slow the progression of microalbuminuria to more severe renal disease. This approach is especially important if hypertension is present and target blood pressure to reduce vascular complications is less than 140/90 mm Hg. The additional use of beta blockers, diuretics, or calcium channel blockers may be indicated.
Control of plasma cholesterol and triglyceride concentrations is important and has been shown to improve outcomes in patients with microalbuminuria (see Hyperlipidemia chapter f or details on optimizing LDL, HDL, and triglycerides).
Combined therapy, which includes behavioral therapy to address diet, exercise, and smoking cessation, and pharmacologic therapy to reduce blood pressure and cholesterol concentrations, has been shown to reduce the progression of diabetic nephropathy.
Weight loss is helpful, perhaps because of its beneficial effects on glucose, blood pressure, and lipid control.
Loss of excess weight reduces blood pressure, proteinuria, and microalbuminuria and stabilizes kidney function. Reducing saturated fat, cholesterol, and animal protein intake may reduce the risk for or progression of nephropathy. Elevated cholesterol is a risk factor for nephropathy and end-stage renal disease. Cholesterol-lowering treatment was found to retard the progression of diabetic nephropathy.
A recent meta-analysis found that restriction of animal protein was associated with a significant improvement in GFR, along with a significant reduction in HgbA1c. High intake of total protein and animal protein has been shown to increase urinary albumin excretion. In short-term studies, proteinuria has been reduced through the use of vegetarian diets and diets deriving protein primarily from soy and other plant sources. These diets also facilitate blood pressure control,  which further helps reduce diabetic nephropathy progression.
Dietary sodium restriction is indicated for a number of reasons, including prevention or treatment of microalbuminuria. It is also important because sodium excess may offset both the antihypertensive and antiproteinuric effects of renin-angiotensin system-blocking drugs.
Neuropathy is a particularly common diabetes complication, affecting approximately half of all diabetes patients. Distal symmetric polyneuropathy is the most common presentation; however, neuropathy can also involve the autonomic nervous system, including the cardiovascular system, and individual nerves.
The disease may present not only with sensory loss but also with paresthesias and dysesthesias. Pathogenesis may occur due to ischemia and metabolic factors, including advanced glycosylation end products. Progression is likely. If severe, neuropathy may lead to joint deformities and infections that ultimately require amputation.
Duration of diabetes.
Smoking, dyslipidemia, hypertension, and obesity may also contribute to risk.
The presence of distal symmetric polyneuropathy can be assessed with simple clinical tests, two of which should be performed annually in patients with diabetes. Altered sensation, whether vibration (128 Hz tuning fork), pain (pin-prick), temperature, or pressure (10-g monofilament at dorsal aspect of great toe), or absence of ankle reflexes suggests neuropathy. The use of more than 1 test increases diagnostic accuracy. Electrophysiologic studies, such as nerve conduction tests, can confirm the diagnosis. Multiple screening instruments are available including the Michigan Neuropathy Screening Test and the United Kingdom screening test. Patients with type 2 diabetes should be screened annually after diagnosis and patients with type 1 should be screened annually 5 years after initial diagnosis.
The presence of autonomic neuropathy can often be assessed by history and physical examination. Incontinence, erectile dysfunction, tachycardia, pupillary dysfunction, and orthostatic hypotension, among other abnormalities, suggest autonomic neuropathy. Gastroparesis and constipation are common signs of gastrointestinal neuropathies. 
Diabetic neuropathy is best prevented, and possibly treated, through A1c controlled with lifestyle interventions. Recently, a meta-analysis showed that clinical neuropathy was not prevented with intensive medication use. In cases of pre-existing neuropathy, symptoms may improve with diet and lifestyle changes, as noted below. The development of cardiovascular autonomic neuropathy can be prevented or slowed by optimizing lifestyle factors such as smokng, as well as by controlling cholesterol and blood pressure.
In addition to optimized glycemic control, foot care is essential. Properly fitted shoes, foot hygiene, daily foot inspection (special mirrors can help patients who have mobility problems), regular nail care (without cutting nails too short), and immediate consultation with a health care provider whenever an abnormality occurs are all important. A comprehensive foot exam that includes inspection and pulse checks should be performed annually.
Medications also may help, but none affords complete alleviation of the painful symptoms of diabetic peripheral neuropathy (DPN). The FDA has approved 3 medications for of DPN: pregabalin, duloxetine, and tapentadol. Other treatments may also be considered. Examples include:
Tricyclic antidepressants, notablyamitriptyline.
Topical lidocaine and capsaicin cream.
Anticonvulsants such as gabapentin, carbamazepine, and lamotrigine. Pregabalin is structurally similar to gabapentin but has a different mechanism of action and may be more effective.
Mexiletine may be tried in consultation with a cardiologist, if pain persists.
Long-acting narcotics (oxycodone CR) and tramadol may be used, but long-term efficacy has not been established and risk of addiction and abuse is a serious concern.
Medications may treat autonomic symptoms, such as erectile dysfunction, gastric abnormalities, and incontinence. These treatments usually improve quality of life but do not alter the disease course.
A combination of a vegan diet and exercise may have particular value in treating neuropathy. In a study of 21 individuals with painful neuropathy, symptoms completely disappeared in 17 and improved in the remainder using a vegan diet along with regular walking over a 2-week period. In a 20-week controlled trial in 33 patients with diabetic neuropathy, a low-fat vegan diet without increased exercise led to improved peripheral nerve function, as measured by skin conductance testing, and reduced pain.
Evidence suggests that in addition to the effect of vegetarian diets on glycemic control, their effect on body weight, blood pressure, lipids, and blood rheology may be relevant to neuropathy. ,
In addition to the benefits of a diet and exercise regimen, some nutritional supplements have shown potential benefit. A systematic review and meta-analysis concluded that IV forms of alpha-lipoic acid significantly improve both nerve conduction velocity and neuropathic symptoms. Oral forms appear to be effective as well, as shown in the The Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN) 1 trial, a multicenter, randomized, double-blind, placebo-controlled study. Although generally considered safe, some evidence indicates a risk for development of insulin autoimmune syndrome (Hirata disease) in Caucasians of European descent who take lipoic acid supplements.
Oral supplementation of the acetyl form of the amino compound L-carnitine (acetyl-L-carnitine, ALC) has also been found helpful for peripheral neuropathy in diabetes. ALC has actually been shown to regenerate nerve fibers Double-blind, placebo-controlled, randomized multicenter trials have found significant improvements in pain, sural nerve fiber numbers, nerve fiber regeneration, nerve conduction velocity and amplitude and pain scores. Nevertheless, the ability of ALC to improve diabetic neuropathy is dependent on glycemic control.
Vitamin B12, in the form of methylcobalamin, appears to be an effective treatment for peripheral neuropathy. Although patients with type 2 diabetes are more likely to develop B12 deficiency (due to metformin use), type 1 patients also frequently develop B12 deficiency due to chronic immune gastritis. Elderly diabetic patients may be at particular risk for peripheral neuropathy due to B12 deficiency. Pharmacologic doses of B12 improve nerve conduction through the regeneration of peripheral nerves. , Meta-analyses have concluded that I.V. combinations of methylcobalamin and lipoic acid are superior to either alone, and prostaglandin E1, methylcobalamin, and lipoic acid are superior to PGE1 and methylcobalamin for diabetic peripheral neuropathy.
Other supplements that have shown benefit in diabetic neuropathy treatment include benfotiamine (a fat soluble form of thiamine), a combination of activated coenzyme forms of certain B-vitamins (L-methylfolate, pyridoxal-5’-phosphate, and methylfolate), and gamma-linolenic acid, a PGE1 precursor. ,
5. Complications Related to Pregnancy
Women with diabetes should try to plan their pregnancies so blood glucose can be well-controlled prior to conception. Good glucose control prior to and during pregnancy decreases the risk of complications for both the mother and baby, including congenital anomalies, miscarriage, macrosomia, birth trauma, respiratory distress, and stillbirth. It can also reduce the need for cesarean section.
Because of the insulin antagonist effect of pregnancy, some women develop diabetes only during pregnancy (gestational diabetes). Gestational diabetes can result in macrosomia, which can increase complications of delivery, including shoulder dystocia and neonatal morbidity. Control of blood sugar (e.g., with insulin) reduces this risk. , Offspring of mothers with either gestational or pregestational diabetes are at higher risk for development of metabolic syndrome and obesity than those born to women without diabetes. ,
See the Diabetes chapter for more treatment information.
Guidelines set forth by the ADA suggest that all women with gestational diabetes receive nutritional counseling by a registered dietitian that is individualized to meet maternal weight, height, and pregnancy needs, consistent with the maternal blood glucose goals that have been established. ADA guidelines further recommend that obese (BMI > 30 kg/m 2) women with gestational diabetes restrict calories by 33% (to ~ 25 kcal/kg actual weight per day). A systematic review concluded that antenatal nutritional therapy in women with gestational diabetes was effective for reducing preeclampsia, excessive gestational weight gain, necessity for cesarean delivery, shoulder dystocia, need for insulin therapy, and perinatal complications, including macrosomia, neonatal hypoglycemia, and high birth weight. A systematic review and meta-analysis of overweight and obese women only found a trend towards a reduction in gestational diabetes and no clear differences for other negative outcomes of diabetic pregnancy.
A recent review of prospective diet trials concluded that a diet higher in complex carbohydrate and fiber, low in simple sugar, and lower in saturated fat may be effective in blunting postprandial hyperglycemia and preventing worsened insulin resistance and excess fetal growth. Previous evidence suggested that a high-fiber diet may be useful for preventing gestational diabetes and its complications. A study of more than 13,000 women found that higher fiber intakes are associated with lower risk for gestational diabetes, while low-fiber diets increase risk. Thus, the type of carbohydrate (rather than the amount) may require consideration for its effect on maternal blood glucose control. No randomized controlled study has yet compared low carbohydrate, low-fiber diets with diets higher in carbohydrates and fiber.
See Diabetes chapter.
What to Tell the Family
The best way to prevent diabetes complications is through healthy lifestyle behaviors and aggressive control cardiovascular risk factors. Cessation of smoking is critical. Diet plays an important role, along with exercise and appropriate medications. Encouraging the entire family to adopt a healthy diet is important, not only to support dietary adherence by the patient, but also to reduce the family’s risk of disease.
All diabetes patients should be screened yearly for retinopathy by an ophthalmologist and have lab work done to monitor for nephropathy. Neuropathy is most likely to be discovered by the patient, but the family can help monitor for blisters or calluses. Special shoes may be needed to prevent infections. For women of child-bearing age, family planning should be encouraged, and should ideally occur when blood glucose levels are well controlled. Pregnant women with diabetes should be under the care of a specialized team.
It is important for the family and patient to understand that because diabetes complications can greatly reduce quality of life, aggressive prevention and/or treatment is imperative.
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