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. Each of these is described below.

Both lifestyle (especially nutrition) and medical interventions play important roles in prevention and treatment of diabetes complications. Control of weight, blood glucose, lipids, and blood pressure is essential. In addition, dietary steps to limit advanced glycation end products (AGEs) are also important. AGEs are toxic compounds formed when glucose interacts with proteins and are a major contributor to macrovascular and microvascular complications.[1]

1. Cardiovascular Complications

Coronary heart disease and cerebrovascular disease cause over 60% of deaths in people with diabetes.[2],[3] Tight control of blood glucose with intensive pharmacological therapy alone has not been found to reduce cardiovascular mortality.[4] Control of cardiac risk factors overall is therefore critical. Apart from hyperglycemia, these include smoking, hypertension, dyslipidemia, obesity, and microalbuminuria (see Coronary Heart Disease, Hypertension, and Dyslipidemias chapters).

Treatment of hypertension. Reducing blood pressure to < 140/90 mm Hg reduces cardiovascular and microvascular disease.[2] For those at higher cardiovascular risk, reducing blood pressure to < 130/80 mm Hg may be recommended, as long as this can be achieved safely. Decreasing blood pressure too quickly or to too low a level may increase the risk of hypotension, syncope, falls, acute kidney injury, and electrolyte abnormalities.[2] Patients with hypertension should monitor their blood pressure at home.

Diet and exercise should be the first line of therapy for blood pressure control in patients with diabetes, as described below. Patients with a blood pressure ≥ 140/90 may also need pharmacologic therapy with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). Additional medications may be required, including diuretics, beta-blockers, and calcium channel blockers (see Hypertension chapter).

Treatment of hyperlipidemia. The American College of Cardiology (ACC) and American Heart Association (AHA) 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 as had been previously recommended (see Dyslipidemias chapter).

In addition to diet and lifestyle changes, all patients with diabetes age 40 and older may benefit from moderate-intensity statin therapy. A high-dose statin may be required for patients who have atherosclerotic cardiovascular disease or related risk factors. The 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.[2] Periodic monitoring of LDL cholesterol and liver function is recommended to check the efficacy and safety of statin therapy (see Dyslipidemias chapter).

Aspirin. Use of aspirin (75-162 mg/day) may reduce cardiovascular mortality in patients who are at high cardiovascular risk, such as those with a history of atherosclerotic cardiovascular disease.[2] Benefits have not been well demonstrated for people who are at low risk or have had no previous cardiac events. Gastrointestinal bleeding may occur in about 5 per 1,000 people using aspirin. The potential risks of bleeding with aspirin therapy should be discussed with patients.

Nutritional Considerations

The adoption of a plant-based diet is associated with significant improvements in cardiovascular risk factors, including weight, blood pressure, and plasma lipids.[5],[6]More specific instructions are discussed in the chapters on coronary heart disease, hyperlipidemia, hypertension, and diabetes.

In countries where diet is centered on grains and vegetables, high in fiber, and very low in animal fat, average cholesterol levels are less than 150 mg/dL.[7] In rural China comprising 500,000 people, there was not 1 death from coronary artery disease in a 3-year period.[8] The diet centered around plant-based foods. Animal products are rarely consumed. A plant-based eating pattern is the only eating pattern that has demonstrated a reversal of coronary artery plaques. A 1-year low-fat vegetarian diet intervention in patients with coronary artery disease demonstrated regression of atherosclerotic plaques indicated by quantitative coronary angiography, while the usual care (control) group resulted in disease progression.[9]

Plant-based diets reduce the AGE formation due to the absence of meat (cooking meat at high temperatures forms AGEs) and due to improved glycemic control.[10] Chronic inflammation associated with cardiovascular disease events is measured by C-reactive protein (CRP). Meat-centered diets increase CRP, while fruits and vegetables can reduce inflammatory biomarkers.[11] Phytochemicals are an important component of plant-based eating patterns that reduce cardiovascular disease risk factors. Only plant-based foods contain phytochemicals that reduce platelet aggregation and blood clots, relax blood vessels, improve insulin sensitivity, and have been found to reduce cardiovascular disease as well as other diet-related conditions.[12]

2. Ophthalmic Complications

Retinopathy

In diabetes, pathologic changes in the retinal vasculature pose a major long-term threat to vision. Retinopathy risk factors include poor blood glucose control, hypertension, smoking, nephropathy, dyslipidemia, diabetes duration, and type of diabetes (it is more common in type 1 than in type 2).

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 distort central vision.

In proliferative retinopathy (neovascularization), fragile, abnormal vessels grow into the vitreous, presumably in response to ischemia. Vitreous hemorrhages cause symptoms ranging from “floaters” to complete visual loss. Ultimately, tractional retinal detachment can result. Retinopathy is not painful, so the condition can progress undetected by the patient.

Glaucoma and Cataracts

Glaucoma and cataracts may develop earlier in diabetes patients, compared with those without diabetes (see Glaucoma and Cataract chapters).

Diagnosis

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 can reveal leakage from microaneurysms, nonperfusion, and other useful information to guide therapy.

Treatment

Good control of blood glucose and blood pressure can reduce the risk of ophthalmic involvement and slow its progression.[13],[14],[15],[16],[17]

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.[18] 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 examination soon after diagnosis, and those with type 1 diabetes should be examined within 5 years of diagnosis.[2] If eye examinations are normal and the patient is in good glycemic control, examinations every 2 years may be considered.

Although physical activity is a fundamental part of diabetes control, individuals with diabetes should be advised to favor aerobic exercise, which lowers intraocular pressure, rather than weightlifting, which has the opposite effect.[19]

Nutritional Considerations

Evidence indicates that control of blood glucose, blood pressure, and blood cholesterol reduces the onset and progression of diabetic retinopathy.[16],[17],[20],[21],[22],[23] 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.[24] In addition, AGEs have been associated with the presence and progression of diabetic retinopathy, and low AGE diets have been shown to improve microvascular function when compared with high AGE diets in individuals with diabetes.[3],[25]

High vitamin A and C intake is associated with a reduction in open-angle glaucoma risk.[26] In addition to lower CRP, HbA1C, and glucose, participants with diabetes who consumed more fruits and vegetables from the NHANES 2003-2007 had a 30% reduced risk of having diabetic retinopathy than participants consuming the least amount of fruits and vegetables.[27]

No controlled clinical trials using nutrition therapies indicate that diet changes reduce cataract risk among individuals with diabetes. In the general population, however, 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.)

3. Chronic Kidney Disease

Chronic kidney disease (CKD) occurs in about 20-40% of patients with diabetes.[2] Globally, diabetes is the leading cause of CKD and end-stage renal failure.[28] In turn, CKD can lead to elevated blood pressure, volume overload, electrolyte abnormalities, metabolic acidosis, anemia, and metabolic bone diseases. Cardiovascular disease is the most common comorbidity of CKD.[2]

Risk Factors

CKD risk factors include family history, duration of diabetes, poor blood glucose control, hypertension, obesity, smoking, and elevated glomerular filtration rate.

In individuals with type 1 diabetes, chronic kidney disease can develop about 10 years after the diabetes diagnosis. However, in type 2 diabetes, CKD may be present at the time of diagnosis. Blacks, Mexican Americans, and Native Americans have a higher prevalence, compared with non-Hispanic whites.[29],[30]

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 is largely mediated by diet and lifestyle rather than genetic factors.[31]

Diagnosis

Kidney function should be determined using a random spot urine collection to determine urinary albumin-to-creatinine ratio (UACR). Values of ≥ 30 mg/g creatinine (Cr) are considered albuminuria. Kidney damage is apparent with an estimated glomerular filtration rate (eGRF) < 60 mL/min1.73 m2. Diagnosis of CKD is made when both kidney dysfunction (albuminuria) and kidney damage (reduced eGFR) are present.

Both urinary albumin and eGFR should be measured yearly in all patients with diabetes.

Treatment

Treatment recommendations for nephropathy are similar for type 1 and type 2 diabetes.

To improve glycemic control, dietary changes are first-line therapy, as noted below. A meta-analysis of studies evaluating the use of multiple medications to reduce HbA1C found no significant reduction in the risk of end-stage renal disease.[4]

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 is < 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 for details on optimizing LDL cholesterol, HDL cholesterol, and triglycerides).[32]

Combined therapy—which includes diet, exercise, and smoking cessation, in addition to pharmacologic therapy to reduce blood pressure and cholesterol concentrations—has been shown to reduce the progression of diabetic nephropathy.[33]

Nutritional Considerations

Nutrition should be a primary intervention for the prevention and treatment of CKD.

Weight loss reduces blood pressure, proteinuria, and albuminuria and stabilizes kidney function.[34] Reducing saturated fat, cholesterol, and animal protein intake may reduce the risk for, or progression of, nephropathy.

In early stages of CKD, target protein intake should be limited to about 0.8 g/kg body weight. Higher levels may contribute to a decline in GFR.[2] A meta-analysis found that restricting animal protein intake was associated with a slowing of the decline of GFR, as well as a significant reduction in HbA1C.[35] Proteinuria can be reduced through the use of vegetarian diets and diets deriving protein primarily from soy and other plant sources.[36],[37] These diets also facilitate blood pressure control, which further helps reduce progression of diabetic nephropathy.[38]

Dietary sodium restriction is indicated for a number of reasons, including prevention or treatment of increased urinary protein excretion. It is also important because sodium excess may offset both the antihypertensive and antiproteinuric effects of renin-angiotensin system-blocking drugs.[39]

Results from the Atherosclerosis Risk in Communities study of 14,686 middle-aged adults followed for 24 years reported that participants following a healthy plant-based diet had a significantly lower incidence of kidney disease.[40] Diets with a high dietary acid load (DAL) from meat, fish, cheese, and refined grains and low in fruits, vegetables, potatoes, and legumes have been found to contribute to the progression of ESRD. An analysis of 1,486 participants in the National Health and Nutrition Survey III (NHANES III) followed for 14.2 years found that those who had the highest DAL had a 3-times-greater risk of developing ESRD.[41]

The National Kidney Foundation promotes a plant-based diet based on vegetables and grains and a reduction in animal-based foods to help reduce the progression of chronic kidney disease, type 2 diabetes, high blood pressure, and heart disease. Even with higher potassium, these diets are protective, reducing metabolic acidosis, as well as enhancing the excretion of potassium due to the higher intake of dietary fiber. Further, phosphorus from plants has a significantly lower absorption rate compared with phosphorus from animal sources and process foods.[42]

4. Neuropathy

Neuropathy affects approximately half of all individuals with diabetes. The condition is often asymptomatic.[2] The risk of neuropathy is increased by poor glycemic control, a longer duration of diabetes, smoking, dyslipidemia, hypertension, and a body mass index > 30.

Peripheral neuropathy may present not only with sensory loss but also with paresthesias and dysesthesias. Progression is likely. If severe, neuropathy may lead to joint deformities and infections that ultimately require amputation.

Clinical indicators of diabetic autonomic neuropathy include hypoglycemia unawareness, incontinence or neurogenic bladder, erectile dysfunction, resting tachycardia, pupillary dysfunction, orthostatic hypotension, and sudomotor dysfunction with either increased or decreased sweating. Gastrointestinal neuropathies can affect any portion of the GI tract and include esophageal dysmotility, gastroparesis, fecal incontinence, and diarrhea.[2]

Diagnosis

Causes for neuropathy other than diabetes should always be considered and include alcohol and other toxins, neurotoxic medications (chemotherapy), vitamin B12 deficiency, hypothyroidism, renal disease, malignancies (multiple myeloma, bronchogenic carcinoma), infections (HIV), chronic inflammatory demyelinating neuropathy, inherited neuropathies, and vasculitis.[2]

The presence of distal symmetric polyneuropathy can be assessed with simple clinical tests. Small fiber function should be assessed with pinprick and temperature sensation. Large fiber function can be assessed through vibration perception, 10 g monofilament, and ankle flexes. Protective sensation can be assessed with the use of a 10 g monofilament.[2] Electrophysiologic studies, such as nerve conduction tests, can confirm the diagnosis of neuropathy.

Helpful screening instruments for peripheral neuropathy include the Michigan Neuropathy Screening Instrument 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.

Treatment

Improving glycemic control helps prevent or delay neuropathy and can also improve neuropathic symptoms.[2],[15] Glycemic control depends first on diet and lifestyle changes. A recent meta-analysis showed that clinical neuropathy was not prevented with intensive medication use.[4]

The development of cardiovascular autonomic neuropathy can be prevented or slowed by optimizing lifestyle factors such as smoking, as well as by controlling cholesterol and blood pressure.[2]

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 examination that includes inspection and pulse checks should be performed annually.

Medications for painful symptoms also may help, but none affords complete relief. The FDA has approved 3 medications for diabetic peripheral neuropathy: pregabalin, duloxetine, and tapentadol.

Other treatments may also be considered. Examples include:

Tricyclic antidepressants, notably amitriptyline.

Venlafaxine.

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.[43]

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.

Nutritional Considerations

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.[44] 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.[45]

Evidence suggests that, in addition to the effect of plant-based diets on glycemic control, their effect on body weight, blood pressure, lipids, and blood rheology may be relevant to the treatment of neuropathy.[46],[47]

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 intravenous forms of alpha-lipoic acid significantly improve both nerve conduction velocity and neuropathic symptoms.[48] Oral forms appear to be effective as well, as shown in the Neurological Assessment of Thioctic Acid in Diabetic Neuropathy (NATHAN1) trial, a multicenter, randomized, double-blind, placebo-controlled study.[49] 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.[50]

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 facilitate regeneration of nerve fibers.[51] 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.[52],[53] Nevertheless, the ability of ALC to improve diabetic neuropathy is dependent on glycemic control.[54]

Vitamin B12 plays an important role in the treatment of 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.[55] Elderly diabetic patients may be at particular risk for peripheral neuropathy due to B12 deficiency.[56] Pharmacologic doses of B12 improve nerve conduction through the regeneration of peripheral nerves.[57],[58] Meta-analyses have concluded that IV 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.[59],[60]

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.[61],[62],[63],[64]

5. Complications Related to Pregnancy

Because of the insulin antagonist effect of pregnancy, some women develop diabetes only during pregnancy (gestational diabetes). Because of the increasing prevalence of weight problems, gestational diabetes (GDM) has been on the rise in the US. Gestational diabetes can result in macrosomia, which can increase complications of delivery, including shoulder dystocia and neonatal morbidity.[65],[66] Offspring of mothers with either gestational or pregestational diabetes are at higher risk for development of metabolic syndrome and overweight than those born to women without diabetes.[67],[68]

Women with diabetes should try to plan their pregnancies so that blood glucose can be well controlled prior to conception. Good glucose control, ideally HbA1C < 6.5% 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. Preconception counseling should be available to all women of childbearing age with preexisting diabetes or those who have had a history of gestational diabetes.

See the Diabetes chapter for more treatment information.

Nutritional Considerations

American Diabetes Association guidelines recommend that all women with gestational diabetes receive individualized nutritional counseling by a registered dietitian. Antenatal nutritional therapy in women with gestational diabetes reduces the risk of complications.[69]

Researchers followed almost 16,000 women from the Nurses’ Health Study II and found that those who followed a plant-based eating pattern and a lower intake of red and processed meat had lower prepregnancy body mass index and a lower risk of gestational diabetes.[70] A recent review of prospective studies 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.[71] 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.[72]

Restricting carbohydrates from plant-based foods may be detrimental to women with gestational diabetes. A study found that women who consumed > 211 g of carbohydrate per day had zero cases of large for gestational age (LGA) infants, while 23% of women who reduced carbohydrate intake (≤ 211 g of carbohydrate per day) had LGA infants.[73]

Orders

See Diabetes chapter.

What to Tell the Family

The best way to prevent diabetes complications is through a healthy diet and lifestyle and aggressive control of cardiovascular risk factors. Cessation of smoking is critical. 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 laboratory 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 childbearing age, family planning should be encouraged, and blood glucose levels should be controlled prior to conception. 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 lead to substantial morbidity and mortality and reduce quality of life, aggressive prevention and/or treatment is imperative.

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