Complications of Diabetes Mellitus

Diabetic retinopathy Diabetic Retinopathy Manifestations of diabetic retinopathy include microaneurysms, intraretinal hemorrhage, exudates, macular edema, macular ischemia, neovascularization, vitreous hemorrhage, and traction retinal... read more is a common cause of adult blindness in the US. It is characterized initially by retinal capillary microaneurysms (background retinopathy) and later by neovascularization (proliferative retinopathy) and macular edema. There are no early symptoms or signs, but focal blurring, vitreous or retinal detachment, and partial or total vision loss eventually develop; rate of progression is highly variable.

Screening and diagnosis are by retinal examination performed by an ophthalmologist, which should be done regularly (usually annually) in both type 1 and type 2 diabetes. Early detection and treatment are critical to preventing vision loss. Treatment for all patients includes intensive glycemic and blood pressure control. Panretinal laser photocoagulation is used for proliferative diabetic retinopathy and sometimes severe nonproliferative diabetic retinopathy. Vascular endothelial growth factor (VEGF) inhibitors such as aflibercept, bevacizumab, and ranibizumab are used for macular edema and can also be used for proliferative retinopathy, but this treatment requires frequent regular visits.

Diabetic nephropathy Diabetic Nephropathy Diabetic nephropathy is glomerular sclerosis and fibrosis caused by the metabolic and hemodynamic changes of diabetes mellitus. It manifests as slowly progressive albuminuria with worsening... read more is a leading cause of chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is long-standing, progressive deterioration of renal function. Symptoms develop slowly and in advanced stages include anorexia, nausea, vomiting, stomatitis, dysgeusia... read more in the US. It is characterized by thickening of the glomerular basement membrane, mesangial expansion, and glomerular sclerosis. These changes cause glomerular hypertension and progressive decline in glomerular filtration rate. Systemic hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome Overview of Nephrotic Syndrome Nephrotic syndrome is urinary excretion of > 3 g of protein/day due to a glomerular disorder plus edema and hypoalbuminemia. It is more common among children and has both primary and secondary... read more or renal failure develops.

Diagnosis is by detection of urinary albumin. Once diabetes is diagnosed (and annually thereafter), urinary albumin level should be monitored so that nephropathy can be detected early. Monitoring can be done by measuring the albumin:creatinine ratio on a spot urine specimen or total urinary albumin in a 24-hour collection. A ratio > 30 mg/g (> 3.4 mg/mmol) or an albumin excretion of 30 to 300 mg/day signifies moderately increased albuminuria (previously called microalbuminuria) and early diabetic nephropathy. An albumin excretion > 300 mg/day is considered severely increased albuminuria (previously called macroalbuminuria), or overt proteinuria, and signifies more advanced diabetic nephropathy. Typically a urine dipstick is positive only if the protein excretion exceeds 300 to 500 mg/day.

Treatment is rigorous glycemic control combined with blood pressure control. An angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) should be used at the earliest sign of albuminuria (albumin-to- creatinine ratio ≥ 30 mg/g), to prevent progression of renal disease because these drugs lower intraglomerular blood pressure and thus have renoprotective effects. However, these drugs have not been shown to be beneficial for primary prevention (ie, in patients who do not have albuminuria). Sodium-glucose cotransporter- 2 (SGLT-2) inhibitors also delay progression of renal disease in selected patients with diabetic nephropathy (estimated glomerular filtration rate [eGRF] < 25 to 30 mL/minute and urine albumin/creatinine ratio > 300 mg/g). Fineronone, a nonsteroidal mineralocorticoid receptor antagonist, was shown to decrease the risk of progression of diabetic kidney disease and cardiovascular events.

Diabetic neuropathy is the result of nerve ischemia due to microvascular disease, direct effects of hyperglycemia on neurons, and intracellular metabolic changes that impair nerve function. There are multiple types, including

Symmetric polyneuropathy is most common and affects the distal feet and hands (stocking-glove distribution); it manifests as paresthesias, dysesthesias, or a painless loss of sense of touch, vibration, proprioception, or temperature. In the lower extremities, these symptoms can lead to blunted perception of foot trauma due to ill-fitting shoes and abnormal weight bearing, which can in turn lead to foot ulceration and infection or to fractures, subluxation, and dislocation or destruction of normal foot architecture (Charcot arthropathy). Small-fiber neuropathy is characterized by pain, numbness, and loss of temperature sensation with preserved vibration and position sense. Patients are prone to foot ulceration and neuropathic joint degeneration and have a high incidence of autonomic neuropathy. Predominant large-fiber neuropathy is characterized by muscle weakness, loss of vibration and position sense, and lack of deep tendon reflexes. Atrophy of intrinsic muscles of the feet and foot drop can occur.

Autonomic neuropathy can cause orthostatic hypotension, exercise intolerance, resting tachycardia, dysphagia, nausea and vomiting (due to gastroparesis), constipation and/or diarrhea (including dumping syndrome), fecal incontinence, urinary retention and/or incontinence, erectile dysfunction and retrograde ejaculation, and decreased vaginal lubrication.

Radiculopathies most often affect the proximal lumbar (L2 through L4) nerve roots, causing pain, weakness, and atrophy of the lower extremities (diabetic amyotrophy), or the proximal thoracic (T4 through T12) nerve roots, causing abdominal pain (thoracic polyradiculopathy).

Cranial neuropathies cause diplopia, ptosis, and anisocoria when they affect the 3rd cranial nerve or motor palsies when they affect the 4th or 6th cranial nerve.

Mononeuropathies cause finger weakness and numbness (median nerve) or foot drop (peroneal nerve). Patients with diabetes are also prone to nerve compression disorders, such as carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome is compression of the median nerve as it passes through the carpal tunnel in the wrist. Symptoms include pain and paresthesias in the median nerve distribution. Diagnosis... read more . Mononeuropathies can occur in several places simultaneously (mononeuritis multiplex). All tend to affect older patients predominantly and usually abate spontaneously over months; however, nerve compression disorders do not.

Diagnosis of symmetric polyneuropathy is by detection of sensory deficits and diminished ankle reflexes. Loss of ability to detect the light touch of a nylon monofilament identifies patients at highest risk of foot ulceration (see figure Diabetic foot screening Diabetic foot screening ). Alternatively, a 128-Hz tuning fork can be used to assess vibratory sense on the dorsum of the first toe.

Electromyography and nerve conduction studies Electromyography (EMG) and Nerve Conduction Studies When determining whether weakness is due to a nerve, muscle, or neuromuscular junction disorder is clinically difficult, these studies can identify the affected nerves and muscles. In electromyography... read more may be needed to evaluate all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as radiculopathy not caused by diabetes and carpal tunnel syndrome.

Management of neuropathy involves a multidimensional approach including glycemic control, regular foot care, and management of pain. Strict glycemic control may lessen neuropathy. Treatments to relieve symptoms include topical capsaicin cream, tricyclic antidepressants (eg, amitriptyline), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine), and antiseizure drugs (eg, pregabalin, gabapentin). Patients with sensory loss should examine their feet daily to detect minor foot trauma and prevent it from progressing to limb-threatening infection.

Large-vessel atherosclerosis Atherosclerosis Atherosclerosis is characterized by patchy intimal plaques (atheromas) that encroach on the lumen of medium-sized and large arteries. The plaques contain lipids, inflammatory cells, smooth muscle... read more is a result of the hyperinsulinemia, dyslipidemias, and hyperglycemia characteristic of diabetes mellitus. Manifestations are

Diagnosis is made by history and physical examination. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and blood pressure, combined with smoking cessation Smoking Cessation Most smokers want to quit and have tried doing so with limited success. Effective interventions include cessation counseling and drug treatment, such as varenicline, bupropion, or a nicotine... read more , daily intake of aspirin (if indicated), and statins. A multifactorial approach that includes management of glycemic control, hypertension, and dyslipidemia may be effective in reducing the rate of cardiovascular events. In contrast with microvascular disease, intensive control of plasma glucose alone has been shown to reduce risk in type 1 diabetes but not in type 2. Certain diabetes drugs decrease the risk of major adverse cardiovascular events, including metformin and some SGLT2-inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists.

Diabetic cardiomyopathy Overview of Cardiomyopathies A cardiomyopathy is a primary disorder of the heart muscle. It is distinct from structural cardiac disorders such as coronary artery disease, valvular disorders, and congenital heart disorders... read more is thought to result from many factors, including epicardial atherosclerosis, hypertension Hypertension Hypertension is sustained elevation of resting systolic blood pressure (≥ 130 mm Hg), diastolic blood pressure (≥ 80 mm Hg), or both. Hypertension with no known cause (primary; formerly, essential... read more and left ventricular hypertrophy, microvascular disease, endothelial and autonomic dysfunction, obesity Obesity Obesity is excess body weight, defined as a body mass index (BMI) of ≥ 30 kg/m². Complications include cardiovascular disorders (particularly in people with excess abdominal fat)... read more , and metabolic disturbances. Patients develop heart failure Heart Failure (HF) Heart failure (HF) is a syndrome of ventricular dysfunction. Left ventricular (LV) failure causes shortness of breath and fatigue, and right ventricular (RV) failure causes peripheral and abdominal... read more due to impairment in left ventricular systolic and diastolic function and are more likely to develop heart failure after myocardial infarction.

Patients with poorly controlled diabetes mellitus are prone to bacterial and fungal infections because of adverse effects of hyperglycemia on granulocyte and T-cell function. In addition to an overall increase in risk for infectious diseases, individuals with diabetes have an increased susceptibility to mucocutaneous fungal infections (eg, oral and vaginal candidiasis) and bacterial foot infections (including osteomyelitis Osteomyelitis Osteomyelitis is inflammation and destruction of bone caused by bacteria, mycobacteria, or fungi. Common symptoms are localized bone pain and tenderness with constitutional symptoms (in acute... read more ), which are typically exacerbated by lower extremity vascular insufficiency and diabetic neuropathy. Hyperglycemia is a well-established risk factor for surgical site infections. People with diabetes have a higher risk for becoming severely ill, hospitalized, or dying from an infection with SARS-CoV-2 virus COVID-19 COVID-19 is an acute, sometimes severe, respiratory illness caused by the novel coronavirus SARS-CoV-2. Prevention is by vaccination and infection control precautions (eg, face masks, handwashing... read more .

Nonalcoholic fatty liver disease Nonalcoholic Fatty Liver Disease (NAFLD) Fatty liver is excessive accumulation of lipid in hepatocytes. Nonalcoholic fatty liver disease (NAFLD) includes simple fatty infiltration (a benign condition called fatty liver), whereas nonalcoholic... read more (NAFLD) is increasingly common and represents an important comorbidity of type 2 diabetes. Some studies show that over half of patients with type 2 diabetes have NAFLD. It can also occur in patients with metabolic syndrome Metabolic Syndrome Metabolic syndrome is characterized by a large waist circumference (due to excess abdominal fat), hypertension, abnormal fasting plasma glucose or insulin resistance, and dyslipidemia. Causes... read more , obesity Obesity Obesity is excess body weight, defined as a body mass index (BMI) of ≥ 30 kg/m². Complications include cardiovascular disorders (particularly in people with excess abdominal fat)... read more , and dyslipidemia Dyslipidemia Dyslipidemia is elevation of plasma cholesterol, triglycerides (TGs), or both, or a low high-density lipoprotein cholesterol level that contributes to the development of atherosclerosis... read more , in the absence of diabetes mellitus. NAFLD requires evidence of hepatic steatosis by imaging or histology and a lack of other causes of fat accumulation (such as alcohol consumption or drugs that cause fat accumulation). NAFLD includes nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). NAFL occurs when there is ≥ 5% hepatic steatosis but no evidence of hepatocellular injury. In contrast, NASH requires both hepatic steatosis (≥ 5%) and inflammation with hepatocyte injury. Fibrosis may also occur in NASH, and can lead to cirrhosis Cirrhosis Cirrhosis is a late stage of hepatic fibrosis that has resulted in widespread distortion of normal hepatic architecture. Cirrhosis is characterized by regenerative nodules surrounded by dense... read more . The pathogenesis of NAFLD is not well understood but is clearly related to insulin resistance leading to accumulation of triglycerides in the liver. The mainstays of treatment are diet, exercise, and weight loss. In patients with diabetes and evidence of NASH, pioglitazone or a GLP-1 receptor agonist such as liraglutide or semaglutide may also be beneficial.

Diabetic foot complications (skin changes, ulceration, infection, gangrene) are common and are attributable to vascular disease, neuropathy, and relative immunosuppression. These complications can lead to lower extremity amputations.

Certain musculoskeletal disorders are more common in patients with diabetes, including muscle infarction, carpal tunnel syndrome Carpal Tunnel Syndrome Carpal tunnel syndrome is compression of the median nerve as it passes through the carpal tunnel in the wrist. Symptoms include pain and paresthesias in the median nerve distribution. Diagnosis... read more , Dupuytren contracture Dupuytren Contracture Dupuytren contracture is progressive contracture of the palmar fascial bands, causing flexion deformities of the fingers. Treatment is with corticosteroid injection, surgery, or injections of... read more , adhesive capsulitis, and sclerodactyly Systemic Sclerosis Systemic sclerosis is a rare chronic disease of unknown cause characterized by diffuse fibrosis and vascular abnormalities in the skin, joints, and internal organs (especially the esophagus... read more .

Patients with diabetes may also develop

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