In patients with diabetes mellitus, years of poorly controlled hyperglycemia lead to multiple, primarily vascular, complications that affect small vessels (microvascular), large vessels (macrovascular), or both.
The mechanisms by which vascular disease develops include
Glycosylation of serum and tissue proteins with formation of advanced glycation end products
Activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction
Accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues
Hypertension and dyslipidemias that commonly accompany diabetes mellitus
Proinflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation
Microvascular disease underlies 3 common and devastating manifestations of diabetes mellitus:
Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected, particularly in the lower extremities. Intensive control of plasma glucose can prevent or delay many of these complications but may not reverse them once established.
Macrovascular disease involves atherosclerosis of large vessels, which can lead to
Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity. Diabetic patients are particularly susceptible to bacterial and fungal infections.
Diabetic retinopathy is the most 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, 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. More advanced retinopathy may require panretinal laser photocoagulation or more rarely vitrectomy. Vascular endothelial growth factor (VEGF) inhibitors are also used for macular edema and as adjunctive therapy for proliferative retinopathy.
Diabetic nephropathy is a leading cause of chronic kidney disease 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 may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome 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 to treat hypertension and, at the earliest sign of albuminuria, 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 recently have been found to delay progression of renal disease in patients with diabetic nephropathy.
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 joint). 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. 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). 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 may be needed for all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as nondiabetic radiculopathy 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 anticonvulsants (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.
Diabetic foot screening
Large-vessel atherosclerosis is a result of the hyperinsulinemia, dyslipidemias, and hyperglycemia characteristic of diabetes mellitus. Manifestations are
Diagnosis is made by history and physical examination; the role of screening tests, such as coronary calcium score, is evolving. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and blood pressure, combined with smoking cessation and daily intake of aspirin and ACE inhibitors. 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.
Diabetic cardiomyopathy is thought to result from many factors, including epicardial atherosclerosis, hypertension and left ventricular hypertrophy, microvascular disease, endothelial and autonomic dysfunction, obesity, and metabolic disturbances. Patients develop heart failure 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), which are typically exacerbated by lower extremity vascular insufficiency and diabetic neuropathy. Hyperglycemia is a well-established risk factor for surgical site infections.
Nonalcoholic fatty liver disease (NAFLD) is increasingly common and represents an important comorbidity of type 2 diabetes. Some studies show that over half of the type 2 diabetes population has NAFLD. It can also occur in patients with metabolic syndrome, obesity, and dyslipidemia, 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 without 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. 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 diabetic patients with evidence of NASH, pioglitazone may also be beneficial.
Diabetic foot complications (skin changes, ulceration, infection, gangrene) are common and are attributable to vascular disease, neuropathy, and relative immunosuppression.
Patients with diabetes may also develop
Ophthalmologic disease unrelated to diabetic retinopathy (eg, cataracts, glaucoma, corneal abrasions, optic neuropathy)
American Diabetes Association: Standards of Medical Care in Diabetes: provides comprehensive guidelines for clinicians
Davies MJ, D'Alessio DA, Fradkin J, et al: Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 41(12): 2669–2701, 2018.
Endocrine Society: Clinical Practice Guidelines: provides guidelines on evaluation and management of patients with diabetes as well as links to other information for clinicians
Powers MA, Bardsley J, Cypress M, et al: Diabetes Self-management Education and Support in Type 2 Diabetes: A Joint Position Statement of the American Diabetes Association, the American Association of Diabetes Educators, and the Academy of Nutrition and Dietetics. Diabetes Care 38(7):1372–1382, 2015.