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Complications of Diabetes Mellitus

By

Erika F. Brutsaert

, MD, New York Medical College

Last full review/revision Sep 2022| Content last modified Sep 2022
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In patients with diabetes mellitus Diabetes Mellitus (DM) Diabetes mellitus is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia... read more , 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

  • Superoxide production

  • 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

  • Arterial microthromboses

  • 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

Calculators for Managing Patients With Diabetes

Diabetic Retinopathy

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 Diabetic Retinopathy 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

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

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 Diabetic foot screening ). Alternatively, a 128-Hz tuning fork can be used to assess vibratory sense on the dorsum of the first toe.

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.

Diabetic foot screening

A 10-g monofilament esthesiometer is touched to specific sites on each foot and is pushed until it bends. This test provides a constant, reproducible pressure stimulus (usually a 10-g force), which can be used to monitor change in sensation over time. Both feet are tested, and presence (+) or absence () of sensation at each site is recorded.

Diabetic foot screening

Macrovascular Disease

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.

Cardiomyopathy

Infection

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 Osteomyelitis ), 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, infection control precautions (eg, face masks, handwashing... read more .

Nonalcoholic Fatty Liver Disease (NAFLD)

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 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 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.

Other Complications of Diabetes Mellitus

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.

Patients with diabetes may also develop

Other Complications of Diabetes Mellitus

More Information

The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.

  • American Diabetes Association: Standards of Medical Care in Diabetes: provides comprehensive guidelines for clinicians

  • Buse JB, Wexler DJ, Tsapas A, et al: 2019 Update to: 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 43(2):487–493, 2020. doi: 10.2337/dci19-0066

  • 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.

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