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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, polyphagia, and
polyuria. Later complications include vascular disease, peripheral
neuropathy, and predisposition to infection. Diagnosis is by measuring
plasma glucose. Treatment is diet, exercise, and drugs that reduce
glucose levels, including insulin and oral antihyperglycemic
drugs. Prognosis varies with degree of glucose control.
There are 2 main categories of diabetes mellitus (DM)—type 1 and type 2, which can be distinguished by a combination of features (see Table 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: General Characteristics of Types 1 and 2 Diabetes Mellitus ). Terms that describe the age of onset (juvenile or adult) or type of treatment (insulin- or non-insulin–dependent) are no longer accurate because of overlap in age groups and treatments between disease types.
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Table 1
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General Characteristics
of Types 1 and 2
Diabetes Mellitus
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Characteristic
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Type 1
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Type 2
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Age at onset
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Most commonly < 30 yr
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Most commonly > 30 yr
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Associated obesity
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No
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Very common
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Propensity to ketoacidosis requiring insulin treatment for control
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Yes
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No
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Plasma levels of endogenous insulin
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Extremely low to undetectable
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Variable; may be low, normal, or elevated depending on degree of insulin resistance and insulin secretory defect
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Twin concordance
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≤ 50%
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> 90%
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Associated with specific HLA-D antigens
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Yes
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No
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Islet cell antibodies at diagnosis
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Yes
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No
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Islet pathology
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Insulitis, selective loss of most β cells
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Smaller, normal-appearing islets; amyloid (amylin) deposition is common
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Prone to develop diabetic complications (retinopathy, nephropathy, neuropathy, atherosclerotic cardiovascular disease)
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Yes
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Yes
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Hyperglycemia responds to oral antihyperglycemic drugs
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No
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Yes, initially in many patients
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Impaired glucose regulation (impaired glucose tolerance, or impaired fasting glucose—see Table 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation) is an intermediate, possibly transitional, state between normal glucose metabolism and DM that becomes common with age. It is a significant risk factor for DM and may be present for many years before onset of DM. It is associated with an increased risk of cardiovascular disease, but typical diabetic microvascular complications generally do not develop.
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Table 2
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Diagnostic Criteria for
Diabetes Mellitus
and Impaired Glucose Regulation
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Test
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Normal
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Impaired Glucose Regulation
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Diabetes
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FPG
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< 100 (< 5.6)
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100–125 (5.6–6.9)
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≥ 126 (≥ 7.0)
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OGTT
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< 140 (< 7.7)
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140–199 (7.7–11.0)
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≥ 200 (≥ 11.1)
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FPG = fasting plasma glucose; OGTT = oral glucose tolerance test, 2 h glucose level.
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Note: All values refer to glucose levels in mg/dL [mmol/L].
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Type
1:
In Type 1 DM (previously called juvenile-onset or insulin-dependent), insulin production is absent because of autoimmune pancreatic β-cell destruction possibly triggered by an environmental exposure in genetically susceptible people. Destruction progresses subclinically over months or years until β-cell mass decreases to the point that insulin concentrations are no longer adequate to control plasma glucose levels. Type 1 DM generally develops in childhood or adolescence and until recently was the most common form diagnosed before age 30; however, it can also develop in adults (latent autoimmune diabetes of adulthood, which often initially appears to be type 2 DM). Some cases of type 1 DM, particularly in nonwhite populations, do not appear to be autoimmune in nature and are considered idiopathic. Type 1 accounts for < 10% of all cases of diabetes.
The pathogenesis of the autoimmune β-cell destruction involves incompletely understood interactions between susceptibility genes, autoantigens, and environmental factors. Susceptibility genes include those within the major histocompatibility complex (MHC)—especially HLA-DR3,DQB1*0201 and HLA-DR4,DQB1*0302, which are present in > 90% of patients with type 1 DM—and those outside the MHC, which seem to regulate insulin production and processing and confer risk for DM in concert with MHC genes. Susceptibility genes are more common in some populations than in others and explain the higher prevalence of type 1 DM in some ethnic groups (Scandinavians, Sardinians).
Autoantigens include glutamic acid decarboxylase, insulin, insulinoma-associated protein, and other proteins in β cells. It is thought that these proteins are exposed or released during normal β-cell turnover or β-cell injury (eg, from infection), activating a cell-mediated immune response resulting in β-cell destruction (insulitis). Glucagon-secreting α cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of) β-cell destruction.
Several viruses (including coxsackievirus, rubella, cytomegalovirus, Epstein-Barr, and retroviruses) have been linked to the onset of type 1 DM. Viruses may directly infect and destroy β cells, or they may cause β-cell destruction indirectly by exposing autoantigens, activating autoreactive lymphocytes, mimicking molecular sequences of autoantigens that stimulate an immune response (molecular mimicry), or other mechanisms.
Diet may also be a factor. Exposure of infants to dairy products (especially cow's milk and the milk protein β casein), high nitrates in drinking water, and low vitamin D consumption have been linked to increased risk of type 1 DM. Early (< 4 mo) or late (> 7 mo) exposure to gluten and cereals increases islet cell autoantibody production. Mechanisms for these associations are unclear.
Type
2:
In type 2 DM (previously called adult-onset or non-insulin–dependent), insulin secretion is inadequate. Often insulin levels are very high, especially early in the disease, but peripheral insulin resistance and increased hepatic production of glucose make insulin levels inadequate to normalize plasma glucose levels. Insulin production then falls, further exacerbating hyperglycemia. The disease generally develops in adults and becomes more common with age. Plasma glucose levels reach higher levels after eating in older than in younger adults, especially after high carbohydrate loads, and take longer to return to normal, in part because of increased accumulation of visceral and abdominal fat and decreased muscle mass.
Type 2 DM is becoming increasingly common in children as childhood obesity has become epidemic: 40 to 50% of new-onset DM in children is now type 2. Over 90% of adults with DM have type 2 disease. There are clear genetic determinants, as evidenced by the high prevalence of the disease within ethnic groups (especially American Indians, Hispanics, and Asians) and in relatives of people with the disease. No genes responsible for the most common forms of type 2 DM have been identified.
Pathogenesis is complex and incompletely understood. Hyperglycemia develops when insulin secretion can no longer compensate for insulin resistance. Although insulin resistance is characteristic in people with type 2 DM and those at risk for it, evidence also exists for β-cell dysfunction and impaired insulin secretion, including impaired first-phase insulin secretion in response to IV glucose infusion, a loss of normally pulsatile insulin secretion, an increase in proinsulin secretion signaling impaired insulin processing, and an accumulation of islet amyloid polypeptide (a protein normally secreted with insulin). Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize β cells, cause β-cell dysfunction (glucose toxicity), or both. These changes typically take years to develop in the presence of insulin resistance.
Obesity and weight gain are important determinants of insulin resistance in type 2 DM. They have some genetic determinants but also reflect diet, exercise, and lifestyle. Adipose tissue increases plasma levels of free fatty acids that may impair insulin-stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also appears to function as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely, (tumor necrosis factor-α, IL-6, leptin, resistin) influence glucose metabolism. Intrauterine growth restriction and low birth weight have also been associated with insulin resistance in later life and may reflect prenatal environmental influences on glucose metabolism.
Miscellaneous
types:
Miscellaneous causes of DM that account for a small proportion of cases include genetic defects affecting β-cell function, insulin action, and mitochondrial DNA (eg, maturity-onset diabetes of youth); pancreatic diseases (eg, cystic fibrosis, pancreatitis, hemochromatosis); endocrinopathies (eg, Cushing's syndrome, acromegaly); toxins (eg, the rodenticide pyriminyl [Vacor]); and drug-induced diabetes, most notably from glucocorticoids, β-blockers, protease inhibitors, and therapeutic doses of niacin . Pregnancy causes some insulin resistance in all women, but only a few develop gestational DM (see Pregnancy Complicated by Disease: Diabetes Mellitus in Pregnancy).
Symptoms and Signs
The most common symptoms of DM are those of hyperglycemia: an osmotic diuresis caused by glycosuria leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. Severe dehydration causes weakness, fatigue, and mental status changes. Symptoms may come and go as plasma glucose levels fluctuate. Polyphagia may accompany symptoms of hyperglycemia but is not typically a primary patient concern. Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections.
Patients with type 1 DM typically present with symptomatic hyperglycemia and sometimes with diabetic ketoacidosis (DKA—see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic Ketoacidosis (DKA)). Some patients experience a long but transient phase of near-normal glucose levels following acute onset of the disease (honeymoon phase) due to partial recovery of insulin secretion.
Patients with type 2 DM may present with symptomatic hyperglycemia but are often asymptomatic, and their condition is detected only on routine testing. In some patients, initial symptoms are those of diabetic complications, suggesting that the disease has been present for some time. In some patients, hyperosmotic coma occurs initially, especially during a period of stress or when glucose metabolism is further impaired by drugs, such as corticosteroids.
Complications
Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small (microvascular) large (macrovascular) vessels 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 DM; arterial microthromboses; and pro-inflammatory and prothrombotic effects of hyperglycemia and hyperinsulinemia that impair vascular autoregulation. Immune dysfunction is another major complication and develops from the direct effects of hyperglycemia on cellular immunity.
Microvascular disease underlies the 3 most common and devastating manifestations of DM: retinopathy, nephropathy, and neuropathy. Microvascular disease may also impair skin healing, so that even minor breaks in skin integrity can develop into deeper ulcers and easily become infected. Intensive control of plasma glucose can prevent many of these complications but may not reverse them once established.
Diabetic
retinopathy:
Diabetic retinopathy is the most common cause of adult blindness in the US (see also Retinal Disorders: Diabetic Retinopathy). It is characterized initially by retinal capillary microaneurysms and later by macular edema and neovascularization. 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. Diagnosis is by retinal examination. Treatment is argon laser photocoagulation or vitrectomy. Strict glycemic control and early detection and treatment are critical to preventing vision loss.
Diabetic
nephropathy:
Diabetic nephropathy (see also Glomerular Diseases: Diabetic Nephropathy) is a leading cause of chronic renal failure 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 GFR. Systemic hypertension may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome or renal failure develops. Diagnosis is by detection of urinary albumin. A urine dipstick positive for protein signifies albumin excretion > 300 mg/day and advanced diabetic nephropathy (or an improperly collected or stored specimen). If the dipstick is negative for protein, the albumin:creatinine ratio on a spot urine specimen or urinary albumin in a 24-h collection should be measured. A ratio > 30 mg/g or an albumin concentration 30 to 300 mg/24 h signifies microalbuminuria and early diabetic nephropathy. Treatment is rigorous glycemic control combined with BP control. An ACE inhibitor, an angiotensin II receptor blocker, or both should be used to treat hypertension at the earliest sign of microalbuminuria or even before, because these drugs lower intraglomerular BP and thus have renoprotective effects.
Diabetic
neuropathy:
Diabetic neuropathy is the result of nerve ischemia from microvascular disease, direct effects of hyperglycemia on neurons, and intracellular metabolic changes that impair nerve function. There are multiple types, including symmetric polyneuropathy (with small- and large-fiber variants) and autonomic neuropathy. 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 from 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's 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 are common.
Autonomic neuropathy can produce orthostatic hypotension, exercise intolerance, resting tachycardia, dysphagia, nausea and vomiting (due to gastroparesis), constipation and diarrhea (including dumping syndrome), fecal incontinence, urinary retention and incontinence, erectile dysfunction and retrograde ejaculation, and decreased vaginal lubrication.
Other forms of diabetic neuropathy include radiculopathies, cranial neuropathies, and mononeuropathies. Radiculopathies most often affect the proximal L2 through L4 nerve roots, causing pain, weakness, and atrophy of the lower extremities (diabetic amyotrophy), or the proximal 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). Diabetics 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 people predominantly and usually abate spontaneously over months.
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 Fig. 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic foot screening. ). 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. Strict glycemic control may lessen neuropathy. Treatments for relief of symptoms include topical capsaicin cream, tricyclic antidepressants (eg, imipramine ), SSRIs (eg, duloxetine ), anticonvulsants (eg, gabapentin , carbamazepine ), and mexiletine . Patients with sensory loss should examine their feet daily to detect minor foot trauma and prevent it from progressing to limb-threatening infection.
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Fig. 1
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Diabetic foot screening.
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A monofilament esthesiometer is touched to specific sites on each foot and is pushed until it bends. This test provides a constant, reproducible light-touch stimulus, 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.
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Macrovascular
disease:
Large-vessel atherosclerosis is a result of the hyperinsulinemia, dyslipidemias, and hyperglycemia characteristic of DM. Manifestations are angina pectoris and MI, transient ischemic attacks and strokes, and peripheral arterial disease.
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 MI. Diagnosis is by history and examination; the role of screening tests is evolving. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and BP, combined with smoking cessation and daily intake of aspirin and ACE inhibitors. In contrast with microvascular disease, intensive control of plasma glucose alone is not an effective preventive measure.
Infection:
Diabetics are prone to bacterial and fungal infections because of adverse effects of hyperglycemia on granulocyte and T-cell function. Most common are 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.
Other
complications:
Diabetic foot complications (skin changes, ulceration, infection, gangrene) are common and are attributable to vascular disease, neuropathy, and relative immunosuppression.
Diabetics have an increased risk of developing some rheumatologic diseases, including muscle infarction, carpal tunnel syndrome, Dupuytren's contracture, adhesive capsulitis, and sclerodactyly. They may also develop ophthalmologic disease unrelated to diabetic retinopathy (eg, cataracts, glaucoma, corneal abrasions, optic neuropathy); hepatobiliary diseases (eg, nonalcoholic fatty liver disease [steatosis and steatohepatitis], cirrhosis, gallstones); and dermatologic disease (eg, tinea infections, lower extremity ulcers, diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic scleroderma, vitiligo, granuloma annulare, acanthosis nigricans [a sign of insulin resistance]). Depression and dementia are also common.
Diagnosis
DM is indicated by typical symptoms and signs and confirmed by measurement of plasma glucose. Measurement after an 8- to 12-h fast (fasting plasma glucose [FPG]) or 2 h after ingestion of a concentrated glucose solution (oral glucose tolerance testing [OGTT]) is best (see Table 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation). OGTT is more sensitive for diagnosing DM and impaired glucose tolerance but is less convenient and reproducible than FPG. It is therefore rarely used routinely, except for diagnosing gestational DM (see Pregnancy Complicated by Disease: Diabetes Mellitus in Pregnancy) and for research purposes.
In practice, DM or impaired fasting glucose regulation is often diagnosed using random measures of plasma glucose or of glycosylated hemoglobin (HbA1c). A random glucose value > 200 mg/dL (> 11.1 mmol/L) may be diagnostic, but values can be affected by recent meals and must be confirmed by repeat testing; testing twice may not be necessary in the presence of diabetic symptoms. HbA1c measurements reflect glucose levels over the preceding 2 to 3 mo. Values > 6.5 mg/dL indicate abnormally high plasma glucose levels. However, assays and reference ranges are not yet standardized, and values may be falsely high or low (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Monitoring). For these reasons, HbA1c is not yet considered as reliable as FPG testing or OGTT for diagnosing DM and should be used mainly for monitoring DM control.
Urine glucose measurement, once commonly used, is no longer used for diagnosis or monitoring because it is neither sensitive nor specific.
Screening:
Screening for DM should be conducted for people at risk of the disease. Those with DM are screened for complications.
Those at high risk of type 1 DM (eg, siblings and children of people with type 1 DM) can be tested for the presence of islet cell or anti-glutamic acid decarboxylase antibodies, which precede onset of clinical disease. However, there are no proven preventive strategies for people at high risk, so such screening is usually reserved for research settings.
Risk factors for type 2 DM include age > 45; obesity; sedentary lifestyle; family history of DM; history of impaired glucose regulation; gestational DM or delivery of a baby > 4.1 kg; history of hypertension or dyslipidemia; polycystic ovary syndrome; and black, Hispanic, or American Indian ethnicity.
Risk of insulin resistance among overweight patients (body mass index ≥ 25 kg/m2) is increased with serum triglycerides ≥ 130 mg/dL (≥ 1.47 mmol/L); triglyceride/high density lipoprotein (HDL) ratio ≥ 3.0 (≥ 1.8); and insulin ≥ 108 pmol/L. People with these characteristics are at particularly high risk and should be screened for DM with a fasting plasma glucose level at least once q 3 yr as long as plasma glucose measurements are normal and at least annually if results reveal impaired fasting glucose levels (see Table 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation).
All patients with type 1 DM should begin screening for diabetic complications 5 yr after diagnosis. For patients with type 2 DM, screening begins at diagnosis. Patients should have their feet examined at least annually for impaired sense of pressure, vibration, pain, or temperature, which is characteristic of peripheral neuropathy. Pressure sense is best tested with a monofilament esthesiometer (see Fig. 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic foot screening.). The entire foot, and especially skin beneath the metatarsal heads, should be examined for skin cracking and signs of ischemia, such as ulcerations, gangrene, fungal nail infections, deceased pulses, and hair loss. Funduscopic examination should be performed by an ophthalmologist; the screening interval is controversial but ranges from annually for patients with established retinopathy to q 3 yr for those without retinopathy on at least one examination. Spot or 24-h urine testing is indicated annually to detect proteinuria or microalbuminuria, and serum creatinine should be measured to assess renal function. Many physicians consider baseline electrocardiography important given the risk of heart disease. Lipid profile should be checked at least annually and more often when abnormalities are present. BP should be measured at every examination.
Treatment
Treatment involves control of hyperglycemia to improve symptoms and prevent complications while minimizing hypoglycemic episodes. Goals for treatment are maintenance of plasma glucose between 80 and 120 mg/dL (4.4 and 6.7 mmol/L) during the day and between 100 and 140 mg/dL (5.6 and 7.8 mmol/L) at bedtime (as determined by home monitoring—see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Monitoring) and maintenance of HbA1c levels < 7%. These goals may be adjusted for patients in whom strict glucose control may be inadvisable, such as the frail elderly; patients with a short life expectancy; patients who experience repeated bouts of hypoglycemia, especially with hypoglycemic unawareness; and patients who cannot communicate the presence of hypoglycemia symptoms (eg, young children).
Key elements for all patients are patient education, dietary and exercise counseling, and monitoring of glucose control. All type 1 diabetics require insulin . Type 2 diabetics who have mildly elevated plasma glucose should be prescribed a trial of diet and exercise followed by a single oral antihyperglycemic drug if lifestyle changes are insufficient, additional oral drugs as needed (combination therapy), and insulin when ≥ 2 drugs are ineffective for meeting recommended goals. Type 2 diabetics who have more significant glucose elevations at diagnosis are typically prescribed lifestyle changes and oral antihyperglycemic drugs simultaneously. Insulin is indicated as initial therapy for women with type 2 DM who are pregnant and for patients who present with acute metabolic decompensation, such as nonketotic hyperosmolar syndrome (NKHS) or DKA. Patients with severe hyperglycemia (plasma glucose > 400 mg/dL) may respond better to oral therapy after glucose levels are normalized with a brief period of insulin treatment. Patients with impaired glucose regulation should receive counseling addressing their risk of developing DM and the importance of lifestyle changes for preventing DM. They should be monitored closely for development of DM symptoms or elevated plasma glucose. Ideal follow-up intervals have not been determined, but annual or biannual checks are probably appropriate.
Patient
education about causes of DM; diet; exercise; drugs; self-monitoring with finger-stick testing; and the symptoms and signs of hypoglycemia, hyperglycemia, and diabetic complications is crucial to optimizing care. Most type 1 diabetics can also be taught how to adjust their insulin doses. Education should be reinforced at every physician visit and hospitalization. Formal diabetes education programs, generally conducted by diabetes nurses and nutrition specialists, are often very effective.
Diet adjusted to individual circumstances can help patients control fluctuations in their glucose level and, for type 2 patients, lose weight. In general, all diabetics need to be educated about a diet that is low in saturated fat and cholesterol and contains moderate amounts of carbohydrate, preferably from whole grain sources with higher fiber content. Although dietary protein and fat contribute to caloric intake (and thus, weight gain or loss), only carbohydrates have a direct effect on blood glucose levels. A low-carbohydrate, high-fat diet improves glucose control for some patients, but its long-term safety is uncertain. Patients with type 1 DM should use carbohydrate counting or the carbohydrate exchange system to match insulin dose to carbohydrate intake and facilitate physiologic insulin replacement. “Counting” the amount of carbohydrate in the meal is used to calculate the preprandial insulin dose. In general, patients require 1 unit of rapid-acting insulin for each 15 g of carbohydrate in a meal. This approach requires detailed patient education and is most successful when guided by a dietician experienced in working with diabetics. Some experts advise use of the glycemic index to delineate between rapid and slowly metabolized carbohydrates, although others believe the index adds little. Patients with type 2 DM should restrict calories, eat regularly, increase fiber intake, and limit intake of refined carbohydrates and saturated fats. Some experts also recommend dietary protein restriction to ≤ 0.8 g/kg/day to prevent progression of early nephropathy (see Glomerular Diseases: Diabetic Nephropathy). Dietitian consultation should complement physician counseling; the patient and the person who prepares the patient's meals should both be present.
Exercise should involve an incremental increase in physical activity to whatever level a patient can tolerate. Some experts believe that aerobic exercise is better than isometric exercise for weight loss and protection from vascular disease, but resistance training also can improve glucose control, and all forms of exercise are beneficial. Patients who experience hypoglycemic symptoms during exercise should be advised to test their blood glucose and ingest carbohydrates or lower their insulin dose as needed to get their glucose slightly above normal just before exercise. Hypoglycemia during vigorous exercise may require carbohydrate ingestion during the workout period, typically 5 to 15 g of sucrose or another simple sugar. Patients with known or suspected cardiovascular disease may benefit from exercise stress testing before beginning an exercise program, while activity goals may need to be modified for patients with diabetic complications such as neuropathy and retinopathy.
Monitoring:
DM control can be monitored using plasma glucose, HbA1C, or fructosamine levels. Self-monitoring of whole blood glucose using fingertip blood, test strips, and a glucose meter is most important. It should be used to help patients adjust dietary intake and insulin and to help physicians recommend adjustments in the timing and doses of drugs. Many different monitoring devices are available. Nearly all require test strips and a means for pricking the skin and obtaining a sample. Most come with control solutions, which should be used periodically to verify proper meter calibration. Choice among devices is usually based on patient preferences for features such as time to results (usually 5 to 30 sec), size of display panel (large screens may benefit patients with poor eyesight), and need for calibration. Meters that allow for testing at sites less painful than fingertips (palm, forearm, upper arm, abdomen, thigh) are also available. Newer devices measure glucose transcutaneously, but their use has been limited by skin irritation and erratic readings. Continuous glucose monitoring systems using a subcutaneous catheter can provide real-time results, including an alarm to warn of hypoglycemia, hyperglycemia, or rapidly changing glucose levels. Such devices are expensive and do not eliminate the need for fingerstick glucose testing, but they may be useful for selected patients.
Patients with poor glucose control and those given a new drug or a new dose of a currently used drug may be asked to self-monitor once (usually morning fasting) to ≥ 5 times/day, depending on the patient's needs and abilities and the complexity of the treatment regimen. Most type 1 diabetics benefit from testing at least 4 times/day.
HbA1C levels reflect glucose control over the preceding 2 to 3 mo and hence assess control between physician visits. HbA1C should be assessed quarterly in type 1 patients and at least annually in type 2 patients whose plasma glucose appears stable (more frequently when control is uncertain). Home testing kits are useful for patients who are able to follow the testing instructions rigorously. Control suggested by HbA1c values sometimes appears to differ from that suggested by daily glucose readings because of falsely elevated or normal values. False elevations may occur with renal insufficiency (urea interferes with the assay), low RBC turnover (as occurs with iron, folate, or vitamin B12 deficiency anemia), high-dose aspirin , and high blood alcohol concentrations. Falsely normal values occur with increased RBC turnover, as occurs with hemolytic anemias and hemoglobinopathies (eg, HbS, HbC) or during treatment of deficiency anemias.
Fructosamine, which is mostly glycosylated albumin but also comprises other glycosylated proteins, reflects glucose control in the previous 1 to 2 wk. Fructosamine monitoring may be used during intensive treatment of DM and for patients with Hb variants or high RBC turnover (which cause false HbA1C results), but it is mainly used in research settings.
Urine glucose monitoring provides a crude indication of hyperglycemia and can be recommended only when blood glucose monitoring is impossible. By contrast, self-measurement of urine ketones is recommended for type 1 diabetics who experience symptoms, signs, or triggers of ketoacidosis, such as nausea or vomiting, abdominal pain, fever, cold or flu-like symptoms, or unusual sustained hyperglycemia (> 250 to 300 mg/dL) on glucose self-monitoring.
Insulin:
Insulin is required for all patients with type 1 DM who become ketoacidotic without it; it is also helpful for management of many patients with type 2 DM. Insulin replacement should ideally mimic β-cell function using 2 insulin types to provide basal and prandial requirements (physiologic replacement); this approach requires close attention to diet and exercise as well as to insulin timing and dose. Most insulin preparations are now recombinant human, practically eliminating the once-common allergic reactions to the drug when it was extracted from animal sources. Except for use of regular insulin IV in hospitalized patients, and the new inhaled form, insulin is administered subcutaneously. A number of analogs, created by modifications of the human insulin molecule that alter subcutaneous absorption rates, are available.
Insulin types are commonly categorized by their time to onset and duration of action (see Table 3: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Onset, Peak, and Duration of Action of Human Insulin Preparations*). However, these parameters vary within and between patients depending on many factors (eg, site and technique of injection, amount of subcutaneous fat, blood flow at the injection site).
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Table 3
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Onset, Peak, and Duration
of Action
of Human Insulin Preparations*
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Insulin Preparation
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Onset of Action
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Peak Action
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Duration of Action
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Rapid-acting
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Lispro, aspart, glulisine†
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5–15 min
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45–75 min
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3–5 h
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Short-acting
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30–60 min
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2–4 h
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6–8 h
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Intermediate-acting
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2–4 h
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6–10 h
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12–18 h
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3–4 h
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8–12 h
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12–18 h
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Long-acting
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4–8 h
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10–16 h
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16–20 h
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1–2 h
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No peak
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24 h
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1–2 h
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No peak
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14–24 h
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Premixed
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30–60 min
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Dual (NPH & R)
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10–16 h
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30–60 min
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Dual (NPH & R)
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10–16 h
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5–15 min
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Dual (NPL & lispro)
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10–16 h
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5–15 min
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Dual (NPA & aspart)
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10–16 h
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R = regular; NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro; NPA = neutral protamine.
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*Times are approximate, assume subcutaneous administration, and may vary with injection technique and factors influencing absorption.
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†Lispro and aspart are also available in premixed forms with intermediate-acting insulins.
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‡Also exists in premixed form (NPH/R).
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Rapid-acting insulins, including lispro and aspart, are rapidly absorbed because reversal of an amino acid pair prevents the insulin molecule from associating into dimers and polymers. They begin to reduce plasma glucose often within 15 min but have short duration of action (< 4 h). These insulins are best used at mealtime to control postprandial spikes in plasma glucose.
Regular insulin is slightly slower in onset (30 to 60 min) than lispro and aspart but lasts longer (6 to 8 h). It is the only form approved for IV use.
Neutral protamine Hagedorn (NPH, or insulin isophane) and lente ( insulin zinc) are intermediate-acting; they do not have significant effects on plasma glucose for up to several hours but remain active for 12 to 18 h. Ultralente (extended insulin human zinc) is the slowest onset insulin (up to 8 h) and has a duration of action of 18 to 24 h. Unlike ultralente, insulin glargine has no discernible peak of action and provides a steady basal effect over 24 h. Combinations of NPH and regular insulin and of insulin lispro and lispro protamine (a form of lispro modified to act like NPH) are commercially available in premixed preparations (see Table 3: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Onset, Peak, and Duration of Action of Human Insulin Preparations*).
Different insulin types can be drawn into the same syringe for injection but should not be premixed in bottles except by a manufacturer. On occasion, mixing insulins may affect rates of insulin absorption, producing variability of effect and making glycemic control less predictable, especially if mixed > 1 h before use. Insulin glargine should never be mixed with any other insulin.
Many prefilled insulin pen devices are available as an alternative to the conventional vial and syringe method. Insulin pens may be more convenient for use away from home and may be preferable for patients with limited vision or manual dexterity. Spring-loaded self-injection devices (for use with a syringe) may be useful for the occasional patient who is fearful of injection, and syringe magnifiers are available for patients with low vision.
Lispro, aspart, or regular insulin can also be given continuously using an insulin pump. Continuous subcutaneous insulin infusion pumps can eliminate the need for multiple daily injections, provide maximal flexibility in the timing of meals, and substantially reduce variability in glucose levels. Disadvantages include cost, mechanical failures leading to interruptions in insulin supply, and the inconvenience of wearing an external device. Frequent and meticulous self-monitoring and close attention to pump function are necessary for safe and effective use of the insulin pump.
Inhaled insulin has rapid onset and short duration of action like insulin lispro and is now available. It is designed for mealtime use, and many patients (including all type 1 diabetics) will still require injectable basal insulin. It cannot be used in smokers or in patients with pulmonary disease. Long-term safety is not known. Inhaled insulin may be an excellent option for the occasional patient with severe needle phobia.
Oligomeric or liposomal oral forms and transmucosal (eg, intranasal, oral spray) or transdermal delivery systems show promise but require further study.
Hypoglycemia is the most common complication of insulin treatment, occurring more often as patients try to achieve strict glucose control and approach near-normoglycemia. Symptoms of mild or moderate hypoglycemia include headache, diaphoresis, palpitations, light-headedness, blurred vision, agitation, and confusion. Symptoms of more severe hypoglycemia include seizures and loss of consciousness. In older patients, hypoglycemia may produce strokelike symptoms of aphasia or hemiparesis and is more likely to precipitate stroke, MI, and sudden death. Type 1 diabetics with long duration of disease may be unaware of hypoglycemic episodes because they no longer experience autonomic symptoms (hypoglycemia unawareness).
Patients should be taught to recognize symptoms of hypoglycemia, which usually respond rapidly to the ingestion of sugar, including candy, juice, and glucose tablets. Typically, 10 to 15 g of glucose or sucrose should be ingested. For patients who are unconscious or unable to swallow, hypoglycemia can be treated immediately with glucagon 1 mg sc or IM or a 50% dextrose solution 50 mL IV (25 g), followed, if necessary, by IV infusion of a 5 or 10% dextrose solution to maintain adequate plasma glucose levels.
Hyperglycemia may follow hypoglycemia either because too much sugar was ingested or because hypoglycemia caused a surge in counter-regulatory hormones (glucagon, epinephrine , cortisol, growth hormone). Too high a bedtime insulin dose can drive glucose down and stimulate a counter-regulatory response, leading to morning hyperglycemia (Somogyi phenomenon). A more common cause of unexplained morning hyperglycemia, however, is a rise in early morning growth hormone (dawn phenomenon). In this case, the evening insulin dose should be increased, changed to a longer-acting preparation, or injected later.
Hypokalemia may be caused by intracellular shifts of K from insulin-induced stimulation of the Na-K pump, but it is uncommon. Hypokalemia more commonly occurs in acute care settings where IV insulin is used.
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