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Diabetes Mellitus (DM)
Diabetes mellitus (DM) is impaired insulin secretion and variable degrees of peripheral insulin resistance leading to hyperglycemia. Early symptoms are related to hyperglycemia and include polydipsia, polyphagia, polyuria, and blurred vision. Later complications include vascular disease, peripheral neuropathy, nephropathy, 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. Complications can be delayed or prevented with adequate glycemic control; heart disease remains the leading cause of mortality in DM.
There are 2 main categories of diabetes mellitus—type 1 and type 2, which can be distinguished by a combination of features (see Table: 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.
Impaired glucose regulation (impaired glucose tolerance, or impaired fasting glucose—see Table: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation*) is an intermediate, possibly transitional, state between normal glucose metabolism and diabetes mellitus that becomes more common with aging. 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 are not very common (albuminuria and/or retinopathy develop in 6 to 10%).
Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small vessels (microvascular), large vessels (macrovascular), or both. (For additional detail, see Complications of Diabetes Mellitus.)
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. Patients with diabetes mellitus are particularly susceptible to bacterial and fungal infections.
In type 1 diabetes mellitus (previously called juvenile-onset or insulin-dependent), insulin production is absent because of autoimmune pancreatic beta-cell destruction possibly triggered by an environmental exposure in genetically susceptible people. Destruction progresses subclinically over months or years until beta-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 DM.
The pathogenesis of the autoimmune beta-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 diabetes mellitus—and those outside the MHC, which seem to regulate insulin production and processing and confer risk of diabetes mellitus in concert with MHC genes. Susceptibility genes are more common among some populations than among others and explain the higher prevalence of type 1 DM in some ethnic groups (Scandinavians, Sardinians).
Autoantigens include glutamic acid decarboxylase, insulin, proinsulin, insulinoma-associated protein, zinc transporter ZnT8, and other proteins in beta cells. It is thought that these proteins are exposed or released during normal beta-cell turnover or beta-cell injury (eg, due to infection), activating primarily a T cell‒mediated immune response resulting in beta-cell destruction (insulitis). Glucagon-secreting alpha cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of) beta-cell destruction.
Several viruses (including coxsackievirus, rubella virus, cytomegalovirus, Epstein-Barr virus, and retroviruses) have been linked to the onset of type 1 DM. Viruses may directly infect and destroy beta cells, or they may cause beta-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 beta 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.
In type 2 diabetes mellitus (previously called adult-onset or non– insulin-dependent), insulin secretion is inadequate because patients have developed resistance to insulin. Hepatic insulin resistance leads to an inability to suppress hepatic glucose production, and peripheral insulin resistance impairs peripheral glucose uptake. This combination gives rise to fasting and postprandial hyperglycemia. Often insulin levels are very high, especially early in the disease. Later in the course of the disease, insulin production may fall, further exacerbating hyperglycemia.
The disease generally develops in adults and becomes more common with increasing age; up to one third of adults > age 65 have impaired glucose tolerance. In older adults, plasma glucose levels reach higher levels after eating than in younger adults, especially after meals with high carbohydrate loads. Glucose levels also 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 among children as childhood obesity has become epidemic. 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. Although several genetic polymorphisms have been identified over the past several years, no single gene responsible for the most common forms of type 2 DM has 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 of it, evidence also exists for beta-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 beta cells, cause beta-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. An inability to suppress lipolysis in 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-alpha, 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 adverse prenatal environmental influences on glucose metabolism.
Miscellaneous causes of diabetes mellitus that account for a small proportion of cases include genetic defects affecting beta-cell function, insulin action, and mitochondrial DNA (eg, maturity-onset diabetes of youth); pancreatic diseases (eg, cystic fibrosis, pancreatitis, hemochromatosis, pancreatectomy); endocrinopathies (eg, Cushing syndrome, acromegaly); toxins (eg, the rodenticide pyriminyl [Vacor]); and drug-induced diabetes, most notably due to glucocorticoids, beta-blockers, protease inhibitors, and therapeutic doses of niacin. Pregnancy causes some insulin resistance in all women, but only a few develop gestational diabetes.
General Characteristics of Types 1 and 2 Diabetes Mellitus
The most common symptoms of diabetes mellitus are those of hyperglycemia. The mild hyperglycemia of early DM is often asymptomatic; therefore, diagnosis may be delayed for many years. More significant hyperglycemia causes glycosuria and thus an osmotic diuresis, 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). Some patients experience a long but transient phase of near-normal glucose levels after 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 during 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, hyperosmolar hyperglycemic state occurs initially, especially during a period of stress or when glucose metabolism is further impaired by drugs, such as corticosteroids.
Diabetes mellitus is indicated by typical symptoms and signs and confirmed by measurement of plasma glucose (1). Measurement after an 8- to 12-h fast (FPG) or 2 h after ingestion of a concentrated glucose solution (oral glucose tolerance testing [OGTT]) is best (see Table: 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 diabetes and for research purposes.
In practice, diabetes mellitus or impaired fasting glucose regulation is often diagnosed using random measures of plasma glucose or of 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 symptoms of diabetes.
HbA1c measurements reflect glucose levels over the preceding 3 mo. HbA1c measurements are now included in the diagnostic criteria for DM:
However, HbA1c values may be falsely high or low (see Diabetes Mellitus (DM) : Monitoring), and tests must be done in a certified clinical laboratory with an assay that is certified and standardized to a reference assay. Point-of-care HbA1c measurements should not be used for diagnostic purposes, although they can be used 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.
Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation*
Impaired Glucose Regulation
FPG (mg/dL [mmol/L])
<100 (< 5.6)
OGTT (mg/dL [mmol/L])
< 140 (<7.7)
≥200 (≥ 11.1)
*See also American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care 39: Supplement 1: S1–S119 , 2016.
FPG = fasting plasma glucose; HbA1c = glycosylated Hb; OGTT = oral glucose tolerance test, 2-h glucose level.
Screening for diabetes mellitus should be conducted for people at risk of the disease. Patients with DM are screened for complications.
People 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 diabetes include
Age ≥ 45
Overweight or obesity
Family history of diabetes mellitus
History of impaired glucose regulation
Gestational diabetes mellitus or delivery of a baby > 4.1 kg
History of hypertension
Dyslipidemia (HDL cholesterol < 35mg/dL or triglyceride level > 250mg/dL)
History of cardiovascular disease
Polycystic ovary syndrome
Black, Hispanic, Asian American, or American Indian ethnicity
People ≥ age 45 and all adults with additional risk factors described above should be screened for DM with an FPG level, HbA1c, or a 2-h value on a 75-g OGTT at least once every 3 yr as long as plasma glucose measurements are normal and at least annually if results reveal impaired fasting glucose levels (see Table: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation*).
All patients with type 1 diabetes mellitus should begin screening for diabetic complications 5 yr after diagnosis. For patients with type 2 DM, screening begins at diagnosis. Typical screening for complications includes
Foot examination should be done 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 Figure: 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 done by an ophthalmologist; the screening interval is typically annually for patients with any retinopathy to every 2 yr for those without retinopathy on a prior examination. If retinopathy shows progression, more frequent evaluation may be needed.
Spot or 24-h urine testing is indicated annually to detect albuminuria, and serum creatinine should be measured annually to assess renal function.
Many physicians consider baseline ECG important given the risk of heart disease. Lipid profile should be checked at least annually and more often when abnormalities are present. Blood pressure should be measured at every examination.
Diet and exercise
For type 1 DM, insulin
For type 2 DM, oral antihyperglycemics, injectable glucagon-like peptide-1 (GLP-1) receptor agonists, insulin, or a combination
To prevent complications, often renin-angiotensin-aldosterone system blockers (ACE inhibitors or angiotensin II receptor blockers), statins, and aspirin
Treatment of diabetes mellitus involves both lifestyle changes and drugs. Patients with type 1 diabetes require insulin. Some patients with type 2 diabetes may be able to avoid or cease drug treatment if they are able to maintain plasma glucose levels with diet and exercise alone. For detailed discussion, see Drug Treatment of Diabetes.
Treatment involves control of hyperglycemia to relieve symptoms and prevent complications while minimizing hypoglycemic episodes.
Goals for glycemic control are
Glucose levels are typically determined by home monitoring of capillary blood glucose (eg, from a fingerstick) 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, patients with dementia). Conversely, providers may recommend stricter HbA1c goals (< 6.5%) in select patients if these goals can be achieved without hypoglycemia. Potential candidates for tighter glycemic control include patients not being treated with drugs that induce hypoglycemia, those who have short duration of diabetes mellitus, those who have a long life expectancy, and who have no cardiovascular disease.
Key elements for all patients are patient education, dietary and exercise counseling, and monitoring of glucose control.
All patients with type 1 DM require insulin therapy.
Patients with type 2 DM and mildly elevated plasma glucose should be prescribed a trial of diet and exercise, followed by an oral antihyperglycemic drug if lifestyle changes are insufficient, additional oral drugs and/or GLP-1 receptor agonist as needed (combination therapy), and insulin when combination therapy is ineffective for meeting recommended goals. Metformin is usually the first oral drug used, although no evidence supports the use of a particular drug or class of drugs; the decision often involves consideration of adverse effects, convenience, and patient preference.
Patients with type 2 DM and more significant glucose elevations at diagnosis are typically prescribed lifestyle changes and one or more 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 hyperosmolar hyperglycemic state (HHS) or diabetic ketoacidosis (DKA). Patients with severe hyperglycemia (plasma glucose > 400 mg/dL [22.2 mmol/L]) may respond better to 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.
Education about causes of DM, diet, exercise, drugs, self-monitoring with fingerstick testing, and the symptoms and signs of hypoglycemia, hyperglycemia, and diabetic complications is crucial to optimizing care. Most patients with type 1 DM 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.
Adjusting diet to individual circumstances can help patients control fluctuations in their glucose level and, for patients with type 2 diabetes mellitus, lose weight.
In general, all patients with DM 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 and can be used for a short time, 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. For example, if a carbohydrate-to-insulin ratio (CIR) of 15 gram:1 unit is used, a patient will require 1 unit of rapid-acting insulin for each 15 g of carbohydrate in a meal. These ratios can vary significantly between patients, depending on their degree of insulin sensitivity and must be tailored to the patient. This approach requires detailed patient education and is most successful when guided by a dietitian experienced in working with patients with diabetes. Some experts have advised use of the glycemic index (a measure of the impact of an ingested carbohydrate-containing food on the blood glucose level) to delineate between rapid and slowly metabolized carbohydrates, although there is little evidence to support this approach.
Patients with type 2 DM should restrict calories, eat regularly, increase fiber intake, and limit intake of refined carbohydrates and saturated fats. Nutrition consultation should complement physician counseling; the patient and the person who prepares the patient’s meals should both be present.
Physical activity should increase incrementally to whatever level a patient can tolerate. Both aerobic exercise and resistance exercise have been shown to improve glycemic control in type 2 diabetes, and several studies have shown a combination of resistance and aerobic exercise to be superior to either alone.
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. Activity goals may need to be modified for patients with complications of diabetes such as neuropathy and retinopathy.
Weight loss drugs, including orlistat, lorcaserin, phentermine/topiramate, and naltrexone/bupropion may be useful in selected patients as part of a comprehensive weight loss program, although lorcaserin may be used only short-term. Orlistat, an intestinal lipase inhibitor, reduces dietary fat absorption; it reduces serum lipids and helps promote weight loss. Lorcaserin is a selective serotonin receptor agonist that causes satiety and thus reduces food intake. Phentermine/topiramate is a combination drug that reduces appetite through multiple mechanisms in the brain. Many of these drugs also have been shown to significantly decrease HbA1c.
Surgical treatment for obesity, such as gastric banding, sleeve gastrectomy, or gastric bypass, also leads to weight loss and improved glucose control (independent of weight loss) in patients who have diabetes mellitus and are unable to lose weight through other means.
Regular professional podiatric care, including trimming of toenails and calluses, is important for patients with sensory loss or circulatory impairment. Such patients should be advised to inspect their feet daily for cracks, fissures, calluses, corns, and ulcers. Feet should be washed daily in lukewarm water, using mild soap, and dried gently and thoroughly. A lubricant (eg, lanolin) should be applied to dry, scaly skin. Nonmedicated foot powders should be applied to moist feet. Toenails should be cut, preferably by a podiatrist, straight across and not too close to the skin. Adhesive plasters and tape, harsh chemicals, corn cures, water bottles, and electric pads should not be used on skin. Patients should change stockings daily and not wear constricting clothing (eg, garters, socks or stockings with tight elastic tops).
Shoes should fit well, be wide-toed without open heels or toes, and be changed frequently. Special shoes should be prescribed to reduce trauma if the foot is deformed (eg, previous toe amputation, hammer toe, bunion). Walking barefoot should be avoided.
Patients with neuropathic foot ulcers should avoid weight bearing until ulcers heal. If they cannot, they should wear appropriate orthotic protection. Because most patients with these ulcers have little or no macrovascular occlusive disease, debridement and antibiotics frequently result in good healing and may prevent major surgery. After the ulcer has healed, appropriate inserts or special shoes should be prescribed. In refractory cases, especially if osteomyelitis is present, surgical removal of the metatarsal head (the source of pressure) or amputation of the involved toe or transmetatarsal amputation may be required. A neuropathic joint can often be satisfactorily managed with orthopedic devices (eg, short leg braces, molded shoes, sponge-rubber arch supports, crutches, prostheses).
Diabetes mellitus control can be monitored by measuring blood levels of
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 dosing 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 blood 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.
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 most do not eliminate the need for daily fingerstick glucose testing, but they may be useful for selected patients (eg, those with hypoglycemia unawareness or nocturnal hypoglycemia).
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 1 (usually morning fasting) to ≥ 5 times/day, depending on the patient’s needs and abilities and the complexity of the treatment regimen. Most patients with type 1 DM benefit from testing at least 4 times/day.
HbA1C levels reflect glucose control over the preceding 3 mo and hence assess control between physician visits. HbA1C should be assessed quarterly in patients with type 1 DM and at least twice per year in patients with type 2 DM when plasma glucose appears stable and 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 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. In patients with chronic kidney disease stages 4 and 5, correlation between HbA1c and glycemic levels is poor and HbA1c can be falsely decreased in these populations.
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 patients with type 1 DM if they 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 [13.9 to 16.7 mmol/L]) during glucose self-monitoring.
Pancreas transplantation and transplantation of pancreatic islet cells are alternative means of insulin delivery; both techniques effectively transplant insulin-producing beta-cells into insulin-deficient (type 1) patients. Indications, tissue sources, procedures, and limitations of both procedures are discussed elsewhere.
The term brittle diabetes has been used to refer to patients who have dramatic, recurrent swings in glucose levels, often for no apparent reason. However, this concept has no biologic basis and should not be used. Labile plasma glucose levels are more likely to occur in patients with type 1 DM because endogenous insulin production is completely absent, and in some patients, counter-regulatory response to hypoglycemia is impaired. Other causes include occult infection, gastroparesis (which leads to erratic absorption of dietary carbohydrates), and endocrinopathies (eg, Addison disease).
Patients with chronic difficulty maintaining acceptable glucose levels should be evaluated for situational factors that affect glucose control. Such factors include inadequate patient education or understanding that leads to errors in insulin administration, inappropriate food choices, and psychosocial stress that expresses itself in erratic patterns of drug use and food intake.
The initial approach is to thoroughly review self-care techniques, including insulin preparation and injection and glucose testing. Increased frequency of self-testing may reveal previously unrecognized patterns and provides the patient with helpful feedback. A thorough dietary history, including timing of meals, should be taken to identify potential contributions to poor control. Underlying disorders should be ruled out by physical examination and appropriate laboratory tests. For some insulin-treated patients, changing to a more intensive regimen that allows for frequent dose adjustments (based on glucose testing) is helpful. In some cases, the frequency of hypoglycemic and hyperglycemic episodes diminishes over time even without specific treatment, suggesting life circumstances may contribute to causation.
Diabetes in children is discussed in more detail elsewhere.
Children with type 1 DM require physiologic insulin replacement as do adults, and similar treatment regimens, including insulin pumps, are used. However, the risk of hypoglycemia, because of unpredictable meal and activity patterns and limited ability to report hypoglycemic symptoms, may require modification of treatment goals. Most young children can be taught to actively participate in their own care, including glucose testing and insulin injections. School personnel and other caregivers must be informed about the disease and instructed about the detection and treatment of hypoglycemic episodes. Screening for microvascular complications can generally be deferred until after puberty.
Children with type 2 DM require the same attention to diet and weight control and recognition and management of dyslipidemia and hypertension as do adults. Most children with type 2 DM are obese, so lifestyle modification is the cornerstone of therapy. Children with mild hyperglycemia generally begin treatment with metformin unless they have ketosis, renal insufficiency, or another contraindication to metformin use. Dosage is 500 to 1000 mg bid. If response is insufficient, insulin may be added. Some pediatric specialists also consider using thiazolidinediones, sulfonylureas, GLP1 receptor agonists, and dipeptidyl peptidase-4 inhibitors as part of combination therapy.
Diabetes in adolescents is discussed in more detail elsewhere. Glucose control typically deteriorates as children with DM enter adolescence. Multiple factors contribute, including pubertal and insulin-induced weight gain; hormonal changes that decrease insulin sensitivity; psychosocial factors that lead to insulin nonadherence (eg, mood and anxiety disorders); family conflict, rebellion, and peer pressure; eating disorders that lead to insulin omission as a means of controlling weight; and experimentation with cigarette, alcohol, and substance use. For these reasons, some adolescents experience recurrent episodes of hyperglycemia and DKA requiring emergency department visits and hospitalization.
Treatment often involves intensive medical supervision combined with psychosocial interventions (eg, mentoring or support groups), individual or family therapy, and psychopharmacology when indicated. Patient education is important so that adolescents can safely enjoy the freedoms of early adulthood. Rather than judging personal choices and behaviors, providers must continually reinforce the need for careful glycemic control, especially frequent blood sugar monitoring and use of frequent, low-dose, fast-acting insulins as needed.
Diabetes mellitus can be a primary reason for hospitalization or can accompany other illnesses that require inpatient care. All diabetic patients with DKA, HHS, or prolonged or severe hypoglycemia should be hospitalized. Patients with hypoglycemia induced by sulfonylureas, poorly controlled hyperglycemia, or acute worsening of diabetic complications may benefit from brief hospitalization. Children and adolescents with new-onset diabetes may also benefit from hospitalization. Control may worsen on discharge when insulin regimens developed in controlled inpatient settings prove inadequate to the uncontrolled conditions outside the hospital.
When other illnesses mandate hospitalization, some patients can continue on their home diabetes treatment regimens. However, glucose control often proves difficult, and it is often neglected when other diseases are more acute. Restricted physical activity and acute illness worsen hyperglycemia in some patients, whereas dietary restrictions and symptoms that accompany illness (eg, nausea, vomiting, diarrhea, anorexia) precipitate hypoglycemia in others—especially when antihyperglycemic drug doses remain unchanged. In addition, it may be difficult to control glucose adequately in hospitalized patients because usual routines (eg, timing of meals, drugs, and procedures) are inflexibly timed relative to diabetes treatment regimens.
In the inpatient setting, oral antihyperglycemic drugs often need to be stopped. Metformin can cause lactic acidosis in patients with renal insufficiency and has to be stopped if contrast agents need to be given and is, therefore, withheld in all but the most stable hospitalized patients. Sulfonylureas can cause hypoglycemia and should also be stopped. Most patients can be appropriately treated with basal insulin without or with supplemental short-acting insulin. Dipeptidyl peptidase-4 inhibitors are relatively safe, even in patients with kidney disease, and they may also be used for postprandial glucose lowering. Sliding-scale insulin should not be the only intervention to correct hyperglycemia; it is reactive rather than proactive, and no data suggest it leads to outcomes equivalent to or better than other approaches. Longer-acting insulins should be adjusted to prevent hyperglycemia rather than just using short-acting insulins to correct it.
Inpatient hyperglycemia worsens short-term prognosis for many acute conditions, most notably stroke and acute myocardial infarction, and often prolongs hospital stay. Critical illness causes insulin resistance and hyperglycemia even in patients without known diabetes mellitus. Insulin infusion to maintain plasma glucose between 140 and 180 mg/dL (7.8 and 8.3 mmol/L) prevents adverse outcomes such as organ failure, may enhance recovery from stroke, and leads to improved survival in patients requiring prolonged (> 5 days) critical care. Previously, glucose target levels were lower; however, it appears that the less stringent targets as described above may be sufficient to prevent adverse outcomes, particularly in patients who do not have heart disease. Severely ill patients, especially those receiving glucocorticoids or pressors, may need very high doses of insulin (> 5 to 10 units/h) because of insulin resistance. Insulin infusion should also be considered for patients receiving TPN and for patients with type 1 DM who cannot ingest anything orally.
The physiologic stress of surgery can increase plasma glucose in patients with DM and induce DKA in those with type 1 DM. For shorter procedures, subcutaneous insulin can be used. In type 1 patients, one half to two thirds of the usual morning dose of intermediate-acting insulin or 70 to 80% of the dose of long-acting insulin (glargine or detemir) can be given the morning before surgery with an IV infusion of a 5% dextrose solution at a rate of 100 to 150 mL/h. During and after surgery, plasma glucose (and ketones if hyperglycemia suggests the need) should be measured at least every 2 h. Glucose infusion is continued, and regular or short-acting insulin is given sc q 4 to 6 h as needed to maintain the plasma glucose level between 100 and 200 mg/dL (5.55 and 11.01 mmol/L) until the patient can be switched to oral feedings and resume the usual insulin regimen. Additional doses of intermediate- or long-acting insulin should be given if there is a substantial delay (> 24 h) in resuming the usual regimen. This approach may also be used for insulin-treated patients with type 2 DM, but frequent measurement of ketones may be omitted.
Some physicians prefer to withhold sc or inhaled insulin on the day of surgery and to give insulin by IV infusion. For patients undergoing a long or major surgery, a continuous insulin infusion is preferable, especially since insulin requirements can increase with the stress of surgery. IV insulin infusion can be given at the same time as intravenous dextrose solution to maintain blood glucose. One approach is to combine glucose, insulin, and potassium in the same bag (GIK regimen), for example, by combining 10% dextrose with 10 mmol potassium, and 15 units of insulin in a 500-mL bag. The insulin doses are adjusted in 5-unit increments. This approach is not used at many institutions because of the frequent remixing and changing of bags needed to adjust to the patient's level of glycemia. A more common approach in the US is to infuse insulin and dextrose separately. Insulin can be infused at a rate of 1 to 2 U/h with 5% dextrose infusing at 75 to 150 mL/h. The insulin rate may need to be decreased for more insulin-sensitive type 1 diabetic patients and increased for more insulin-resistant type 2 diabetic patients. 10 % dextrose may also be used. It is important, especially in type 1 diabetes not to stop insulin infusion, to avoid development of DKA Insulin adsorption onto IV tubing can lead to inconsistent effects, which can be minimized by preflushing the IV tubing with insulin solution. Insulin infusion is continued through recovery, with insulin adjusted based on the plasma glucose levels obtained in the recovery room and at 1- to 2-h intervals thereafter.
Most patients with type 2 DM who are treated with oral antihyperglycemic drugs maintain acceptable glucose levels when fasting and may not require insulin in the perioperative period. Most oral drugs, including sulfonylureas and metformin, should be withheld on the day of surgery, and plasma glucose levels should be measured preoperatively and postoperatively and every 6 h while patients receive IV fluids. Oral drugs may be resumed when patients are able to eat, but metformin should be withheld until normal renal function is confirmed 48 h after surgery.
No treatments definitely prevent the onset or progression of type 1 diabetes mellitus. Azathioprine, corticosteroids, and cyclosporine induce remission of early type 1 DM in some patients, presumably through suppression of autoimmune beta-cell destruction. However, toxicity and the need for lifelong treatment limit their use. In a few patients, short-term treatment with anti-CD3 monoclonal antibodies reduces insulin requirements for at least the first year of recent-onset disease by suppressing autoimmune T-cell response.
Type 2 DM usually can be prevented with lifestyle modification. Weight loss of as little as 7% of baseline body weight, combined with moderate-intensity physical activity (eg, walking 30 min/day), may reduce the incidence of DM in high-risk people by > 50%. Metformin and acarbose have also been shown to reduce the risk of DM in patients with impaired glucose regulation. Thiazolidinediones may also be protective. However, further study is needed before thiazolidinediones can be recommended for routine preventive use.
Type 1 diabetes is caused by an absence of insulin due to autoimmune-mediated inflammation in pancreatic beta cells.
Type 2 diabetes is caused by hepatic insulin resistance (causing an inability to suppress hepatic glucose production), peripheral insulin resistance (which impairs peripheral glucose uptake) in combination with a beta-cell secretory defect.
Microvascular complications include nephropathy, neuropathy, and retinopathy.
Macrovascular complications involve atherosclerosis resulting in coronary artery disease, TIA/stroke, and peripheral arterial insufficiency.
Diagnose by elevated fasting plasma glucose level and/or elevated HbA1c, and/or 2-h value on OGTT.
Do regular screening for complications.
Treat with diet, exercise, and insulin, and/or oral antihyperglycemic drugs.
Often, give ACE inhibitors, statins, and aspirin to prevent complications.