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Diabetes Mellitus (DM)

by Preeti Kishore, MD

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 DM—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 DM 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 (microalbuminuria and/or retinopathy develop in 6 to 10%) .

Etiology

Type 1

  • Insulin production absent because of autoimmune pancreatic β-cell destruction

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 DM.

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 of DM 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 β cells. It is thought that these proteins are exposed or released during normal β-cell turnover or β-cell injury (eg, due to infection), activating primarily a T 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 virus, cytomegalovirus, Epstein-Barr virus, and retroviruses) have been linked to the onset of type 1 DM. Viruses may directly infect and destroy βcells, 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

  • Resistance to insulin

In type 2 DM (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: 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. 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 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. 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-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 adverse 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 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 Diabetes Mellitus in Pregnancy (Gestational Diabetes)).

General Characteristics of Types 1 and 2 Diabetes Mellitus

Characteristic

Type 1

Type 2

Age at onset

Most commonly <30 yr

Most commonly >30 yr

Associated obesity

Uncommon

Very common

Propensity to ketoacidosis requiring insulin treatment for control

Yes

No

Plasma levels of endogenous insulin

Extremely low to undetectable

Variable; may be low, normal, or elevated depending on degree of insulin resistance and insulin secretory defect

Twin concordance

50%

> 90%

Associated with specific HLA-D antigens

Yes

No

Pancreatic autoantibodies at diagnosis

Yes, but may be absent

No

Islet pathology

Insulitis, selective loss of most β cells

Smaller, normal-appearing islets; amyloid (amylin) deposition common

Prone to develop diabetic complications (retinopathy, nephropathy, neuropathy, atherosclerotic cardiovascular disease)

Yes

Yes

Hyperglycemia responds to oral antihyperglycemic drugs

No

Yes, initially in many patients

Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation

Test

Normal

Impaired Glucose Regulation

Diabetes

FPG (mg/dL [mmol/L])

<100 (< 5.6)

100–125 (5.6–6.9)

126 (7.0)

OGTT (mg/dL [mmol/L])

< 140 (<7.7)

140–199 (7.7–11.0)

200 ( 11.1)

HbA 1c (%)

< 5.7

5.7–6.4

≥ 6.5

FPG = fasting plasma glucose; HbA 1c = glycosylated Hb; OGTT = oral glucose tolerance test, 2-h glucose level.

Symptoms and Signs

The most common symptoms of DM 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—see 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, 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 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 DM; arterial microthromboses; and proinflammatory 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

  • 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, 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

  • Angina pectoris and MI

  • Transient ischemic attacks and strokes

  • Peripheral arterial disease

Diabetic retinopathy

Diabetic retinopathy is the most common cause of adult blindness in the US (see also Diabetic Retinopathy). 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 is by retinal examination, which should be done regularly (usually annually) in both type 1 and type 2 DM. Early detection and treatment are critical to preventing vision loss. Treatment for all patients includes intensive glycemic and BP control. More advanced proliferative retinopathy may require panretinal laser photocoagulation or more rarely vitrectomy. Vascular endothelial growth factor (VEGF) inhibitors are promising new drugs for macular edema and as adjunctive therapy for proliferative retinopathy.

Diabetic nephropathy

Diabetic nephropathy (see also Diabetic Nephropathy) is a leading cause of chronic kidney disease in the US. It is characterized by thickening of the glomerular basement membrane, mesangial expansion, and glomerular sclerosis. These changes cause glomerular hypertension and progressive decline in 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. Once diabetes is diagnosed (and annually thereafter), urinary microalbumin 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-h collection. A ratio > 30 mg/g or an albumin excretion 30 to 300 mg/24 h signifies microalbuminuria and early diabetic nephropathy. A urine dipstick positive for protein signifies albumin excretion > 300 mg/day and advanced diabetic nephropathy (or an improperly collected or stored specimen).

Treatment is rigorous glycemic control combined with BP control. An ACE inhibitor or an angiotensin II receptor blocker should be used to treat hypertension and, at the earliest sign of microalbuminuria, to prevent progression of renal disease because these drugs lower intraglomerular BP and thus have renoprotective effects. These drugs have not been shown to be beneficial for primary prevention (ie, in patients who do not have microalbuminuria).

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 (with small- and large-fiber variants)

  • Autonomic neuropathy

  • Radiculopathy

  • Cranial neuropathy

  • Mononeuropathy

Symmetric polyneuropathy is most common and affects the distal feet and hands (stocking-glove distribution); it manifests as paresthesias, dysesthesias, or a painless loss of sense of touch, vibration, proprioception, or temperature. In the lower extremities, these symptoms can lead to blunted perception of foot trauma due to ill-fitting shoes and abnormal weight bearing, which can in turn lead to foot ulceration and infection or to fractures, subluxation, and dislocation or destruction of normal foot architecture (Charcot joint).

Small-fiber neuropathy is characterized by pain, numbness, and loss of temperature sensation with preserved vibration and position sense. Patients are prone to foot ulceration and neuropathic joint degeneration and have a high incidence of autonomic neuropathy.

Predominant large-fiber neuropathy is characterized by muscle weakness, loss of vibration and position sense, and lack of deep tendon reflexes. Atrophy of intrinsic muscles of the feet and foot drop are common.

Autonomic neuropathy can cause 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.

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). Patients with DM are also prone to nerve compression disorders, such as carpal tunnel syndrome. Mononeuropathies can occur in several places simultaneously (mononeuritis multiplex). All tend to affect older patients predominantly and usually abate spontaneously over months; however, nerve compression disorders do not.

Diagnosis of symmetric polyneuropathy is by detection of sensory deficits and diminished ankle reflexes. Loss of ability to detect the light touch of a nylon monofilament identifies patients at highest risk of foot ulceration (see Figure: Diabetic foot screening.). Alternatively, a 128-Hz tuning fork can be used to assess vibratory sense on the dorsum of the first toe. Electromyography and nerve conduction studies may be needed for all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as nondiabetic radiculopathy and carpal tunnel syndrome.

Management of neuropathy involves a multidimensional approach including glycemic control, regular foot care, and management of pain. Strict glycemic control may lessen neuropathy. Treatments for relief of symptoms include topical capsaicin cream, tricyclic antidepressants (eg, imipramine), serotonin-norepinephrine reuptake inhibitors (eg, duloxetine), anticonvulsants (eg, pregabalin, 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.

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.

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

  • Peripheral arterial disease

Diagnosis is made by history and physical examination; the role of screening tests, such as coronary Ca score, 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. 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 but not in type 2 DM.

Cardiomyopathy

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.

Infection

Patients with poorly controlled DM 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.

Patients with DM have an increased risk of developing some rheumatologic diseases, including muscle infarction, carpal tunnel syndrome, Dupuytren 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 systemic sclerosis, vitiligo, granuloma annulare, acanthosis nigricans [a sign of insulin resistance]). Depression and dementia are also common.

Diagnosis

  • Fasting plasma glucose (FPG) levels

  • Glycosylated Hb (HbA 1c )

  • Sometimes oral glucose tolerance testing

DM is indicated by typical symptoms and signs and confirmed by measurement of plasma glucose. 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 DM (see Diabetes Mellitus in Pregnancy (Gestational Diabetes)) and for research purposes.

In practice, DM or impaired fasting glucose regulation is often diagnosed using random measures of plasma glucose or of HbA 1c . 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. HbA 1c measurements reflect glucose levels over the preceding 3 mo. HbA 1c measurements are now included in the diagnostic criteria for DM:

  • HbA 1c 6.5% = DM

  • HbA 1c 5.7 to 6.4% = prediabetes or at risk of DM

However, HbA 1c values may be falsely high or low (see 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 HbA 1c 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.

Pearls & Pitfalls

  • Point-of-care HbA 1c tests are not accurate enough to be used for initial diagnosis of diabetes.

Screening for disease

Screening for DM 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 DM include age > 45; overweight or 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, Asian American, or American Indian ethnicity.

Risk of insulin resistance among overweight people (body mass index 25 kg/m 2 ) 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 > age 45 and all adults with additional risk factors described above should be screened for DM with an FPG level, HbA 1c , 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).

Screening for complications

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. Typical screening for complications includes

  • Foot examination

  • Funduscopic examination

  • Urine testing for proteinuria and microalbuminuria

  • Measurement of serum creatinine and lipid profile

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 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 controversial but ranges from annually for patients with established retinopathy to every 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 ECG 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

  • Diet and exercise

  • For type 1 DM, insulin

  • For type 2 DM, oral antihyperglycemics, insulin , or both

  • Often ACE inhibitors, statins, and aspirin to prevent complications

Goals and methods

Treatment involves control of hyperglycemia to relieve symptoms and prevent complications while minimizing hypoglycemic episodes.

Goals for glycemic control are

  • Blood glucose between 80 and 120 mg/dL (4.4 and 6.7 mmol/L) during the day

  • Blood glucose between 100 and 140 mg/dL (5.6 and 7.8 mmol/L) at bedtime

  • HbA 1c levels <7%

Glucose levels are typically determined by home monitoring (see Monitoring) and maintenance of HbA 1c 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).

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 .

Patients with type 2 DM and 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. 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 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 [22,2 mmol/L]) 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

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.

Diet

Adjusting diet to individual circumstances can help patients control fluctuations in their glucose level and, for patients with type 2 DM, 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. 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 dietitian experienced in working with diabetic patients. Some experts advise use of the glycemic index to delineate between rapid and slowly metabolized carbohydrates, although others believe the index adds little value.

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 Diabetic Nephropathy). Nutrition consultation should complement physician counseling; the patient and the person who prepares the patient’s meals should both be present.

Exercise

Physical activity should increase incrementally to whatever level a patient can tolerate. Some experts believe that aerobic exercise is better than resistance 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 by measuring blood levels of

  • Glucose

  • HbA 1c

  • Fructosamine

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 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.

HbA 1C levels reflect glucose control over the preceding 3 mo and hence assess control between physician visits. HbA 1C 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 HbA 1c 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 B 12 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 HbA 1C 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.

Insulin

Insulin is required for all patients with type 1 DM if they 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, 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: Onset, Peak, and Duration of Action of Human Insulin Preparations*). However, these parameters vary within and among patients depending on many factors (eg, site and technique of injection, amount of subcutaneous fat, blood flow at the injection site).

Onset, Peak, and Duration of Action of Human Insulin Preparations*

Insulin Preparation

Onset of Action

Peak Action

Duration of Action

Rapid-acting

Lispro, aspart, glulisine

5–15 min

45–75 min

3–5 h

Short-acting

Regular

30–60 min

2–4 h

6–8 h

Intermediate-acting

NPH

About 2 h

4–12 h

18–26 h

Long-acting

Glargine

1–2 h

No peak

24 h

Detemir

1–2 h

No peak

14–24 h

Premixed

70% NPH/30% regular

30–60 min

Dual (NPH & R)

10–16 h

50% NPH/50% regular

30–60 min

Dual (NPH & R)

10–16 h

75% NPL/25% lispro

5–15 min

Dual (NPL & lispro)

10–16 h

70% NPA/30% aspart

5–15 min

Dual (NPA & aspart)

10–16 h

*Times are approximate, assume subcutaneous administration, and may vary with injection technique and factors influencing absorption.

Lispro and aspart are also available in premixed forms with intermediate-acting insulins.

NPH also exists in premixed form (NPH/regular).

NPA = neutral protamine; NPH = neutral protamine Hagedorn; NPL = neutral protamine lispro.

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 for IV use.

Neutral protamine Hagedorn (NPH, or insulin isophane) is intermediate-acting; onset of action is about 2 h after injection, peak effect is 4 to 12 h after injection, and duration of action is 18 to 26 h.

Long-acting insulins, insulin glargine and insulin detemir, unlike NPH, have no discernible peak of action and provide 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: 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.

Oligomeric or liposomal oral forms and transmucosal (eg, intranasal, oral spray) or transdermal delivery systems show promise but require further study.

Complications of insulin treatment

The most common complication is

  • Hypoglycemia

Uncommon complications include

  • Hypokalemia

  • Local allergic reactions

  • Generalized allergic reaction

  • Local fat atrophy or hypertrophy

  • Circulating anti- insulin antibodies

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 cause strokelike symptoms of aphasia or hemiparesis and is more likely to precipitate stroke, MI, and sudden death. Patients with type 1 DM of long duration 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, 15 g of glucose or sucrose should be ingested. Patients should check their glucose levels 15 min after glucose or sucrose ingestion and ingest an additional 15 g if their glucose level is not > 80 mg/dL (4.4 mmol/L). 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 due to insulin -induced stimulation of the Na-K pump, but it is uncommon. Hypokalemia more commonly occurs in acute care settings when body stores may be depleted and IV insulin is used.

Local allergic reactions at the site of insulin injections are rare, especially with the use of human insulins , but they may still occur in patients with latex allergy because of the natural rubber latex contained in vial stoppers. They can cause immediate pain or burning followed by erythema, pruritus, and induration—the latter sometimes persisting for days. Most reactions spontaneously disappear after weeks of continued injection and require no specific treatment, although antihistamines may provide symptomatic relief.

Generalized allergic reaction is extremely rare with human insulins but can occur when insulin is restarted after a lapse in treatment. Symptoms develop 30 min to 2 h after injection and include urticaria, angioedema, pruritus, bronchospasm, and anaphylaxis. Treatment with antihistamines often suffices, but epinephrine and IV glucocorticoids may be needed. If insulin treatment is needed after a generalized allergic reaction, skin testing with a panel of purified insulin preparations and desensitization should be done.

Local fat atrophy or hypertrophy at injection sites is relatively rare and is thought to result from an immune reaction to a component of the insulin preparation. Either may resolve by rotation of injection sites.

Circulating anti- insulin antibodies are a very rare cause of insulin resistance. This type of insulin resistance can sometimes be treated by changing insulin preparations (eg, from animal to human insulin ) and by administering corticosteroids if necessary.

Insulin regimens for type 1 DM

Regimens range from twice/day split-mixed (eg, split doses of rapid- and intermediate-acting insulins ) to more physiologic basal-bolus regimens using multiple daily injections (eg, single fixed [basal] dose of long-acting and variable prandial [bolus] doses of rapid-acting insulin) or an insulin pump. Intensive treatment, defined as glucose monitoring 4 times/day and 3 injections/day or continuous insulin infusion, is more effective than conventional treatment (1 to 2 insulin injections daily with or without monitoring) for preventing diabetic retinopathy, nephropathy, and neuropathy. However, intensive therapy may result in more frequent episodes of hypoglycemia and weight gain and is generally effective only in patients who are able and willing to take an active role in their self-care.

In general, most patients with type 1 DM can start with a total dose of 0.2 to 0.8 units of insulin /kg/day. Obese patients may require higher doses. Physiologic replacement involves giving 40 to 60% of the daily insulin dose as an intermediate- or long-acting preparation to cover basal needs, with the remainder given as a rapid- or short-acting preparation to cover postprandial increases. This approach is most effective when the dose of rapid- or short-acting insulin is determined by a sliding scale that takes into account preprandial blood glucose and anticipated meal content. Dose can be adjusted 1 to 2 units for each 50 mg/dL (2.8 mmol/L) above or below target glucose level. This physiologic regimen allows greater freedom of lifestyle because patients can skip or time-shift meals and maintain normoglycemia. However, no specific insulin regimen has proved more effective than others, and these recommendations are for initiation of therapy; thereafter, choice of regimens generally rests on physiologic response and patient and physician preferences.

Insulin regimens for type 2 DM

Regimens for type 2 DM also vary. In many patients, glucose levels are adequately controlled with lifestyle changes or oral drugs, but insulin should be added when glucose remains inadequately controlled by 2 oral drugs. Although uncommon, adult-onset type 1 DM may be the cause. Insulin should replace oral drugs in women who become pregnant. The rationale for combination therapy is strongest for use of insulin with oral biguanides and insulin sensitizers. Regimens vary from a single daily injection of long- or intermediate-acting insulin (usually at bedtime) to the multiple-injection regimen used by patients with type 1 DM. In general, the simplest effective regimen is preferred. Because of insulin resistance, some patients with type 2 DM require very large doses (> 2 units/kg/day). A common complication is weight gain, which is mostly attributable to reduction in loss of glucose in urine and improved metabolic efficiency.

Oral antihyperglycemic drugs

Oral antihyperglycemic drugs (see Table: Characteristics of Oral Antihyperglycemics and see Table: Combination Oral Antihyperglycemics by Class) are the primary treatment for type 2 DM, although insulin is often added when 2 oral drugs fail to provide adequate glycemic control. Oral antihyperglycemic drugs may

  • Enhance pancreatic insulin secretion (secretagogues)

  • Sensitize peripheral tissues to insulin (sensitizers)

  • Impair GI absorption of glucose

Drugs with different mechanisms of action may be synergistic.

Characteristics of Oral Antihyperglycemics

Generic Name

Daily Dosage

Duration of Action

Comments

Insulin secretagogues: Sulfonylureas

Augment pancreatic β-cell insulin secretion

Can be used alone or in combination with other oral drugs and insulin

Major adverse effects: Hypoglycemia, possibly weight gain

Acetohexamide*

250 mg once/day–750 mg bid

12–24 h

Chlorpropamide*

100 mg once/day–750 mg once/day

24–36 h

Chlorpropamide: May cause hyponatremia and flushing after alcohol ingestion

Tolbutamide*

250 mg once/day–1500 mg bid

12 h

Tolazamide*

100 mg once/day–500 mg bid

14–16 h

Glyburide, regular-release

1.25 mg once/day–10 mg bid

12–24 h

Glipizide and glyburide: No evidence of increased effectiveness of doses above 10 mg/day

Glyburide, micronized

0.75 mg once/day–6 mg bid

12–24 h

Glipizide, regular-release

2.5 mg once/day–20 mg bid

12–24 h

Glipizide, extended-release

2.5–20 mg once/day

24 h

Glimepiride

1–8 mg once/day

24 h

Insulin secretagogues: Short-acting

Augment pancreatic β-cell insulin secretion

Can be used alone or in combination with other oral drugs and insulin

Nateglinide

60–120 mg tid with meals

3–4 h

Repaglinide

0.5–4 mg tid with meals

3–4 h

Insulin sensitizers: Biguanides

Augment suppression of hepatic glucose production by insulin

Can be used alone or in combination with other oral drugs and insulin

Major adverse effects: Lactic acidosis (rare)

Contraindicated in at-risk patients, including those with renal insufficiency, heart failure, metabolic acidosis, hypoxia, alcoholism, or dehydration

Does not cause hypoglycemia

Other adverse effects: GI distress (diarrhea, nausea, pain), vitamin B 12 malabsorption

Potentiates weight loss

Metformin, regular-release

500 mg once/day–1250 mg bid

6–10 h

Metformin, extended-release

500 mg–2 g once/day

24 h

Insulin sensitizers: Thiazolidinediones

Augment suppression of hepatic glucose production by insulin

Can be used alone or in combination with other oral drugs and insulin

Major adverse effects: Weight gain, fluid retention, anemia (mild)

Hepatotoxicity rare, but liver function monitoring required

Pioglitazone

15–45 mg once/day

24 h

Pioglitazone: May increase risk of bladder cancer, heart failure, and fractures

Rosiglitazone

2–8 mg once/day

24 h

Rosiglitazone: May increase low-density lipoprotein cholesterol and may increase risk of heart failure, angina, MI, stroke, and fractures

α-Glucosidase inhibitors

Intestinal enzyme inhibitors

Used as monotherapy or combination therapy with other oral drugs or insulin to decrease postprandial plasma glucose levels

Must be taken with the first bite of meal

GI adverse effects (flatulence, diarrhea, bloating) common but may decrease over time

Started with small dose (25 mg/day) and gradually titrated over several weeks

Acarbose

25–100 mg tid with meals

6–10 h

Miglitol

25–100 mg tid with meals

6–10 h

Dipeptidyl peptidase-4 (DPP4) inhibitors

Saxagliptin

2.5–5 mg once/day

24 h

Dosage reduced (2.5 mg) for patients with moderate to severe renal insufficiency

Sitagliptin

100 mg once/day

24 h

Low risk of hypoglycemia; weight-neutral

Used as monotherapy or combination therapy with metformin or a thiazolidinedione

Dosage reduced (25–50 mg/day) for patients with renal insufficiency

Linagliptin

5 mg once/day

24 h

No dosage adjustment required for renal or hepatic insufficiency

Sodium-glucose co-transporter 2 (SGLT2) inhibitors

Canagliflozin

100 or 300 mg once/ day

24 h

May cause weight loss, orthostatic hypotension, yeast infections, and UTIs

Use higher dose only with normal renal function

Dapagliflozin

5–10 mg once/day

24 h

May cause weight loss, hypotension, hypovolemia yeast infections, and UTIs

Use cautiously in the elderly and in patients with renal impairment

*1st-generation sulfonylureas.

2nd-generation sulfonylureas.

Combination Oral Antihyperglycemics by Class

Drugs

Available Strengths (mg/mg)

Sulfonylurea/biguanide

Glipizide/metformin

2.5/250, 2.5/500, 5/500

Glyburide/metformin

1.25/250, 2.5/500, 5/500

Thiazolidinedione/biguanide

Pioglitazone/metformin

15/500, 15/850

Rosiglitazone/metformin

1/500, 2/500, 4/500, 2/1000, 4/1000

Thiazolidinedione/sulfonylurea

Pioglitazone/glimepiride

30/2, 30/4

Rosiglitazone/glimepiride

4/1, 4/2, 4/4

Dipeptidyl peptidase-4 inhibitor/biguanide

Linagliptin/metformin

2.5/500.2.5/850, 2.5/1000

Saxagliptin/metformin, extended-release

5/1000, 5/500, 2.5/1000

Sitagliptin/metformin

50/500, 50/1000

Sulfonylureas (SUs) are insulin secretagogues. They lower plasma glucose by stimulating pancreatic β-cell insulin secretion and may secondarily improve peripheral and hepatic insulin sensitivity by reducing glucose toxicity. First-generation drugs (see Table: Characteristics of Oral Antihyperglycemics) are more likely to cause adverse effects and are used infrequently. All SUs promote hyperinsulinemia and weight gain of 2 to 5 kg, which over time may potentiate insulin resistance and limit their usefulness. All also can cause hypoglycemia. Risk factors include age > 65, use of long-acting drugs (especially chlorpropamide, glyburide, or glipizide), erratic eating and exercise, and renal or hepatic insufficiency. Hypoglycemia caused by long-acting drugs may last for days after treatment cessation, occasionally causes permanent neurologic disability, and can be fatal. For these reasons, some physicians hospitalize hypoglycemic patients, especially older ones. Chlorpropamide also causes the syndrome of inappropriate ADH secretion. Most patients taking SUs alone eventually require additional drugs to achieve normoglycemia, suggesting that SUs may exhaust β-cell function. However, worsening of insulin secretion and insulin resistance is probably more a feature of DM itself than of drugs used to treat it.

Short-acting insulin secretagogues (repaglinide, nateglinide) stimulate insulin secretion in a manner similar to SUs. They are faster acting, however, and may stimulate insulin secretion more during meals than at other times. Thus, they may be especially effective for reducing postprandial hyperglycemia and appear to have lower risk of hypoglycemia. There may be some weight gain, although apparently less than with SUs. Repaglinide appears to be as effective as SUs or metformin in lowering glucose levels. Nateglinide may be somewhat less effective and therefore more appropriate for patients with mild hyperglycemia. Patients who have not responded to other oral drug classes (eg, SUs, metformin) are not likely to respond to these drugs.

Biguanides lower plasma glucose by decreasing hepatic glucose production (gluconeogenesis and glycogenolysis). They are considered peripheral insulin sensitizers, but their stimulation of peripheral glucose uptake may simply be a result of reductions in glucose from their hepatic effects. Biguanides also lower lipid levels and may also decrease GI nutrient absorption, increase β-cell sensitivity to circulating glucose, and decrease levels of plasminogen activator inhibitor 1, thereby exerting an antithrombotic effect. Metformin is the only biguanide commercially available in the US. It is at least as effective as SUs in reducing plasma glucose, rarely causes hypoglycemia, and can be safely used with other drugs and insulin . In addition, metformin does not cause weight gain and may even promote weight loss by suppressing appetite. However, the drug commonly causes GI adverse effects (eg, dyspepsia, diarrhea), which for most people recede with time. Less commonly, metformin causes vitamin B 12 malabsorption, but clinically significant anemia is rare. Contribution of metformin to life-threatening lactic acidosis is controversial, but the drug is thought to be contraindicated in patients at risk of acidemia (including those with renal insufficiency [creatinine 1.4 mg/dL], heart failure, hypoxia or severe respiratory disease, alcoholism, other forms of metabolic acidosis, or dehydration). The drug should be withheld during surgery, administration of IV contrast, and any serious illness. Many people receiving metformin monotherapy eventually require an additional drug.

Thiazolidinediones (TZDs) decrease peripheral insulin resistance ( insulin sensitizers), but their specific mechanisms of action are not well understood. The drugs bind a nuclear receptor primarily present in fat cells (peroxisome-proliferator-activated receptor-γ [PPAR-γ]) that is involved in the transcription of genes that regulate glucose and lipid metabolism. TZDs also increase HDL levels, lower triglycerides, and may have anti-inflammatory and anti-atherosclerotic effects. TZDs are as effective as SUs and metformin in reducing HbA 1c . Because the drug class is relatively new, data on long-term safety and effectiveness are not available. Though one TZD (troglitazone) caused acute liver failure, currently available drugs have not proven hepatotoxic. Nevertheless, periodic monitoring of liver function is recommended. TZDs may cause peripheral edema, especially in patients taking insulin , and may worsen heart failure in susceptible patients. Weight gain, due to fluid retention and increased adipose tissue mass, is common and may be substantial (> 10 kg) in some patients. Rosiglitazone may increase risk of heart failure, angina, MI, stroke, and fracture. Pioglitazone may increase the risk of bladder cancer, heart failure, and fractures.

α-Glucosidase inhibitors (AGIs) competitively inhibit intestinal enzymes that hydrolyze dietary carbohydrates; carbohydrates are digested and absorbed more slowly, thereby lowering postprandial plasma glucose. AGIs are less effective than other oral drugs in reducing plasma glucose, and patients often stop the drugs because they may cause dyspepsia, flatulence, and diarrhea. But the drugs are otherwise safe and can be used in combination with all other oral drugs and with insulin .

Dipeptidyl peptidase-4 inhibitors (eg, sitagliptin, saxagliptin, linagliptin) prolong the action of endogenous glucagon-like peptide-1 (GLP-1) by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4), which is involved in the breakdown of GLP-1.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors (canagliflozin and dapagliflozin) inhibit SGLT2 in the proximal tubule of the kidney, which blocks glucose reabsorption thus causing glycosuria, and lowering plasma glucose. They may also cause modest weight loss.

Bromocriptine is a dopamine agonist that lowers HbA 1c about 0.5% by an unknown mechanism. Although approved for type 2 DM, it is not commonly used because of potential adverse effects.

Injectable antihyperglycemic drugs

Injectable antihyperglycemic drugs other than insulin are the GLP-1 agonists and the amylin analog, pramlintide (see Table: Characteristics of Injectable Non-Insulin Antihyperglycemic Drugs). These drugs are used in combination with other antihyperglycemics.

GLP-1 agonists (eg, exenatide [an incretin hormone], liraglutide) enhance glucose-dependent insulin secretion and slow gastric emptying. Exenatide may also reduce appetite and promote weight loss and stimulate β-cell proliferation. It is given by injection 5 or 10 μg bid before meals and may be used in combination with oral antihyperglycemics. Other GLP-1 agonists include liraglutide given once/day and a long-acting form of exenatide given once/wk.

The amylin analog pramlintide mimics amylin, a pancreatic β-cell hormone that helps regulate postprandial glucose levels. Pramlintide suppresses postprandial glucagon secretion, slows gastric emptying, and promotes satiety. It is given by injection and is used in combination with mealtime insulin . Patients with type 1 DM are given 30 to 60 mcg sc before meals, and those with type 2 DM are given 120 mcg.

Characteristics of Injectable Non-Insulin Antihyperglycemic Drugs

Generic Name

Daily Dosage

Duration of Action

Comments

Glucagon-like peptide-1 (GLP-1) agonists

Exenatide

5 mcg or 10 mcg sc bid before meals

4–6 h

Low risk of hypoglycemia; may promote modest weight loss

Used in combination with a sulfonylurea, metformin, or both

Started with 5-mcg dose to minimize nausea, which is the most common adverse effect

Increased risk of pancreatitis

Exenatide, once/wk

2 mg sc once/wk

7 days

Less nausea reported than with twice/day regimen

Risk of pancreatitis Thyroid C-cell tumors ( medullary carcinoma) noted in rodents

Long-term safety unknown

Liraglutide

1.2–1.8 mg sc once/day

24 h

Increased risk of pancreatitis

Thyroid C-cell tumors (medullary carcinoma) noted in rodents

Amylin analog

Pramlintide

For type 1 diabetes mellitus: 30–60 mcg sc before meals

For type 2 diabetes mellitus: 120 mcg sc before meals

2–4 h

For use in combination with insulin , but injected using a separate syringe

May need to adjust insulin dose to avoid hypoglycemia

Nausea common but declining with time

May promote modest weight loss

Other antihyperglycemic treatments

Transplantation of pancreatic or islet cells is an alternative means of insulin delivery; both techniques effectively transplant insulin -producing β-cells into insulin -deficient (type 1) patients. Indications, tissue sources, procedures, and limitations of both procedures are discussed elsewhere (see Pancreas Transplantation).

Other oral antihyperglycemic drugs are under investigation. These drugs include PPAR-α and PPAR-γ agonists (ragaglitazar, tesaglitazar), non-TZD insulin sensitizers, including recombinant human insulin -like growth factor-1 (IGF-1); and phosphodiesterase inhibitors, which augment pancreatic insulin secretion.

Adjunctive treatments

Measures to prevent or treat complications of DM are critical, including

  • ACE inhibitors or angiotensin II receptor blockers

  • Statins

  • Weight loss measures

  • Foot care

  • Vaccinations

ACE inhibitors or angiotensin II receptor blockers are indicated for patients with evidence of early nephropathy (microalbuminuria or proteinuria), even in the absence of hypertension, and are a good choice for treating hypertension in patients who have DM and who have not yet shown renal impairment.

ACE inhibitors also help prevent cardiovascular events in patients with DM. Aspirin 81 to 325 mg once/day provides cardiovascular protection and should be used by most adults with DM in the absence of a specific contraindication.

Statins are currently recommended by the American Heart Association/American College of Cardiology guidelines for all diabetic patients 40 to 75 yr of age. Moderate to high intensity treatment is used, and there are no target lipid levels. For patients < 40 or > 75, statins are given based upon individual assessment of the risk:benefit ratio and patient preference. Patients with type 2 DM tend to have high levels of triglycerides and small, dense low-density lipoproteins (LDL) and low levels of HDL; they should receive aggressive treatment with the same treatment goals as those of patients with known coronary artery disease (LDL < 100 mg/dL [< 2.6 mmol/L], HDL > 40 mg/dL [> 1.1 mmol/L], and triglycerides < 150 mg/dL [< 1.7 mmol/L]—see Table: National Cholesterol Education Program Adult Treatment Panel III Approach to Dyslipidemias).

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. All of these drugs may be useful in selected patients as part of a comprehensive weight loss program, although lorcaserin may be used only short-term. All of these drugs have been shown to significantly decrease HbA 1c . 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 DM 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 (see Treatment). 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).

All patients with DM should be vaccinated against Streptococcus pneumoniae (once) and influenza virus (annually).

Special Populations and Settings

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.

Children

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 have severe obesity, 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, an insulin secretagogue (such as a SU or repaglinide) or insulin may be added. TZDs are generally avoided because long-term safety is unknown.

Adolescents

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.

Hospitalization

Diabetes can be a primary reason for hospitalization or can accompany other illnesses that require inpatient care. All diabetic patients with DKA, NKHS, or prolonged or severe hypoglycemia should be hospitalized. Others with SU-induced hypoglycemia, poorly controlled hyperglycemia, or acute worsening of diabetic complications may benefit from brief hospitalization, as do children and adolescents with new-onset disease. 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, many patients do well without any change in drugs. However, glucose control may prove 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. Inpatients who are able to eat may continue usual outpatient regimens; others may be appropriately treated with basal insulin without or with supplemental short-acting insulin . 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 MI, and often prolongs hospital stay. Critical illness causes insulin resistance and hyperglycemia even in patients without known DM. 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.

Surgery

The physiologic stress of surgery can increase plasma glucose in patients with DM and induce DKA in those with type 1 DM. For 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 (monitoring is done at 2- to 4-h intervals), 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 insulin on the day of surgery and to give insulin by IV infusion. One approach is to add 6 to 10 units of regular insulin to 1 L of 5% dextrose in 0.9% saline solution or water infused initially at 100 to 150 mL/h on the morning of surgery based on the plasma glucose level. Alternatively, separate insulin (1 to 2 units/h) and dextrose (75 to 125 mL/h of 5% dextrose) infusions may be used and allow for easier titration. 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 SUs 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.

Prevention

Type 1

No treatments definitely prevent the onset or progression of type 1 DM. Azathioprine, corticosteroids, and cyclosporine induce remission of early type 1 DM in some patients, presumably through suppression of autoimmune β-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

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. TZDs may also be protective, perhaps by inducing PPAR-γ activity but require further study before they can be recommended for routine preventive use.

Complications

Risk of DM complications can be decreased by strict control of plasma glucose, defined as HbA 1c < 7%, and by control of hypertension and lipid levels (see Overview of Hypertension : General Treatment and see Dyslipidemia : Treatment). Specific measures for prevention of progression of complications once detected are described under Complications (see Diabetes Mellitus (DM) : Complications) and Treatment (see Diabetes Mellitus (DM) : Treatment).

Key Points

  • Type 1 diabetes involves absence of insulin due to autoimmune-mediated inflammation in pancreatic β cells.

  • Type 2 diabetes involves varying degrees hepatic insulin resistance (causing an inability to suppress hepatic glucose production), peripheral insulin resistance (which impairs peripheral glucose uptake) in combination with a β-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 HbA 1c , 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.

Resources In This Article

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • NIACOR, NIASPAN
  • NEURONTIN
  • LEVOPHED
  • CYMBALTA
  • QUTENZA
  • TOFRANIL
  • LYRICA
  • TEGRETOL
  • GLUCOPHAGE
  • ADRENALIN
  • DIABINESE
  • STARLIX
  • ONGLYZA
  • AVANDIA
  • DIABETA, GLYNASE
  • TRADJENTA
  • ACTOS
  • GLUCOTROL
  • AMARYL
  • PRANDIN
  • PARLODEL
  • GLYSET
  • JANUVIA
  • PRECOSE
  • BYETTA
  • SYMLIN
  • VICTOZA
  • ADIPEX-P
  • TOPAMAX
  • BELVIQ
  • ALLI, XENICAL
  • NEORAL, SANDIMMUNE
  • IMURAN

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