Diabetes Mellitus

Српски / Srpski: Šematski prikaz oslobađanja i...

Српски / Srpski: Šematski prikaz oslobađanja insulina. (Photo credit: Wikipedia)

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English: Overview of the most significant poss...

English: Overview of the most significant possible symptoms of diabetes. See Wikipedia:Diabetes#Signs_and_symptoms for references. Model: Mikael Häggström. To discuss image, please see Template talk:Häggström diagrams (Photo credit: Wikipedia)

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Age-standardised disability-adjusted life year...

Age-standardised disability-adjusted life year (DALY) rates from Diabetes mellitus by country (per 100,000 inhabitants). (Photo credit: Wikipedia)

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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, and polyuria. Later complications include vascular disease, peripheral neuropathy, and predisposition to infection. Diagnosis is by measuring plasma glucose. Treatment is diet, exercise, and drugs that reduce glucose levels, including insulin and oral antihyperglycemic drugs. Prognosis varies with degree of glucose control.

There are 2 main categories of DM—type 1 and type 2, which can be distinguished by a combination of features (see Table 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: General Characteristics of Types 1 and 2 Diabetes Mellitus). Terms that describe the age of onset (juvenile or adult) or type of treatment (insulin- or non–insulin-dependent) are no longer accurate because of overlap in age groups and treatments between disease types.

Table 1

General Characteristics of Types 1 and 2 Diabetes Mellitus

Characteristic
Type 1
Type 2

Age at onset
Most commonly 30 yr

Associated obesity
No
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

Islet cell antibodies at diagnosis
Yes
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

Impaired glucose regulation (impaired glucose tolerance, or impaired fasting glucose—see Table 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation) is an intermediate, possibly transitional, state between normal glucose metabolism and DM that becomes common with age. It is a significant risk factor for DM and may be present for many years before onset of DM. It is associated with an increased risk of cardiovascular disease, but typical diabetic microvascular complications generally do not develop.

Table 2

Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation

Test
Normal
Impaired Glucose Regulation
Diabetes

FPG
< 100 (< 5.6)
100–125 (5.6–6.9)
≥ 126 (≥ 7.0)

OGTT
< 140 (< 7.7)
140–199 (7.7–11.0)
≥ 200 (≥ 11.1)
FPG = fasting plasma glucose; OGTT = oral glucose tolerance test, 2-h glucose level.
Note: All values refer to glucose levels in mg/dL (mmol/L).

Etiology

Type 1: In Type 1 DM (previously called juvenile-onset or insulin-dependent), insulin production is absent because of autoimmune pancreatic β-cell destruction possibly triggered by an environmental exposure in genetically susceptible people. Destruction progresses subclinically over months or years until β-cell mass decreases to the point that insulin concentrations are no longer adequate to control plasma glucose levels. Type 1 DM generally develops in childhood or adolescence and until recently was the most common form diagnosed before age 30; however, it can also develop in adults (latent autoimmune diabetes of adulthood, which often initially appears to be type 2 DM). Some cases of type 1 DM, particularly in nonwhite populations, do not appear to be autoimmune in nature and are considered idiopathic. Type 1 accounts for 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, insulinoma-associated protein, and other proteins in β cells. It is thought that these proteins are exposed or released during normal β-cell turnover or β-cell injury (eg, due to infection), activating a cell-mediated immune response resulting in β-cell destruction (insulitis). Glucagon-secreting α cells remain unharmed. Antibodies to autoantigens, which can be detected in serum, seem to be a response to (not a cause of) β-cell destruction.

Several viruses (including coxsackievirus, rubella virus, cytomegalovirus, Epstein-Barr virus, and retroviruses) have been linked to the onset of type 1 DM. Viruses may directly infect and destroy β cells, or they may cause β-cell destruction indirectly by exposing autoantigens, activating autoreactive lymphocytes, mimicking molecular sequences of autoantigens that stimulate an immune response (molecular mimicry), or other mechanisms.

Diet may also be a factor. Exposure of infants to dairy products (especially cow’s milk and the milk protein β casein), high nitrates in drinking water, and low vitamin D consumption have been linked to increased risk of type 1 DM. Early ( 7 mo) exposure to gluten and cereals increases islet cell autoantibody production. Mechanisms for these associations are unclear.

Type 2: In type 2 DM (previously called adult-onset or non–insulin-dependent), insulin secretion is inadequate. Often insulin levels are very high, especially early in the disease, but peripheral insulin resistance and increased hepatic production of glucose make insulin levels inadequate to normalize plasma glucose levels. Insulin production then falls, further exacerbating hyperglycemia. The disease generally develops in adults and becomes more common with age. Plasma glucose levels reach higher levels after eating in older than in younger adults, especially after high carbohydrate loads, and take longer to return to normal, in part because of increased accumulation of visceral and abdominal fat and decreased muscle mass.

Type 2 DM is becoming increasingly common 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 for it, evidence also exists for β-cell dysfunction and impaired insulin secretion, including impaired first-phase insulin secretion in response to IV glucose infusion, a loss of normally pulsatile insulin secretion, an increase in proinsulin secretion signaling impaired insulin processing, and an accumulation of islet amyloid polypeptide (a protein normally secreted with insulin). Hyperglycemia itself may impair insulin secretion, because high glucose levels desensitize β cells, cause β-cell dysfunction (glucose toxicity), or both. These changes typically take years to develop in the presence of insulin resistance.

Obesity and weight gain are important determinants of insulin resistance in type 2 DM. They have some genetic determinants but also reflect diet, exercise, and lifestyle. Adipose tissue increases plasma levels of free fatty acids that may impair insulin-stimulated glucose transport and muscle glycogen synthase activity. Adipose tissue also appears to function as an endocrine organ, releasing multiple factors (adipocytokines) that favorably (adiponectin) and adversely (tumor necrosis factor-α, IL-6, leptin, resistin) influence glucose metabolism. Intrauterine growth restriction and low birth weight have also been associated with insulin resistance in later life and may reflect prenatal environmental influences on glucose metabolism.

Miscellaneous types: Miscellaneous causes of DM that account for a small proportion of cases include genetic defects affecting β-cell function, insulin action, and mitochondrial DNA (eg, maturity-onset diabetes of youth); pancreatic diseases (eg, cystic fibrosis, pancreatitis, hemochromatosis); endocrinopathies (eg, Cushing’s syndrome, acromegaly); toxins (eg, the rodenticide pyriminyl [Vacor]); and drug-induced diabetes, most notably from glucocorticoids, β-blockers, protease inhibitors, and therapeutic doses of niacin

. Pregnancy causes some
insulin resistance in all women, but only a few develop gestational DM (see Pregnancy Complicated by Disease: Diabetes Mellitus in Pregnancy (Gestational Diabetes)).

Symptoms and Signs

The most common symptoms of DM are those of hyperglycemia: an osmotic diuresis caused by glycosuria leading to urinary frequency, polyuria, and polydipsia that may progress to orthostatic hypotension and dehydration. Severe dehydration causes weakness, fatigue, and mental status changes. Symptoms may come and go as plasma glucose levels fluctuate. Polyphagia may accompany symptoms of hyperglycemia but is not typically a primary patient concern. Hyperglycemia can also cause weight loss, nausea and vomiting, and blurred vision, and it may predispose to bacterial or fungal infections.

Patients with type 1 DM typically present with symptomatic hyperglycemia and sometimes with diabetic ketoacidosis (DKA—see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic Ketoacidosis (DKA)). Some patients experience a long but transient phase of near-normal glucose levels 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 on routine testing. In some patients, initial symptoms are those of diabetic complications, suggesting that the disease has been present for some time. In some patients, hyperosmotic coma occurs initially, especially during a period of stress or when glucose metabolism is further impaired by drugs, such as corticosteroids.

Complications

Years of poorly controlled hyperglycemia lead to multiple, primarily vascular complications that affect small vessels (microvascular), large (macrovascular) vessels, or both. The mechanisms by which vascular disease develops include glycosylation of serum and tissue proteins with formation of advanced glycation end products; superoxide production; activation of protein kinase C, a signaling molecule that increases vascular permeability and causes endothelial dysfunction; accelerated hexosamine biosynthetic and polyol pathways leading to sorbitol accumulation within tissues; hypertension and dyslipidemias that commonly accompany DM; arterial microthromboses; and 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 many of these complications but may not reverse them once established.

Diabetic retinopathy: Diabetic retinopathy is the most common cause of adult blindness in the US (see also Retinal Disorders: Diabetic Retinopathy). It is characterized initially by retinal capillary microaneurysms and later by macular edema and neovascularization. There are no early symptoms or signs, but focal blurring, vitreous or retinal detachment, and partial or total vision loss eventually develop; rate of progression is highly variable. Diagnosis is by retinal examination. Treatment is argon laser photocoagulation or vitrectomy. Strict glycemic control and early detection and treatment are critical to preventing vision loss.
Diabetic Retinopathy—Proliferative

Diabetic nephropathy: Diabetic nephropathy (see also Glomerular Disorders: Diabetic Nephropathy) is a leading cause of chronic renal failure in the US. It is characterized by thickening of the glomerular basement membrane, mesangial expansion, and glomerular sclerosis. These changes cause glomerular hypertension and progressive decline in GFR. Systemic hypertension may accelerate progression. The disease is usually asymptomatic until nephrotic syndrome or renal failure develops.

Diagnosis is by detection of urinary albumin. A urine dipstick positive for protein signifies albumin excretion > 300 mg/day and advanced diabetic nephropathy (or an improperly collected or stored specimen). If the dipstick is negative for protein, the albumin:creatinine ratio on a spot urine specimen or urinary albumin in a 24-h collection should be measured. A ratio > 30 mg/g or an albumin concentration 30 to 300 mg/24 h signifies microalbuminuria and early diabetic nephropathy.

Treatment is rigorous glycemic control combined with BP control. An ACE inhibitor, an angiotensin II receptor blocker, or both should be used to treat hypertension at the earliest sign of microalbuminuria or even before, because these drugs lower intraglomerular BP and thus have renoprotective effects.

Diabetic neuropathy: Diabetic neuropathy is the result of nerve ischemia 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’s joint).

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

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

Autonomic neuropathy can 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 Fig. 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic foot screening.). Electromyography and nerve conduction studies may be needed for all forms of neuropathy and are sometimes used to exclude other causes of neuropathic symptoms, such as nondiabetic radiculopathy and carpal tunnel syndrome. Strict glycemic control may lessen neuropathy. Treatments for relief of symptoms include topical capsaicin cream, tricyclic antidepressants (eg, imipramine

), SNRIs (eg,
duloxetine

), anticonvulsants (eg, gabapentin

, carbamazepine

), and mexiletine

.
Patients with sensory loss should examine their feet daily to detect minor foot trauma and prevent it from progressing to limb-threatening infection.
Fig. 1

Diabetic foot screening.

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

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 by history and examination; the role of screening tests is evolving. Treatment is rigorous control of atherosclerotic risk factors, including normalization of plasma glucose, lipids, and BP, combined with smoking cessation and daily intake of aspirin

and
ACE inhibitors. In contrast with microvascular disease, intensive control of plasma glucose alone is not an effective preventive measure.

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’s contracture, adhesive capsulitis, and sclerodactyly. They may also develop ophthalmologic disease unrelated to diabetic retinopathy (eg, cataracts, glaucoma, corneal abrasions, optic neuropathy); hepatobiliary diseases (eg, nonalcoholic fatty liver disease [steatosis and steatohepatitis], cirrhosis, gallstones); and dermatologic disease (eg, tinea infections, lower-extremity ulcers, diabetic dermopathy, necrobiosis lipoidica diabeticorum, diabetic systemic sclerosis, vitiligo, granuloma annulare, acanthosis nigricans [a sign of insulin resistance]). Depression and dementia are also common.

Diagnosis

Fasting plasma glucose levels

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 (fasting plasma glucose [FPG]) or 2 h after ingestion of a concentrated glucose solution (oral glucose tolerance testing [OGTT]) is best (see Table 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diagnostic Criteria for Diabetes Mellitus and Impaired Glucose Regulation). OGTT is more sensitive for diagnosing DM and impaired glucose tolerance but is less convenient and reproducible than FPG. It is therefore rarely used routinely, except for diagnosing gestational DM (see Pregnancy Complicated by Disease: Diabetes Mellitus in Pregnancy (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 glycosylated Hg (HbA1c). A random glucose value > 200 mg/dL (> 11.1 mmol/L) may be diagnostic, but values can be affected by recent meals and must be confirmed by repeat testing; testing twice may not be necessary in the presence of diabetic symptoms. HbA1c measurements reflect glucose levels over the preceding 2 to 3 mo. HbA1c measurements are now included in the diagnostic criteria for DM:

HbA1c ≥ 6.5% = DM

HbA1c 5.7 to 6.4% = prediabetes or at risk of DM

However, and values may be falsely high or low (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Monitoring), and tests must be done in a certified clinical laboratory. HbA1c is also 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.

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; obesity; sedentary lifestyle; family history of DM; history of impaired glucose regulation; gestational DM or delivery of a baby > 4.1 kg; history of hypertension or dyslipidemia; polycystic ovary syndrome; and black, Hispanic, or American Indian ethnicity.

Risk of insulin resistance among overweight people (body mass index ≥ 25 kg/m2) is increased with serum triglycerides ≥ 130 mg/dL (≥ 1.47 mmol/L); triglyceride/high-density lipoprotein (HDL) ratio ≥ 3.0 (≥ 1.8); and insulin ≥ 108 pmol/L. People with these characteristics are at particularly high risk and should be screened for DM with an FPG level 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 2: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: 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 Fig. 1: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Diabetic foot screening.). The entire foot, and especially skin beneath the metatarsal heads, should be examined for skin cracking and signs of ischemia, such as ulcerations, gangrene, fungal nail infections, deceased pulses, and hair loss.

Funduscopic examination should be 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 electrocardiography important given the risk of heart disease. Lipid profile should be checked at least annually and more often when abnormalities are present. BP should be measured at every examination.

Treatment

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

HbA1c levels < 7%

Glucose levels are typically determined by home monitoring (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Monitoring) and maintenance of HbA1c levels 400 mg/dL) may respond better to oral therapy after glucose levels are normalized with a brief period of insulin

treatment.

Patients with impaired glucose regulation should receive counseling addressing their risk of developing DM and the importance of lifestyle changes for preventing DM. They should be monitored closely for development of DM symptoms or elevated plasma glucose. Ideal follow-up intervals have not been determined, but annual or biannual checks are probably appropriate.

Patient education: 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, 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.

Patients with type 2 DM should restrict calories, eat regularly, increase fiber intake, and limit intake of refined carbohydrates and saturated fats. Some experts also recommend dietary protein restriction to ≤ 0.8 g/kg/day to prevent progression of early nephropathy (see Glomerular Disorders: 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 isometric exercise for weight loss and protection from vascular disease, but resistance training also can improve glucose control, and all forms of exercise are beneficial.

Patients who experience hypoglycemic symptoms during exercise should be advised to test their blood glucose and ingest carbohydrates or lower their insulin dose as needed to get their glucose slightly above normal just before exercise. Hypoglycemia during vigorous exercise may require carbohydrate ingestion during the workout period, typically 5 to 15 g of sucrose or another simple sugar.

Patients with known or suspected cardiovascular disease may benefit from exercise stress testing before beginning an exercise program, while activity goals may need to be modified for patients with diabetic complications such as neuropathy and retinopathy.

Monitoring: DM control can be monitored by measuring blood levels of

Glucose

HbA1c

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 and to help physicians recommend adjustments in the timing and doses of drugs.

Many different monitoring devices are available. Nearly all require test strips and a means for pricking the skin and obtaining a sample. Most come with control solutions, which should be used periodically to verify proper meter calibration. Choice among devices is usually based on patient preferences for features such as time to results (usually 5 to 30 sec), size of display panel (large screens may benefit patients with poor eyesight), and need for calibration. Meters that allow for testing at sites less painful than fingertips (palm, forearm, upper arm, abdomen, thigh) are also available.

Continuous glucose monitoring systems using a subcutaneous catheter can provide real-time results, including an alarm to warn of hypoglycemia, hyperglycemia, or rapidly changing glucose levels. Such devices are expensive and do not eliminate the need for fingerstick glucose testing, but they may be useful for selected patients.

Patients with poor glucose control and those given a new drug or a new dose of a currently used drug may be asked to self-monitor 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 2 to 3 mo and hence assess control between physician visits. HbA1C should be assessed quarterly in patients with type 1 DM and at least annually in patients with type 2 DM whose plasma glucose appears stable (more frequently when control is uncertain). Home testing kits are useful for patients who are able to follow the testing instructions rigorously.

Control suggested by HbA1c values sometimes appears to differ from that suggested by daily glucose readings because of falsely elevated or normal values. False elevations may occur with renal insufficiency (urea interferes with the assay), low RBC turnover (as occurs with iron, folate, or vitamin B12 deficiency anemia), high-dose aspirin

, and high blood alcohol
concentrations. Falsely normal values occur with increased RBC turnover, as occurs with hemolytic anemias and hemoglobinopathies (eg, HbS, HbC) or during treatment of deficiency anemias.

Fructosamine, which is mostly glycosylated albumin but also comprises other glycosylated proteins, reflects glucose control in the previous 1 to 2 wk. Fructosamine monitoring may be used during intensive treatment of DM and for patients with Hb variants or high RBC turnover (which cause false HbA1C results), but it is mainly used in research settings.

Urine glucose monitoring provides a crude indication of hyperglycemia and can be recommended only when blood glucose monitoring is impossible. By contrast, self-measurement of urine ketones is recommended for 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) 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 3: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: 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).

Table 3

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

3–4 h
8–12 h
12–18 h

Long-acting

4–8 h
10–16 h
16–20 h

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 insulinmolecule from associating into dimers and polymers. They begin to reduce plasma glucose often within 15 min but have short duration of action ( 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: 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. 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 where 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.

Insulin resistance occurs mostly in patients with type 2 DM. The causes are usually obesity and genetic factors. Circulating anti-insulin antibodies are a rare cause. 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 (2.7 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 4: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Characteristics of Oral Antihyperglycemics and Table 5: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Combination Oral Antihyperglycemics) 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.
Table 4

Characteristics of Oral Antihyperglycemics
This table is presented as a PDF and requires the free Adobe PDF reader. Get Adobe Reader

Table 5

Combination Oral Antihyperglycemics

Classes
Drugs
Available Strengths (mg/mg)

Sulfonylurea/biguanide
Glipizide

/
metformin

2.5/250, 2.5/500, 5/500

Sulfonylurea/biguanide
Glyburide

/
metformin

1.25/250, 2.5/500, 5/500

Thiazolidinedione/biguanide
Pioglitazone

/
metformin

15/500, 15/850

Thiazolidinedione/biguanide
Rosiglitazone

/
metformin

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

Thiazolidinedione/sulfonylurea
Pioglitazone

/
glimepiride

30/2, 30/4

Thiazolidinedione/sulfonylurea
Rosiglitazone

/
glimepiride

4/1, 4/2, 4/4

Dipeptidyl peptidase-4 inhibitor/biguanide
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 4: Diabetes Mellitus and Disorders of Carbohydrate Metabolism: 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 B12 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 HbA1c.
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.

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) block glucagon-like
peptide-1 (GLP-1) breakdown by inhibiting the enzyme dipeptidyl peptidase-4 (DPP-4). Vildagliptin, a similar drug, is being developed.

Injectable antihyperglycemic drugs: Injectable antihyperglycemic drugs other than insulin

are the GLP-1 agonists and the amylin analog, pramlintide

(see Diabetes Mellitus and
Disorders of Carbohydrate Metabolism: Combination Oral Antihyperglycemics). 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, including a long-acting form of exenatide

, are being developed.

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 µg sc before meals, and those with type 2 DM are given 120 μg.

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 Transplantation: 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. ACE inhibitors, angiotensin II receptor blockers, or both 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. 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 [ 40 mg/dL [> 1.1 mmol/L], and triglycerides < 150 mg/dL [ 5 days) critical care. 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 HbA1c < 7%, and by control of hypertension and lipid levels (see Hypertension: General Treatment and see Lipid Disorders: Treatment). Specific measures for prevention of progression of complications once detected are described under Complications (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Complications) and Treatment (see Diabetes Mellitus and Disorders of Carbohydrate Metabolism: Treatment).

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