Type 1 Diabetes Mellitus Treatment & Management

Treatment of type 1 diabetes mellitus (DM) requires a multidisciplinary approach by the physician, nurse, and dietitian.

In patients with new-onset type 1 diabetes, lifelong insulin therapy must be started. Many patients present with diabetic ketoacidosis (DKA). On occasion, the patient with new-onset type 1 diabetes who presents with mild manifestations and who is judged to be compliant can begin insulin therapy as an outpatient. However, this approach requires close follow-up and the ability to provide immediate and thorough education about the use of insulin; the signs, symptoms, and treatment of hypoglycemia; and the need to self-monitor blood glucose levels.

A study by Orban et al found that costimulation modulation of activated T cells with abatacept slowed reduction in beta-cell function over a 2-year period of administration. However, this effect was reduced after 6 months of treatment, suggesting that T-cell activation lessens over time. Further studies are needed.^[51]

Ludvigsson et al tested glutamic acid decarboxylase (GAD)-alum in patients with newly diagnosed type 1 diabetes, with the aim of preserving pancreatic beta-cell function. Studies over a 15-month period failed to reveal a significant loss of stimulated C-peptide secretion or any improvement in clinical outcomes (ie, glycated hemoglobin, daily dose of insulin, and rate of hypoglycemia).^[52]

Benefits and potential risks of tight glycemic control

The fact that chronic hyperglycemia is associated with an increased risk of microvascular complications of type 1 DM was demonstrated in the Diabetes Control and Complications Trial (DCCT).^[53] In that trial, intensive therapy designed to maintain normal blood glucose levels greatly reduced the development and progression of retinopathy, microalbuminuria, proteinuria, and neuropathy, as assessed over 7 years.

The subsequent Epidemiology of Diabetes Interventions and Complications Study (EDIC), an observational study that continues to follow the patients previously enrolled in the DCCT, demonstrated that benefit continued after the DCCT trial ended in 1993.^{[54, 55]}

Benefits include not only continued reductions in the rates of microvascular complications but also significant differences in cardiovascular events and overall mortality. These benefits occurred in spite of the fact that subjects in the intensively treated group and those in the standard treatment group maintained similar hemoglobin A_1C (HbA_1c) levels (approximately 8%) starting one year after the formal trial ended. Therefore, it is postulated that a “metabolic memory” exists, and that better early glycemic control sets the stage for outcomes many years in the future.

HbA_1c and heart failure were positively associated in a study of 20,985 patients with type 1 diabetes. Thus, improved glycemic control should prevent heart failure as well.^[56]

Although tight glycemic control is beneficial, an increased risk of severe hypoglycemia accompanies lower blood glucose levels. For many, the HbA_1c target should be less than 7%, with a premeal blood glucose level of 80–130 mg/dL. However, targets should be individualized. Individuals with recurrent episodes of severe hypoglycemia, cardiovascular disease, advanced complications, substance abuse, or untreated mental illness may require higher targets, such as an HbA_1c of less than 8% and preprandial glucose levels of 100–150 mg/dL. The 2011 AACE guidelines support the creation of individualized targets that consider these factors as part of a comprehensive treatment plan.^[57]

In patients with type 1 DM, recurrent and chronic hypoglycemia has been linked to cognitive dysfunction.^[58] This has important implications in the management of children with type 1 DM.^[59] Jacobson et al investigated this relationship using a multivariate analysis with microvascular, macrovascular, and subclinical macrovascular risk factors and decrements in cognitive function overtime. On univariate analysis, smoking history was found to correlate with decrements in learning, memory, spatial information processing, and psychomotor efficiency. In multivariable models, HbA1c levels and retinal and renal complications were linked to cognitive declines. No relationship was found with macrovascular risk factors or severe hypoglycemic events. This information is useful in advising patients with type 1 DM interested in preserving cognitive function.

Hyperglycemia, as measured by HbA1c, does not contribute to the risk profile for worsening Alzheimer disease beyond serving as a surrogate for diabetes mellitus.^[60]

The 2011 ADA standard recommends individualized glycemic goals for children and adolescents, based on age, awareness of hypoglycemia, frequency of hypoglycemia, and response to treatment. A table of plasma blood glucose and HbA1c targets for children by age group is provided.^[61]

Although patients with type 1 diabetes have normal incretin response to meals, administration of exogenous glucagonlike peptide 1 (GLP-1) reduces peak postprandial glucose by 45%. Long-term effects of exogenously administered GLP-1 analogs warrant further studies.^[62]

Self-monitoring of glucose levels

Optimal diabetic control requires frequent self-monitoring of blood glucose levels. Frequent monitoring allows for rational adjustments in insulin doses. Most patients with type 1 DM require 2 or more injections of insulin daily, with doses adjusted based on self-monitoring of blood glucose levels. In general, individuals with type 1 DM should test a minimum of 4 times per day—before each meal and at bedtime.

Subcutaneous continuous glucose sensors are now available, making the continuous glucose monitor (CGM) possible. These devices measure interstitial glucose levels every 1-5 minutes, providing alarms when glucose levels are too high or too low or are rapidly rising or falling. CGM transmits to a receiver, which is either a pager like device or is integral to an insulin pump. Looking at the continuous glucose graph and responding to the alarms can help patients avoid serious hyperglycemia or hypoglycemia.

Several drawbacks exist; first, there is a lag between glucose levels in the interstitial space and capillary blood, so the levels recorded by the CGM may differ from a fingerstick (capillary) glucose. For that reason, the trends (whether the glucose levels are rising or falling) tend to be more helpful. Second, patients may overtreat hyperglycemia (repeatedly giving insulin because the glucose levels do not fall rapidly enough—a phenomenon known as stacking) as well as overtreat lows (the glucose levels rise slowly with ingestion of carbohydrate).

Patients using CGM and/or insulin pumps can often provide very detailed information as to their insulin regimens as well as recent alterations in blood glucose levels.

Types of insulin

By definition, patients with type 1 DM require lifelong treatment with insulin to promote glucose utilization. Rapid-, short-, intermediate-, and long-acting insulin preparations are available. Although pork, beef, and beef-pork insulins were previously used, recombinant human insulin is used almost exclusively in the United States. Commercially prepared mixtures of insulin are also available.

Rapid-acting insulins include regular insulin, lispro, glulisine, and aspart insulin. Regular insulin is a preparation of zinc insulin crystals in solution. Its onset of action is 0.5-1 hour, it peaks at 2.5-5 hours, and duration of action is 6-8 hours. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline at B28,29 in the B chain. Aspart insulin has aspartic acid substituted for proline in position 28 of the B chain. Both of these insulins are absorbed more quickly and have a rapid onset (5-10 min), peak (1 h), and duration (4 h) of action. Therefore, they have the advantage that they may be administered shortly before eating. Semilente insulin is like regular insulin and is a slightly slower rapid-acting insulin. It contains zinc insulin microcrystals in an acetate buffer and is not readily available in the United States.

Intermediate-acting insulins include neutral protamine Hagedorn (NPH) insulin, which contains a mixture of regular and protamine zinc insulin, and Lente insulin, which contains 30% Semilente insulin and 70% Ultralente insulin in an acetate buffer.

Long-acting insulins include Ultralente insulin, containing large zinc insulin crystals in an acetate buffer, and insulin glargine, a newer long-acting insulin that has no peak and produces a relatively stable level lasting more than 24 hours. Both insulins can supply basal 24-hour insulin with a single daily injection.

In a study by Suissa et al, insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use. The risk tended to increase after 5 years, significantly so for the women who had taken insulin before starting glargine.^[63]

Furthermore, a study by Johnson et al found that patients receiving insulin glargine had the same incidence rate for all cancers as those not receiving insulin glargine. Overall, no increase in breast cancer rates was associated with insulin glargine use, although patients who used only insulin glargine had a higher rate of cancer than those who used another type of insulin. This was attributed to allocation bias and differences in baseline characteristics.^[64]

Mixtures of insulin preparations with different onsets and durations of action frequently are administered in a single injection by drawing measured doses of 2 preparations into the same syringe immediately before use. The exception is insulin glargine, which should not be mixed with any other form of insulin. Preparations that contain a mixture of 70% NPH and 30% regular human insulin (ie, Novolin 70/30, Humulin 70/30) are available, as is Humulin 50/50, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use. In addition, a 25/75 mixture of NPH and lispro insulin is available.

A new basal insulin, insulin degludec, was found to be safe and effective and compared favorably with insulin glargine in a phase II clinical trial of patients with type 1 DM.^[65] Both regular human insulin (RHI) and rapid-acting insulin analogs (RAIA) are effective at lowering postprandial hyperglycemia in various basal bolus insulin regimens used in type 1 DM. While RAIAs may be slightly better at lowering HbA_1c, the differences are clinically insignificant.^[66]

Common insulin regimens

Although emergency physicians rarely start new therapy for patients with diabetes, being acquainted with the various forms of insulin and the common regimens is useful.

When treating patients with type 1 DM, the goal is to provide insulin in a manner that is as physiologic as possible. Insulin replacement is given as a basal insulin (either long-acting [glargine or detemir] or intermediate-acting [NPH]) and preprandial (premeal) insulin (either rapid-acting [lispro, aspart, or glulisine] or short-acting [regular]). For patients on intensive insulin regimens (multiple daily injections or insulin pumps), the preprandial dose is based on the carbohydrate content of the meal (the carbohydrate ratio) plus a correction dose if their blood glucose level is elevated (eg, 2 additional units of rapid-acting insulin to correct the blood glucose from a level of 200 mg/dL to a target of 100 mg/dL). This method allows patients more flexibility in caloric intake and activity, but it requires more blood glucose monitoring and attention to the control of their diabetes.

Common insulin regimens include the following:

• Split or mixed, such as NPH with rapid-acting (eg, lispro, aspart, or glulisine) or regular insulin before breakfast and supper
• Split or mixed variant: NPH with rapid-acting or regular insulin before breakfast, rapid-acting or regular insulin before supper, NPH before bedtime (designed to reduce fasting hypoglycemia by giving the NPH latter in the evening)
• Multiple daily injections (MDI), a long-acting insulin (eg, glargine or detemir) once a day in the morning or evening (or twice a day in about 20% of patients), and a rapid-acting insulin before meals or snacks (dose adjusted based on the carbohydrate intake and the blood glucose level)
• Continuous subcutaneous insulin infusion (CSII), rapid-acting insulin infused continuously 24 hours a day through an insulin pump at one or more basal rates, with additional boluses given before each meal, and correction doses administered if blood glucose levels exceed target levels

Insulin is sensitive to heat and exposure to oxygen. Once a bottle of insulin is open, it should be used for no more than 28 days and then discarded, even if insulin remains in the bottle. Use of old insulin can result in a lack of clinical effectiveness. Insulin in a pump reservoir for longer than 3 days may lose its clinical effectiveness (although insulin aspart has now been approved for use for up to 6 days in a pump). Sometimes, insulin distributed from the pharmacy has been exposed to heat or other environmental factors and may be less active. If a patient is experiencing unexplained high blood sugar levels, new insulin vials should be opened and used.

A short-term trial using an anti-CD3 monoclonal antibody, teplizumab, found an encouraging trend of preservation of beta-cell function with reduction in daily insulin requirements. However, rash was almost 3 times more common than in those receiving placebo.^[67]

Lipid reduction

Lund et al studied the effect of metformin on plasma lipids in type 1 diabetes mellitus over 1 year.^[68] Following a 1-month washout period on placebo, patients (n=100) were randomized to receive metformin (1000 mg PO bid) or placebo. Compared with placebo, metformin significantly reduced total cholesterol and low-density lipoprotein (LDL) cholesterol.

Liraglutide combined with metformin provides greater sustained glycemic control and weight reduction when compared with sitagliptin and metformin combination.^[69]

Persistent lipid abnormalities remain in patients with diabetes despite evidence supporting benefits of lipid-modifying drugs. Statin dose up-titration and the addition of other lipid-modifying agents are needed.^[70]

Type 1 DM patients require insulin therapy to control initial hyperglycemia and maintain serum electrolytes and hydration. At times, the first incidence of DKA is followed by a symptom-free period during which patients do not need treatment. This “honeymoon period” follows the initial treatment, in which the disease remits and the patient requires little or no insulin. This remission is due to a partial return of endogenous insulin, which may last for several weeks or months (and sometimes 1-2 y). Ultimately, however, the disease recurs, and patients require insulin therapy.

During a flight (200 mm Hg pressure decrease), excess insulin delivery of 0.623% of cartridge volume was demonstrated due to bubble formation and expansion of preexisting bubbles.^[71]

A study by de la Pena et al found that although overall insulin exposure and effects of 500 U/mL of insulin are similar to 100 U/mL of insulin, peak concentration was significantly lower at 500 U/mL of insulin, and the effect after the peak was prolonged; areas under the curve were similar for both doses. This observation should help guide therapy.^[72]

Initiation of insulin therapy in adults

The initial daily dose is calculated depending upon the weight of the patient. This dose is usually divided so that one half is administered before breakfast, one fourth before dinner, and one fourth at bedtime. After selecting the initial dose, adjust the amounts, types, and timing depending on plasma glucose levels. Adjust the dose to maintain preprandial plasma glucose at 80-150 mg/dL (ie, 4.44-8.33 mmol/L). The insulin dose is often adjusted in increments of 10% at a time, and the effects are assessed over about 3 days before making any further changes. More frequent adjustments of regular insulin can be made if risk of hypoglycemia is present.

The 2011 American College of Physicians guidelines recommend a target blood glucose level of 140-200 mg/dL if insulin therapy is used to manage patients with diabetes in nonsurgical (medical) ICUs.^[73] These guidelines were based on a review of 21 trials in intensive care, perioperative care, myocardial infarction, stroke, or brain injury settings.^[74] No convincing evidence suggested that intensive insulin therapy reduced short-term or long-term mortality, infection rates, length of hospital stay, or the need for renal replacement therapy. The recommendation of 200 mg/dL as the upper target departs from the 2009 AACE/ADA consensus statement on inpatient glycemic control, which recommended a target range of 140-180 mg/dL in critically ill patients.^[75]

A novel insulin algorithm based on physiological insulin demand evoked by foods in healthy individuals can be used as a tool to estimate mealtime insulin dose in patients with type 1 diabetes.^[76]

Initiation of insulin therapy in children

Children with moderate hyperglycemia but without ketonuria or acidosis may be started with a single daily subcutaneous injection of 0.3-0.5 U/kg of intermediate-acting insulin alone.

Children with hyperglycemia and ketonuria but without acidosis or dehydration may be started on 0.5-0.7 U/kg of intermediate-acting insulin and subcutaneous injections of 0.1 U/kg of regular insulin at 4- to 6-hour intervals.

Insulin schedules

Multiple subcutaneous insulin injections are administered to control hyperglycemia after meals and to maintain normal plasma glucose levels throughout the day. This may increase the risks of hypoglycemia. Therefore, patients should be well educated about their disease and about self-monitoring of plasma glucose levels.

About 25% of the total daily dose is administered as intermediate-acting insulin at bedtime, with additional doses of rapid-acting insulin before each meal (4-dose regimen). These patients may need additional intermediate- or long-acting insulin in the morning for all-day coverage. Patients should adjust their daily dosage(s) based on their self-monitoring of glucose levels before each meal and at bedtime. Patients should also assess their plasma glucose levels at 2-4 o’clock in the morning at least once per week during the first few weeks of treatment and thereafter as indicated.

Continuous subcutaneous insulin infusion

This intensive insulin treatment uses a small battery-operated infusion pump that administers a continuous subcutaneous infusion of rapid-acting insulin. This provides selected, programmed basal rate(s) of insulin and a manually administered bolus dose before each meal. The patient self-monitors preprandial glucose levels to adjust the bolus dose(s). This method provides better control than with multiple injections. Hypoglycemia is common initially with pump therapy, but once metabolic control is achieved, the risk is the same as with multiple injections. Bergenstal et al determined that sensor-augmented pump therapy led to better glycemic control, and more patients reached targets when using this technology, compared to injection therapy.^[77]

Increased bedtime doses of hypoglycemic agents with nighttime peaks in action may correct early morning hyperglycemia but may be associated with undesirable nocturnal hypoglycemia. Targeted continuous subcutaneous insulin infusion programming can facilitate the prevention of early morning hyperglycemia in selected patients.

Local allergic reactions

Generalized insulin allergy is rare. Symptoms occur immediately after the injection and include urticaria, angioedema, pruritus, bronchospasm, and, rarely, circulatory shock. It may be treated with antihistamines. Some cases may require epinephrine and IV steroids.

Local allergic reactions can occur at the site of insulin injections and can cause pain, burning, local erythema, pruritus, and induration. These complications are less common with human insulin than observed previously with animal insulins. Such reactions usually resolve spontaneously without any intervention.

Local fat atrophy or hypertrophy at injection sites is not unusual and usually improves by switching to human insulin and injecting it directly into the affected area. Patients do not require any specific treatment of local fat hypertrophy, but injection sites should be rotated.

Plasma glucose monitoring is very important for better control of the disease. All patients with type 1 DM should learn how to self-monitor and record their blood glucose levels with home analyzers and adjust their insulin doses accordingly.

Insulin-dependent patients ideally should test their plasma glucose daily before meals, in some cases 1-2 hours after meals, and at bedtime. In practice, however, patients often obtain 2-4 measurements each day, including fasting levels and at various other times, including preprandially and at bedtime.

In patients with well-controlled diabetes, physicians must monitor blood glucose level and HbA_1c every 3 months.

Instruct patients with type 1 DM in the method of testing for urine ketones using commercially available reagent strips. Also, advise patients to test for urine ketones whenever they develop symptoms of a cold, flu, or other intercurrent illness; nausea, vomiting, or abdominal pain; polyuria; or an unexpectedly high plasma glucose level on self-monitoring. Recommend testing for ketones in all urine samples from patients with type 1 DM who exhibit persistent, rapid, and marked fluctuation in their degree of hyperglycemia.

Hypercholesterolemia and hypertension increase the risk for specific late complications and require special attention and appropriate treatment. Although physicians can safely use beta-blockers (eg, propranolol) in most patients, these agents can mask the adrenergic symptoms of insulin-induced hypoglycemia and can impair the normal counter-regulatory response. ACE inhibitors are the drugs of choice for hypertension because of their renal protective action, especially early in the course of the disease.

The 2011 ADA standard of care states that systolic blood pressure less than 130 mm Hg is an appropriate goal for most patients with diabetes and hypertension, but the guideline recommends modifying systolic blood pressure targets based on individual patient characteristics. Diastolic blood pressure should be less than 80 mm Hg.^[61]

Microalbuminuria and macroalbuminuria are not permanent features of most diabetic children and adolescents.^[78] Regression of microalbuminuria is common; female gender, absence of retinopathy, better glucose control, lower blood pressure, and better lipid control favor this outcome.^[79] Where albuminuria persists, the use of ACE inhibitors and good metabolic control are effective in inducing remission.

Progression and regression of kidney disease are common even after development of persistent microalbuminuria. Intensive glycemic control, lower blood pressure, and favorable lipid profile are associated with improved outcome.^[80]

Hypoglycemia may be due to change in insulin dose, a small or missed meal, or strenuous exercise. Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake, has gastroparesis, or is vomiting. Common symptoms of hypoglycemia are light-headedness, dizziness, confusion, shakiness, sweating, and headache.

Patients should be educated about these symptoms and to respond rapidly with sugar intake. These patients should be advised to carry candy or sugar cubes. Family members can be taught to administer a subcutaneous injection of glucagon. In an emergency situation, initial treatment is a bolus injection of 25 mL of 50% glucose solution followed by a continuous glucose infusion.

Repeated hypoglycemia may be an aggravating factor in preclinical atherosclerosis. Thus, when designing treatment plans aimed at reducing glycemic burden and decreasing/preventing vascular complications, hypoglycemic episodes might negate some benefits.^[81]

Controversy surrounds the lasting cognitive consequences of severe hypoglycemia in youths with type 1 diabetes. In one study, EEGs and cognition studies were performed at baseline and 16 years later in patients with type 1 diabetes; no association between early severe hypoglycemia and subsequent reduced adult cognition or EEG changes was found.^[82]

Acute hyperglycemia, even when not associated with DKA or hyperglycemic hyperosmolar state (HHS), is harmful for a number of reasons. If the blood glucose level exceeds the renal threshold for glucose (>240 mg/dL in a healthy person, but diminished with advancing age, renal insufficiency, and pregnancy), an osmotic diuresis ensues, with loss of glucose, electrolytes, and water. Hyperglycemia impairs leukocyte function through a variety of mechanisms. Patients with diabetes have an increased rate of wound infection, and hyperglycemia impairs wound healing.

In patients with known, poorly controlled type 1 diabetes, no absolute level of blood glucose elevation requires admission to the hospital or the administration of insulin in the ED. In general, lowering the patient’s glucose level in the ED does not correct the underlying cause and has no long-term effect on the patient’s glucose levels. Therefore, a plan for lowering and monitoring the patient’s glucose levels is needed. Adequacy of follow-up is extremely important. Whether insulin is given in the ED is of less consequence and can be decided on an individual basis.

Patients with type 1 diabetes mellitus (DM) can have coexisting illnesses that aggravate hyperglycemia, such as infection, coronary artery disease, or fever; additionally, certain medications can aggravate the condition.

Go to Hyperosmolar Hyperglycemic State for complete information on this topic.

Diabetic ketoacidosis

DKA involves acute metabolic changes in the body due to lack of insulin or poor response to insulin due to stress or illness. It is characterized by hyperglycemia, ketosis, and acidosis, leading to osmotic diuresis and dehydration. The key to treatment of DKA is volume repletion, insulin therapy, and specific metabolic corrections.

Go to Diabetic Ketoacidosis for complete information on this topic.

Dawn and Somogyi phenomena

The dawn phenomenon is the normal tendency of the blood glucose to rise in the early morning before breakfast. This rise in glucose, which may be due to the nocturnal spikes in growth hormone causing insulin resistance, is probably enhanced by increased hepatic gluconeogenesis secondary to the diurnal rise in serum cortisol. Augmented hepatic gluconeogenesis and glycogen cycling are known in patients with type 1 diabetes mellitus. However, both abnormalities, regardless of the duration of diabetes, can be corrected with intensified insulin therapy.^[83]

In some patients, however, nocturnal hypoglycemia may be followed by a marked increase in fasting plasma glucose with an increase in plasma ketones (Somogyi phenomenon). Thus, both the dawn and Somogyi phenomena are characterized by morning hyperglycemia, but the latter is considered to be rebound (counter-regulation) hyperglycemia. The existence of true Somogyi phenomenon is a matter of intense debate.

In cases of dawn phenomenon, the patient should check blood glucose levels at 2-4 am. The dawn and Somogyi phenomena can be ameliorated by administering intermediate insulin at bedtime.

Use of insulin

The insulin coverage, with a sliding scale for insulin administration, should not be the only intervention, because it is reactive, rather than proactive, in correcting hyperglycemia. Also, insulin may be used inappropriately when hyperglycemia reflects hepatic gluconeogenesis in response to previously uncorrected hypoglycemia.

Continue intermediate (ie, neutral protamine Hagedorn [NPH], Lente) insulin at 50-70% of the daily dose divided bid or, occasionally, tid. Administer supplemental regular insulin on a sliding scale. Blood glucose should be monitored before meals and at bedtime.

People with diabetes are susceptible to various types of infections. The most common sites affected are the skin and urinary tract system.

Ear, nose, and throat infections

Two head and neck infections that are associated with high rates of morbidity and mortality are malignant otitis externa and rhinocerebral mucormycosis; these are seen almost exclusively in patients with diabetes.

With malignant or necrotizing otitis externa, prompt surgical consultation is mandatory for malignant otitis externa because surgical debridement is often an essential part of therapy. Intravenous antipseudomonal antibiotics should be started immediately in patients with invasive disease. Patients with diabetes with severe otitis externa but no evidence of invasive disease can be treated with an otic antibiotic drop and oral ciprofloxacin; they require close follow-up.

Treatment of rhinocerebral mucormycosis consists of controlling the predisposing hyperglycemia and acidemia, giving intravenous amphotericin B, and immediate surgical debridement. Until the diagnosis is confirmed, antistaphylococcal antibiotic therapy is appropriate.

Urinary tract infections

The treatment of cystitis is essentially the same as that in patients without diabetes, except that longer courses of therapy are generally recommended (eg, 7 d for uncomplicated cystitis). Individuals with a neurogenic bladder due to diabetic neuropathy may not empty their bladder well and may require urologic referral.

Treatment of pyelonephritis does not differ for patients with diabetes, but a lower threshold for hospital admission is appropriate. First, pyelonephritis makes control of diabetes more difficult by causing insulin resistance; in addition, nausea may limit the patient’s ability to maintain normal hydration. The ensuing hyperglycemia further compromises their immune response. Second, patients with diabetes are more susceptible than others to complications of pyelonephritis (eg, renal abscess, emphysematous pyelonephritis, renal papillary necrosis, gram-negative sepsis). In one study, more than 70% of cases of emphysematous pyelonephritis occurred in patients with diabetes.^[84] Surgery is indicated after diagnosis.

Skin and soft tissue infections

Treatment with a penicillinase-resistant synthetic penicillin or a first-generation cephalosporin has been effective for the outpatient treatment of minor skin and soft tissue infections, but the increasing prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) must now be considered when selecting an antibiotic. Patients with diabetes do not appear to have a higher prevalence of CA-MRSA than comparable patients without diabetes.

Outpatient treatment of minor infections is appropriate for patients who are reliable, who monitor their blood glucose and urine ketone levels, and who have access to close follow-up.

For necrotizing infections of the skin, subcutaneous tissues, fascia, or muscle, surgical debridement is necessary for necrotizing infections. Gram stains and surface cultures are not helpful; antibiotic coverage should reflect the range of potential pathogens.

Go to Bullous Disease of Diabetes and Diabetic Ulcers for complete information on these topics.

Osteomyelitis

If osteomyelitis is apparent on physical examination (eg, if the wounds are deep enough to expose tendons or bone), radiography, or MRI, the patient should be admitted for intravenous antibiotics. If osteomyelitis is suspected but the soft tissue infection or metabolic disturbances do not warrant admission, the patient can be discharged for outpatient workup.

Patients with preproliferative or proliferative retinopathy must immediately be referred for ophthalmologic evaluation because laser therapy is effective in this condition, especially before actual hemorrhage occurs.

Often, the first hemorrhage is small and is noted by the patient as a fleeting, dark area, or “floater,” in the field of vision. Because subsequent hemorrhages can be larger and more serious, the patient should be referred immediately to an ophthalmologist for possible laser therapy. Patients with retinal hemorrhage should be advised to limit their activity and keep their head upright (even while sleeping), so that the blood settles to the inferior portion of the retina, thus obscuring less central vision.

Patients with active proliferative diabetic retinopathy are at increased risk of retinal hemorrhage if they receive thrombolytic therapy; therefore, this condition is a relative contraindication to the use of thrombolytic agents.

Although metabolic control and smoking cessation remain protective, hypertension affects progression to severe retinopathy, thus validating the concept of multifactorial intervention.^[85]

Go to Diabetic Retinopathy and Macular Edema, Diabetic for complete information on these topics.

Extreme care should be exercised when using any nephrotoxic agent in a patient with diabetes. Potentially nephrotoxic drugs should be avoided whenever possible. Renally excreted or potentially nephrotoxic drugs should be given at reduced doses appropriate to the patient’s serum creatinine level.

In particular, caution should be used when contrast-enhanced studies are being considered in patients with diabetes having a creatinine level greater than 2 mg/dL; such studies should absolutely be avoided in patients with a creatinine level greater than 3 mg/dL. Patients with diabetes who must undergo such studies should be well hydrated before, during, and after the study, and their renal function should be carefully monitored.^[86] A better solution is to seek equivalent clinical information by using an alternative study that does not require the use of contrast material (eg, sonography, noncontrast CT, MRI).

The 2011 ADA standard of care recommends annual screening for nephropathy. All adults with diabetes should have serum creatinine measured at least annually. In adults (and children aged 10 years or older) who have had type 1 DM for 5 or more years, annual assessment of urine albumin excretion is appropriate. When chronic kidney disease is present, reduction of protein intake may improve renal function. If kidney disease is advanced, difficult to manage, or its etiology is unclear, consider referral to a physician with experience in kidney disease patient care.^[61]

Hypertensive patients with diabetes must be referred for long-term management of their blood pressure. If antihypertensive therapy is started in the ED, an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) should be used because these classes of agents decrease proteinuria and slow the decline in renal function independent of the effect on blood pressure.^[87] ACE inhibitors and ARBs tend to increase the serum potassium levels and therefore should be used with caution in patients with renal insufficiency or elevated serum potassium levels.

Go to Diabetic Nephropathy for complete information on this topic.

Autonomic dysfunction can involve any part of the sympathetic or parasympathetic chains and produce myriad manifestations.^{[35, 88]} Patients likely to seek care in the ED are those with diabetic gastroparesis and vomiting, severe diarrhea, bladder dysfunction and urinary retention, or symptomatic orthostatic hypotension. Treatment of gastroparesis is symptomatic, and symptoms tend to wax and wane. Patients with gastroparesis may benefit from metoclopramide or erythromycin.

Before these therapies are started, the degree of dehydration and metabolic imbalance must be assessed, and other serious causes of vomiting must be excluded. In severe cases, gastric pacing has been used. Patients with disabling orthostatic hypotension may be treated with salt tablets, support stockings, or fludrocortisone. Alleviating the functional abnormalities associated with the autonomic neuropathy is often difficult and frustrating for both doctor and patient. The patient's physician should be involved in devising a long-term treatment plan.

Go to Diabetic Neuropathy and Diabetic Lumbosacral Plexopathy for complete information on these topics.

Patients with diabetes presenting with wounds, infections, or ulcers of the foot should be treated intensively.^[89] In addition to appropriate use of antibiotics, avoidance of further trauma to the healing foot by using crutches, wheelchairs, or bed rest is mandatory. Patients should be treated by a podiatrist or an orthopedist with experience in the care of diabetic foot disease. If bone or tendon is visible, osteomyelitis is present, and hospitalization for intravenous antibiotics is often necessary. Many patients need a vascular evaluation in conjunction with local treatment of the foot ulcer because a revascularization procedure may be required to provide adequate blood flow for wound healing.

Because curing ulcers and foot infections is difficult, their prevention is extremely important.^[90] At one clinic, the rate of amputation was halved after patients were required to remove their shoes and socks at every visit. The emergency physician can facilitate this practice by briefly inspecting the feet of patients with diabetes and by educating them about the need for proper foot care. Patients with distal sensory neuropathy to pinprick or light touch, decreased peripheral pulses, moderate-to-severe onychomycosis, or impending skin breakdown should be referred to a podiatrist.

Charcot joint is a type of arthropathy observed in people with diabetes. It is a progressive deterioration of foot joints caused by underlying neuropathy. Tarsometatarsal and midtarsal joints are affected most commonly. Other neuromuscular foot deformities also may be present. Early diagnosis and treatment is important to prevent further joint degeneration.

A study by Belch et al found no evidence that nonviral 1 fibroblast growth factor (NV1FGF) is effective in reduction of amputation rate or death in patients with critical limb ischaemia.^[91]

Go to Diabetic Foot and Diabetic Foot Infections for complete information on this topic.

Subtle differences in the pathophysiology of atherosclerosis in patients with diabetes result in both earlier development and a more malignant course. Therefore, lipid abnormalities must be treated aggressively to lower the risk of serious atherosclerosis.^[92] This is important from an epidemiological point of view and has bearing on treatment strategies that must be used to mitigate the risk.^[93]

Prediction of cardiovascular risk in diabetic patients based on the lipid profile is not affected by the timing of blood specimen. Therefore, it may be unnecessary to insist on fasting blood samples to test lipid profile.^[94]

In diabetic adolescents and children, nocturnal hypertension was significantly associated with daytime blood pressure and carotid intima-media thickness (cIMT), which could be precursors to atherosclerotic cardiovascular disease later in life. This study warrants confirmation and longitudinal follow-up.^[95]

Patients with diabetes may have increased incidence of silent ischemia.^[39] However, silent ischemia is common in many patients with CAD, and the apparently increased incidence may be because patients with diabetes are more likely than others to have CAD to begin with. Nevertheless, an electrocardiogram (ECG) is prudent in patients with diabetes and a serious illness or who present with generalized weakness, malaise, or other nonspecific symptoms that are not expected to be due to myocardial ischemia.

One of the first steps in managing type 1 DM is diet control. According to ADA policy, dietary treatment is based upon nutritional assessment and treatment goals. Diet recommendations should be made in view of the patient’s eating habits and lifestyle.

Diet management includes education about the timing, size, frequency, or composition of meals to avoid hypoglycemia or postprandial hyperglycemia.^[96] All patients on insulin should receive a comprehensive diet plan that includes a daily caloric intake prescription; recommendations for amounts of dietary carbohydrate, fat, and protein; and how to divide calories between meals and snacks. A professional dietitian should be involved to create the individual diet plan.

In these patients, the caloric distribution is important; a recommended distribution consists of 20% of daily calories for breakfast, 35% for lunch, 30% for dinner, and 15% for late evening snack.

The minimum protein requirement for good nutrition is 0.9 g/kg/d (range = 1-1.5 g/kg/d), but a reduced protein intake is indicated in cases of nephropathy.

Fat intake should be limited to 30% or less of the total calories, and a low-cholesterol diet is recommended.

Patients should consume sucrose in moderation and increase their fiber intake. In some cases, midmorning and midafternoon snacks are important to avoid hypoglycemia.

Exercise is an important aspect of diabetes management. Patients should be encouraged to exercise regularly. Educate the patients about the effects of exercise on the blood glucose level. If patients are planning to participate in rigorous exercise for more than 30 minutes, they may develop hypoglycemia. To prevent hypoglycemia, they either can decrease the insulin by 10-20% or can have an extra snack. These patients must maintain their hydration status during exercise.

Serious medical illness and surgery produce a state of increased insulin resistance and relative insulin deficiency. Hyperglycemia can occur, even in patients without diabetes, because of stress-induced insulin resistance plus the use of dextrose-containing intravenous fluids. Increases in glucagon, catecholamines, cortisol, and growth hormone levels antagonize the effects of insulin, and the alpha-adrenergic effect of increased catecholamine levels inhibits insulin secretion. Counterregulatory hormones also directly increase hepatic gluconeogenesis.

In certain circumstances, such as following cardiovascular surgery and during treatment in a surgical ICU, it has been shown to be very important to maintain near-normal blood glucose levels (around 100 mg/dL) using insulin in patients with acute hyperglycemia of illness.^[97] Much less data exist on optimal blood glucose levels in hospitalized patients with preexisting diabetes whose hyperglycemia reflects both their diabetes and a stress response to illness. Nonetheless, to manage patients in the hospital with preexisting diabetes, it is necessary to modify treatment regimens to compensate for both the decreased caloric intake and increased physiologic stress. Near-normal blood glucose levels should be maintained in medical and surgical patients with diabetes for the following reasons:

• To prevent the development of ketosis
• To prevent electrolyte abnormalities and volume depletion secondary to osmotic diuresis
• To prevent impairment of leukocyte function that occurs when blood glucose levels are elevated
• To prevent impairment of wound healing that occurs when glucose levels are elevated

Patients with type 1 diabetes must take in insulin and carbohydrate at all times to prevent ketosis. It is strongly recommended that continuous intravenous infusions of dextrose and insulin be used in patients who are undergoing general anesthesia or who are critically ill. Blood glucose levels must be measured with a glucose meter every hour, and the rates of insulin and dextrose infusion adjusted accordingly to prevent hypoglycemia or persistent hyperglycemia.^[98] Algorithms are available for insulin infusions, and use of a preprinted order facilitates administration and reduces dosing errors.

Frequent blood glucose monitoring is not always possible, and patients with less serious illness or those undergoing minor surgery may do as well with subcutaneously injected insulin. A basal bolus insulin regimen rather than sliding scale regular insulin should be used in these patients.^[24]

The same principles of providing a constant source of insulin and carbohydrate apply to patients with type 1 diabetes who must also take nothing by mouth (NPO) for medical reasons. Patients should receive a basal insulin, such as glargine or detemir insulin, with additional correction doses using regular insulin or a rapid-acting insulin (eg, lispro). To avoid hypoglycemia, regular insulin should not be given more often than every 3-4 hours because a dose is effective for up to 6 hours. Rapid-acting insulins may be given every 3 hours. Once the patient is eating, a preprandial insulin dose can be added.

Cardiovascular disease or renal dysfunction increases surgical morbidity and mortality, and diabetic autonomic neuropathy increases the risk of cardiovascular instability. The emergency physician caring for patients with diabetes who require emergency surgery must notify the surgeon and the anesthesiologist of the patient’s condition, consult medical specialists when appropriate, and promptly initiate a thorough medical evaluation.

Perioperative blood glucose management

Surgical procedures, inclusive of presurgery emotional stress, the effects of general anesthesia, and the trauma of the procedure, can markedly increase plasma glucose levels and induce DKA in patients with type 1 DM.

In patients going to surgery who have not received a dose of intermediate-acting insulin that day, an injection of one third to one half of the patient’s total daily dose as NPH insulin or 80% of the dose as glargine (Lantus) or detemir (Levemir) insulin before surgery is often effective. At the same time, an intravenous infusion containing 5% glucose in either 0.9% sodium chloride solution or water should be started at a rate of 1 L (50 g glucose) over 6-8 hours (or 125-150 mL/h). Blood glucose levels should be checked every 2 hours during surgery, and small doses of regular or rapid-acting insulin (lispro [Humalog], aspart [NovoLog], or glulisine [Apidra]) insulin should be given if values are greater than 140 mg/dL.

After the operation, check plasma glucose levels and assess for a reaction to ketones. Unless a change in dosage is indicated, repeat the preoperative dose of insulin when the patient recovers from the anesthesia and continue the glucose infusion.

Monitor plasma glucose and ketones at 2- to 4-hour intervals and administer regular insulin every 4-6 hours as needed to maintain the plasma glucose level at 100-250 mg/dL (ie, 5.55-13.88 mmol/L). Continue until the patient can be switched to oral feedings and a 2- or 3-dose insulin schedule.

Some physicians prefer to withhold subcutaneous insulin on the day of the operation and to add 6-10 units of regular insulin to 1 L of 5% glucose in 0.9% sodium chloride solution or water infused initially at 150 mL/h on the morning of the operation, depending on the plasma glucose level. The infusion is continued through recovery, with insulin adjustments depending on the plasma glucose levels obtained in the recovery room and at 2- to 4-hour intervals thereafter. The use of an intravenous insulin infusion in the postoperative period after major surgical procedures now is considered the standard of care in most hospitals.

Go to Perioperative Management of the Diabetic Patient for complete information on this topic.

Because pregnant patients with type 1 DM are at risk for multiple poor maternal and fetal outcomes, it is essential to provide these patients with prepregnancy counseling, good glycemic control prior to and during pregnancy, and a complete medical evaluation. High-risk areas include exacerbation of existing hypertension, renal insufficiency, retinopathy, and more frequent congenital anomalies. These patients should be referred to obstetricians specializing in high-risk pregnancies.

In women with type 1 diabetes, postprandial glucose control is significantly impaired in late gestation. It is largely accounted for by slower glucose disposal.^[99] Early prandial insulin should help accelerate glucose disposal and potentially improve or ameliorate postprandial hyperglycemia in late pregnancy.

Little evidence supports any substantial increase in childhood type 1 diabetes risk following pregnancy complicated by preeclampsia.^[100]

Despite advanced age, multiparity, obesity, and social disadvantage, patients with type 2 diabetes were found to have better glycemic control, fewer large for gestational age infants, fewer preterm deliveries, and fewer neonatal care admissions compared with patients with type 1 diabetes. This suggests that better tools are needed to improve glycemic control in patients with type 1 diabetes.^[101]

Go to Diabetes Mellitus and Pregnancy for complete information on this topic.

Pancreatic transplantation is a possibility in some referral centers and is performed most commonly with simultaneous kidney transplantation for end-stage renal disease.

Go to Perioperative Management of the Diabetic Patient for complete information on this topic.

Due to significant improvement in prediction of type 1 DM, several prevention trials are ongoing (eg, the Diabetes Prevention Trial – Type 1 [DPT-1] and the European Nicotinamide Diabetes Intervention Trial [ENDIT]).

The objective of DPT-1, a multicenter US trial, is to determine whether antigen-based (insulin) treatment of nondiabetic relatives prevents or delays the onset of clinical disease. As compared to the general population, in which the risk of developing type 1 diabetes is 1 per 300, the risk increases 15- to 20-fold in relatives of people with type 1 diabetes, especially first-degree relatives.

Antigen-based immunotherapy with 2 or 3 doses of glutamic acid decarboxylase formulated with aluminum hydroxide (GAD-alum) vaccine for 4-12 weeks in patients with newly diagnosed type-1 diabetes did not alter the course of loss of insulin secretion during the first year. Although antigen-based therapies are desirable and effective in animal studies, translation to human autoimmune disease remains troubling.^[102]

Accurate assignment of risk in these relatives is determined by assessing immune, genetic, and metabolic markers. The strategy for DPT-1 was to screen for islet cell antibodies (ICA), which further enhances risk, in approximately 100,000 first- and second-degree relatives who are younger than 45 years. This trial was one of the first large multicenter, randomized, placebo-controlled trials attempting prevention of diabetes in high-risk patients. It was organized to determine if either subcutaneous insulin or oral insulin could prevent or delay the onset of type 1 diabetes.

Both strategies showed excellent safety profiles. However, the DPT-1 failed to show therapeutic benefit for either approach. Posthoc analysis of DPT-1 data showed subjects who received oral insulin experienced considerable delays in the onset of diabetes. This observation lead to an appropriately powered study by TrialNet to see if oral insulin can be used to delay the onset of type 1 diabetes. This study is currently underway.

The ENDIT study will prospectively address whether nicotinamide will reduce the rate of progression to DM in relatives. Forty thousand first-degree relatives (aged 5-40 y) have been screened, with 552 subjects (ICA titers ≥20 Juvenile Diabetes Foundation [JDF] U) randomized to nicotinamide or placebo. This study is designed with 90% power to detect a 35% reduction in disease (placebo group estimated at 40% risk over 5 y). The ENDIT study failed to show any benefit.

These patients should be referred to an endocrinologist for multidisciplinary management. They should also have a complete retinal examination by an ophthalmologist at least once a year. Those patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist.