AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

Diabetes mellitus (DM) is a multisystem disease with both biochemical and anatomical consequences. It is a chronic disease of carbohydrate, fat, and protein metabolism caused by the lack of insulin. In type 1 diabetes, insulin is functionally absent because of the destruction of the beta cells of the pancreas. Type 1 DM occurs most commonly in juveniles but can occur in adults, especially in those in their late 30s and early 40s. Unlike people with type 2 DM, those with type 1 DM generally are not obese and may present initially with diabetic ketoacidosis (DKA).

Pathophysiology

Type 1 DM is a catabolic disorder in which circulating insulin is very low or absent, plasma glucagon is elevated, and the pancreatic beta cells fail to respond to all insulin-secretory stimuli. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism.

Type 1 DM is an autoimmune disease. The pancreas shows lymphocytic infiltration and destruction of insulin-secreting cells of the islets of Langerhans, causing insulin deficiency. Approximately 85% of patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. Most islet cell antibodies are directed against glutamic acid decarboxylase (GAD) within pancreatic B cells.

One theory regarding the etiology of type 1 DM is that it results from damage to pancreatic beta cells from an infectious or environmental agent. It triggers the immune system in a genetically susceptible individual to develop an autoimmune response against altered pancreatic beta cell antigens or molecules in beta cells that resemble a viral protein. Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. Prevalence is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Approximately 95% of patients with type 1 DM have either human leukocyte antigen (HLA)-DR3 or HLA-DR4. HLA-DQs are considered specific markers of type 1 DM susceptibility.

Environmental agents that have been hypothesized to induce an attack on beta cell function include viruses (eg, mumps, rubella, Coxsackie B4), toxic chemicals, exposure to cow's milk in infancy, and cytotoxins.

Recent evidence suggests a role for vitamin D in the pathogenesis and prevention of diabetes mellitus.

Frequency

United States

Roughly 5-15% of all cases of diabetes are type 1 DM. It is the most common metabolic disease of childhood, with a yearly incidence of 15 cases per 100,000 people younger than 18 years. Approximately 1 million Americans have type 1 DM, and physicians diagnose 10,000 new cases every year.

According to the American Diabetes Association, there are 20.8 million children and adults in the United States, or 7% of the population, who have diabetes. While an estimated 14.6 million have been diagnosed, unfortunately, 6.2 million people (or nearly one-third) are undiagnosed. Fifty-four million people are prediabetes status. In people younger than 20 years, 176,500 cases, or 0.22% of all people in this age group, have diabetes. About one in every 400-600 children and adolescents has type 1 DM. Two million adolescents (or 1 in 6 overweight adolescents) aged 12-19 years have prediabetes status. In people aged 20 years or older, 1.5 million new cases of diabetes were diagnosed  in 2005.

International

Scandinavia has the highest prevalence rates for type 1 DM (ie, approximately 20% of the total number of people with DM), while China and Japan have the lowest prevalence rates, with less than 1% of all people with diabetes. Some of these differences may relate to definitional issues and the completeness of reporting.

Mortality/Morbidity

Type 1 DM is associated with a high morbidity and premature mortality due to complications. The annual financial cost from diabetes overall exceeds $100 billion, almost $1 of every $7 dollars of US health expenditures in terms of medical care and loss of productivity. Advances in treatment that permit tight glycemic control and control of comorbidities (hyperlipidemia) can greatly reduce the incidence of microvascular and macrovascular complications.

As a result of these complications, people with diabetes have an increased risk of developing ischemic heart disease, cerebral vascular disease, peripheral vascular disease with gangrene of lower limbs, chronic renal disease, reduced visual acuity and blindness, and autonomic and peripheral neuropathy.

Race

Type 1 DM is more common among non-Hispanic whites, followed by African Americans and Hispanic Americans. It is comparatively uncommon among Asians.

Sex

Type 1 DM is more common in men than in women.

Age

Type 1 DM usually starts in children aged 4 years or older, with the peak incidence of onset at age 11-13 years, coinciding with early adolescence and puberty. Also, a relatively high incidence exists in people in their late 30s and early 40s, when it tends to present in a less aggressive manner, ie, early hyperglycemia without ketoacidosis and gradual onset of ketosis.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

The most common symptoms of type 1 diabetes mellitus (DM) are polyuria, polydipsia, and polyphagia, along with lassitude, nausea, and blurred vision, all of which are due to the hyperglycemia itself. The disease onset may be sudden, with the presentation of an infection. It is not unusual for type 1 DM to present with ketoacidosis; it may occur de novo or develop with the stress of illness or surgery. An explosive onset of symptoms in a young lean patient with ketoacidosis always has been considered diagnostic of type 1 DM.

• Polyuria and thirst: Polyuria is due to osmotic diuresis secondary to hyperglycemia. Thirst is due to the hyperosmolar state and dehydration.
• Polyphagia with weight loss: The weight loss with a normal or increased appetite is due to depletion of water and a catabolic state with reduced glycogen, proteins, and triglycerides.
• Fatigue and weakness: This may be due to muscle wasting from the catabolic state of insulin deficiency, hypovolemia, and hypokalemia.
• Muscle cramps: This is due to electrolyte imbalance.
• Nocturnal enuresis: Severe enuresis secondary to polyuria can be an indication of onset of diabetes in young children.
• Blurred vision: This also is due to the effect of the hyperosmolar state on the lens and vitreous humor. Glucose and its metabolites cause dilation of the lens, altering its normal focal length.
• Gastrointestinal symptoms: Nausea, abdominal discomfort or pain, and change in bowel movements may accompany acute DKA. Acute fatty liver may lead to distention of the hepatic capsule, causing right upper quadrant pain. Persistent abdominal pain may indicate another serious abdominal cause of DKA, eg, pancreatitis. Chronic gastrointestinal symptoms in the later stage of diabetes are due to visceral autonomic neuropathy.
• Patients may maintain their normal weight or exhibit wasting, depending on the interval between the onset of the disease and initiation of treatment.
• Peripheral neuropathy: This presents as numbness and tingling in both hands and feet, in a glove and stocking pattern. It is bilateral, symmetric, and ascending neuropathy, which results from many factors, including the accumulation of sorbitol in peripheral sensory nerves due to sustained hyperglycemia.
• Symptoms at the time of the first clinical presentation can usually be traced back several days to several weeks; however, beta cell destruction may have started months, or even years, before the onset of clinical symptoms.

Physical

In new cases of diabetes, physical examination findings are usually normal, except in DKA, wherein signs of Kussmaul respiration, dehydration, hypotension, and, in some cases, altered mental status are present.

In established cases, patients should be examined every 3 months for macrovascular and microvascular complications. They should have funduscopic examination for retinopathy and monofilament testing for peripheral neuropathy.

Causes

The etiology of type 1 DM has a strong genetic component. Nevertheless, identical twins have a concordance rate for type 1 DM of less than 50%. Extragenetic factors also may contribute, which are discussed in Pathophysiology.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Maturity-onset diabetes of youth (MODY), a rare autosomal dominant condition found primarily in whites
Secondary hyperglycemia
Disorders of target tissues (liver, muscles, adipose tissue)
Endocrine disorders - Endocrine tumor causing increased production of growth hormone, glucocorticoids, catecholamines, glucagon, and somatostatin; Addison disease; Graves disease; Hashimoto thyroiditis; acanthosis nigricans (genetic disorders with insulin resistance)

Drugs - Thiazide diuretics, phenytoin, glucocorticoids
Chronic pancreatitis
Cystic fibrosis
Prader-Willi syndrome - Mental retardation, muscular hypotonia, obesity, short stature, and hypogonadism associated with diabetes mellitus (DM)

Nondiabetic glycosuria

Renal glycosuria - Glucose appears in urine despite normal glucose concentration in blood. This glucose may be due to an autosomal genetic disorder or dysfunction of the proximal renal tubule (eg, Fanconi syndrome, chronic renal failure), or it may be due to increased glucose load on tubules by the elevated glucose filtration rate during pregnancy.

Peripheral neuropathy due to alcohol and vitamin B-12 deficiency

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Blood glucose: In asymptomatic patients, physicians diagnose diabetes mellitus (DM) using the American Diabetes Association (ADA) recommendation of 2 different fasting plasma glucose levels of greater than 125 mg/dL (ie, >6.99 mmol/L). In symptomatic patients, a random glucose of 200 mg/dL suggests diabetes. All finger stick capillary glucose levels must be confirmed in serum or plasma to make the diagnosis.
• Serum electrolytes
• Urinalysis for glucose, ketones, and protein: Urine ketones are not reliable for diagnosing or monitoring DKA. Rather, the plasma acetone, and, specifically, the beta-hydroxybutyrate level, is a reliable indicator of DKA.
• White blood cell count and blood and urine cultures to rule out infection
• Glycosylated hemoglobin (Hb) or Hb A1c
• • Hb A1c is the stable product of nonenzymatic irreversible glycosylation of the beta chain of Hb by plasma glucose and is formed at rates that increase with increasing plasma glucose levels.
  • Most physicians periodically determine Hb A1c to estimate plasma glucose control during the preceding 1-3 months. Hb A1c is not a specific test for diagnosing diabetes; however, elevated Hb A1c often indicates existing diabetes.
  • Glycated hemoglobin predicts the progression of diabetic microvascular complications. The reference range for nondiabetic people is 6% in most laboratories. levels of 9% and above indicate poor glycemic control in people with diabetes, and the ADA recommends levels of less than 8%—or better, less than 7%.
  • Fructosamine levels also test for glucose levels. Fructosamine is formed by a chemical reaction of glucose with plasma protein and reflects glucose control in the previous 1-3 weeks. This assay, therefore, may show a change in control before Hb A1c and often is helpful when applying intensive treatment and in short-term clinical trials.
• Oral glucose tolerance test with insulin levels: Although this test is usually considered unnecessary to make the diagnosis in type 1 DM, with the dramatic increase of type 2 diabetes in the young population, assessment of insulin secretion may become more important.
• To determine whether the individual has type 1 rather than type 2 DM, an insulin and/or C-peptide level below 5 µU/mL, or 0.6 ng/mL, suggests type 1. C-peptide is formed during conversion of proinsulin to insulin. A high positive titre of glutamic acid decarboxylase antibodies also suggests type 1 DM. An exception is the individual with type 2 DM who presents with a very high glucose, eg, above 300 mg/dL, who temporarily has a low insulin and/or C-peptide level but who will recover insulin production once normal glucose is restored.
• Islet cell antibodies
• Thyroxine (T4) and thyroid antibodies

Other Tests

• Intravenous glucose test for possible early detection of subclinical diabetes
• HLA typing may be considered.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Treatment of this disease requires a multidisciplinary approach by physician, nurse, and dietitian.

• Type 1 diabetes mellitus (DM) patients require insulin therapy to control initial hyperglycemia and maintain serum electrolytes and hydration. At times, the first incidence of ketoacidosis 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.
• 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.
• 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 glucoses 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.

Surgical Care

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

Consultations

These patients should be referred to an endocrinologist for multidisciplinary management.

• These patients should have a complete retinal examination by an ophthalmologist at least once a year.
• The patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist.

Diet

One of the first steps in managing type 1 DM is diet control. According to the ADA policy, the diet 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. 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.

Activity

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.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Insulin injected subcutaneously is the first-line therapy in the treatment of type 1 diabetes. The different types of insulin are based upon their times of onset and durations of action. Short-, intermediate-, and long-acting insulins are available. Regular, lispro, and aspart insulins are the only types that can be administered intravenously.

• Human insulin currently is the only species of insulin available in the United States, and it is less antigenic than previously used animal-derived varieties.
• Rapid-acting insulins include regular insulin, lispro, and aspart insulin. Regular insulin is a preparation of zinc insulin crystals in solution. Its onset of action is 0.5-1 h, it peaks at 2.5-5 h, and duration of action is 6-8 h. Lispro insulin is a form of regular insulin that is genetically engineered with the reversal of the amino acids lysine and proline 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 glargine insulin, 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.
• 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 glargine insulin, 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.

Drug Category: Rapid-, short-, and intermediate-acting insulins

Rapid- and short-acting insulins have the most rapid onsets of action and are used whenever quick glucose utilization is needed (eg, before meals, when blood glucose >250 mg/dL). They stimulate proper utilization of glucose by the cells and reduce blood sugar levels.

Intermediate-acting insulins have slower onsets of action and longer durations of action and are usually administered in combination with faster-acting insulins to maximize benefits of a single injection.

Drug Category: Long-acting insulins

These insulins offer a very long duration of action and, when combined with faster-acting insulins, offer better glucose control for some patients.

Drug Category: Amylin analogs

Elicit endogenous amylin effects by delaying gastric emptying, decreasing postprandial glucagon release, and modulating appetite.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Hypoglycemia/hyperglycemia (DKA)
• • 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.
  • Regular insulin doses may cause hypoglycemia if the patient becomes anorectic or has another cause for reduced food intake, has gastroparesis, or is vomiting.
  • 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, 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.
• Care during surgical procedures
• • 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 who normally take 1-2 daily injections of insulin, a third to a half of the usual morning dose can be administered in the morning before the operation and an IV infusion of 5% glucose in either 0.9% sodium chloride solution or water administered at a rate of 1 L (50 g glucose) over 6-8 hours. For additional information, see Perioperative Medication Management and Perioperative Management of the Diabetic Patient .
  • 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.

Further Outpatient Care

• The primary care physician should help patients both to acknowledge and to understand the course of diabetes, and the physician should reassure patients about the prognosis. Patients with diabetes should be taught that they have a chronic condition that requires lifestyle modification. Patients should be made aware that they are likely to have chronic complications if they do not take control of their disease.
• 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 sugar level and Hb A1c 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 if they find 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.
  • Because people with diabetes have an increased risk of acute renal failure, perform radiographic studies that require IV injection of contrast dyes only when absolutely necessary and only when the patient is well hydrated.
  • 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.
• 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.

Deterrence/Prevention

• Due to significant improvement in prediction of type 1 DM, several prevention trials are ongoing (eg, Diabetes Prevention Trial – Type 1 [DPT-1], European Nicotinamide Diabetes Intervention Trial [ENDIT]).
• • Diabetes Prevention Trial - Type 1: The objective of this multicenter US trial was 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. 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 80,000 first- and second-degree relatives who are younger than 45 years. Researchers randomized subjects who fall into the high-risk group (ie, 5-y risk >50%) to receive either an annual 4-day intravenous insulin infusion followed by twice-daily low doses of subcutaneous injections of ultralente insulin or to be in a closely observed group.
  • The European Nicotinamide Diabetes Intervention Trial: 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 ³20 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). Analysis of data is expected in 2003.
• Pilot studies, nondiabetic relatives: Pilot studies conducted in high-risk nondiabetic relatives in the United States and in Germany (Fuchtenbusch) further suggest that parenteral insulin therapy may delay the onset of the disease.

Complications

Complications can be acute or chronic.

• Acute complications include the following:
• • Hypoglycemia
  • Local allergic reactions
  • DKA
• Chronic complications are further subdivided into macrovascular, microvascular, and miscellaneous.
• • Macrovascular complications
  • • Atherosclerosis
    • Cerebrovascular disease
    • Ischemic heart disease
    • Ischemia of lower limb (ie, gangrene)
  • Microvascular complications
  • • Peripheral neuropathy
    • Peripheral neuropathy with trophic ulceration
    • Diabetic retinopathy, cataract, glaucoma
    • Diabetic nephropathy
  • Miscellaneous complications
  • • Skin infections
    • Necrobiosis lipoidica

A more detailed discussion of some of the possible complications is as follows:

• Hypoglycemia
• • This may be due to change in insulin dose, a small or missed meal, or strenuous exercise. Common symptoms are light-headedness, dizziness, confusion, shakiness, sweating, and headache.
  • Patients should be educated about symptoms of hypoglycemia 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 emergency, initial treatment is a bolus injection of 25 mL of 50% glucose solution followed by a continuous glucose infusion.
  • 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. However, in some patients, 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 due to rebound (counter-regulation) hyperglycemia. 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.
• Local allergic reactions
• • 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.
  • These reactions usually resolve spontaneously without any intervention.
  • 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.
• Diabetic ketoacidosis
• • DKA is 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.
• Macrovascular complications (ie, atherosclerosis): People with diabetes experience accelerated atherosclerosis. It affects small arterioles with the following predominant effects:
• • Heart: Coronary atherosclerosis often occurs earlier and is more severe and extensive than in those without diabetes, increasing the risk of ischemic heart disease.
  • Brain: Atherosclerosis of the internal carotid and vertebrobasilar arteries and their branches predisposes to cerebral ischemia.
  • Lower extremity: Severe atherosclerosis of the iliofemoral and smaller arteries of the lower legs predisposes to gangrene. Ischemia of a single toe or ischemic areas on the heel are characteristic of diabetic peripheral vascular disease. This is due to the involvement of much smaller and more peripheral arteries.
  • Kidneys: Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. It is a significant component of multiple renal lesions in diabetes. Nephropathy is a significant life-threatening complication and is due to the adverse effects of glucose-induced preglomerular vasodilation on glomerular hemodynamics. Glomerulosclerosis is initiated early in the course of diabetic nephropathy by exacerbated expression of cytokines like tumor growth factor beta 1. However, not all people with type 1 DM are at risk of nephropathy because of some polymorphisms in the various factors involved in its pathogenesis, which can modulate the course of this disease from one person to the other. Although end-stage renal disease (ESRD) is one of the most severe complications of type 1 DM, the incidence of ESRD has been very low, 2.2% at 20 years after diagnosis and 7.8% at 30 years after diagnosis.¹
• Microvascular disease
• • This is a significant feature of diabetes and causes multiple pathological complications. Hyaline arteriosclerosis, a characteristic pattern of wall thickening of small arterioles and capillaries is wide- spread and is responsible for ischemic changes in the kidney, retina, brain, and peripheral nerves.
  • In the kidneys, this wall thickening leads to diabetic nephropathy, which is characterized by proteinuria, glomerular hyalinization (Kimmelstiel-Wilson), and chronic renal failure.
• In the retina, this condition causes diabetic retinopathy. It is the leading cause of blindness in the United States in people younger than 60 years and affects the eyes in the following different ways:
• • Background retinopathy: This complication is due to retinal small vessel abnormality leading to hard exudates, hemorrhages, and microaneurysms. It does not affect acuity.
  • Proliferative retinopathy: This is due to extensive proliferation of new retinal small blood vessels. A sudden loss of vision can occur due to vitreous hemorrhage from proliferating new vessels or retinal detachment.
  • Maculopathy: This complication is due to edema and hard exudate or retinal ischemia. It causes a marked reduction of acuity.
  • Cataract: This is frequent in people with diabetes.
  • Glaucoma: This condition relates to the neovascularization of the iris, rubeosis iridis.
• In the brain, the condition causes lacunar infarction and ischemic white matter degeneration.
• In the peripheral nerves, diabetes causes peripheral neuropathy. Four types of diabetic neuropathies develop, including (1) peripheral distal symmetrical polyneuropathy, predominantly sensory; (2) autonomic neuropathy; (3) proximal painful motor neuropathy; and (4) cranial mononeuropathy (ie, III, IV, VI). Sensory and autonomic neuropathy are due to axonal degeneration and segmental demyelination. Motor neuropathy and cranial mononeuropathy are due to vascular disease in blood vessels supplying nerves.
• Infections: People with diabetes are susceptible to various types of infections. The most common sites affected are the skin and urinary tract system. Increased risk of staphylococcal follicular skin infections, superficial fungal infections, cellulitis, erysipelas, and oral or genital candidal infections exists. These patients develop frequent lower urinary tract infections and are at increased risk of acute pyelonephritis.
• Necrobiosis lipoidica: 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.
• 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.

Prognosis

Controlling blood glucose, Hb A1c, lipids, blood pressure, and weight are important prognostic factors and predict the development of long-term macrovascular and microvascular complications. More than 60% of patients with type 1 DM fare reasonably well over the long term. Many of the rest develop blindness, end-stage renal disease, and, in some cases, early death. If a patient with type 1 DM survives the period 10-20 years after onset of disease without fulminant complications, he or she has a high probability of reasonably good health. Other factors affecting long-term outcomes are the patient's education, awareness, motivation, and intelligence level.

Patient Education

• Education is the most important aspect of diabetes management. The physician or the health care provider should educate the patient and, in the case of children, the parents about the disease process, management, goals, and long-term complications. They should be made aware of the signs and symptoms of hypoglycemia and ways to manage it.
• A dietitian should provide specific diet control education to the patient and family.
• A nurse should educate the patient about self–insulin injection and performing finger sticks for blood glucose level monitoring.
• For excellent patient education resources, visit eMedicine's Diabetes Center. Also, see eMedicine's patient education article Diabetes.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

The physician is often required to evaluate diabetes control in regards to personal and commercial drivers' licenses, pilots' licenses, and employment. Legal issues are often different in different locations. Loss of consciousness due to hypoglycemia is an event that a physician is often legally required to report.

Special Concerns

• People with diabetes are at high risk of acute renal failure under certain circumstances. Therefore, administer the intravenous contrast media required for some radiological studies cautiously and only when it is necessary in a well-hydrated patient.
• Because pregnancy in patients with type 1 diabetes is at risk for multiple poor maternal and fetal outcomes, prepregnancy counseling, good glycemic control prior to and during pregnancy, and complete medical evaluation are essential. 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.
• Adequate education for managing hypoglycemia is essential. Self-treatment techniques and glucagon use by family in emergencies are important skills.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Nov 2, 2007