Diabetes Mellitus, Type 1

Article Last Updated: Oct 19, 2007

AUTHOR AND EDITOR INFORMATION

William H Lamb, MD, FRCP, FRCPCH, Clinical Lecturer, Department of Child Health, The General Hospital, Bishop Auckland, UK
William H Lamb is a member of the following medical societies: British Medical Association
Editors: Arlan L Rosenbloom, MD, Adjunct Distinguished Service Professor Emeritus, Department of Pediatrics, University of Florida College of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; George P Chrousos, MD, FAAP, MACP, MACE, Professor and Chair, Department of Pediatrics, Athens University Medical School; Merrily P M Poth, MD, Professor, Department of Pediatrics and Neuroscience, Uniformed Services University of the Health Sciences; Stephen Kemp, MD, PhD, Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas and Arkansas Children's Hospital

 

INTRODUCTION

Background

Diabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or relative deficiency of insulin, an anabolic hormone. Insulin is produced by the beta cells of the islets of Langerhans located in the pancreas, and the absence, destruction, or other loss of these cells results in type 1 diabetes (insulin-dependent diabetes mellitus [IDDM]). Most children with diabetes have IDDM and a lifetime dependence on exogenous insulin.

Type 2 diabetes (non–insulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. Most patients with NIDDM have insulin resistance, and their beta cells lack the ability to overcome this resistance. Although this form of diabetes was previously uncommon in children, in some, countries 20% or more of new patients with diabetes in childhood and adolescence have NIDDM, a change associated with increased rates of obesity. Other patients may have inherited disorders of insulin release leading to maturity onset diabetes of the young (MODY).

This chapter addresses only IDDM.

Pathophysiology

Insulin is essential to process carbohydrates, fat, and protein. Insulin reduces blood glucose levels by allowing glucose to enter muscle cells and by stimulating the conversion of glucose to glycogen (glycogenesis) as a carbohydrate store. Insulin also inhibits the release of stored glucose from liver glycogen (glycogenolysis) and slows the breakdown of fat to triglycerides, free fatty acids, and ketones. It also stimulates fat storage. Additionally, insulin inhibits the breakdown of protein and fat for glucose production (gluconeogenesis) in both liver and kidneys.

Hyperglycemia (ie, random blood glucose concentration more than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to uninhibited gluconeogenesis and prevents the use and storage of circulating glucose. The kidneys cannot reabsorb the excess glucose load, causing glycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and protein breakdown leads to ketone production and weight loss. Without insulin, a child with IDDM wastes away and eventually dies from diabetic ketoacidosis (DKA).

An excess of insulin prevents the release of glucose into the circulation and results in hypoglycemia (blood glucose concentrations of < 60 mg/dL or 3.5 mmol/L). Glucose is the sole energy source for erythrocytes, kidney medulla, and the brain.

Frequency

United States

Overall incidence is approximately 15 cases per 100,000 individuals annually and probably increasing. An estimated 3 children out of 1000 develop IDDM by age 20 years.

International

DM exhibits wide geographic variation in incidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 persons in China, to 41.4 cases per 100,000 in Finland. Substantial variations exist between nearby countries with differing lifestyles, such as Estonia and Finland, and between genetically similar populations such as those in Iceland and Norway. Even more striking are the differences in incidence between mainland Italy (8.4/100,000) and the Island of Sardinia (36.9/100,000). These variations strongly support the importance of environmental factors in the development of IDDM. Most countries report that incidence rates have at least doubled or more in the last 20 years. Incidence appears to increase with distance from the equator.

Mortality/Morbidity

Information on mortality rates is difficult to ascertain without complete national registers of childhood diabetes, although age-specific mortality is probably double that of the general population. Particularly at risk are children aged 1-4 years who may die with DKA at the time of diagnosis. Adolescents are also a high-risk group. Most deaths result from delayed diagnosis or neglected treatment and subsequent cerebral edema during treatment for DKA, although untreated hypoglycemia also causes some deaths. Unexplained death during sleep may also occur.

IDDM complications are comprised of 3 major categories: acute complications, long-term complications, and complications caused by associated autoimmune diseases.

• Acute complications reflect the difficulties of maintaining a balance between insulin therapy, dietary intake, and exercise. Acute complications include hypoglycemia, hyperglycemia, and DKA.
• Long-term complications arise from the damaging effects of prolonged hyperglycemia and other metabolic consequences of insulin deficiency on various tissues. While long-term complications are rare in childhood, maintaining good control of diabetes is important to prevent complications from developing in later life. The likelihood of developing complications appears to depend on the interaction of factors such as metabolic control, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), pubertal status, and gender.Long-term complications include the following:
  • Retinopathy
  • Cataracts
  • Hypertension
  • Progressive renal failure
  • Early coronary artery disease
  • Peripheral vascular disease
  • Neuropathy, both peripheral and autonomic
  • Increased risk of infection
• Associated autoimmune diseases are common with IDDM, particularly in children who have the human leukocyte antigen DR3 (HLA-DR3). Some conditions may precede development of diabetes; others may develop later. As many as 20% of children with diabetes have thyroid autoantibodies.

Race

• Different environmental effects on IDDM development complicate the influence of race, but racial differences clearly exist.
• Whites have the highest reported incidence of IDDM; Chinese have the lowest.
• IDDM is 1.5 times more likely to develop in American whites than in American blacks or Hispanics.
• Current evidence suggests that when immigrants from an area with low incidence move to an area with higher incidence, their IDDM rates tend to increase toward the higher level.

Sex

• The influence of sex varies with the overall incidence rates.
• Males are at greater risk in regions of high incidence, particularly older males, whose incidence rates often show seasonal variation.
• Females appear to be at a greater risk in low-incidence regions.

Age

• Generally, incidence rates increase with age until mid-puberty then decline after puberty, but IDDM can occur at any age. Onset in the first year of life, though unusual, can occur and must be considered in any infant or toddler, because these children have the greatest risk for mortality if diagnosis is delayed. Their symptoms may include the following:
  • Severe monilial diaper/napkin rash
  • Unexplained malaise
  • Poor weight gain or weight loss
  • Increased thirst
  • Vomiting and dehydration, with a constantly wet napkin/diaper
• Where prevalence rates are high, a bimodal variation of incidence has been reported that shows a definite peak in early childhood (ie, 4-6 y) and a second, much greater peak of incidence during early puberty (ie, 10-14 y).

 

CLINICAL

History

• The most easily recognized symptoms are secondary to hyperglycemia, glycosuria, and ketoacidosis (KA).
• Hyperglycemia: Hyperglycemia alone may not cause obvious symptoms, although some children report general malaise, headache, and weakness. They may also appear irritable and become ill-tempered. The main symptoms of hyperglycemia are secondary to osmotic diuresis and glycosuria.
• Glycosuria: This condition leads to increased urinary frequency and volume (eg, polyuria), which is particularly troublesome at night (eg, nocturia) and often leads to enuresis in a previously continent child. These symptoms are easy to overlook in infants because of their naturally high fluid intake and diaper/napkin use.
• Polydipsia: Increased thirst, which may be insatiable, is secondary to the osmotic diuresis causing dehydration.
• Weight loss: Insulin deficiency leads to uninhibited gluconeogenesis, causing breakdown of protein and fat. Weight loss may be dramatic, even though the child's appetite usually remains good. Failure to thrive and wasting may be the first symptoms noted in an infant or toddler and may precede frank hyperglycemia.
• Nonspecific malaise: While this condition may be present before symptoms of hyperglycemia, or as a separate symptom of hyperglycemia, it is often recognized only retrospectively.
• Symptoms of ketoacidosis
• • Severe dehydration
  • Smell of ketones
  • Acidotic breathing (ie, Kussmaul respiration), masquerading as respiratory distress
  • Abdominal pain
  • Vomiting
  • Drowsiness and coma
• Other nonspecific findings
• • Hyperglycemia impairs immunity and renders a child more susceptible to recurrent infection, particularly of the urinary tract, skin, and respiratory tract.
  • Candidiasis may develop, especially in groin and flexural areas.

Physical

• Apart from wasting and mild dehydration, children with early diabetes have no specific clinical findings.
• Physical examination may reveal findings associated with other autoimmune endocrinopathies, which have a higher incidence in children with IDDM (eg, thyroid disease with symptoms of overactivity or underactivity and possibly a palpable goiter).
• Cataract is a rare presenting problem, typically occurring in girls with a long prodrome of mild hyperglycemia.
• Necrobiosis lipoidica usually, but not exclusively, occurs in people with diabetes. Necrobiosis most often develops on the front of the lower leg as a well-demarcated, red, atrophic area. The condition is associated with injury to dermal collagen, granulomatous inflammation, and ulceration. The cause of necrobiosis is unknown, and the condition is difficult to manage.

Causes

Most cases (95%) of IDDM are the result of environmental factors interacting with a genetically susceptible person. This interaction leads to the development of autoimmune disease directed at the insulin-producing cells of the pancreatic islets of Langerhans. These cells are progressively destroyed, with insulin deficiency usually developing after the destruction of 90% of islet cells.

• Genetic issues
• • Clear evidence exists for a genetic component to IDDM.
  • Monozygotic twins have a 60% lifetime concordance for developing IDDM, although only 30% do so within 10 years after the first twin is diagnosed. In contrast, dizygotic twins have only an 8% risk of concordance, which is similar to the risk among other siblings.
  • The frequency of diabetes developing in children with a diabetic mother is 2-3% and 5-6% if the father has IDDM. The risk to children rises to almost 30% if both parents are diabetic.
  • HLA class II molecules DR3 and DR4 are associated strongly with IDDM. More than 90% of whites with IDDM express 1 or both of these molecules, compared to 50-60% in the general population.
  • Patients expressing DR3 also risk developing other autoimmune endocrinopathies and celiac disease. These patients are more likely to develop diabetes at a later age, to have positive islet cell antibodies, and to appear to have a longer period of residual islet cell function.
  • Patients expressing DR4 are usually younger at diagnosis and more likely to have positive insulin antibodies, yet they are unlikely to have other autoimmune endocrinopathies.
  • The expression of both DR3 and DR4 carries the greatest risk of IDDM; these patients have characteristics of both the DR3 and DR4 groups.
• Environmental factors
• • Environmental factors are important because even identical twins have only a 30-60% concordance for IDDM, and because incidence rates vary in genetically similar populations under different living conditions.
  • No single factor has been identified, but infections and diet are considered the 2 most likely environmental candidates.
  • Viral infections may be the most important environmental factor in the development of IDDM, probably by initiating or modifying an autoimmune process. Instances have been reported of a direct toxic effect of infection in congenital rubella. A recent survey suggests enteroviral infection during pregnancy carries an increased risk of IDDM in the offspring. Paradoxically, IDDM's incidence is higher in areas where the overall burden of infectious disease is lower.
  • Dietary factors are also relevant. Breastfed infants have a lower risk for IDDM, and a direct relationship exists between per capita cow milk consumption and incidence of diabetes. Some cow's milk proteins (eg, bovine serum albumin) have antigenic similarities to an islet cell antigen. Nitrosamines, chemicals found in smoked foods and some water supplies, are known to cause IDDM in animal models; however, no definite link has been made with humans.
• Chemical causes: Streptozotocin and RH-787, a rat poison, selectively damage islet cells and can cause IDDM.
• Other causes
• • Congenital absence of the pancreas or islet cells
  • Pancreatectomy
  • IDDM secondary to pancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic uremic syndrome)
  • Wolfram syndrome (diabetes insipidus, DM, optic atrophy, deafness [DIDMOAD])
  • Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (The risk is said to be around 1% in Down and Turner syndromes.)

 

DIFFERENTIALS

Diabetes Insipidus

Hyperthyroidism

Pheochromocytoma
Renal Glucosuria
Toxicity, Salicylate

Other Problems to be Considered

Type 2 diabetes (NIDDM)
Maturity onset diabetes of the young (MODY)
Psychogenic polydipsia
Nephrogenic diabetes insipidus
High-output renal failure
Transient hyperglycemia with illness and other stress
Steroid therapy
Factitious illness (Münchhausen syndrome by proxy)

WORKUP

Lab Studies

• The need for and extent of laboratory studies vary, depending upon the general state of the child's health. For most children, only urine testing for glucose and blood glucose measurement are required for a diagnosis of diabetes. Other conditions associated with diabetes require several tests at diagnosis and at later review. (See Diabetic Ketoacidosis for information on laboratory studies needed to manage cases of DKA.)
• Urine glucose
• • A positive urine glucose test suggests but is not diagnostic for IDDM. Diagnosis must be confirmed by test results showing elevated blood glucose levels.
  • Test urine of ambulatory patients for ketones at the time of diagnosis.
• Urine ketones
• • Ketones in the urine confirm lipolysis and gluconeogenesis, which are normal during periods of starvation.
  • With hyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency and potential DKA.
• Blood glucose
• • Apart from transient illness- or stress-induced hyperglycemia, a random whole-blood glucose concentration more than 200 mg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood glucose concentration exceeding 120 mg/dL (7 mmol/L). In the absence of symptoms, the physician must confirm these results on a different day. Most children with diabetes detected because of symptoms have a blood glucose level of at least 250 mg/dL (14 mmol/L).
  • Blood glucose tests using capillary blood samples, reagent sticks, and blood glucose meters are the usual methods for monitoring day-to-day diabetes control.
• Glycated hemoglobin
• • Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) are the result of a nonenzymatic reaction between glucose and hemoglobin. A strong correlation exists between average blood-glucose concentrations over an 8- to 10-week period and the proportion of glycated hemoglobin. The percentage of HbA1c is more commonly measured. Normal values vary according to the laboratory method used, but nondiabetic children generally have values in the low-normal range. At diagnosis, diabetic children unmistakably have results above the upper limit of the reference range.
  • Measurement of HbA1c levels is the best method for medium- to long-term diabetic control monitoring. The Diabetes Control and Complications Trial (DCCT) has demonstrated that patients with HbA1c levels around 7% had the best outcomes relative to long-term complications. Check HbA1c levels every 3 months. Most clinicians aim for HbA1c values of 7-9%. Values less than 7% are associated with an increased risk of severe hypoglycemia; values more than 9% carry an increased risk of long-term complications.
• Renal function tests: If the child is otherwise healthy, renal function tests are typically not required.
• Islet cell antibodies
• • Islet cell antibodies may be present at diagnosis but are not needed to diagnose IDDM.
  • Islet cell antibodies are nonspecific markers of autoimmune disease of the pancreas and have been found in as many as 5% of unaffected children. Other autoantibody markers of type 1 diabetes are known, including insulin antibodies. More antibodies against islet cells are known (eg, those against glutamate decarboxylase [GAD antibodies]), but these are generally unavailable for routine testing.
• Thyroid function tests
• • Because early hypothyroidism has few easily identifiable clinical signs in children, children with IDDM may have undiagnosed thyroid disease.
  • Untreated thyroid disease may interfere with diabetes management. Check thyroid function regularly (every 2-5 years or annually if thyroid antibodies are present).
• Antithyroid antibodies: This test indicates risk of present or potential thyroid disease.
• Antigliadin antibodies
• • Some children with IDDM may have or develop celiac disease. Positive antigliadin antibodies, especially specific antibodies (eg, antiendomysial, antitransglutaminase) are important risk markers.
  • If antibody tests are positive, a jejunal biopsy is required to confirm or refute a diagnosis of celiac disease.

Imaging Studies

• No routine imaging studies are required.

Other Tests

• Oral glucose tolerance test (OGTT)
• • While unnecessary to diagnose IDDM, an OGTT can exclude the diagnosis of diabetes when hyperglycemia or glycosuria are recognized in the absence of typical causes (eg, intercurrent illness, steroid therapy) or when the patient's condition includes renal glucosuria.
  • Obtain a fasting blood sugar level, then administer a PO glucose load (2 g/kg for children aged <3 y, 1.75 g/kg for children aged 3-10 y [max 50 g], or 75 g for children aged >10 y). Check the blood glucose concentration again after 2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) or a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. Mild elevations, however, may not indicate diabetes when the patient has no symptoms and no diabetes-related antibodies.
  • A modified OGTT can also be used to identify cases of MODY that often present as type 1 diabetes, if, in addition to blood glucose levels, insulin or c-peptide (insulin precursor) levels are measured at fasting, 30 minutes, and 2 hours. Type 1 diabetics cannot produce more than tiny amounts of insulin. People with MODY or type 2 diabetes show variable and substantial insulin production in the presence of hyperglycemia.
• Lipid profile
• • Lipid profiles are usually abnormal at diagnosis because of increased circulating triglycerides caused by gluconeogenesis.
  • Apart from hypertriglyceridemia, primary lipid disorders rarely result in diabetes.
  • Hyperlipidemia with poor metabolic control is common.
• Urinary albumin: Beginning at age 12 years, perform an annual urinalysis to test for a slightly increased albumin excretion rate (AER), referred to as microalbuminuria, which is an indicator of risk for diabetic nephropathy.

 

TREATMENT

Medical Care

• All children with IDDM require insulin therapy.
• Only children with significant dehydration, persistent vomiting, or metabolic derangement, or with serious intercurrent illness, require inpatient management and intravenous rehydration.
• A well-organized diabetes care team can provide all necessary instruction and support in an outpatient setting. The only immediate requirement is to train the child or family to check blood glucose levels, to administer insulin injections, and to recognize and treat hypoglycemia. The patient and/or family should have 24-hour access to advice and know how to contact the team.

Consultations

• Always involve an experienced dietitian in the patient's care, typically as a regular member of the diabetes care team.
• Ophthalmology review may be needed at diagnosis if a cataract is suspected. All children with diabetes aged 12 years and older need a careful annual eye examination, either by direct ophthalmoscopy or high-quality retinal photography to identify and, if necessary, treat diabetes-related eye complications.
• Access to psychological counseling and support is desirable, preferably from a member of the diabetes care team.

Diet

Dietary management is an essential component of diabetes care. Diabetes is an energy metabolism disorder, and before insulin was discovered, children with diabetes could be kept alive by a diet severely restricted in carbohydrate and energy intake. These measures led to a long tradition of strict carbohydrate control and unbalanced diets. More recent dietary management of diabetes emphasizes a healthy, balanced diet, high in carbohydrates and fiber and low in fat.

• The following are universal recommendations:
• • Carbohydrates should provide 50-60% of daily energy intake. (No more than 10% of carbohydrates should be from sucrose or other refined carbohydrates.)
  • Fat should provide less than 30%.
  • Protein should provide 10-20%.
  • View these recommendations in the patient's cultural context.
• The aim of dietary management is to balance the child's food intake with insulin dose and activity and to keep blood glucose concentrations as close as possible to reference ranges, avoiding extremes of hyperglycemia and hypoglycemia.
• The ability to estimate the carbohydrate content of food (carb counting) is particularly useful for those children who give fast-acting insulin at meal times either by injection or insulin pump, as it allows for a more precise matching of food and insulin.
• • Adequate intake of complex carbohydrates (eg, cereals) is important before bedtime to avoid nocturnal hypoglycemia, especially for children having twice-daily injections of mixed insulin.
  • The dietitian should develop a diet plan for each child to suit individual needs and circumstances. Regularly review and adjust the plan to accommodate the patient's growth and lifestyle changes.
  • Low-carbohydrate diets as a management option for diabetes control have regained popularity in recent years. Logic dictates that the lower the carbohydrate intake, the less insulin is required. No trials of low-carbohydrate diets in children with type 1 diabetes have been reported, and such diets cannot be recommended at the present.

Activity

• IDDM requires no restrictions on activity; exercise has real benefits for a child with diabetes.
• Most children can adjust their insulin dosage and diet to cope with all forms of exercise.
• Children and their caretakers must be able to recognize and treat symptoms of hypoglycemia.
• • Hypoglycemia following exercise is most likely after prolonged exercise involving the legs, such as walking, running or cycling. It may occur many hours after exercise has finished and even affect insulin requirements the following day.
  • A large presleep snack is advisable following intensive exercise.

 

MEDICATION

Insulin is always required to treat IDDM. Attempts are being made to develop alternative routes to subcutaneous administration. In January 2006, a human insulin (rDNA origin) inhalant powder (Exubera) was been approved by the FDA for use in adults. Although insulin was originally derived from animal sources, recombinant human insulin and the newer 'designer' insulin analogues are now most commonly used. On October 18, 2007, Pfizer Inc announced that it is no longer making inhaled insulin (Exubera). The decision is not based on any safety concerns but is due to economic feasibility resulting from too few patients taking the inhaled insulin. Pfizer will work with physicians to transition patients from inhaled insulin to other treatment options over the next several months.

Insulin has 3 basic formulations: short-acting (eg, regular, soluble, lispro, aspart, glulisine), medium- or intermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, ultralente, glargine).

Regular or soluble insulin is bound to either protamine (eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duration of action. Combinations of isophane and regular, lispro or aspart insulins are also available in a variety of concentrations that vary around the world, ranging from 10/90 mixtures (ie, 10% regular, 90% isophane) to 50/50 mixtures.

The recent development of insulin analogues have attempted to address some of the shortcomings of traditional insulin. Insulins lispro and aspart have a more rapid onset of action and shorter duration, making them more suitable for bolusing at mealtimes and for short-term correction of hyperglycemia. An intermediate-acting insulin, detemir, has a similar profile of action to isophane but is more pharmacologically predictable, while glargine has a relatively flat profile of action, lasting some 18-26 hours and seems especially suitable as a once-daily basal injection. Despite their apparent advantages over traditional insulins, no evidence suggests a long-term advantage of the analogue insulins in terms of metabolic control or complication rates.

With so many various insulins and mixtures available, a wide range of possible injection regimens exist. These can be broadly categorized into 4 types, as follows:

• Twice-daily combinations of short- and intermediate-acting insulin.
• Multiple injection regimens, using once- or twice-daily injections of long- or intermediate-acting insulin and short-acting insulins given at each meal
• A combination of the above 2 regimens, with a morning injection of mixed insulin, an afternoon premeal injection of short-acting insulin and an evening injection of intermediate- or long-acting insulin
• Continuous subcutaneous insulin infusion (CSII) using an insulin pump

While controlled clinical trials suggest improved short-term metabolic control in children using multiple injections or CSII, international comparisons do not support any particular insulin regimen, and all have their advantages and disadvantages.

A wide variety of insulin-injection devices exist, including a simple syringe and needle, semiautomatic pen injector devices, and needle-free jet injectors. Increasing numbers of young people use insulin pumps to deliver continuous SC insulin, with bolus doses at meal times.

Tailor the insulin dose to the individual child's needs. For instance, if using a twice-daily regimen, then, as a rule of thumb, prepubertal children require between 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and 30-40% in the evening. Insulin resistance is a feature of puberty, and some adolescents may require up to 2 U/kg/d. About one third of the administered insulin is a short-acting formulation and the remainder is a medium- to long-acting formulation. Basal bolus regimens have a higher proportion of short-acting insulin. Typically, 50% of the total daily dose is given as long- or intermediate-acting insulin. CSII uses only short-acting insulins, most often the analogues lispro or aspart.

Drug Category: Antidiabetic agents

These agents are used for treatment of insulin-dependent DM and also for NIDDM unresponsive to treatment with diet and/or PO hypoglycemics.

Drug Name
Insulin lispro (Humalog)

Description
Onset of action is 10-30 min, peak activity is 1-2 h, and duration of action is 2-4 h.

Adult Dose
0.5-1 U/kg/d SC initially; adjust doses to achieve premeal and bedtime blood glucose levels of 80-140 mg/dL (4-7.5 mMol/L)

Pediatric Dose
0.5-1 U/kg/d SC initially
Adjust doses to achieve premeal and bedtime blood glucose levels of:
<5 years: 100-200 mg/dL (5.5-10 mMol/L)
>5 years: 80-140 mg/dL (4-7.5 mMol/L)

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Due to prompt onset of action, administer within 15 min before or immediately after a meal; monitor glucose carefully; dose adjustments may be necessary in renal and hepatic dysfunction

Drug Name
Regular insulin (Humulin R, Novolin R)

Description
Onset of action is 0.25-1 h, peak activity is 1.5-4 h, and duration of action is 5-9 h.

Adult Dose
Adjust to needs

Pediatric Dose
Adjust to needs

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Dose adjustments may be necessary in renal and hepatic dysfunction

Drug Name
Insulin NPH (Humulin N, Novolin N)

Description
Onset of action is 3-4 h, peak effect is in 8-14 h, and usual duration of action is 16-24 h.

Adult Dose
Adjust to needs

Pediatric Dose
Adjust to needs

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Dose adjustments may be necessary in renal and hepatic dysfunction

Drug Name
Protamine zinc (Ultralente)

Description
Onset of action is 2-3 h, peak activity is 4-8 h, and duration of action is 8-16 h.

Adult Dose
Adjust to needs

Pediatric Dose
Adjust to needs

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin; medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAOIs, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Dose adjustments may be necessary in renal and hepatic dysfunction

Drug Name
Insulin aspart (NovoLog)

Description
Onset of action is 10-30 min, peak activity is 1-2 h, and duration of action is 3-6 h. Homologous with regular human insulin, with the exception of single substitution of amino acid proline by aspartic acid in position B28. Produced by recombinant DNA technology. Insulin lowers blood glucose levels by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Inhibits lipolysis in the adipocyte. Inhibits proteolysis. Enhances protein synthesis. Insulin is the principal hormone required for proper glucose use in normal metabolic processes.

Adult Dose
0.5-1 U/kg/d SC initially; adjust doses to achieve premeal and bedtime blood glucose levels of 80-140 mg/dL (4-7.5 mMol/L)

Pediatric Dose
0.5-1 U/kg/d SC initially
Adjust doses to achieve premeal and bedtime blood glucose levels of:
<5 years: 100-200 mg/dL (5.5-10 mMol/L)
>5 years: 80-140 mg/dL (4-7.5 mMol/L)

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid hormone, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin
Medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAO inhibitors, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
B - Usually safe but benefits must outweigh the risks.

Precautions
Hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; due to prompt onset of action, administer within 15 min before or immediately after a meal; monitor glucose carefully; dose adjustments may be necessary in renal and hepatic dysfunction

Drug Name
Insulin glargine (Lantus)

Description
Long-acting insulin analogue. Typical onset of action from 1-2 h, duration 20-26 h

Adult Dose
Usually 50% of total daily dose of insulin (0.25-0.5 U/kg); adjust to needs

Pediatric Dose
Licensed age varies between nations (2-6 y); adjust dose as indicated but similar to adult

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Medications that may decrease hypoglycemic effects of insulin include acetazolamide, AIDS antivirals, asparaginase, phenytoin, nicotine, isoniazid, diltiazem, diuretics, corticosteroids, thiazide diuretics, thyroid hormone, estrogens, ethacrynic acid, calcitonin, oral contraceptives, diazoxide, dobutamine, phenothiazines, cyclophosphamide, dextrothyroxine, lithium carbonate, epinephrine, morphine sulfate, and niacin
Medications that may increase hypoglycemic effects of insulin include calcium, ACE inhibitors, alcohol, tetracyclines, beta blockers, lithium carbonate, anabolic steroids, pyridoxine, salicylates, MAO inhibitors, mebendazole, sulfonamides, phenylbutazone, chloroquine, clofibrate, fenfluramine, guanethidine, octreotide, pentamidine, and sulfinpyrazone

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Administer at the same time each day; use only if solution is clear and colorless; administer SC only; do not mix with any other insulin or solution; hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin; monitor glucose carefully; dose adjustments of insulin may be necessary in patients diagnosed with renal and hepatic dysfunction

Drug Name
Insulin glulisine (Apidra)

Description
Human insulin analog produced by rDNA technology using a nonpathogenic laboratory strain of E coli (K12). Differs from human insulin by replacement of asparagine at B3 position with lysine, and the lysine at the B29 position is replaced by glutamic acid.
Insulin regulates glucose metabolism by stimulating peripheral glucose uptake by skeletal muscle and fat, and inhibits hepatic glucose production.
Glucose lowering is equipotent to regular human insulin when administered IV. After SC administration, insulin glulisine has more rapid onset and shorter duration of action compared to regular human insulin. Useful to regulate mealtime blood glucose elevation.

Adult Dose
Individualize dose; intended for intermittent SC injection with meals or use by external infusion pump

Pediatric Dose
0.5-1 U/kg/d SC initially;
Adjust doses to achieve premeal and bedtime blood glucose levels of:
<5 years: 100-200 mg/dL (5.5-10 mMol/L)
>5 years: 80-140 mg/dL (4-7.5 mMol/L)

Contraindications
Documented hypersensitivity; hypoglycemia

Interactions
Corticosteroids, danazol, diazoxide, diuretics, sympathomimetic agents (eg, epinephrine, albuterol, terbutaline), glucagon, isoniazid, phenothiazines, growth hormone, thyroid hormone, estrogen, progestogens, protease inhibitors, and atypical antipsychotics (eg, olanzapine, clozapine) may increase blood glucose and reduce glucose lowering effect of insulin; oral antidiabetic agents, ACE inhibitors, disopyramide, fibrates, fluoxetine, MAOIs, pentoxifylline, propoxyphene, salicylates, and sulfonamides may decrease blood glucose and cause additive effects to insulin

Pregnancy
C - Safety for use during pregnancy has not been established.

Precautions
Hyperthyroidism may increase renal clearance of insulin and may need more insulin to treat hyperkalemia; hypothyroidism may delay insulin turnover, requiring less insulin to treat hyperkalemia; due to prompt onset of action, administer within 15 min before or immediately after a meal; monitor glucose carefully; dose adjustments may be necessary in renal and hepatic dysfunction

 

FOLLOW-UP

Further Inpatient Care

• Where a diabetes care team is available, admission is usually required only for children with DKA.

Further Outpatient Care

• Regular outpatient review with a specialized diabetes team improves both short- and long-term outcomes. Most teams have a nurse specialist or educator, a dietitian, and a pediatrician with training in diabetes care. Other members could include a psychologist, a social worker, and an exercise specialist. Involvement with the team is intense over the first few weeks after diagnosis while family members learn about diabetes management.
• Conduct a structured examination and review at least once annually to examine the patient for possible complications. Examination and review should include the following:
• • Growth assessment
  • Injection site examination
  • Retinoscopy or other retinal screening such as photography
  • Examination of hands, feet, and peripheral pulses for signs of limited joint mobility, peripheral neuropathy, and vascular disease
  • Evaluation for signs of associated autoimmune disease
  • Blood pressure
  • Urine examination for microalbuminuria

In/Out Patient Meds

• Insulin
• Blood glucose testing strips
• Urine ketone testing tablets or strips
• Blood ketone testing strips (also available)

Deterrence/Prevention

• Actively discourage patients from smoking because it markedly increases the risk of developing cardiovascular complications.
• Discuss issues of sexual health with older children. Provide young women with information on pregnancy planning to ensure the best possible outcomes for themselves and their offspring.
• For older adolescents, discuss the effects of alcohol and illegal substance use on diabetic control.

Complications

• Hypoglycemia
  • Hypoglycemia is probably the most disliked and feared complication of diabetes, from the point of view of the child and the family. Children hate the symptoms of a hypoglycemic episode and the loss of personal control it may cause.
  • Insulin inhibits glucogenesis and glycogenolysis, while stimulating glucose uptake. In nondiabetic individuals, insulin production by the pancreatic islet cells is suppressed when blood glucose levels fall below 83 mg/dL (4.6 mmol/L). If insulin is injected in a treated diabetic child who has not eaten adequate amounts of carbohydrates, blood glucose levels progressively fall.
  • The brain depends upon glucose as a fuel. As glucose levels drop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, cortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms include sweatiness, shaking, confusion, behavioral changes, and, eventually, coma when blood glucose levels fall below 30-40 mg/dL. The glucose level at which symptoms develop varies greatly from individual to individual (and from time to time in the same individual), depending in part on the duration of diabetes, frequency of hypoglycemic episodes, rate of fall of glycemia, and overall control.
  • Manage mild hypoglycemia by giving rapidly absorbed PO carbohydrate or glucose; for a comatose patient, administer an intramuscular injection of the hormone glucagon, which stimulates the release of liver glycogen and releases glucose into the circulation. Where appropriate, an alternative therapy is intravenous glucose (preferably no more than a 10% glucose solution). All treatments for hypoglycemia provide recovery in approximately 10 minutes.
  • Occasionally, a child with hypoglycemic coma may not recover within 10 minutes, despite appropriate therapy. Under no circumstances should further treatment be given, especially intravenous glucose, until the blood glucose level is checked and still found subnormal. Overtreatment of hypoglycemia can lead to cerebral edema and death. If coma persists, seek other causes.
  • Hypoglycemia is a particular concern in children younger than 4 years because the condition may lead to possible intellectual impairment later in life.
• Hyperglycemia
  • In an otherwise healthy individual, blood glucose levels usually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood sugar levels rise if insulin is insufficient for a given glucose load. The renal threshold for glucose reabsorption is exceeded when blood glucose levels exceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of polyuria and polydipsia.
  • All children with diabetes experience episodes of hyperglycemia.
• Diabetic ketoacidosis
  • DKA is much less common than hypoglycemia, but it is potentially far more serious, creating a life-threatening medical emergency.
  • Ketosis usually does not occur when insulin is present. In its absence, however, severe hyperglycemia, dehydration, and ketone production contribute to the development of DKA.
• DKA usually follows increasing hyperglycemia and symptoms of osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of subcutaneous insulin, may present with ketosis and more normal blood glucose levels. They are more likely to present with nausea, vomiting, and abdominal pain, symptoms similar to food poisoning.
• Injection-site hypertrophy
  • If children persistently inject their insulin into the same area, subcutaneous tissue swelling may develop, causing unsightly lumps and adversely affecting insulin absorption. Rotating the injection sites resolves the condition.
  • Fat atrophy can also occur, possibly in association with insulin antibodies. This condition is much less common but more disfiguring.
• Diabetic retinopathy
  • The most common cause of acquired blindness in many developed nations, diabetic retinopathy is rare in the prepubertal child or within 5 years of onset of diabetes.
  • Prevalence and severity of retinopathy increases with age and is greatest in patients whose diabetic control is poor. Prevalence rates seem to be declining, yet an estimated 80% of people with IDDM develop retinopathy.
  • Diabetic retinopathy's first symptoms are dilated retinal venules and the appearance of capillary microaneurysms, a condition known as background retinopathy. These changes may be reversible or their progression may be halted with improved diabetic control, although some patient's conditions may worsen initially.
  • Subsequent changes in background retinopathy are characterized by increased vessel permeability and leaking plasma that form hard exudates, followed by capillary occlusion and flame-shaped hemorrhages. The patient may not notice these changes unless the macula is involved. Laser therapy may be required at this stage to prevent further visual loss. Proliferative retinopathy follows with further vascular occlusion, retinal ischemia, proliferation of new retinal blood vessels and fibrous tissue, then progressing to hemorrhage, scarring, retinal detachment, and blindness. Prompt retinal laser therapy may prevent blindness in the later stages, so regular screening is vital.
• Diabetic nephropathy and hypertension
  • Diabetic nephropathy's exact mechanism is unknown. Peak incidence is in postadolescents, 10-15 years after diagnosis, and may involve up to 30% of people with IDDM.
  • Microalbuminuria is the first evidence of nephropathy. The exact definition varies slightly between nations but an increased AER is commonly defined as a ratio of first morning–void urinary albumin levels to creatinine levels that exceeds 10 mg/mmol, or as a timed overnight AER of more than 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. Glomerular hyperfiltration occurs, as do abnormalities of the glomerular basement membrane and glomeruli.
  • In a patient with nephropathy, AER increases until frank proteinuria develops, and this may progress to renal failure. Blood pressure rises with increased AER, and hypertension accelerates the progression to renal failure.
  • Progression may be delayed or halted by improved diabetes control, by administration of angiotensin-converting enzyme inhibitors (ACE inhibitors), and by aggressive blood pressure control.
  • Regular urine screening for microalbuminuria provides opportunities for early identification and treatment to prevent renal failure.
• A child younger than 15 years with persistent proteinuria may have a nondiabetic cause and should be referred to a pediatric nephrologist for further assessment.
• Diabetic neuropathy affects both the peripheral and autonomic nerves. Hyperglycemic effects on axons and microvascular changes in endoneural capillaries are amongst the proposed mechanisms.
• Autonomic changes involving cardiovascular control (eg, heart rate, postural responses) have been described in as many as 40% of children with diabetes. Cardiovascular control changes become more likely with increasing duration and worsening control.
• In adults, peripheral neuropathy usually occurs as a distal sensory loss.

• Macrovascular disease

• While this complication is not seen in pediatric patients, it is a significant cause of morbidity and premature mortality in adults with diabetes.
• People with IDDM have twice the risk of fatal myocardial infarction (MI) and stroke than people unaffected with diabetes; for women, the MI risk is 4 times greater. People with IDDM also have 4 times greater risk for atherosclerosis.
• The combination of peripheral vascular disease and peripheral neuropathy can cause serious foot pathology.
• Smoking, hypertension, hyperlipidemia, and poor diabetic control greatly increase the risk of vascular disease.

• Associated autoimmune diseases are relatively common in children and include the following:

• Hypothyroidism affects 2-5% of children with diabetes.
• Hyperthyroidism affects 1% of children with diabetes; the condition is usually discovered at the time of diabetes diagnosis.
• Although Addison disease is uncommon, affecting fewer than 1% of children with diabetes, it is a life-threatening condition that may reduce the insulin requirement and increase the frequency of hypoglycemia. (These effects may also be the result of unrecognized hypothyroidism.)
• Celiac disease, associated with an abnormal sensitivity to gluten in wheat products, is probably a form of autoimmune disease and may occur in as many as 5% of children with IDDM.
• Necrobiosis lipoidica is probably another form of autoimmune disease. This condition is usually, but not exclusively, found in patients with IDDM. Necrobiosis lipoidica affects 1-2% of children and may be more common in children with poor diabetic control.

• Limited joint mobility, primarily affecting hands and feet, is believed to be associated with poor diabetic control.

• Originally described in approximately 30% of patients with IDDM, limited joint mobility occurs in 50% of patients older than 10 years who have had diabetes longer than 5 years. The condition restricts joint extension, making it difficult to press the hands flat against each other. The skin of patients with severe joint involvement has a thickened and waxy appearance.
• Limited joint mobility is associated with increased risks for diabetic retinopathy and nephropathy. Improved diabetes control over the past several years appears to have reduced the frequency of these additional complications by an approximate 4-fold factor. More recent patients also have markedly fewer severe joint mobility limitations.

Prognosis

• Apart from severe DKA or hypoglycemia, IDDM has little immediate morbidity.
• The risk of complications relates to diabetic control. With good management, patients can expect to lead full, normal, and healthy lives. Nevertheless, the average life expectancy of a child diagnosed with type 1 diabetes has been variously suggested to be reduced by 13-19 years, compared with their nondiabetic peers.

Patient Education

• Education is a continuing process involving the child, family, and all members of the diabetes team. The following strategies may be used:
• • Formal education sessions in a clinic setting
  • Opportunistic teaching at clinics or at home in response to crises or difficulties such as acute illness
  • Therapeutic camping or other organized events
  • Patient-organized meetings
  • Information from national organizations and patient groups, including the following:
    • Children with Diabetes (This "online community for kids, families, and adults with diabetes" is an excellent resource with good links.)
    • International Society for Pediatric and Adolescent Diabetes
    • International Diabetes Federation
    • Diabetes UK
    • American Diabetes Association
    • Juvenile Diabetes Foundation International
• Children should wear some form of medical identification such as a medic alert bracelet or necklace.
• For excellent patient education resources, see eMedicine's Diabetes Center. Also, visit eMedicine's patient education article Diabetes.
• REFERENCES

• Barera G, Bonfanti R, Viscardi M, et al. Occurrence of celiac disease after onset of type 1 diabetes: a 6-year prospectivelongitudinal study. Pediatrics. May 2002;109(5):833-8. [Medline]. [Full Text].
• Barkai L, Madacsy L. Cardiovascular autonomic dysfunction in diabetes mellitus. Arch Dis Child. Dec 1995;73(6):515-8. [Medline].
• Brink SJ. How to apply the experience from the diabetes control and complications trial to children and adolescents?. Ann Med. Oct 1997;29(5):425-38. [Medline].
• CDC. National Diabetes Fact Sheet. United States. 2003;Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2003.pdf. [Full Text].
• Chiarelli F, Verrotti A, Catino M, et al. Hypoglycaemia in children with type 1 diabetes mellitus. Acta Paediatr Suppl. Jan 1999;88(427):31-4. [Medline].
• Clar C, Waugh N, Thomas S. Routine hospital admission versus out-patient or home care in children at diagnosisof type 1 diabetes mellitus. Cochrane Database Syst Rev. 2003;CD004099. [Medline].
• DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. Sep 30 1993;329(14):977-86. [Medline].
• Dahl-Jorgensen K. Modern insulin therapy in children and adolescents. Acta Paediatr Suppl. Jan 1999;88(427):25-30. [Medline].
• Dahlquist G, Kallen B. Mortality in childhood-onset type 1 diabetes: a population-based study. Diabetes Care. Oct 2005;28(10):2384-7. [Medline].
• Danne T, Deiss D, Hopfenmuller W, et al. Experience with insulin analogues in children. Horm Res. 2002;57 Suppl 1:46-53. [Medline].
• Danne T, Mortensen HB, Hougaard P, et al. Persistent differences among centers over 3 years in glycemic control and hypoglycemiain a study of 3,805 children and adolescents with type 1 diabetes from the Hvidأ¸re Study Group. Diabetes Care. Aug 2001;24(8):1342-7. [Medline]. [Full Text].
• DiLiberti JH, Lorenz RA. Long-term trends in childhood diabetes mortality: 1968-1998. Diabetes Care. Aug 2001;24(8):1348-52. [Medline].
• Edge J, Matyka K. Acute Complications of Diabetes. In: Childhood and Adolescent Diabetes (Court S, Lamb B eds) John Wiley & Sons. 1997;201-224.
• Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin dependent diabetes 1990-96. Arch Dis Child. Oct 1999;81(4):318-23. [Medline]. [Full Text].
• Hathout E, Lakey J, Shapiro J. Islet transplant: an option for childhood diabetes?. Arch Dis Child. Jul 2003;88(7):591-4. [Medline]. [Full Text].
• Hershey T, Perantie DC, Warren SL, et al. Frequency and timing of severe hypoglycemia affects spatial memory in children with type 1 diabetes. Diabetes Care. Oct 2005;28(10):2372-7. [Medline]. [Full Text].
• Hyoty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes. Jun 1995;44(6):652-7. [Medline].
• Infante JR, Rosenbloom AL, Silverstein JH, et al. Changes in frequency and severity of limited joint mobility in children withtype 1 diabetes mellitus between 1976-78 and 1998. J Pediatr. Jan 2001;138(1):33-7. [Medline].
• Jones CA, Leese GP, Kerr S, et al. Development and progression of microalbuminuria in a clinic sample of patients with insulin dependent diabetes mellitus. Arch Dis Child. Jun 1998;78(6):518-23. [Medline]. [Full Text].
• Kaufman FR, Halvorson M, Carpenter S. Association between diabetes control and visits to a multidisciplinary pediatric diabetes clinic. Pediatrics. May 1999;103(5 Pt 1):948-51. [Medline]. [Full Text].
• Lamb WH. Aetiology, epidemiology, immunology, environmental factors, genetics and prevention. In: Court S, Lamb B, eds. Childhood and Adolescent Diabetes. John Wiley & Sons. 1997;1-16.
• Mandrup-Poulsen T, Nerup J. Pathogenesis of childhood diabetes. In: Kelnar CJH, ed. Childhood and Adolsecent Diabetes. Chapman and Hall, London. 1995;183-189.
• Mohn A, Di Michele S, Di Luzio R, et al. The effect of subclinical hypothyroidism on metabolic control in children andadolescents with Type 1 diabetes mellitus. Diabet Med. Jan 2002;19(1):70-3. [Medline].
• Mortensen HB, Hougaard P. Comparison of metabolic control in a cross-sectional study of 2,873 children and adolescents with IDDM from 18 countries. The Hvidore Study Group on Childhood Diabetes [published erratum appears in Diabetes Care 1997 Jul;20(7):1216]. Diabetes Care. May 1997;20(5):714-20. [Medline].
• Narayan KM, Boyle JP, Thompson TJ, et al. Lifetime risk for diabetes mellitus in the United States. JAMA. Oct 8 2003;290(14):1884-90. [Medline].
• Patterson CC, Carson DJ, Hadden DR. Epidemiology of childhood IDDM in Northern Ireland 1989-1994: low incidence in areas with highest population density and most household crowding. Northern Ireland Diabetes Study Group. Diabetologia. Sep 1996;39(9):1063-9. [Medline].
• Porter JR, Barrett TG. Acquired non-type 1 diabetes in childhood: subtypes, diagnosis, and management. Arch Dis Child. Dec 2004;89(12):1138-44. [Medline]. [Full Text].
• Rosenbloom AL, Joe JR, Young RS, Winter WE. Emerging epidemic of type 2 diabetes in youth. Diabetes Care. Feb 1999;22(2):345-54. [Medline]. [Full Text].
• Rosenbloom AL, Hunt SS. Prognosis of imparied glucose tolerance in children with stress hyperglycemia, symptoms of hypoglycemia, or asymptomatic glucosuria. J Pediatr. Sep 1982;101(3):340-4. [Medline].
• Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients withdiabetes mellitus. Cochrane Database Syst Rev. 2004;CD003287. [Medline].
• Silink M. Childhood diabetes: a global perspective. Horm Res. 2002;57 Suppl 1:1-5. [Medline].
• Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the AmericanDiabetes Association. Diabetes Care. Jan 2005;28(1):186-212. [Medline]. [Full Text].
• Silverstein JH, Gordon G, Pollock BH, Rosenbloom AL. Long-term glycemic control influences the onset of limited joint mobility in type 1 diabetes. J Pediatr. Jun 1998;132(6):944-7. [Medline].
• Svensson M, Eriksson JW, Dahlquist G. Early glycemic control, age at onset, and development of microvascular complicationsin childhood-onset type 1 diabetes: a population-based study in northern Sweden. Diabetes Care. Apr 2004;27(4):955-62. [Medline]. [Full Text].
• Thompson C, Greene S. Diabetes in the older teenager and young adult. In: Court S, Lamb B, eds. Childhood and Adolescent Diabetes. John Wiley & Sons. 1997;67-86.
• Willi SM, Planton J, Egede L, Schwarz S. Benefits of continuous subcutaneous insulin infusion in children with type1 diabetes. J Pediatr. Dec 2003;143(6):796-801. [Medline].
• d''Annunzio G, Malvezzi F, Vitali L, et al. A 3-19-year follow-up study on diabetic retinopathy in patients diagnosed in childhood and treated with conventional therapy. Diabet Med. Nov 1997;14(11):951-8. [Medline].

 

Reference Link:

http://www.emedicine.com/ped/topic581.htm