PEDS Diabetes



PEDIATRIC DIABETES

Jassin M. Jouria, MD

Dr. Jassin M. Jouria is a medical doctor, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serves as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e-module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.

ABSTRACT

Type 1 diabetes mellitus, previously known as juvenile diabetes, is a chronic and progressive metabolic disorder. The onset of pediatric type 1 diabetes mellitus can occur at any pre-pubertal age. School nurses, teachers or other personnel trained to perform diabetes care, as part of the interdisciplinary pediatric diabetes healthcare team (DHC), support glycemic monitoring, insulin administration and carbohydrate counting of meals, as well as educating the patient about their disease, its management and treatment. All health professionals, part of the interdisciplinary pediatric diabetes healthcare team, provide continuous support as patients grow independent and become more capable of self-management of the disease.

Continuing Nursing Education Course Director & Planners

William A. Cook, PhD,
Director; Douglas Lawrence, MA, Webmaster;

Susan DePasquale, CGRN, MSN, FPMHNP-BC, Lead Nurse Planner

Accreditation Statement

is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation.

Credit Designation

This educational activity is credited for 8.5 hours. Pharmacology content is 2.5 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity.

Course Author & Planner Disclosure Policy Statements

It is the policy of to ensure objectivity, transparency, and best practice in all Continuing Nursing Education (CNE) activities. All authors and course planners participating in the planning or implementation of a CNE activity are expected to disclose to course participants any relevant conflict of interest that may arise.

Statement of Need

Knowledge of diabetes research and medical management is important to safe care for the pediatric diabetic patient. Educating health teams and patients, as well as their caregivers, about medical management and lifestyle choices is integral to diabetic health and wellness.

Course Purpose

To provide nurses and associates knowledge of the main and less common forms of diabetes to support patients and families during treatment.

Learning Objectives

1. List current hypotheses for the cause of Type I DM.

2. Identify the types of neuropathy caused by pediatric diabetes.

3. Describe the role of beta cells in the pancreas.

4. Explain the relationship between Type I DM and autoimmune disorders.

5. Explain types of insulin, usage and various ways to administer insulin.

6. Describe the role of exercise in the management of pediatric diabetes.

7. Describe how diabetic ketoacidosis should be managed with children.

8. Explain how schools/day care centers can contribute child diabetes care.

9. Explain how carbohydrates impact pediatric diabetic management.

10. Identify the importance of medical identification.

Target Audience

Advanced Practice Registered Nurses, Registered Nurses, Licensed Practical Nurses, and Associates

Course Author & Director Disclosures

Jassin M. Jouria, MD; William S. Cook, PhD; Douglas Lawrence, MA; Susan DePasquale, CGRN, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Activity Review Information

Reviewed by Susan DePasquale, CGRN, MSN, FPMHNP-BC.

Start Date: 7/14/2014 Termination Date: 7/14/2017

Please take time to complete the self-assessment Knowledge Questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course

1) What is the high blood glucose correction factor for a type 1 diabetic patient weighing 160 lbs?

a. 50 mg/dL

b. 45 mg/dL

c. 60 mg/dL

d. 65 mg/dL

2) Which type of diabetic neuropathy affects the heart, blood vessels and digestive system?

a. Focal neuropathy

b. Peripheral neuropathy

c. Autonomic neuropathy

d. Proximal neuropathy

3) Which type of insulin has a natural cloudy appearance?

a. Rapid acting insulin

b. Regular insulin

c. Intermediate acting insulin

d. Long acting insulin

4) Which of the following is intermediate acting insulin?

a. NPH

b. Glargine

c. Aspart

d. Lantus

5) What is the bolus insulin dose to cover a patient’s plans to consume 60 grams of carbohydrate for lunch. The patient’s Insulin: CHO ratio is 1:10.

a. 10U

b. 8U

c. 5U

d. 6U

6) Insulin absorption is fastest and most predictable injected in the:

a. Upper outer arm

b. Abdomen

c. Anterior lateral thigh

d. Buttocks

7) All of the following administration strategies minimize pain at the injection site of insulin EXCEPT:

a. Injecting insulin at warm temperature

b. Eliminating air bubbles in the syringe before injection

c. Keeping the muscles at the site of injection relaxed, when injecting

d. Penetrating the skin quickly

8) Which of the following strategies does not help pediatric patients overcome their fear of needles and injection?

a. Using a pillow for trial injections

b. Using a covered safety needle to conceal the needle

c. Allowing the syringe to rest on their skin before injection

d. Injecting insulin without looking at the injection site

9) The following is NOT a standard insulin self-administration route:

a. Subcutaneous injection with insulin pens

b. Subcutaneous injection with insulin prefilled syringes

c. Intramuscular injection with insulin pens

d. Subcutaneous infusion using CSII devices

10) Which of the following blood glucose test results is diagnostic for type 1 diabetes mellitus?

a. Random whole-blood glucose concentration > 200 mg/dL

b. Fasting whole-blood glucose concentration > 120 mg/dL

c. An HB1AC value of more than 6.5%

d. All of the above

Introduction

Pediatric diabetes can be a scary and life-changing diagnosis. However, with proper management, patients with pediatric diabetes can live long, full lives. Patients with pediatric diabetes—and their parents and caregivers—will take their cues from health care professionals when it comes to managing diabetes. Having an in-depth knowledge of the pathophysiology and management techniques of diabetes will allow health clinicians to provide reassuring knowledge and treatment options to their patients. Knowledge and information are powerful tools for every member of the healthcare management team to provide optimal care and a high quality of life for the patient.

Type 1 diabetes mellitus, previously known as juvenile diabetes, is a chronic and progressive metabolic disorder wherein the body is unable to produce insulin to meet its energy needs. The condition is a result of autoimmune destruction of the beta cells in the pancreas. As its former name suggests, the disease has an early onset, usually before 18 years of age. Once diagnosed, an individual will require lifelong insulin treatment and monitoring for complications.

Type 1 diabetes mellitus is also known as insulin-dependent diabetes mellitus (IDDM) because the pancreas is completely unable to produce insulin, as opposed to type 2 diabetes mellitus, which is where the pancreas produces insufficient amounts of insulin to sustain the energy requirements of the body.

According to the CDC, type 1 diabetes is caused by mechanisms much different from those that cause type 2 diabetes mellitus. Despite prolific research into the origins of the disease, the exact etiology of both types of diabetes remains unclear. Nevertheless, studies in the recent years have primarily pointed out its onset as following exposure to environmental stimuli such as a virus and certain dietary factors in genetically predisposed individuals. However, because of the very early onset of the disease in pediatric populations, the role of genetic factors is also a very important consideration.

The onset of pediatric type 1 diabetes mellitus can occur at any pre-pubertal age, however, the peak incidence usually increases with age until mid-puberty and then declines. This means that the majority of these patients are school-age children whose care and wellbeing is entrusted to the school and day care personnel for the majority of their day. In this case, it is the school nurses, teachers or other personnel trained to perform diabetes care, as part of the interdisciplinary pediatric diabetes healthcare (DHC) team, who are responsible for them especially when it comes to glycemic monitoring, insulin administration and carbohydrate counting of meals. They are also partly responsible for educating the patient about their disease, its management and treatment.

It is important for all health professionals, not just nurses, who are part of the interdisciplinary pediatric diabetes healthcare (DHC) team to be able to provide continuous counseling as patients grow older, and lean toward independent and self-management of the disease. The course is intended to enhance and reinforce the knowledge of health professionals on type 1 diabetes mellitus in pediatric patients, especially with regards to their diagnosis, management, treatment and overall long-term health education.

Pathophysiology

Type 1 diabetes mellitus is a result of the autoimmune destruction of the beta cells of the pancreas.

Hypotheses

Current studies have several hypotheses on the etiologic origins of the disease, pathologic mechanisms and presentation, and progression to microvascular comorbidities. The pathophysiologic mechanisms at play primarily involve both genetic and environmental factors, and are discussed in detail below.

Genetic Factors

The genetic component of this form of diabetes is complex and involves multiple genes but there is also high risk among siblings, especially monozygotic twins.1 A study by Tseck, et al. found dizygotic twins to possess a 5-6 percent concordance rate for type 1 diabetes mellitus2 while monozygotic twins are half more likely to have similar diagnosis upon reaching 40 years old.3

Children of parents with type 1 diabetes mellitus are also at greater risk for the same disease themselves. However, the risk differs depending on which of the parents has the disease. Those with mothers who have diabetes possess the relatively small risk of 2-3 percent to develop the disease themselves, as compared to those with fathers who have diabetes, which increases their risk of developing it to 5-6 percent. However, if both parents have diabetes, the risk for a child to also develop diabetes increases to about 30 percent. Additionally, the risk is relatively greater if the onset of the parent(s) disease happened prior to the age of 11 years old, and relatively lesser if the onset happened at a later age.

The genetic component of diabetes is also apparent in the important difference seen in its frequency of occurrence among various ethnic groups. Type 1 diabetes mellitus is very common in individuals with European ancestry, with those from northern Europe significantly more affected compared to those from the Mediterranean region.4 It is most uncommon among people of East Asian descent.5

Studies on genome-wide association found several loci linked with diabetes, although there were not enough causal relations found. The regions most commonly linked to other autoimmune diseases, the major histocompatibility complex (MHC), is also where various susceptibility loci for diabetes, specifically, class II human leukocyte antigen (HLA) DR and DQ haplotypes (the detected amino acids involved in the disease process), are found.6,7,8

A list of DR-DQ haplotypes linked to greater risk for diabetes type I is found below, in hierarchical order:6

• DRB1*0301 - DQA1*0501 - DQB1*0201 (odds ratio [OR] 3.64)

• DRB1*0405 - DQA1*0301 - DQB1*0302 (OR 11.37)

• DRB1*0401 - DQA1*0301 - DQB*0302 (OR 8.39)

• DRB1*0402 - DQA1*0301 - DQB1*0302 (OR 3.63)

• DRB1*0404 - DQA1*0301 - DQB1*0302 (OR 1.59)

• DRB1*0801 - DQB1*0401 - DQB1*0402 (OR 1.25)

Approximately 90-95 percent of young children diagnosed with the disease are carriers of the HLA-DR3 DQB1*0201, HLA-DR4 DQB1*0302, or both. Children who carry haplotypes DR3 and DR4 heterozygotes are the most susceptible. As mentioned previously, the individuals who carry the aforementioned haplotypes and therefore, at most risk, are primarily of European descent. There is not enough study data on other ethnic populations.

An important gene that plays a role in the pathophysiology of type 1 diabetes mellitus is the insulin gene (INS). It encodes for the pre-proinsulin peptide, which is close to a variable number of tandem repeats (VNTR) polymorphism at chromosome 11p15.5.9 Various VNTR alleles can promote both resistance and susceptibility to type 1 diabetes mellitus via their action on insulin gene (INS) transcription in the thymus gland.

Environmental factors

Environmental triggers may also contribute to the development of type 1 diabetes mellitus. These triggers include viruses such as enterovirus,12 mumps, rubella, and coxsackievirus B4, toxic drugs and chemicals, cytotoxins, and exposure to cow’s milk during infancy.13

It is important to remember that a combination of factors may be at play, instead of just one. A study by Lempainen, et al. found that evidence of an enterovirus infection as early as 1 year of age was tied to the appearance of type 1 diabetes mellitus–related autoimmunity among children exposed to cow's milk before the age of 3 years old. This finding strongly suggests a relationship between the two factors. In addition, the finding also offers a possible explanation for the conflicting findings obtained in studies that only studied these factors individually.14

The finding of one meta-analysis points to a weak but important linear elevation in the risk of pediatric type 1 diabetes mellitus associated with increasing maternal age.15 However, there is insufficient evidence to support any substantial increase in type 1 diabetes mellitus risk in children after preeclampsia complications during pregnancy.16

A study by Simpson, et al. based in Denver, Colorado, followed children at increased risk of diabetes since 1993 and did not find any link between vitamin D intake nor 25-hydroxyvitamin D levels during childhood to be linked with autoimmune destruction of the islets of Langerhans nor progression to type 1 diabetes mellitus.17 Another risk factor for the development of type 1 diabetes mellitus may be upper respiratory infection during the first year of life. A data analyzed 148 children who were carriers of genetic markers of the disease and found that upper respiratory infections in the first year of life were linked to greater risk for type 1 diabetes mellitus.18,19

There are toxic substances that have been studied in terms of the effects on the pancreas. RH-787, a rat poison, and Streptozotocin, an FDA-approved drug for the treatment of metastatic cancer of the pancreatic islet cells, are known to exert selective damage to the islet cells and cause type 1 diabetes mellitus. Additionally, studies have found that nitrosamines, which are carcinogenic chemicals found in many processed foods such as smoked meat and certain water supplies, can also cause type 1 diabetes mellitus in animal models. However, there are currently no studies that found explicit pathologic association between these chemicals and humans. Over the years, there has also been a hypothesis involving the linear increase in the incidence of type 1 diabetes mellitus with corresponding increase in the distance from the equator. It may be that a decreased exposure to ultraviolet (UV) light and subsequently, lower vitamin D levels may be the missing link, which is the explanation for this hypothesis.27

Other Factors

Other factors considered to play a role in the development of type 1 diabetes mellitus include:28

• Congenital absence of the pancreas or islet cells,

• Pancreatectomy,

• Pancreatic damage such as chronic pancreatitis, hemochromatosis and cystic fibrosis,

• Wolfram syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, deafness (DIDMOAD), and

• Chromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome.

Disease Mechanisms

In the pancreas, approximately 1,000 beta cells are found in a circular formation called islets of Langerhans. The beta cells secrete the hormone insulin, which is responsible for regulating carbohydrate and fat metabolism in the body. The hormone is responsible for the movement of glucose from the blood and into the cells of the liver, skeletal muscles, and fat tissue.29 Lack of insulin results in the build up of glucose in the blood, a condition called hyperglycemia.

The islets of Langerhans are found all over the pancreas and compose 1-2% of its mass. The autoimmune-mediated attack on the beta cells interferes with insulin production within the organ, thus, also interrupting the regulatory functions associated with the hormone.29

The beta cells are initially attacked by the activated cytotoxic T-lymphocytes (CTLs), which target specific islets and destroy them. When CTLs are activated, cytokines are released, which in turn, trigger the production and movement of activated macrophages and autoantibodies towards the site of inflammation. It is the combined inflammatory activities of the autoantibodies, macrophages and CTLs, which are responsible for the overall destruction of pancreatic tissue and produce the succeeding pathologic conditions.29

It is important to note that the autoimmune destruction of the pancreatic tissue has significant physiological consequences. The damaged beta cells impair an individual's ability to respond to alternating blood glucose levels due to the absence or lack of insulin. As mentioned above, insulin is the hormone that regulates carbohydrate, fat, and protein metabolism. Normally, these molecules are readily absorbable by the cells and insulin facilitates their cellular uptake and synthesis into glycogen, triglycerides and proteins, respectively.29 Specifically, insulin regulates carbohydrate (glucose) metabolism, based on glucose levels and cellular needs.29 The role of insulin is further outlined below:

• Insulin allows for the passive diffusion of glucose into cells by opening the glucose transport proteins (GLUT 1-5);

• Insulin stimulates glycogenesis, or the conversion of glucose to glycogen, for cellular storage in the cells;

• Insulin prevents glycogenolysis, or the conversion of glycogen to glucose in favor of cellular glycogen storage and reduction of glucose output by the liver; and, glucose inhibits gluconeogenesis, or the metabolism of glucose from amino acids, by decreasing amino acid levels available to the liver and inhibiting hepatic glucogeneic enzymes.

Insulin also promotes protein synthesis, thereby enhancing the activity of cellular mechanisms. The result is the increased consumption of glucose and reduction of blood glucose levels. It is important to note that insulin is the only hormone which downregulates blood glucose, and thus, it is not uncommon for individuals with type 1 diabetes mellitus to experience acute periods of hyperglycemia. Despite the high levels of glucose in the blood, these individuals are starved for energy because the cells are unable to utilize the blood glucose without insulin.29

Disease Presentation

As mentioned previously, type 1 diabetes mellitus is the result of infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas by lymphocytes. As beta-cell mass diminishes, insulin secretion also decreases until it diminishes completely to the point where blood glucose levels cannot be set back to normal levels without the administration of exogenous insulin.

The destruction of 80-90% of the beta cells is followed by the development of hyperglycemia, which may be pronounced enough to precipitate the diagnosis of diabetes. In order to overturn this catabolic condition, prevent ketosis, and set lipid and protein metabolism back to normal, patients are given exogenous insulin, usually in the form of injections.

Signs and symptoms

The signs and symptoms of type 1 diabetes mellitus in children are:

1. Polydipsia

2. Polyphagia

3. Glycosuria

4. Weight loss

5. Unexplained fatigue

6. Greater frequency of infections

7. Symptoms of ketoacidosis

Each of these symptoms is discussed in detail below.

Polydipsia and polyuria

Polydipsia simply means increased thirst. In the case of children with type 1 diabetes mellitus, they may experience an insatiable thirst brought on by frequent urination, or polyuria.

The significant osmotic diuresis that ensues can cause dehydration if not treated. This is especially inconvenient for both parents and children because it leads to frequent urination during the night (nocturnal enuresis), leading to interrupted sleep.

Polyuria and nocturnal enuresis in children should make parents aware that there is something wrong, particularly if the child was previously continent. In infants, these symptoms are easier to overlook due to their naturally high fluid intake and diaper use.

Polyphagia

Polyphagia means excessive hunger. In type 1 diabetes mellitus, the inadequate glucose received by the cells produces the hunger trigger in the brain.

Glycosuria

Glycosuria refers to an abnormal condition wherein glucose is found in the urine. The kidneys normally reabsorb glucose, but in the case of diabetes mellitus, the excess glucose in the blood (hyperglycemia) and damaged renal arteries can compromise the reabsorptive capacity of the kidneys.

Weight loss

Weight loss is also seen among children with type 1 diabetes mellitus. Deregulated gluconeogenesis is caused by insulin insufficiency, which also leads to uncontrolled metabolism of protein and fat in the body. They usually exhibit dramatic weight loss despite normal appetite and healthy eating habits.

In infants, weight loss is apparent in the child’s failure to thrive and wasting. These can occur prior to the onset of obvious hyperglycemia.

Unexplained fatigue

Unexplained fatigue is also another symptom of type 1 diabetes mellitus. This symptom may already be present prior to the onset of other symptoms such as hyperglycemia. Because of its non-specific nature and a wide explanation for its causes, this is often overlooked and only recognized retrospectively.

Symptoms of ketoacidosis

The symptoms of ketoacidosis are:

• Severe dehydration

• Fruity breath (Kussmaul respiration)

• Abdominal pain

• Vomiting

• Drowsiness and coma

Other symptoms

Other symptoms of diabetes mellitus are associated with hyperglycemia. High blood glucose levels lead to decreased immune resistance, rendering diabetic children more susceptible to a variety of recurrent infections, such as urinary tract infections, skin infections, and respiratory tract infections. Candidiasis may also develop, especially in the groin and in flexural areas.

Hyperglycemia

Hyperglycemia will be discussed at greater length later on in the study; it simply means elevated blood glucose levels. It is a result of insulin deficiency, which in turn causes deregulated gluconeogenesis. It causes the body to improperly use and store circulating glucose.

As mentioned previously, hyperglycemia also affects the kidneys. High blood glucose levels render the kidneys incapable of reabsorbing the excess glucose load, causing glycosuria, polyuria, polyphagia, and dehydration. Greater fat and protein metabolism leads to ketone production and weight loss. A child with type 1 diabetes mellitus, who does not have insulin to regulate the blood glucose levels, wastes away, drastically loses weight and, if untreated, can lead to death from diabetic ketoacidosis.

Hypoglycemia

Insulin inhibits glucogenesis and glycogenolysis. It stimulates cellular glucose uptake. In non-diabetic children, insulin production by the pancreatic islet cells is suppressed when blood glucose levels decrease to less than 83 mg/dL. Whereas, children with type 1 diabetes mellitus do not have insulin and, therefore, the mechanism is not regulated. Hypoglycemia can result from administration of insulin in children who have not consumed adequate amounts of carbohydrates, leading to the dangerous progressive fall of blood glucose levels.

Glucose is the fuel for all cellular activities. All organs depend on it, including the brain. When glucose levels fall below 65 mg/dL, counter-regulatory hormones such as glucagon, cortisol, and epinephrine are released, resulting in the symptoms of hypoglycemia. These symptoms include shaking, sweatiness, confusion, behavioral changes, and, changes in consciousness levels. If blood glucose levels fall below 30-40 mg/dL, coma ensues. The level of glucose at which symptoms develop and appear depends on the individual, including comorbidities, severity, frequency of hypoglycemic episodes, the rate of fall of hypoglycemia, and overall glycemic control.

Etiology, Progression and Comorbidities

Autoimmunity

Based on current research data, autoimmunity is considered the primary factor in the pathophysiology of type 1 diabetes mellitus. Individuals who are carriers of the genetic haplotypes are especially susceptible to developing the disease following a bout of viral infections that trigger the production of antibodies against a viral protein, which in turn stimulate an autoimmune response against antigenically alike beta cell components.

About 85% of type 1 diabetes mellitus patients possess circulating islet cell antibodies, with the majority of them also possessing detectable anti-insulin antibodies prior to the start of insulin therapy. Among the most commonly found islet cell antibodies are those targeting the enzyme found within the beta cells of the pancreas called glutamic acid decarboxylase (GAD).

The occurrence of type 1 diabetes mellitus is also considerably greater in patients with other autoimmune diseases, such as Hashimoto thyroiditis, Graves disease, and Addison’s disease. A study by Pilia, et al. found greater amounts of islet cell antibodies (IA2) and anti-GAD antibodies in patients with autoimmune thyroiditis.20 Findings from another study by Philippe, et al. using CT scans, glucagon stimulation test results, and fecal elastase-1 measurements21 noted that reduced pancreatic volume occurred in both individuals with type 1 and type 2 diabetes mellitus. These findings explain the link between exocrine dysfunction and diabetes mellitus.

Neuropathy

Diabetic neuropathy is a major complication of poorly controlled diabetes mellitus. It is caused by the degeneration of axons and segmental demyelination. There are multiple pathologic factors at play, such as the buildup of sorbitol in the peripheral sensory nerves from persistent hyperglycemia. Motor neuropathy and cranial mononeuropathy are the culmination of vascular disease in blood vessels supplying nerves.30

There are four types of diabetic neuropathies, and they are classified according to the organs they affect. These types of neuropathies are outlined in the following table and further explained in the section below.

|Type of neuropathy |Organs affected |

|Peripheral neuropathy |Toes, feet, legs, hands, arms |

|Autonomic neuropathy |Heart and blood vessels, digestive system, urinary tract, sex organs, sweat glands, |

| |eyes, lungs |

|Proximal neuropathy |Thighs, hips, buttocks, legs |

|Focal neuropathy |Eyes, facial muscles, ears, pelvis and lower back, chest, abdomen, thighs, legs, feet |

Peripheral neuropathy

Peripheral neuropathy is also known as distal symmetric neuropathy. The damage is to the peripheral nerves of the arms and legs. Diabetic individuals who present with peripheral neuropathy usually indicate their feet and legs being affected first before their hands and arms. Acquired peripheral neuropathy can also occur in diabetic children.

The symptoms of peripheral neuropathy are often aggravated at night and include the following:30

• Numbness

• Heat and pain insensitivity

• Paresthesia

• Sharp cramps

• Greater sensitivity to touch

• Loss of balance and coordination

Peripheral neuropathy can also lead to muscle weakness and loss of reflexes, particularly at the ankles. The combined muscle weakness and loss of reflexes leads to changes in gait and causes the affected patient to walk differently.

The muscle and loss of reflex changes described above lead to foot deformities such as hammertoes and the collapse of the mid-foot. Because of the insensitivity to pain and pressure, many patients may not notice the sores and blisters that have developed on their foot. This is especially a cause for concern because untreated open wounds can become infected.

Diabetics have compromised circulation and immune systems, making them susceptible to acquiring infections to the internal structures such as the bone and blood. If left untreated, a wound that began as a small sore can become large enough to require amputation. However, when these wounds are given prompt medical attention they usually heal in time.30

Autonomic neuropathy

In autonomic neuropathy the damage is to the nerves, which primarily control the cardiovascular system. These include the nerves of the heart and blood vessels that regulate blood pressure and blood glucose levels. It also damages other internal organs, causing impaired and abnormal digestion, respiratory function, urination, sexual response, and vision. Additionally, the homeostatic mechanism that regulates blood glucose levels is affected. The result is the absence of warning symptoms of hypoglycemia.30

The warning symptoms of hypoglycemia include palpitations, shakiness, and sweating. However, in people with autonomic neuropathy, these symptoms may not occur at all, making hypoglycemia unrecognizable and overlooked medically. It is important to remember that conditions other than neuropathy can also cause unrecognizable hypoglycemia.30

Proximal neuropathy

Proximal neuropathy is also known as diabetic amyotrophy. This type occurs more frequently among older diabetics, and those with type 2 form of the disease. One of its most notable symptoms includes a one-sided pain that begins in the thighs, hips, buttocks, or legs.30

Damage to the nerves on the legs causes weakness and inability to switch from a sitting to a standing position without aid. Treatment is usually needed for the weakness and pain. Recovery time differs individually, based on the type of nerve damage.30

Focal neuropathy

Unlike other types of diabetic neuropathy, the onset of focal neuropathy is sudden. As outlined previously in the table, it affects the nerves of the eyes, face, pelvis, ears, and legs.30 Symptoms of focal neuropathy include the following:30

• inability to focus the eye

• double vision

• pain behind one eye

• Bell's palsy

• severe pain in the lumbar or pelvic region

• pain in the front of a thigh

• pain in the chest, stomach, or side

• pain on the outside of the shin or inside of the foot

• chest or abdominal pain

Focal neuropathy can be painful and unpredictable. Its prevalence is high among older diabetic patients. On the other hand, the pain and neuropathic symptoms improve on their own over a period of weeks or months, and do not lead to long-term damage.30

Diabetics are also more prone to developing nerve entrapment syndromes. The most common of these is carpal tunnel syndrome, which causes symptoms such as numbness, hand tingling, and muscle weakness or pain. A nerve entrapment affecting the lower legs can cause pain on the outer shin or the inner foot.30

Angiopathy

A study by Barchetta, et al. using nailfold video capillaroscopy found a greater occurrence of capillary changes in patients with diabetes, especially those with comorbid retinopathy. This finding reaffirms the involvement of microvessels in both types 1 and type 2 diabetes mellitus.22

Microvascular disease leads to multiple complications in people with diabetes. For instance, hyaline arteriosclerosis, a condition characterized by thickening of small arterioles and capillaries, is a very common finding and responsible for ischemic changes in the retina, brain, kidneys, and peripheral nerves. Atherosclerosis of the major kidney arteries and their intrarenal branches leads to chronic nephron ischemia, which is an important part of multiple renal lesions in diabetes.

An important predictor of the development of coronary artery calcification in individuals with type 1 diabetes mellitus is vitamin D deficiency.23 A study by Joergensen, et al. found that vitamin D deficiency in type 1 diabetes mellitus is a predictor of mortality but not development of microvascular complications.24

Nephropathy

Another microvascular complication resulting from diabetes mellitus is the characteristic wall thickening of small arterioles and capillaries of the kidneys, which in turn can very well lead to diabetic nephropathy. Diabetic nephropathy is characterized by proteinuria, glomerular hyalinization, and chronic renal failure. Aggravated expression of cytokines (i.e., tumor growth factor (TGF) beta-1) is a component of the pathophysiology of glomerulosclerosis, which starts early in the course of diabetic nephropathy.

Genetic polymorphisms also exert an influence on the development of diabetic nephropathy. Single-nucleotide polymorphisms play a role in the development for diabetic nephropathy in various individuals with type 1 diabetes mellitus.25

Double diabetes

In certain regions where rates of type 2 diabetes mellitus and obesity are high, individuals with type 1 diabetes mellitus may share genetic and environmental factors that cause them to exhibit features of type 2 diabetes mellitus such as reduced insulin sensitivity. This condition is termed double diabetes.

A study by Epstein, et al. of 207 patients with type 1 diabetes mellitus using estimated glucose disposal rate (eGDR) to evaluate insulin resistance found that the mean eGDR was significantly lower (meaning, insulin resistance was higher) in black patients (5.66 mg/kg/min) compared to Hispanic patients (6.70 mg/kg/min) and white patients (7.20 mg/kg/min). Additionally, low eGDR was associated with a marked increase in the risk of vascular complications of diabetes such as cardiovascular disease, chronic kidney disease, and diabetic retinopathy.26

Heart and blood vessels

Damage to the nerves of the heart and blood vessels impairs the body's regulatory control of blood pressure and heart rate. Diabetic children with autonomic damage to the cardiovascular system are prone to feeling light-headed and faint when standing up after long periods of sitting. This is because of the sudden drop of blood pressure after a change in body position. Additionally, damage to the cardiac nerves can also result in a constantly elevated heart rate despite the change in body functions and physical activity.30

Digestive system

Damage to the nerves of the digestive system often leads to constipation. Other effects include slow gastric emptying, a condition called gastroparesis. Severe gastroparesis can lead to constant nausea and vomiting, bloating, and loss of appetite. Additionally, the abnormal digestion of food leads to fluctuating blood glucose levels.30

Another digestive organ that can sustain neural damage is the esophagus, which leads to symptoms such as swallowing difficulties. If left untreated, these problems can combine together and result in massive weight loss.30

Urinary and reproductive systems

Nerve damage also affects sexual function and urination. Autonomic neuropathy causes incomplete bladder emptying, thus, allowing for the growth of bacteria in the urinary system. This predisposes diabetic individuals to recurring urinary tract infections.30 Additionally, autonomic neuropathy affecting the bladder causes urinary incontinence, which may be embarrassing for school-age children.30

Sweat glands

Damage to the nerves that control sweating can result in impaired regulation of body temperature. Children with autonomic neuropathy affecting the sweat glands can exhibit symptoms such as profuse sweating at night or during meals.30

Eyes

Autonomic neuropathy can affect the nerves of the pupils. The result is decreased sensitivity to changes in light. A good example is when a diabetic individual is unable to see properly in a well-lit room or have difficulty driving at night.30

Diagnosis

The diagnosis of type 1 diabetes mellitus in the pediatric and adolescent population is usually straightforward and requires little to no specialized testing. They usually present with a several-week history of polyuria, polydipsia, polyphagia (the 3 P’s symptoms of diabetes), and weight loss, with hyperglycemia, glycosuria, ketonemia, and ketonuria.

When evaluating children for type 1 diabetes mellitus, it is important for clinicians and other health professionals to consider in the differential diagnosis the following conditions:28

• Maturity Onset Diabetes of the Young (MODY)

• Steroid treatment

• Type 2 diabetes mellitus

• Diabetes insipidus

• Transient hyperglycemia with illness and other stress

• High-output renal failure

• Psychogenic polydipsia

• Münchhausen syndrome

Children with Maturity Onset Diabetes of the Young (MODY) may exhibit symptoms of type 1 diabetes mellitus. The following notes may help clinicians and health professionals recognize MODY:28

• Long-standing family history of diabetes, usually two or more generations, with the age of diagnosis falling with each successive generation;

• Chronic low insulin requirements, especially with good glycemic control; and

• Onset of diabetes at birth or within the first year of life.

Genetic testing is expensive and can be substituted by testing for islet autoantibodies in patients suspected of having maturity-onset diabetes of the young. The presence of these antibodies is the same in patients with MODY as in the non-diabetic groups. A positive test for positive islet autoantibodies eliminates MODY as a possible diagnosis.40

Differential Diagnosis from Type 2 Diabetes Mellitus

The 2011 American Association of Clinical Endocrinologists (AACE) guidelines recommend that clinicians and other healthcare practitioners entrusted with the care of pediatric diabetics do the following in order to differentiate between type 1 and type 2 diabetes mellitus:38

1. Measure insulin levels,

2. Measure C-peptide levels and immune markers such as glutamic acid decarboxylase [GAD] autoantibodies, and

3. Obtain detailed family history.

An oral glucose tolerance test (OGTT) is not needed in the diagnosis of type 1 diabetes mellitus. However, the significant increase of type 2 diabetes mellitus merits the evaluation of insulin secretion in the pediatric population.

C-peptide is a product of the conversion of pro-insulin to insulin. An insulin or C-peptide level below 5 µU/mL is suggestive of type 1 diabetes mellitus. A fasting C-peptide level more than 1 ng/dL in a patient with diabetes for more than one year suggests type 2 diabetes mellitus, except if the glucose level is elevated and insulin or C-peptide level is temporarily low. These patients are more likely to recover insulin production once normal glucose is restored.32

Non-diagnostic tests

There are a variety of laboratory tests carried out to diagnose or confirm the diagnosis of type 1 diabetes mellitus, all of which are based on the health of the child. For most children, only urine testing for glucose and blood glucose measurement is required for a diagnosis of the disease. Other conditions associated with diabetes require several tests at diagnosis.

Urinalysis

Urinalysis is a standard test requiring a sample of urine from patients. One of the findings indicative of diabetes mellitus is the presence of glucose and ketone bodies in the urine sample. A positive urine glucose test is indicative but not diagnostic for type 1 diabetes mellitus. This test must be followed by a blood glucose test to confirm elevated blood glucose levels.28

A urine sample of ambulatory patients should be tested for the presence of ketone bodies at the time of diagnosis.28 The presence of ketone bodies in the urine, ketonuria, confirms the occurrence of lipolysis and gluconeogenesis, which are metabolic processes that normally only happen during cellular starvation. In fact, the combined presence of ketonuria, hyperglycemia and glycosuria are strong indications of insulin deficiency and potential diabetic ketoacidosis.28

It should be noted that the presence of ketone bodies in the urine is not reliable for either the diagnosis or monitoring of diabetic ketoacidosis (DKA), although its measurement is useful in screening a hyperglycemic patient for ketonemia.28 The plasma acetone level or the beta-hydroxybutyrate level is a better indicator of diabetic ketoacidosis, along with plasma bicarbonate measurements.28

Urinary albumin

Children with type 1 diabetes mellitus should be regularly monitored for the development of diabetic comorbidities such as nephropathy. Starting at 12 years old, a urinalysis testing for a slightly elevated albumin excretion rate (AER), a condition known as microalbuminuria, should be conducted yearly.

Microalbuminuria is an indicator of risk for diabetic nephropathy. In fact, it is the first indication of nephropathy.

Early identification of microalbuminuria provides opportunities for early resolution and prevention of renal failure. Microalbuminuria is characterized by glomerular hyperfiltration, and by abnormal functioning of glomerular basement membrane and glomeruli.28

Fructosamine test

Fructosamine is the product of a chemical reaction between glucose and plasma protein. Fructosamine levels, although not diagnostic, can also test for glucose levels. They reflect glucose control in the previous 1-3 weeks. Therefore, this test method may show changes in glycemic control before HbA1c testing can be done. In addition, it is also helpful in cases of intensive treatment and in short-term clinical trials.32

White blood count

A white blood cell (WBC) count and blood and urine cultures are performed to rule out infection.

Antibody testing

Since type 1 diabetes mellitus has strong etiologic autoimmune origins, antibody testing for the presence of islet cell antibodies, insulin antibodies, glutamate decarboxylase (GAD) antibodies, thyroid antibodies, and antigliadin antibodies should be considered.28

Islet cell antibodies

Screening for islet antibodies in low-risk children with no symptoms is not recommended.36 However, children at high risk such as those who have first-degree relatives with diabetes may be good candidates for annual screening for the presence of anti-islet antibodies before reaching the age of ten, along with an additional screening during adolescence.37

Islet cell antibodies are non-specific disease markers of autoimmune diseases affecting the pancreas. Their presence at diagnosis may indicate but are not needed to diagnose type 1 diabetes mellitus. They have been found in approximately 5% of children without type 1 diabetes mellitus.28

Other antibody markers of type 1 diabetes mellitus include:28

• Insulin antibodies

• Glutamate decarboxylase (GAD) antibodies

Thyroid antibodies

The presence of thyroid antibodies may indicate a risk of developing thyroid disease. On the other hand, it is not uncommon for children with type 1 diabetes mellitus to also have an undiagnosed thyroid condition such as hypothyroidism. This is because hypothyroidism, in its initial stages, has few easily recognizable clinical signs in children. The diagnosis of this disease is important because if left untreated, it may interfere with diabetes management.28

Generally, children with hypothyroidism have lower insulin requirements compared to those who do not have the disease. They also experience more episodes of hypoglycemia. On the other hand, children with hyperthyroidism have greater insulin requirements and are more prone to hyperglycemic episodes. This is why it is very important for clinicians and health professionals to be wary of this comorbidity when starting insulin therapy since insulin requirements can easily fluctuate.28 Thyroid function tests should be conducted regularly, usually every 2-5 years if thyroid antibodies are present.28

Antigliadin antibodies

The presence of antigliadin antibodies is suggestive of celiac disease. If positive, a jejunal biopsy must be conducted to confirm or refute the diagnosis. Once celiac disease is confirmed, the diabetic patient must start on a gluten-free diet for life. The disease can be identified in about 4% to 9% of children with type 1 diabetes mellitus, although more than half of them do not have outward symptoms (asymptomatic).28 Children with type 1 diabetes are at greater risk of developing classic celiac disease within the first 10 years of diabetic life.

Recent studies suggest that a gluten-free diet improves intestinal and extra-intestinal symptoms of celiac disease. The same studies suggest that it may even prevent its sequelae.28

Lipid profile

Children with type 1 diabetes usually have abnormal lipid profiles because of increased triglycerides (hypertriglyceridemia) in the circulation released due to gluconeogenesis. Hyperlipidemia is common with poor metabolic control but can quickly be restored to normal when metabolic control improves.

Blood glucose monitoring tests

Random and fasting blood glucose is covered here. Aside from the signs and symptoms of temporary stress-induced hyperglycemia, a random whole-blood glucose concentration exceeding 200 mg/dL is diagnostic for diabetes. A fasting whole-blood glucose concentration more than 120 mg/dL is also diagnostic for diabetes. On the other hand, if the signs and symptoms of hyperglycemia are not present, the clinician must confirm the results of these tests on a different day. It is very common for children with diabetes to be detected because of hyperglycemic symptoms accompanied by blood glucose levels of at least 250 mg/dL.28

Children with type 1 diabetes need to monitor their blood glucose levels several times a day using capillary blood samples, reagent sticks, and blood glucose meters. A finger-stick glucose test is usually recommended in the emergency department for almost all patients with confirmed diabetes mellitus. All finger-stick capillary glucose levels require serum or plasma tests to confirm the diagnosis. All other lab studies must either be chosen or foregone depending on the individual clinical situation. Intravenous glucose testing may also be considered to detect subclinical diabetes early.28

It is important to note that individually measured glucose levels can vary significantly from estimated glucose averages measured using hemoglobin A1c (HbA1c) tests.31 It is therefore, important to proceed with caution especially if the measurements were taken to estimate rather than accurately measure glucose concentration. The difference between the two measurements has a potential influence on clinical decisions regarding treatment and management.

Glycosylated hemoglobin

Glycosylated hemoglobin derivatives, such as HbA1a, HbA1b, and HbA1c, are products of non-enzymatic reaction between glucose and hemoglobin. There is a strong correlation between the average blood glucose levels taken over a period of 8 to 10 weeks and the proportion of glycosylated hemoglobin in the blood. For the diagnosis of type 1 diabetes mellitus, the percentage of HbA1c is the most common product measured. In fact, the measurement of HbA1c levels is the best method for monitoring medium to long-term blood glucose levels.28

HbA1c is formed when the beta chain of hemoglobin is irreversibly glycosylated by plasma glucose. Its rate of formation increases with rising plasma glucose levels. HbA1c levels provide an approximation of plasma glucose levels of the preceding 1-3 months. The reference range for non-diabetics is 6% in most laboratories. Glycosylated hemoglobin levels can help predict the development and progression of microvascular complications associated with diabetes mellitus.28

The American Diabetes Association (ADA) guidelines recommend the measurement of HbA1c at least once every 6 months in diabetics who meet their treatment goals and exhibit stable glycemic control. On the other hand, the ADA recommends HbA1c testing every 3 months for diabetics whose insulin therapy was altered or unable to meet glycemic targets.33

HbA1c testing has not always been widely recognized and used as today in the diagnosis of diabetes mellitus. This drawback is attributed to the lack of international standardization and insensitivity for the identification of milder forms of glucose intolerance. However, this all changed in 2009 when a panel consisting of members of the ADA, the European Association for the Study of Diabetes, and the International Diabetes Association reached consensus and recommended HbA1c testing for the diagnosis of both types 1 and 2 diabetes mellitus.34 The committee specifically recommended the test for patients with suspected type 1 diabetes mellitus who do not exhibit the classic symptoms of the disease such as polyuria, polydipsia, polyphagia, unexplained weight loss, and do not have a random glucose level of 200 mg/dL.

The ADA panel recommended that HbA1c levels ≥6.5% to be indicative of diabetes. These results should be accompanied by diagnostic confirmation through repeat testing if clinical symptoms are absent. However, glucose testing remains the diagnostic choice for pregnant women and in cases where HbA1c testing is unavailable.34 The panel mentioned the following advantages of HbA1c testing over glucose measurement:34

• It provides long-term glucose monitoring

• It presents less biologic variability

• It does not have fasting or timed sample requirements

• It is currently the standard used in making disease management decisions

The results of the Diabetes Control and Complications Trial (DCCT) discovered that patients with HbA1c levels of approximately 7% possessed the best prognosis when it comes to long-term diabetic complications. Currently, many clinicians aim for HbA1c levels between 7-9%, which is the target range. Levels 9% put diabetics at greater risk for long-term complications of the disease. The International Society for Pediatric and Adolescent Diabetes (ISPAD) recommends a pediatric target level of 7.5% or less.28

Normal HbA1c levels vary slightly depending on the laboratory method used, however; children without type 1 diabetes mellitus usually have levels between the low to normal range. At diagnosis, these levels are usually well above the upper limit of the reference range. Their HbA1c levels should be checked every 3 months.28 Clinicians must remember that there are various methods of measuring HbA1c levels, and the differences between these assays can be significant and unpredictable.

Oral glucose tolerance test (OGTT)

OGTT is not needed in the diagnosis of type 1 diabetes mellitus, although it can help in the differential diagnosis. It helps exclude the diagnosis of diabetes when hyperglycemia or glycosuria is identified without the usual causes such as recent illness, steroid therapy or when the patient also exhibits renal glucosuria.28

This OGTT is done by first obtaining a fasting blood sugar level followed by the administration of an oral glucose load according to the ages specified below:28

• 2 g/kg for pediatric patients < 3 years old

• 1.75 g/kg for pediatric patients between 3-10 years old

• 75 g for pediatric patients >10 years old

Next, the blood glucose concentration is checked after 2 hours. A fasting whole-blood glucose level more than 120 mg/dL or a 2-hour value more than 200 mg/dL is indicative of diabetes. However, it is important to note that mild elevations may not always indicate diabetes, especially when the patient exhibits no symptoms and have not tested positive for diabetes-related antibodies.28

A modified OGTT may be used to single out cases of MODY, if in addition to blood glucose levels, insulin or c-peptide levels are measured at fasting, 30 minutes, and 2 hours. Children with type 1 diabetes mellitus produce very negligible, if at all, amounts of insulin, while those with MODY or type 2 diabetes mellitus can produce variable and substantial insulin in the presence of hyperglycemia.28

The criteria for the diagnosis of type 1 diabetes mellitus are outlined in the table below. Any child who fits into any of the three criteria has type 1 diabetes mellitus.

|Casual plasma glucose |Fasting plasma glucose |Oral glucose tolerance test |

| | | |

|[pic]≥ 200 mg/dL accompanied by classic symptoms |[pic]≥ 126 mg/dL |≥ 200 mg/dL |

|such as polydipsia, polyuria, and unexplained | | |

|weight loss | | |

Diabetes Management

Initial care

After the diagnosis, initial diabetic care can begin. It generally depends on several factors such as:

• Age of the child,

• The ability to provide outpatient education,

• The clinical severity of the child at presentation, and

• The geographic proximity of the patient to a tertiary care center.

Ideally, children who are newly diagnosed with type 1 diabetes should be initially evaluated by a diabetes healthcare team whose members are qualified to provide advice and counseling on the latest in pediatric management of type 1 diabetes mellitus. The team ideally should consist of the following members:

• Pediatrician with training on diabetes care

• Pediatric endocrinologist

• Nurse educator

• Dietitian/nutritionist, and

• Mental health professional

Other health professionals may also be included in the team, including the following:48

• Psychologist

• Social worker

• Exercise specialist

Regardless of the sources of care available, all healthcare professionals involved in the care of children with diabetes should have a good grasp of the developmental stages of childhood and adolescence and how each one impacts diabetes management differently. A study by Kaufman, et al. found that both short and long term outcomes are enhanced with regular outpatient review with a specialized diabetes team.48 The involvement and coordination among these team members during the first weeks of diagnosis is crucial to the prognosis of the patient. It is usually during this time that the family members learn about diabetes management.49,50

The diabetes healthcare team is useful in helping newly diagnosed children start their glycemic control program. The start can be overwhelming both to the team and to the patients and the family. Since self-management is one of the major goals of the team, they may want to impart the following useful tips to these patients.

• Start slowly:

For example, the nurse educator may first teach the patient how to check the blood glucose level several times each day. Once the patient has adapted to the routine, the nurse educator might want to teach the patient how to self-administer multiple daily injections next. Once the patient has learned this, the exercise specialist might incorporate a new exercise program and help the nutritionist make the necessary changes in the diet to accommodate the program’s energy requirements.

• Be honest and open to changes:

The school psychologist or nurse might want to encourage newly diagnosed patients to be honest and open to the upcoming major changes in their lifestyle.

• Set realistic goals:

The team needs to assure patients that blood glucose levels will not always be on target levels every time. With enough practice and experience, patients can develop the skill at choosing correct insulin doses for various situations.

Children diagnosed with type 1 diabetes mellitus require a lifetime therapy with insulin. The following are also required to manage the disease successfully:

• Glycemic monitoring

• Lifestyle changes

• Diet

• Monitoring for the development of diabetic complications

All of these elements are discussed in detail in the succeeding pages.

It is important for all healthcare professionals involved in the management of type 1 diabetes mellitus to create effective strategies that help these pediatric patients and their parents achieve glycemic control targets through a combination of proper lifestyle and diet changes, patient education and frequent glucose monitoring. A well-organized healthcare team can offer the patient education and support in an outpatient setting. Some of the immediate requirements following a confirmed diabetes diagnosis are the education and training of the patient and family on:

• Blood glucose level (glycemic) monitoring,

• Insulin therapy, and

• Recognition and treatment of hypoglycemic symptoms.

Hypoglycemia becomes harder to recognize over time, and severe hypoglycemic episodes can happen spontaneously. It is therefore important to reiterate the warning signs and symptoms of hypoglycemia to children (and parents) who maintain low blood sugar levels and who already have a history of frequent hypoglycemic episodes. Inappropriate or inadequate treatment of hypoglycemia can result in serious consequences.

As mentioned previously, microvascular complications such as retinopathy and nephropathy are common among diabetics. Therefore, frequent monitoring for their development should be a regular part of the management plan.

Glycemic Monitoring

A tight glycemic control decreases both the onset and development of diabetes-related complications in adults and adolescents with type 1 diabetes.40,41 Solid attempts to reach the recommended glycemic goals should be made (see table below).

|Age |HbA1c (%) |Fasting plasma |Two-hour post-prandial plasma| |

|(in years) | |glucose |glucose |Considerations |

| ................
................

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