TYPE 1 DIABETES MILLITUS (T1DM)
According to WHO, the number of people with diabetes has risen from 108 million in 1980 to 422 million in 2014. The global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. In 2012, an estimated 1.5 million deaths were directly caused by diabetes and another 2.2 million deaths were attributable to high blood glucose.(1) WHO projects that diabetes will be the 7th leading cause of death in 2030.(2)
In 2015, the International Diabetes Federation’s (IDF) Diabetes Atlas estimates that:(3)
- One in 11 adults has diabetes (415 million)
- One in two (46.5%) adults with diabetes is undiagnosed
- One in seven births is affected by gestational diabetes
- Three-quarters (75%) of people with diabetes live in low- and middle-income countries
- Every six seconds a person dies from diabetes (5.0 million deaths)
Type 1 diabetes can occur at any age, but tends to develop in childhood,(4) so it has long been called ‘juvenile diabetes’. As of 2014, an estimated 387 million people have diabetes worldwide,(5) of which T1DM accounts for between 5% and 10%.(6)
Pakistan ranks at number six in terms of number of people with diabetes worldwide. It was estimated that in 2000 there were 5.2 million diabetic patients and this will rise to 13.9 million by 2020, leading Pakistan to 4th most populous country for patients with diabetes mellitus.(7) According to WHO prevalence of diabetes in Pakistan is 9.8%.(8) According to diabetes international federation, there were over 7 million cases of diabetes in Pakistan in 2015.(9)
According to the National Health Survey of Pakistan, 25% of patients over the age of 45 years suffer Diabetes Mellitus. Further analysis of this data revealed that prevalence of DM among population aged 15 years and above was 5.4% with significant ethnic differences.(10)
Incidence of type 1 diabetes was estimated to be 1.02/100000 per year in Karachi, Pakistan.(11) Rates of gestational diabetes in Pakistan range from 3.2% to 3.5%, comparable to Western populations but the rates of complications both to mother and foetus were found to be higher possibly due to poor glycaemic control.(12-14)
Type 1 DM is the culmination of lymphocytic infiltration and destruction of insulin-secreting beta cells of the islets of Langerhans in the pancreas. As beta-cell mass declines, insulin secretion decreases until the available insulin no longer is adequate to maintain normal blood glucose levels. After 80-90% of the beta cells are destroyed, hyperglycemia develops and diabetes may be diagnosed. Patients need exogenous insulin to reverse this catabolic condition, prevent ketosis, decrease hyperglucagonemia, and normalize lipid and protein metabolism.
Currently, autoimmunity is considered the major factor in the pathophysiology of type 1 DM. In a genetically susceptible individual, viral infection may stimulate the production of antibodies against a viral protein that trigger an autoimmune response against antigenically similar beta cell molecules.
Approximately 85% of type 1 DM patients have circulating islet cell antibodies, and the majority also have detectable anti-insulin antibodies before receiving insulin therapy. The most commonly found islet cell antibodies are those directed against glutamic acid decarboxylase (GAD), an enzyme found within pancreatic beta cells.
The prevalence of type 1 DM is increased in patients with other autoimmune diseases, such as Graves disease, Hashimoto thyroiditis, and Addison disease. Pilia et al found a higher prevalence of islet cell antibodies (IA2) and anti-GAD antibodies in patients with autoimmune thyroiditis.(15)
A study by Philippe et al used computed tomography (CT) scans, glucagon stimulation test results, and fecal elastase-1 measurements to confirm reduced pancreatic volume in individuals with DM.(16) This finding, which was equally present in both type 1 and type 2 DM, may also explain the associated exocrine dysfunction that occurs in DM.
Polymorphisms of the class II human leukocyte antigen (HLA) genes that encode DR and DQ are the major genetic determinants of type 1 DM. Approximately 95% of patients with type 1 DM have either HLA-DR3 or HLA-DR4. Heterozygotes for those haplotypes are at significantly greater risk for DM than homozygotes. HLA-DQs are also considered specific markers of type 1 DM susceptibility. In contrast, some haplotypes (e.g. HLA-DR2) confer strong protection against type 1 DM.(17)
SENSORY AND AUTONOMIC NEUROPATHY: Sensory and autonomic neuropathy in people with diabetes are caused by axonal degeneration and segmental demyelination. Many factors are involved, including the accumulation of sorbitol in peripheral sensory nerves from sustained hyperglycemia. Motor neuropathy and cranial mononeuropathy result from vascular disease in blood vessels supplying nerves.
ANGIOPATHY: Using nailfold video capillaroscopy, Barchetta et al detected a high prevalence of capillary changes in patients with diabetes, particularly those with retinal damage. This reflects a generalized microvessel involvement in both type 1 and type 2 DM.(18)
Microvascular disease causes multiple pathologic complications in people with diabetes. Hyaline arteriosclerosis, a characteristic pattern of wall thickening of small arterioles and capillaries, is widespread and is responsible for ischemic changes in the kidney, retina, brain, and peripheral nerves.
Atherosclerosis of the main renal arteries and their intrarenal branches causes chronic nephron ischemia. It is a significant component of multiple renal lesions in diabetes.
Vitamin D deficiency is an important independent predictor of development of coronary artery calcification in individuals with type 1 DM.(19) Joergensen et al determined that vitamin D deficiency in type 1 diabetes may predict all causes of mortality but not development of microvascular complications.(20)
NEPHROPATHY: In the kidneys, the characteristic wall thickening of small arterioles and capillaries leads to diabetic nephropathy, which is characterized by proteinuria, glomerular hyalinization (Kimmelstiel-Wilson), and chronic renal failure. Exacerbated expression of cytokines such as tumor growth factor beta 1 is part of the pathophysiology of glomerulosclerosis, which begins early in the course of diabetic nephropathy.
Genetic factors influence the development of diabetic nephropathy. Single-nucleotide polymorphisms affecting the factors involved in its pathogenesis appear to influence the risk for diabetic nephropathy in different people with type 1 DM.(21)
DOUBLE DIABETES: In areas where rates of type 2 DM and obesity are high, individuals with type 1 DM may share genetic and environmental factors that lead to their exhibiting type 2 features such as reduced insulin sensitivity. This condition is termed double diabetes.
Type 1 diabetes is probably triggered by one or more environmental agents and usually progresses over many months or years, during most of which the subject is asymptomatic and euglycemic. A large percentage of the functioning beta cells are lost before hyperglycemia appears.
The rate of progression of the immune injury is highly variable, even among high-risk subjects who have one or more of the relevant serum autoantibodies. In some subjects, as an example, progression is so slow that diabetes does not occur for many years or perhaps ever.(22-25) These subjects presumably regain tolerance in some way, e.g. regulatory T cells (Tregs) become more numerous or helper T cells become less numerous or active. One report described a 10-year follow-up in 18 non-diabetic twins of type 1 diabetes probands: the eight twins who developed diabetes had persistently high numbers of CD8 HLA DR+ T cells, whereas the 10 twins who remained euglycemic did not.(26)
Early therapy is likely to preserve more beta cells, but may also result in some patients being treated unnecessarily. There is also concern that treatment of a subject in whom the disease is not progressing might increase the risk of type 1 diabetes by disrupting the balance between helper and suppressor activity, a sequence that has been demonstrated in BioBreeding (BB) rats and NOD (Non-obese diabetic) mice.(27,28) However, delaying therapy runs the risk that fewer beta cells will be left to preserve.
SIGN AND SYMPTOMS:
Childhood type 1 diabetes mellitus (T1DM) can present in several different ways.(29)
- Classic new onset of chronic polydipsia, polyuria, and weight loss with hyperglycemia and ketonemia (or ketonuria)
- Diabetic ketoacidosis
- Silent (asymptomatic) incidental discovery
CLASSIC NEW ONSET: Hyperglycemia without acidosis is the most common presentation of childhood T1DM in most populations. Patients typically present with the following symptoms:
- POLYURIA: Polyuria occurs when the serum glucose concentration rises significantly above 180mg / dL (10 mmol / L), exceeding the renal threshold for glucose, which leads to increased urinary glucose excretion. Glycosuria causes osmotic diuresis (i.e. polyuria) and hypovolemia. Polyuria may present as nocturia, bedwetting, or daytime incontinence in a previously continent child.
- POLYDIPSIA: Polydipsia is due to enhanced thirst because of increased serum osmolality from hyperglycemia and hypovolemia. Despite the hypovolemia, patients may not have the classic signs of dry mucus membranes or decreased skin turgor.
- WEIGHT LOSS: Weight loss is a result of hypovolemia and increased catabolism. Insulin deficiency in diabetic children impairs glucose utilization in skeletal muscle and increases fat and muscle breakdown. Initially, appetite is increased, but over time, children are more thirsty than hungry, and ketosis leads to nausea and anorexia, contributing to weight loss.
Patients with these symptoms usually present in the ambulatory setting appearing slightly ill, with vague complaints, such as weight loss and lethargy.(30) The classic symptoms of polyuria and polydipsia are present in more than 90 percent of patients, but these are not always the initial complaints and may become apparent only after obtaining a careful history (e.g. nocturia and bedwetting, increased frequency and / or unusually wet diapers, and persistent thirst). Weight loss is a presenting symptom in about half of children.
Other presentations include perineal candidiasis, which is a relatively common presenting symptom in young children and in girls.(30) Visual disturbances are common because of alterations in the osmotic milieu of the lens, and to a lesser extent the aqueous and vitreous humors leading to changes in refractive index.(31) Children with longstanding hyperglycemia may present with cataracts.(32,33)
Type 1 diabetes increases the risk for many serious health complications. There are two important approaches to preventing complications from type 1 diabetes:
- Good control of blood glucose and keeping glycosylated hemoglobin (A1C) levels below or around 7%. This approach can help prevent complications due to vascular (blood vessel) abnormalities and nerve damage (neuropathy) that can cause major damage to organs, including the eyes, kidneys, and heart.
- Managing risk factors for heart disease. Blood glucose control helps the heart, but it is also very important that people with diabetes control blood pressure, cholesterol levels, and other factors associated with heart disease.
DIABETIC KETOACIDOSIS: Diabetic ketoacidosis (hyperglycemia and ketoacidosis) is the second most common form of presentation for T1DM in most populations. Symptoms are similar but usually more severe than those of patients without acidosis. In addition to polyuria, polydipsia, and weight loss, patients with ketoacidosis may present with a fruity-smelling breath and neurologic findings including drowsiness and lethargy. DKA can be misinterpreted as an acute vomiting illness because classic pediatric symptoms of dehydration (decreased urination) are masked by the polyuria that is associated with glycosuria.
The reported frequency of diabetic ketoacidosis (DKA) as the initial presentation for childhood T1DM is approximately 30 percent, but varies from 15 to 67 percent.(34,35,36) Young children (<six years of age) or those from an adverse socioeconomic background are more likely to have DKA as their initial presentation of T1DM. Among children younger than age three years, more than half had DKA as their initial presentation of T1DM.(35)
Children with DKA require hospitalization, rehydration, and insulin replacement therapy.
HYPERGLYCEMIC HYPEROSMOLAR NONKETONIC SYNDROME (HHNS): Hyperglycemic hyperosmolar nonketonic syndrome (HHNS) is a serious complication of diabetes that involves a cycle of increasing blood sugar levels and dehydration, without ketones. HHNS usually occurs with type 2 diabetes, but it can also occur with type 1 diabetes. It is often triggered by a serious infection or another severe illness, or by medications that lower glucose tolerance or increase fluid loss (especially in people who are not drinking enough fluids).
Symptoms of HHNS include high blood sugar levels, dry mouth, extreme thirst, dry skin, and high fever. HHNS can lead to loss of consciousness, seizures, coma, and death.
HYPOGLYCEMIA: Hypoglycemic symptoms may be adrenergic, due to sympathetic neural activation and epinephrine release, and neuroglycopenic, resulting from direct effects of hypoglycemia on the central nervous system. Behavioral changes also occur and are probably a consequence of adrenergic and neuroglycopenic responses. Clinicians should inquire about symptoms of hypoglycemia during the routine care of a child with T1DM.
- Adrenergic symptoms: Tremor, pallor, rapid heart rate, palpitations, and diaphoresis.
- Neuroglycopenic symptoms: Fatigue, lethargy, headaches, behavior changes, drowsiness, unconsciousness, seizures, or coma. The severity of the neuroglycopenic symptoms increases with the severity of hypoglycemia and resultant central nervous system energy deprivation.
- Behavioral symptoms: Behavioral symptoms include irritability, agitation, erratic behavior, quietness or tantrums, and are most common in younger children.
HEART DISEASE AND STROKE: Patients with type 1 diabetes are 10 times more at risk for heart disease than healthy patients. Heart attacks account for 60% of deaths in patients with diabetes, while strokes account for 25% of such deaths.(37) Diabetes affects the heart in many ways:
- Both type 1 and 2 diabetes accelerate the progression of atherosclerosis (hardening of the arteries). Diabetes is often associated with low HDL ("good" cholesterol) and high triglycerides. This can lead to coronary artery disease, heart attack, or stroke.
- In type 1 diabetes, high blood pressure (hypertension) usually develops if the kidneys become damaged. High blood pressure is another major cause of heart attack, stroke, and heart failure. Children with diabetes are also at risk for hypertension.
- Impaired nerve function (neuropathy) associated with diabetes also causes heart abnormalities.
KIDNEY DAMAGE (NEPHROPATHY): Symptoms of kidney failure may include swelling in the feet and ankles, itching, fatigue, and pale skin color. Diabetic nephropathy, also known as KimmelstielWilson syndrome or nodular diabetic glomerulosclerosis or intercapillary glomerulonephritis, is a clinical syndrome characterized by albuminuria (>300 mg/day or >200 mcg/min) confirmed on at least two occasions 3-6 months apart, permanent and irreversible decrease in glomerular filtration rate (GFR), and arterial hypertension.(38)
NEUROPATHY: Diabetes reduces or distorts nerve function, causing a condition called neuropathy. Neuropathy refers to a group of disorders that affect nerves. The two main types of neuropathy are:
- Peripheral (affects nerves in the toes, feet, legs, hand, and arms)
- Autonomic (affects nerves that help regulate digestive, bowel, bladder, heart, and sexual function)
Peripheral neuropathy particularly affects sensation. It is a common complication for nearly half of people who have lived with type 1 or type 2 diabetes for more than 25 years. The most serious consequences of neuropathy occur in the legs and feet and pose a risk for ulcers and, in unusually severe cases, amputation. Peripheral neuropathy usually starts in the fingers and toes and moves up to the arms and legs (called a stocking-glove distribution). Symptoms include:
- Burning sensations
- Loss of the sense of warm or cold
- Numbness (if the nerves are severely damaged, the patient may be unaware that a blister or minor wound has become infected)
- Deep pain
Autonomic neuropathy can cause:
- Digestive problems (such as constipation, diarrhea, nausea, and vomiting)
- Bladder infections and incontinence
- Erectile dysfunction
- Heart problems
- Rapid heart rates
- Lightheadedness when standing up (orthostatic hypotension)
FOOT ULCERS AND AMPUTATIONS: About 15% of patients with diabetes have serious foot problems. People with diabetes who are overweight, smokers, and have a long history of diabetes tend to be at most risk. People who have the disease for more than 20 years and are insulin-dependent are at the highest risk. Related conditions that put people at risk include peripheral neuropathy, peripheral artery disease, foot deformities, and a history of ulcers.
Foot ulcers usually develop from infections, such as those resulting from blood vessel injury. Numbness from nerve damage, which is common in diabetes, compounds the danger since the patient may not be aware of injuries. About one-third of foot ulcers occur on the big toe.
CHARCOT FOOT: Charcot foot or Charcot joint (medically referred to as neuropathic arthropathy) is a degenerative condition that affects the bones and joints in the feet. It is associated with the nerve damage that occurs with neuropathy. Early changes appear similar to an infection, with the foot becoming swollen, red, and warm. Gradually, the affected foot can become deformed. The bones may crack, splinter, and erode, and the joints may shift, change shape, and become unstable.
RETINOPATHY AND EYE COMPLICATIONS: Diabetes accounts for thousands of new cases of blindness annually and is the leading cause of new cases of blindness in adults ages 20 - 74. The most common eye disorder in diabetes is retinopathy. People with diabetes are also at higher risk for developing cataracts and certain types of glaucoma.
RESPIRATORY INFECTIONS: People with diabetes face a higher risk for influenza and its complications, including pneumonia. Everyone with diabetes should have annual influenza vaccinations and a vaccination against pneumococcal pneumonia.
URINARY TRACT INFECTIONS: Women with diabetes face a significantly higher risk for urinary tract infections, which are likely to be more complicated and difficult to treat than in the general population.
HEPATITIS: Patients with diabetes are at increased risk for contracting the hepatitis B virus, which is transmitted through blood and other bodily fluids. Exposure to the virus can occur through sharing finger-stick devices or blood glucose monitors. Adults newly diagnosed with type 1 or type 2 diabetes should get hepatitis B vaccinations.
DEPRESSION: Diabetes doubles the risk for depression. Depression, in turn, may increase the risk for hyperglycemia and complications of diabetes.
OSTEOPOROSIS: Type 1 diabetes is associated with slightly reduced bone density, putting patients at risk for osteoporosis and possibly fractures.
OTHER COMPLICATIONS: Diabetes increases the risk for other conditions, including:
- Hearing loss
- Periodontal disease
- Carpal tunnel syndrome and other nerve entrapment syndromes
- Nonalcoholic fatty liver disease, also called nonalcoholic steatohepatitis (NASH); a particular danger for people who are obese
SPECIFIC COMPLICATIONS IN WOMEN: Women with diabetes have an increased risk of recurrent yeast infections. In terms of sexual health, diabetes may cause decreased vaginal lubrication, which can lead to pain or discomfort during intercourse.
Women with diabetes should also be aware that certain types of medication can affect their blood glucose levels. For example, birth control pills can raise blood glucose levels. Long-term use (more than 2 years) of birth control pills may increase the risk of health complications.
DIABETES AND PREGNANCY: Pregnancy in a patient with existing diabetes can increase the risk for birth defects. Therefore, it is important that women with pre-existing diabetes (both type 1 and type 2) who are planning on becoming pregnant strive to maintain good glucose control for 3 - 6 months before pregnancy.
DIABETES AND MENOPAUSE: The changes in estrogen and other hormonal levels that occur during perimenopause can cause major fluctuations in blood glucose levels. Women with diabetes also face an increased risk of premature menopause, which can lead to higher risk of heart disease.
Type 1 diabetes mellitus (T1DM) is one of several different types of diabetes mellitus. The initial step is to diagnose diabetes. The second step is to differentiate T1DM from other causes of diabetes based upon the clinical presentation of the patient and laboratory studies.
DIAGNOSTIC CRITERIA FOR DIABETES: Diabetes mellitus is diagnosed based upon one of the following four signs of abnormal glucose metabolism:(39,40)
- Fasting plasma glucose ≥126mg / dL (7 mmol / L) on more than one occasion. Fasting is defined as no caloric intake for at least eight hours.
- Random venous plasma glucose ≥200mg / dL (11.1 mmol / L) in a patient with classic symptoms of hyperglycemia
- Plasma glucose ≥200mg / dL (11.1 mmol / L) measured two hours after a glucose load of 1.75 g / kg (maximum dose of 75 g) in an oral glucose tolerance test (OGTT). Most children and adolescents are symptomatic and have plasma glucose concentrations well above ≥200 mg / dL (11.1 mmol / L); thus, OGTT is seldom necessary to diagnose T1DM.
- Glycated hemoglobin (A1C) ≥6.5 percent (using an assay that is certified by the National Glycohemoglobin Standardization Program). This criterion is more useful to diagnosis of type 2 diabetes mellitus (T2DM) in adults, and should be confirmed by hyperglycemia.
Based upon the guidelines of the American Diabetes Association (ADA), these diagnostic criteria resemble those used in adults with diabetes. Unless unequivocal symptomatic hyperglycemia is present, the diagnosis should be confirmed by repeat testing.
A1C measures the percent of hemoglobin A bound to glucose via non-enzymatic glycation, and indicates the average blood sugar levels for 10 to 12 weeks before the time of measurement. A1C ≥6.5 percent is now an accepted criterion for diagnosis of diabetes in adults.(40) However, the diagnostic utility of A1C for children is less well established than for adults. A1C values ≥6.5 percent are diagnostic of diabetes in adults, but levels <6.5 percent do not exclude diabetes.
Individuals with abnormal hemoglobins or rapid destruction of red blood cells may have a measured A1C value that does not accurately reflect their average blood sugar values. The accuracy of measurements in individuals with abnormal hemoglobins will improve with use of improved techniques for assessing A1C and with standardization of A1C measurements. For example, hemoglobin variants and derivatives interfere very minimally with the commercially available boronate-affinity chromatography technique.(41) However, rapid turnover of hemoglobin will still affect the reported A1C level.
Glycosuria is suggestive of diabetes, but not diagnostic. For example, patients with renal glucosuria or Fanconi syndrome will present with glycosuria but have normal plasma glucose concentration. Similarly, the presence of islet-specific autoantibodies supports the diagnosis of T1DM, but is not sufficient to make the diagnosis.
A white blood cell (WBC) count and blood and urine cultures may be performed to rule out infection.
Urine ketones are not reliable for diagnosing or monitoring diabetic ketoacidosis (DKA), although they may be useful in screening to see whether a hyperglycemic individual may have some degree of ketonemia. The plasma acetone level—specifically, the beta-hydroxybutyrate level—is a more reliable indicator of DKA, along with measurement of plasma bicarbonate or arterial pH as clinically required.
TYPE 1 VERSUS TYPE 2 DIABETES: T1DM is characterized primarily by insulin deficiency, whereas type 2 diabetes (T2DM) is characterized primarily by insulin resistance with relative insulin deficiency. As the incidence of T2DM increases in children and adolescents, it becomes increasingly important to distinguish type 1 from type 2 disease, because long-term management differs.
No set of criteria or diagnostic test can consistently distinguish between T1DM and T2DM. Therefore, differentiating between the two types is based upon a combination of the clinical presentation and history, often supported by laboratory studies.
- Body habitus: Patients with T2DM are usually obese (body mass index [BMI] ≥95thpercentile for age and gender). In contrast, children with T1DM are usually not obese and often have a recent history of weight loss, although up to 25 percent are overweight (BMI ≥85th to 95th percentile).(42)
- Age: Patients with T2DM generally present after the onset of puberty, whereas those with T1DM often present at an earlier age. About 45 percent of children with T1DM present before 10 years of age.(43) By contrast, almost all cases of T2DM present after 10 years of age.
- Insulin resistance: Patients with T2DM frequently have acanthosis nigricans (a sign of insulin resistance), hypertension, dyslipidemia, and polycystic ovary syndrome (in girls). These findings are less likely in children with T1DM.
- Family history: Up to 10 percent of patients with T1DM have an affected close relative, whereas 75 to 90 percent of those with T2DM have an affected close relative.(44,45)
LABORATORY TESTING: The following laboratory tests are often helpful in differentiating between T1DM and T2DM. It is suggested to include them in the evaluation:
- Antibodies: Although there is no specific test to distinguish between the two types of diabetes, T1DM is suggested by the presence of circulating, islet-specific, pancreatic autoantibodies against glutamic acid decarboxylase (GAD65), the 40K fragment of tyrosine phosphatase (IA2), insulin,and / or zinc transporter 8 (ZnT8). However, the absence of pancreatic autoantibodies does not rule out the possibility of T1DM. Up to 30 percent of individuals with the classical appearance and presentation of T2DM have positive autoantibodies and may have a slowly progressive type of autoimmune diabetes.(46)
- Insulin and C-peptide levels: High fasting insulin and C-peptide levels suggest T2DM. Levels are inappropriately low or in the normal range relative to the concomitant plasma glucose concentration in T1DM. At presentation, insulin and C-peptide levels may be suppressed by severe hyperglycemia and illness. It is usually best to assess these levels after the newly diagnosed patient has recovered from acute illness.
Insulin deficiency in T1DM most commonly results from autoimmune destruction of pancreatic beta cells and is referred to as type 1A diabetes (approximately 85 percent).(47) Patients with clinical features of T1DM but without detectable autoantibodies are categorized as having type 1B diabetes (approximately 15 percent). In these patients, there is no evidence of autoimmune beta-cell destruction and no other cause has been identified.
OTHER CAUSES OF HYPERGLYCEMIA: In the previously healthy child, diabetes mellitus is by far the most common cause of clinically significant hyperglycemia. Other considerations include:
- Critically ill patients: Patients with septic shock or other critical illnesses often have abnormalities in glycemic control, leading to either hypoglycemia or hyperglycemia.
- Medication: Children receiving intravenous infusions containing glucose, or those who receive acute sympathomimetic agents or high-dose glucocorticoids, may display elevations in blood glucose that revert to normal after treatment is complete.
- Neonatal hyperglycemia: Causes of hyperglycemia in a neonate include excessive glucose infusion, prematurity, stress, sepsis, drugs, and transient or permanent neonatal diabetes mellitus.
OTHER CAUSES OF DIABETES: Following are the diseases that cause diabetes:
- Diseases of the exocrine system: Cystic fibrosis, hereditary hemochromatosis, and chronic pancreatitis.
- Endocrine abnormalities in glucose regulation: Cushing syndrome, growth-hormone excess, glucagon-secreting tumors, catecholamine excess in pheochromocytoma. With the exception of Cushing syndrome, these are all extremely rare. This possibility should be evaluated in patients presenting with Cushingoid features (such as central obesity, facial plethora, dorsocervical fat pad, and delayed linear growth). This is usually best accomplished by measuring 24-hour urinary cortisol excretion or salivary cortisol at 11 PM or midnight two or more times; additional testing may be required. It is important to recognize that children with Cushing syndrome may not manifest the classic features seen in adults. However, a deceleration of growth velocity despite increasing weight should raise concern for Cushing syndrome in a growing child. It is very rare for a child with Cushing syndrome to present with hyperglycemia, although relatively common in adults.
- Drug-induced diabetes: A number of drugs (e.g. glucocorticoids, HIV protease inhibitors,cyclosporine, L-asparaginase, and tacrolimus) and atypical antipsychotic agents can impair glucose tolerance by inhibiting insulin secretion, increasing hepatic glucose production, or causing insulin resistance.
- Monogenic diabetes (formerly referred to as maturity onset diabetes of the young, or MODY): Monogenic diabetes is a clinically heterogeneous disorder characterized by non-insulin dependent diabetes presenting at a young age, with autosomal dominant transmission and lack of autoantibodies. Many different genetic abnormalities have been identified, each leading to a different type of disease. Monogenic diabetes should be suspected in a patient presenting with non-insulin-dependent diabetes at a young age (<25 years), with autosomal dominant transmission across three generations, lack of islet autoantibodies, and lack of acanthosis nigricans. The diagnosis of monogenic diabetes is made by performing diagnostic genetic testing by direct sequencing of the gene.
- Neonatal diabetes mellitus: Neonatal diabetes is a rare cause of hyperglycemia in infants. It can be transient or permanent, and usually is caused by mutations in one of several genes that encode proteins that affect the function of the pancreatic beta-cell (e.g. proteins that are subunits of the ATP-sensitive potassium channel). Most of the infants are small for gestational age, and they present with weight loss, volume depletion, hyperglycemia, and glucosuria with or without ketonuria and ketoacidosis.
Treatment of type 1 DM requires lifelong insulin therapy. A multidisciplinary approach by the physician, nurse, and dietitian, with regular specialist consultation, is needed to control glycemia, as well as to limit the development of its devastating complications and manage such complications when they do occur.
INITIAL MANAGEMENT: The initial phase begins at the time of diagnosis. In these first few days, the family begins to understand the disease process and is trained to successfully measure blood glucose concentrations, administer insulin, recognize and treat hypoglycemia, and measure blood or urine ketone concentration.
- Basic understanding: The diabetes team teaches the patient and family the cause and treatment of type 1 diabetes, how to maintain a daily schedule and record of blood glucose test results, insulin administration, and the timing and carbohydrate content of meals and snacks.
- Blood glucose testing: Families must master blood glucose testing. A variety of easy-to-use blood glucose meters are available for this purpose. The parents or caregivers are instructed on the frequency and timing of blood glucose testing, depending upon the needs of their child.
- Insulin administration: Training includes teaching the family about the different types of prescribed insulin, how to measure and inject insulin, and how to rotate injection sites. Family members and caretakers must learn about the duration and action of the various types of insulin prescribed for their child. They must also understand how to adjust the insulin dose based upon blood glucose concentrations and carbohydrate intake.
- Hypoglycemia: Families are taught to recognize the signs and symptoms of hypoglycemia. Detection of hypoglycemia is particularly difficult in the nonverbal young child and infant in whom the signs of hypoglycemia are nonspecific. Parents are trained to check a blood glucose level and, if this is too low, to intervene with dietary measuresand / or
- Blood or urine ketones: Families are taught to check urine for ketones or measure blood beta-hydroxybutyrate concentration at times of illnessand/or if two consecutive blood glucose readings are greater than 250 mg / dL (13.9 mmol / L). This is especially important in young children, insulin pump users, or those with a history of diabetic ketoacidosis (DKA).
Patients with diabetes should wear a medical emergency bracelet / necklace to enable suitable intervention by emergency personnel should an emergency situation arise (i.e. hypoglycemia or DKA).
AGE-BASED CARE: The management plan of childhood-onset type 1 diabetes depends on the child's age, cognitive ability, and emotional maturity, which affect his or her ability to communicate symptoms and participate in self-management.
The following discussion on age-based management is compatible with the American Diabetes Association (ADA) guidelines for the care of children and adolescents with type 1 diabetes.(48)
INFANTS: Infants (younger than one year of age) with diabetes have the highest risk of severe hypoglycemia.(29,49) Hypoglycemia is difficult to detect because infants are unable to communicate their symptoms and clinical signs are nonspecific (e.g. poor feeding, lethargy, jitteriness, hypotonia).
Infants with severe hypoglycemia can present with seizures or coma, which may have permanent neurologic sequelae. In addition, repeated prolonged episodes of hypoglycemia as well as persistent hyperglycemia may have deleterious effects on brain development and learning, especially in children younger than five years of age.
TODDLERS: The issues surrounding the care of toddlers (one to three years of age) are similar to those in infants. The parents must learn to manage diabetes and be responsible for the daily care of the patient and also learn to recognize episodes of hypoglycemia. Avoiding hypoglycemia can be challenging because of the erratic food intake and activity levels of toddlers. This problem can be addressed by frequent blood glucose monitoring (or possibly the use of continuous glucose monitoring), and use of an insulin pump or other flexible dosing systems.
PRESCHOOL AND EARLY SCHOOL-AGED CHILDREN: For preschool and early school-aged children (three to seven years of age), parents still provide most of the daily diabetes care. However, some of these patients can begin to participate in their own care by testing their blood glucose or preparing materials.
As these children enter daycare or school, childcare providers and school nurses must be involved in their diabetes care.
SCHOOL-AGED CHILDREN: For school-aged children (8 to 11 years of age), optimal care consists of shared responsibility, so that the child begins to assume some of the daily management of their diabetes but has close adult supervision and support. The child can learn to administer the routine insulin injections, but still needs significant assistance and supervision for management decisions that are not routine. All glucose testing and insulin administration should be under adult supervision.
ADOLESCENTS: Adolescence naturally is a time of increasing independence and self-assertiveness, but also of risk-taking. Therefore, determining the appropriate extent of adult involvement can be challenging. Although adolescents can be responsible for the daily management of their diabetes, minimal or no adult supervision results in poor glycemic control. While shared management between the adolescent and parents is associated with better glycemic control, parent-child conflict over daily management leads to poor control, and adolescent depression of even a mild degree can interfere with family involvement and diabetes control.
TRANSITION INTO ADULT CARE: Young adults tend to decrease the frequency of contact with their diabetes care provider after transition to an adult program, and those with fragmented care have poorer glycemic control and a higher rate of hospitalization. Self-care behaviors tend to deteriorate during this transitional time, and in many institutions transition practices are not optimal. Strategies to facilitate transition to adult health care include longer or more frequent initial visits, use of a transition coordinator, or transition to a clinic designed for young adults.
Daily blood glucose levels are used to monitor glycemic control and adjust management. The most widely used clinical test to evaluate long-term glycemic control is blood glycated hemoglobin (also called A1C, hemoglobin A1C, glycohemoglobin, or glycosylated hemoglobin).
BLOOD GLUCOSE MONITORING:
Optimal glycemic control is dependent upon frequently monitoring blood glucose and appropriate adjustment of insulin dose. Ongoing monitoring allows the child and family to become familiar with the patient's glycemic response to different types and amount of foods, exercise, and stress.
Frequent monitoring has been shown to improve glycemic control in children(50,51,52) and decrease the frequency of severe hypoglycemic episodes.(53)
To prevent the development of diabetic ketoacidosis (DKA), patients must check for urine or blood ketones when blood glucose is persistently ≥250 mg / dL (13.9 mmol / L), or during acute episodes of increased stress, including intercurrent illnesses.(54) Patients who have hyperglycemia and positive urine ketones or increased blood ketone concentrations should be treated with additional insulin (with or without additional carbohydrates) and increased fluid intake, combined with meticulous monitoring of blood glucose and ketone concentrations.
FINGERSTICKS: Blood glucose should be tested at least four times a day (in the fasting state: before meals and at bedtime); more frequent monitoring is often required, depending on the environment and social situation.(48,54)
Blood glucose is typically monitored using a blood glucose meter, which requires a small sample of blood (0.3 to 1 microliter) obtained by fingerstick. Some devices permit blood sampling from the forearm; this technique is less painful than using the side of the finger, but provides a blood sample which is not as close to arterial blood as that from the finger tip and may not identify hypoglycemia as quickly as a finger tip sample.
CONTINUOUS GLUCOSE MONITORING: Subcutaneous glucose sensors that continuously measure interstitial fluid glucose levels are now available and approved for use in children. They are useful for optimizing glycemic control in motivated patients and also for management of patients with a history of hypoglycemia unawareness.(48)
Several different types of CGM devices have been developed:
- CGM without real-time feedback: The first generation of CGM devices provided blood glucose data only after downloading by the physician, and did not provide real-time feedback to the patient.
- CGM with real-time feedback: The newer generation of CGM devices report blood glucose levels to the patient in real time.
Several devices are approved by the US Food and Drug Administration (FDA) and are commercially available.
- Sensor-augmented insulin pump: This refers to CGM used in conjunction with an insulin pump; the patient or family manually adjusts the insulin dose based on the CGM results. This approach generally leads to improved glycemic control but requires a highly motivated user and good diabetes management skills.
- Sensor-augmented insulin pump with threshold-suspend: This is a partially closed loop glucose monitoring and insulin infusion system that can respond to hypoglycemia by stopping the insulin infusion; the device has been approved by the FDA.(55)
- Automated closed-loop insulin pump: Studies are currently evaluating the safety and efficacy of a fully automated closed loop system of insulin delivery based on continuous glucose sensing, sometimes known as an "artificial pancreas."
Insulin therapy is the mainstay of treatment for type 1 diabetes mellitus. The goal of insulin therapy is to replace the deficient hormone and to attain normoglycemia. However, this goal remains elusive because of the difficulty in replicating the minute-to-minute variations of physiologic insulin secretion and the difference in delivery of exogenous insulin action compared with normal secretion of endogenous insulin directly into the portal vein.
There are many different insulin preparations and delivery systems available.
PREPARATIONS: Insulin types can be classified by their onset and duration of action:
- Rapid-acting (e.g. lispro, aspart, glulisine)and / or short-acting insulins (e.g. regular insulin) are typically administered as a premeal bolus (typically 5 to 15 minutes before the meal for the rapid-acting insulins, and 20 to 30 minutes before meals for the short-acting type) based on
- Carbohydrate content of food and
- The blood glucose level.
- Intermediate-acting Neutral Protamine Hagedorn (NPH) insulin is usually given two or three times a day, but may be given in a targeted manner in combination with long-acting insulins. Intermediate-acting insulin thus provides some coverage for meals (e.g. NPH insulin given before breakfast will cover lunch).
- Long-acting insulin preparations (e.g.insulin glargine and insulin detemir) are given once or twice a day. In general, if a single injection is used, it should be given in the evening in order to assure insulin availability during the night and suppress a counterregulatory hormone response by morning. However, some small children who are at more risk of hypoglycemia do better with administration in the morning hours.
Insulin is administered by needle and syringe, pen, or pump.
- Needle and syringe: An advantage of needle and syringe is that NPH and short- or rapid-acting insulins can be mixed in a single injection, thereby reducing the number of injections. However,insulin glargine and detemir cannot be mixed with any other form of insulin and must be administered separately.
- Pens: Pens are supplied pre-filled with insulin and may be either disposable or reusable.
VALUE OF AN INTENSIVE REGIMEN:
Insulin management can be categorized as "intensive" or "conventional," depending on the frequency and type of insulin dosing. In general, intensive regimens are recommended because they are more likely to meet glycated hemoglobin (A1C) targets and have better clinical outcomes.(48)
TYPES OF INTENSIVE REGIMENS: An intensive regimen is delivered either by multiple daily injections (MDI) or by continuous insulin infusion (pump). The choice of intensive regimen is based upon patient, family, cost considerations, and clinician preferences.
- Multiple daily injections: The MDI regimen combines a baseline level of insulin using a long-acting insulin analog (insulin glargineor detemir) with premeal / snack boluses of rapid- or short-acting insulin. This approach results in more stable glycemic control and fewer episodes of hypoglycemia than the conventional approach in children
Insulin glargine is the long-acting analog most commonly used in pediatric patients. It usually has duration of action 24 to 26 hours, but the half-life is shorter in some patients, requiring division of the daily dose into two injections per day.
Although the US Food and Drug Administration (FDA) has only approved insulin glargine in children six years of age or older, the use of insulin glargine appears to be beneficial in younger children as well.
- Insulin pump: The insulin pump (continuous subcutaneous insulin infusion) is increasingly used in the pediatric population. A position statement of the American Diabetes Association (ADA), European Society for Pediatric Endocrinology, and others recommends that insulin pump therapy should be considered for patients with one or more of the following characteristics:(55)
- Recurrent severe hypoglycemia
- Wide fluctuations in blood glucose levels (regardless of A1C)
- Suboptimal diabetes control (A1C exceeds target range for age)
- Microvascular complicationsand / orrisk factors for macrovascular complications
- Good metabolic control, but insulin regimen that compromises lifestyle
Other situations in which the insulin pump may be helpful include young children and infants, adolescents with eating disorders, pregnant adolescents, ketosis-prone individuals, and competitive athletes.(55)
INVESTIGATIONAL THERAPIES FOR TYPE 1 DIABETES:
The following aspects of type 1 diabetes are important subjects of investigation but are not yet incorporated into routine clinical care of children:
- Diabetes prevention: A number of attempts to use immune modulation early in the course of type 1 diabetes have been reported, but long-term success is elusive as yet. These include trials of a vaccine against glutamic acid decarboxylase (GAD),rituximab, teplizumab, and other immunomodulators for patients with newly diagnosed diabetes.
- Artificial pancreas: "Closed loop" insulin pump devices, which deliver insulin based on real time glucose concentrations and are controlled by a computer driven algorithm, are currently in active development.
- Adjunctive therapies: Supplementing insulin therapy with agents likemetformin, amylin analogs (pramlintide), and glucagon-like peptide 1 (GLP-1) receptor agonists (e.g. exenatide) has been studied in adults with type 1 diabetes, but the safety and efficacy of these agents has not been established. Among these adjunctive therapies, pramlintide is the most promising based on studies in adults, but requires careful management to avoid severe hypoglycemia.
- Transplantation: Techniques for pancreas or islet cell transplantation for patients with type 1 diabetes continues to evolve. Currently, pancreas transplantation is limited to adults with serious progressive complications of diabetes in whom the quality of life is unacceptable, including those with end-stage renal disease who require a kidney transplant.
OTHER MANAGEMENT ISSUES:
Other issues that need to be addressed in the management of children and adolescents with type 1 diabetes include nutrition, exercise, and psychosocial factors that impact on glycemic control.
NUTRITION: Prescriptive nutritional therapy depends in large part on the choice of insulin regimen. Ideally, meal planning should provide a consistent carbohydrate intake. This is especially true for children on a conventional fixed insulin regimen who require a nutritional prescription. Meal planning must be individualized to accommodate the child's food preference and cultural eating patterns and schedules.
Many patients have experienced weight loss when diabetes is first diagnosed. The lost weight is generally regained during the first few weeks of therapy due to insulin, hydration, and adequate energy intake. During this time of increased consumption, children often require large amounts of insulin to control their blood glucose levels. After the weight loss is corrected, ongoing assessment of growth (e.g. weight, height, body mass index [BMI]) is necessary to monitor adequacy of dietary intake and glycemic control.(56)
EXERCISE: Regular exercise has important health and social benefits for children and adolescents with type 1 diabetes mellitus and should be encouraged. In patients with diabetes, the intensity and duration of exercise affects the physiologic response and risk for hypoglycemia. Hypoglycemia can occur during or immediately after exercise, or be delayed by several hours. The physiologic response to exercise also depends upon the plasma insulin concentration at the time of exercise. Exercise also can trigger hyperglycemia under certain circumstances.
Children who participate in sport activities require increased monitoring of blood glucose (before, after, and at regular intervals during prolonged strenuous activity) and appropriate adjustment of insulin dosing. School personnel and coaches need to recognize symptoms of hypoglycemia and know how to treat hypoglycemia. Afternoon or evening exercise may cause hypoglycemia later that night. Therefore, it is prudent for patients to check blood glucose during the overnight period after strenuous exercise.
PSYCHOSOCIAL ISSUES: It is suggested to assess for depression, anxiety, school absences, family conflict, and other mental health challenges during most routine visits for diabetes care. This is especially important for children 10 years and older and for those who are not adhering to the diabetes management regimen.
Depression and anxiety are common in older children, and adolescents with diabetes and their parents; adolescents are at risk for an eating disorder. In older children and adolescents, family conflict arises over the level of adult involvement in the care of the patient during a normal developmental period of increasing independence and self-assertiveness. These psychological issues lead to poorer glycemic control and an increased risk of hospitalization and episodes of diabetic ketoacidosis (DKA).
Comprehensive management of diabetes that addresses these psychosocial issues can improve glycemic control and reduce hospitalization even in the high-risk adolescent.
GOALS OF THERAPY:
Both in children and adults, the goal of management is to maintain glucose control as near to normal as safely possible (i.e. balance the risks of long-term complications of diabetes and hypoglycemia). The targeted goal of this glycemic balance varies based upon the risk of hypoglycemia, which is age dependent.
To review “American Diabetes Association - Standards of medical care in diabetes” guidelines, please click on below link:
To review European Society for Pediatric Endocrinology (ESPE) / Lawson Wilkins Pediatric Endocrine Society (LWPES) consensus statement on diabetic ketoacidosis in children and adolescents” please click on below link:
CONSULTATION AND COUNCELLING:
Patients with type 1 DM should be referred to an endocrinologist for multidisciplinary management. They should also undergo a complete retinal examination by an ophthalmologist at least once a year. Those patients with significant proteinuria or a reduced creatinine clearance should be referred to a nephrologist. Patients with significant foot involvement should see a podiatrist.
LONG TERM MONITORING:
The frequency of follow-up visits is tailored to the needs of the child and family. Visits are more frequent during the initial educational phase, when the patient and family require intensive training in self-care management, and during periods when adjustment of glycemic control and insulin dose are problematic. More frequent visits are also necessary when major changes in insulin regimen are made (e.g. commencing insulin pump therapy).
Once the family is well trained and a management plan is established and stable, follow-up of at least every three months is recommended to review glycemic control and adjust management as needed.(48) However, families must be trained to perform interim adjustments and to contact the diabetes team for assistance in adjustment of insulin dosing between visits.
ROUTINE MONITORING: Routine follow-up should be performed at least four times a year and includes the following:(48)
- Height and weight: Monitor for normal growth, with vigilance for weight gain that is either insufficient or excessive.
- Blood pressure: Screen for hypertension.
- Pubertal assessment: Identify the patient's stage of puberty to anticipate changes in insulin requirements; insulin resistance and insulin requirements increase in early puberty.
- Thyroid: Check for thyroid enlargement to screen for autoimmune hypothyroidism, a condition that is associated with type 1 diabetes.
- Skin: Examine the child's usual insulin injection sites for evidences of lipohypertrophy or atrophy that can alter insulin absorption rates. Also examine the sites used for blood glucose monitoring to make sure there is no skin irritation.
- Eyes: A general eye examination is an appropriate part of the routine evaluation. However, a funduscopic examination without dilation of the pupils is of little value as a screen for retinopathy because diabetic retinopathy usually starts at the periphery of the retina.
- Extremities: A foot examination should be performed annually in children ≥10 years of age. As the disease duration increases, extremity examination for evidence of limited joint mobility (sclerodactyly, joint or finger stiffness) or peripheral neuropathy (feet).
LABORATORY EVALUATION: Laboratory evaluation includes evaluation of glycemic control and screening for long-term sequelae:
- A1C, to evaluate glycemic control: Perform every three months.
- Urine albumin-to-creatinine ratio in a spot specimen, to screen for nephropathy: Perform annually beginning when the child is 10 years old (or at onset of puberty if earlier), and has had diabetes for five years. A normalalbumin / creatinine result is <30 mg / g (<3.4 mg / mmol).
- Celiac disease screening: Perform a celiac-specific antibody test (e.g. tissue transglutaminase, tTG), at diagnosis.(48) It is suggested to repeat the screen approximately every two to three years thereafter, or if suggestive symptoms develop (e.g. gastrointestinal symptoms or unexplained hypoglycemia).
- Lipid profile, to screen for dyslipidemia (as recommended in the ADA guidelines: Initiate screening at age 10 years (or onset of puberty begins if earlier). Perform earlier for children with risk factors for cardiovascular disease, including obesity or a family history of early cardiovascular disease.
- If results are normal (low-density lipoprotein [LDL] <100mg/dL),repeat the screen every five years.
- If results are abnormal, screen annually.
- If the initial screen is normal but the child's diabetes is in poor control (e.g. A1C >9 percent), it is suggested to screen at least every two years because children who are in poor glycemic control may manifest new lipid abnormalities.
- Thyroid stimulating hormone (TSH), to screen for autoimmune hypothyroidism: Perform every one or two years, or if features of hypothyroidism, or if an enlarged thyroid are evident.
Offer following precautions to patients:
ACTIVITIES FOR YOUR CHILD WITH TYPE 1 DIABETES: Being active is most beneficial when it's done on a regular basis.
Take advantage of the many opportunities you have each day to set a good example for your child. Take the stairs instead of the elevator. If you live a short distance to shops, then opt not to drive and walk with your child instead. Go on a walk together after dinner.
The ultimate goal is to get your child moving. A good guideline to follow is that your child should get 1 hour of physical activity in each day. That might sound like a lot, but remember, it doesn't have to be strenuous activity.
BLOOD GLUCOSE AND PHYSICAL ACTIVITY: Physical activity can cause blood glucose to drop. If your child's blood glucose level falls too low, it can cause hypoglycemia.
Here are a few ways you can help lessen the effect of physical activity on your child's blood glucose level:
- Give your child extra carbohydrates before the activity.
- Check your child's blood glucose level before, during, and after the activity.
- Prepare a kit that contains snacks, glucose tablets, fruit juice, water, and any medications that your doctor recommends for your child to take to practices and games.
- Be sure to check blood sugar levels more frequently after the activity and overnight to assess if insulin doses need to be adjusted.
Preventive foot care can significantly reduce the risk of ulcers and amputation. Some tips for preventing problems include:
- Inspect your feet daily and watch for changes in color or texture, odor, and firm or hardened areas, which may indicate infection and potential ulcers.
- When washing the feet, the water should be warm (not hot) and the feet and areas between the toes should be thoroughly dried afterward.
- Apply moisturizers, but NOT between the toes.
- Gently use pumice to remove corns and calluses (do not use medicated pads or try to shave the corns or calluses by yourself).
- Trim toenails short and file the edges to avoid cutting adjacent toes.
- Well-fitting footwear is very important. Make sure your shoe is wide enough. Avoid high heels, sandals, thongs, and going barefoot. Shoes with a rocker sole reduce pressure under the heel and front of the foot and may be particularly helpful. Custom-molded boots increase the surface area over which foot pressure is distributed. This reduces stress on the ulcers and allows them to heal.
- Change shoes often during the day.
- Wear socks, particularly with extra padding (which can be specially purchased).
- Avoid tight stockings or any clothing that constricts the legs and feet.
- Consult a specialist in foot care for any problems.
Patients with diabetes should be given the following immunizations:
- All standard childhood immunizations, on a standard schedule.
- Annual influenza vaccine (also recommended for all individuals six months of age and older). Children with diabetes should receive the inactivated (injectable) vaccine rather than the live attenuated (intranasal) form of the vaccine.
- Pneumococcal vaccine: Children with diabetes should receive the pneumococcal conjugate vaccine, which is recommended for all children. They should also be given thepneumococcal polysaccharide vaccine because they are considered to be at high risk for invasive pneumococcal disease.
There is no evidence for an association between immunizations and the development of type 1 diabetes.
- Global report on diabetes. World Health Organization, Geneva, 2016. (http://www.who.int/diabetes/global-report/en/)
- Projections of global mortality and burden of disease from 2002 to 2030. Mathers CD, Loncar D. PLoS Med, 2006, 3(11):e442.
- Frese T, Sandholzer H. The epidemiology of type 1 diabetes mellitus. In: Escher S, Li A, eds. type 1 diabetes. InTech, 2013:1–22.
- International Diabetes Federation. Key findings 2014. http://www.idf.org/diabetesatlas/update-2014
- Melmed S, Polonsky SK, et al. Williams textbook of endocrinology. 12th edn. Philadelphia: Elsevier/Saunders, 2011.
- Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of Diabetes: estimates for year 2000 and projections for 2030. Diabetes Care 2004; 27: 1047-53
- Jafar TH, Levey AS, White FM, Gul A, Jessani S, Khan AQ, Jafary FH, Schmidt CH, Chaturvedi N. Ethnic differences and determinants of diabetes and central obesity among South Asians of Pakistan. Diabet Med 2004; 21:716-23
- Staines A, Hanif S, Ahmed S, McKinney PA, Shera S, Bodansky HJ. Incidence of insulin dependent diabetes mellitus in Karachi, Pakistan. Arch Dis Child 1997;76:121-3.
- Ahkter J, Qureshi R, Rahim F et al. Diabetes in pregnancy in Pakistani women: prevalence and complications in an indigenous south Asian community. Diabet Med 1996;13:189- 91.
- Khan KS, Rizvi JH, Qureshi RN, Mazhar R. Gestational diabetes in a developing country, experience of screening at the Aga Khan University Medical Centre, Karachi. J Pak Med Assoc 1991;41:31-3.
- Rizvi JH, Rasul S, Malik S, Rehamatuallh A, Khan MA. Experience with screening for abnormal glucose tolerance in pregnancy: maternal and perinatal outcome. Asia Oceania J Obstet Gynaecol 1992;18:99-105.
- Pilia S, Casini MR, Cambuli VM, et al. Prevalence of Type 1 diabetes autoantibodies (GAD and IA2) in Sardinian children and adolescents with autoimmune thyroiditis.Diabet Med. 2011 Aug. 28(8):896-9
- Philippe MF, Benabadji S, Barbot-Trystram L, et al. Pancreatic volume and endocrine and exocrine functions in patients with diabetes.Pancreas. 2011 Apr. 40(3):359-63
- Noble JA, Valdes AM. Genetics of the HLA region in the prediction of type 1 diabetes.Curr Diab Rep. 2011 Dec. 11(6):533-42
- Barchetta I, Riccieri V, Vasile M, et al. High prevalence of capillary abnormalities in patients with diabetes and association with retinopathy.Diabet Med. 2011 Sep. 28(9):1039-44
- Young KA, Snell-Bergeon JK, Naik RG, Hokanson JE, Tarullo D, Gottlieb PA, et al. Vitamin D deficiency and coronary artery calcification in subjects with type 1 diabetes.Diabetes Care. 2011 Feb. 34(2):454-8
- Joergensen C, Hovind P, Schmedes A, Parving HH, Rossing P. Vitamin d levels, microvascular complications, and mortality in type 1 diabetes.Diabetes Care. 2011 May. 34(5):1081-5
- Zhang D, Efendic S, Brismar K, Gu HF. Effects of MCF2L2, ADIPOQ and SOX2 genetic polymorphisms on the development of nephropathy in type 1 Diabetes Mellitus.BMC Med Genet. 2010 Jul 28. 11:116
- McCulloch DK, Klaff LJ, Kahn SE, et al. Nonprogression of subclinical beta-cell dysfunction among first-degree relatives of IDDM patients. 5-yr follow-up of the Seattle Family Study. Diabetes 1990; 39:549.
- Bärmeier H, McCulloch DK, Neifing JL, et al. Risk for developing type 1 (insulin-dependent) diabetes mellitus and the presence of islet 64K antibodies. Diabetologia 1991; 34:727.
- Tarn AC, Thomas JM, Dean BM, et al. Predicting insulin-dependent diabetes. Lancet 1988; 1:845.
- Greenbaum CJ, Sears KL, Kahn SE, Palmer JP. Relationship of beta-cell function and autoantibodies to progression and nonprogression of subclinical type 1 diabetes: follow-up of the Seattle Family Study. Diabetes 1999; 48:170.
- Peakman M, Leslie RD, Alviggi L, et al. Persistent activation of CD8+ T-cells characterizes prediabetic twins. Diabetes Care 1996; 19:1177.
- Mordes JP, Desemone J, Rossini AA. The BB rat. Diabetes Metab Rev 1987; 3:725.
- Kolb H. Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 1987; 3:751.
- Haller MJ, Atkinson MA, Schatz D. Type 1 diabetes mellitus: etiology, presentation, and management. Pediatr Clin North Am 2005; 52:1553
- Quinn M, Fleischman A, Rosner B, et al. Characteristics at diagnosis of type 1 diabetes in children younger than 6 years. J Pediatr 2006; 148:366.
- Sonmez B, Bozkurt B, Atmaca A, et al. Effect of glycemic control on refractive changes in diabetic patients with hyperglycemia. Cornea 2005; 24:531.
- Falck A, Laatikainen L. Diabetic cataract in children. Acta Ophthalmol Scand 1998; 76:238.
- Datta V, Swift PG, Woodruff GH, Harris RF. Metabolic cataracts in newly diagnosed diabetes. Arch Dis Child 1997; 76:118.
- Wolfsdorf J, Glaser N, Sperling MA, American Diabetes Association. Diabetic ketoacidosis in infants, children, and adolescents: A consensus statement from the American Diabetes Association. Diabetes Care 2006; 29:1150.
- Klingensmith GJ, Tamborlane WV, Wood J, et al. Diabetic ketoacidosis at diabetes onset: still an all too common threat in youth. J Pediatr 2013; 162:330.
- Dabelea D, Rewers A, Stafford JM, et al. Trends in the prevalence of ketoacidosis at diabetes diagnosis: the SEARCH for diabetes in youth study. Pediatrics 2014; 133:e938.
- American Diabetes Association. Standards of medical care in diabetes -- 2012. Diabetes Care. 2012 Jan;35 Suppl 1:S11-63.
- Adler AI, Stevens RJ, Manley SE, Bilous WR, Cull AC, Holman RR (2003) Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney int. 225-232.
- Silverstein J, Klingensmith G, Copeland K, et al. Care of children and adolescents with type 1 diabetes: a statement of the American Diabetes Association. Diabetes Care 2005; 28:186.
- American Diabetes Association. Standards of medical care in diabetes--2011. Diabetes Care 2011; 34 Suppl 1:S11.
- Bry L, Chen PC, Sacks DB. Effects of hemoglobin variants and chemically modified derivatives on assays for glycohemoglobin. Clin Chem 2001; 47:153.
- Liu LL, Lawrence JM, Davis C, et al. Prevalence of overweight and obesity in youth with diabetes in USA: the SEARCH for Diabetes in Youth study. Pediatr Diabetes 2010; 11:4.
- Writing Group for the SEARCH for Diabetes in Youth Study Group, Dabelea D, Bell RA, et al. Incidence of diabetes in youth in the United States. JAMA 2007; 297:2716.
- Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an epidemiologic review and a public health perspective. J Pediatr 2000; 136:664.
- Copeland KC, Zeitler P, Geffner M, et al. Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline. J Clin Endocrinol Metab 2011; 96:159.
- Klingensmith GJ, Pyle L, Arslanian S, et al. The presence of GAD and IA-2 antibodies in youth with a type 2 diabetes phenotype: results from the TODAY study. Diabetes Care 2010; 33:1970.
- Dabelea D, Pihoker C, Talton JW, et al. Etiological approach to characterization of diabetes type: the SEARCH for Diabetes in Youth Study. Diabetes Care 2011; 34:1628.
- Chiang JL, Kirkman MS, Laffel LM, et al. Type 1 diabetes through the life span: a position statement of the American Diabetes Association. Diabetes Care 2014; 37:2034.
- Lteif AN, Schwenk WF 2nd. Type 1 diabetes mellitus in early childhood: glycemic control and associated risk of hypoglycemic reactions. Mayo Clin Proc 1999; 74:211.
- 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 1993; 329:977.
- Ziegler R, Heidtmann B, Hilgard D, et al. Frequency of SMBG correlates with HbA1c and acute complications in children and adolescents with type 1 diabetes. Pediatr Diabetes 2011; 12:11.
- Miller KM, Beck RW, Bergenstal RM, et al. Evidence of a strong association between frequency of self-monitoring of blood glucose and hemoglobin A1c levels in T1D exchange clinic registry participants. Diabetes Care 2013; 36:2009.
- Haller MJ, Stalvey MS, Silverstein JH. Predictors of control of diabetes: monitoring may be the key. J Pediatr 2004; 144:660.
- Rewers MJ, Pillay K, de Beaufort C, et al. ISPAD Clinical Practice Consensus Guidelines 2014. Assessment and monitoring of glycemic control in children and adolescents with diabetes. Pediatr Diabetes 2014; 15 Suppl 20:102.
- Phillip M, Battelino T, Rodriguez H, et al. Use of insulin pump therapy in the pediatric age-group: consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2007; 30:1653.
- Kulkarni K, Castle G, Gregory R, et al. Nutrition Practice Guidelines for Type 1 Diabetes Mellitus positively affect dietitian practices and patient outcomes. The Diabetes Care and Education Dietetic Practice Group. J Am Diet Assoc 1998; 98:62.