Module 2.

Blood nand endocrine system diseases in children .

Lesson 4.

Topic:

 

Diabetes in children. Etiology, npathogenesis, clinical manifestations, diagnosis, differential diagnosis, ntreatment, prevention, prognosis of diabetes in children.  Insulin therapy. nHyperglycemic and hypoglycemic coma: etiology, pathogenesis, clinical nmanifestations, diagnosis, differential diagnosis, emergency care and nprevention. Outlook.

Diabetes mellitus (DM) in children.

The term diabetes mellitus ndescribes a metabolic disorder of multiple naetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulisecretion, insulin action, or both (Fig. 1). The effects of diabetes mellitus include nlong–term damage, dysfunction and failure of various organs. Diabetes mellitus may present with ncharacteristic symptoms such as nthirst, polyuria, blurring of vision, and weight nloss. In its most severe forms, ketoacidosis or a non–ketotic hyperosmolar state may develop and lead to nstupor, coma and, in absence of effective ntreatment, death. Often symptoms are not nsevere, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long ntime before the diagnosis is made. The long–term effects of diabetes mellitus include nprogressive development of the specific complications of retinopathy nwith potential blindness, nephropathy that may lead to renal failure, and/or nneuropathy with risk of foot ulcers, amputation, Charcot joints, and features of nautonomic dysfunction, including sexual dysfunction. People with ndiabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular ndisease. Several pathogenetic nprocesses are involved in the development of diabetes. These include processes which destroy the nbeta cells of the pancreas with consequent insulin deficiency, and others that nresult in resistance to insulin action. The abnormalities of carbohydrate, fat and nprotein metabolism are due to deficient action of insulin on target tissues nresulting from insensitivity or lack of insulin.

Fig. 1. Pathogenesis nof DM type 1.

Diagnosis and diagnostic ncriteria.

If a diagnosis of diabetes is made, the clinician must nfeel confident that the diagnosis is fully established since the consequences nfor the individual are considerable and lifelong. The requirements for ndiagnostic confirmation for a person presenting with severe symptoms and gross nhyperglycaemia differ from those for the asymptomatic person with blood glucose nvalues found to be just above the diagnostic cut–off value. Severe hyperglycaemia ndetected under conditions of acute infective, traumatic, circulatory or other nstress may be transitory and should not in itself be regarded as diagnostic of diabetes. nThe diagnosis of diabetes in an asymptomatic subject should never be nmade on the basis of a single abnormal blood glucose value. For the asymptomatic nperson, at least one additional plasma/blood glucose test result with a value ithe diabetic range is essential, either fasting, from a random (casual) sample, or nfrom the oral glucose tolerance test (OGTT). If such samples fail to confirm the ndiagnosis of diabetes mellitus, it will usually be advisable to maintain surveillance nwith periodic re–testing until the diagnostic situation becomes clear. Ithese circumstances, the clinician should take into consideration such additional factors nas ethnicity, family history, age, adiposity, and concomitant disorders, nbefore deciding on a diagnostic or therapeutic course of action. An alternative nto blood glucose estimation or the OGTT has long been sought to simplify the ndiagnosis of diabetes. Glycated haemoglobin, reflecting naverage glycaemia over a period of weeks, was thought to provide such a ntest. Although in certain cases it gives equal or almost equal nsensitivity and specificity to glucose measurement, it is not available in many nparts of the world and is not well enough standardized for its use to be recommended at nthis time.

n

Diabetes nin children

Diabetes in children usually presents with severe nsymptoms, very high blood glucose levels, marked glycosuria, nand ketonuria. In most children the diagnosis is confirmed without delay by blood glucose nmeasurements, and treatment (including insulin injection) is initiated immediately, often as a nlife–saving measure. An OGTT is neither necessary nor appropriate for diagnosis isuch circumstances. A small proportion of children and adolescents, however, npresent with less severe symptoms and may require fasting blood glucose measurement nand/or an OGTT for diagnosis.

Diagnostic ncriteria

The clinical diagnosis of diabetes is often prompted nby symptoms such as increased thirst and urine volume, recurrent ninfections, unexplained weight loss and, in severe cases, drowsiness and coma; nhigh levels of glycosuria are usually present. A single nblood glucose estimation in excess of the diagnostic values indicated in Figure n2 (black zone) establishes nthe diagnosis in such cases. Figure 2 nalso defines levels of blood glucose below which a diagnosis of diabetes is unlikely inon–pregnant individuals. These criteria are as in the WHO 1985 report. For clinical npurposes, an OGTT to establish diagnostic status need only be considered if casual blood nglucose values lie in the uncertain range (i.e. between the levels that establish or nexclude diabetes) and fasting blood glucose levels are below those which establish the ndiagnosis of diabetes. If an OGTT is performed, it is sufficient to measure the blood nglucose values while fasting and at 2 hours after a 75 g noral glucose load (Annexe 1). For children the oral glucose load is related to body weight: 1.75 g per kg. The diagnostic ncriteria in children are the same as for adults. Diagnostic interpretations of nthe fasting and 2–h post–load concentrations ion–pregnant subjects are shown in Table n1.

 

 

Figure 2: Unstandardized (casual, random) blood glucose values in the diagnosis of diabetes in mmol l-1 (mg dl-1). Taken from the 1985 WHO Study Group Report.

 

Classification (Tables 2, nTable 3).

It is recommended that the terms “insulin–dependent ndiabetes mellitus” and “non–insulin–dependent diabetes mellitus” and their nacronyms “IDDM” and “NIDDM” no longer be used. These terms have beeconfusing and frequently resulted in patients being classified on the basis of treatment nrather than pathogenesis.

ü     The terms Type 1 and Type 2 should nbe reintroduced. The aetiological type named Type 1 nencompasses the majority of cases which are nprimarily due to pancreatic islet nbeta–cell destruction and are prone to ketoacidosis. Type 1 includes those cases attributable to an autoimmune process, as well as those nwith beta– cell destruction and who are prone nto ketoacidosis for which neither an aetiology nor a pathogenesis is known (idiopathic). It does not include those nforms of beta–cell destruction or failure to nwhich specific causes can be assigned (e.g. cystic nfibrosis, mitochondrial defects, etc.). Some subjects with this type can be identified at nearlier clinical stages than “diabetes mellitus”.

ü     The type named Type 2 includes the commomajor form of diabetes which results from defect(s) in insulin secretion, nalmost always with a major contribution from insulin resistance. It nhas been argued that a lean phenotype of Type 2 diabetes mellitus in adults found in the nIndian sub–continent may be very distinct from the more characteristic form nof Type 2 found in Caucasians. Not enough information is available, however, to characterize such nsubjects separately.

ü     A recent international workshop reviewed the evidence for, and ncharacteristics of, diabetes mellitus seen in undernourished populations. nWhilst it appears that malnutrition may influence the expression of several ntypes of diabetes, the evidence that diabetes can be caused by malnutritioor protein deficiency per se is not nconvincing. Therefore, it is recommended that the class n“Malnutrition–related diabetes” (MRDM) be deleted. The former subtype of nMRDM, Protein– deficient Pancreatic Diabetes (PDPD or PDDM), may be nconsidered as a malnutrition modulated or modified form of diabetes mellitus for nwhich more studies are needed. The other former subtype of MRDM, Fibrocalculous Pancreatic nDiabetes (FCPD), is now classified as a disease of the exocrine pancreas, fibrocalculous pancreatopathy, which may lead to diabetes mellitus.

ü     The class “Impaired Glucose Tolerance” is now classified nas a stage of impaired glucose regulation, since it can be observed iany hyperglycaemic disorder, and is itself not diabetes.

ü     A clinical stage of Impaired Fasting Glycaemia has beeintroduced to classify individuals who have fasting glucose values above nthe normal range, but below those diagnostic of diabetes.

ü     Gestational Diabetes is retained but now encompasses the groups nformerly classified as Gestational Impaired Glucose Tolerance (GIGT) and nGestational Diabetes Mellitus (GDM).

Table 2. Aetiological Classification of Disorders of

Glycaemia

––––––––––––––––––––––––––––––––––––––––––––––––

Type 1 (beta-cell ndestruction, usually leading to absolute

insulin deficiency)

Autoimmune

Idiopathic

Type 2 (may nrange from predominantly insulin resistance

with relative insulin deficiency to a npredominantly

secretory defect with or without insulin resistance)

Other specific types

Genetic defects of beta-cell function

Genetic defects in insulin action

Diseases of the exocrine pancreas

Endocrinopathies

Drug- or chemical-induced

Infections

Uncommon forms of immune-mediated diabetes

Other genetic syndromes sometimes associated nwith

diabetes

Gestational diabetes

 

Table 3 Other Specific Types of Diabetes

––––––––––––––––––––––––––––––––––––––––––––––––

Genetic defects of beta-cell function

Chromosome 20, HNF4a (MODY1)

Chromosome 7, glucokinase n(MODY2)

Chromosome 12, HNF1a (MODY3)

Chromosome 13, IPF-1 (MODY4)

Mitochondrial DNA 3243 mutation

Others

Genetic defects in insulin action

Type A insulin resistance

Leprechaunism

Rabson-Mendenhall syndrome

Lipoatrophic diabetes

Others

Diseases of the exocrine pancreas

Fibrocalculous pancreatopathy

Pancreatitis

Trauma / pancreatectomy

Neoplasia

Cystic fibrosis

Haemochromatosis

Others

Endocrinopathies

Cushing’s syndrome

Acromegaly

Phaeochromocytoma

Glucagonoma

Hyperthyroidism

Somatostatinoma

Others

Drug- or chemical-induced

Infections

Congenital rubella

Cytomegalovirus

Others

Uncommon forms of nimmune-mediated diabetes

Insulin autoimmune syndrome (antibodies to insulin)

Anti-insulin receptor antibodies

“Stiff Man” syndrome

Others

Other genetic syndromes

––––––––––––––––––––––––––––––––––––––––––––––––

Laboratory methods of examination iDM.

Measurement of glucose in blood Reductiometric methods n(the Somogyi–Nelson, the ferricyanide and neocuprine autoanalyser methods) nare still in use for blood glucose measurement. The o–toluidine nmethod also remains in use but enzyme–based methods are widely available, for nboth laboratory and near–patient use. Highly accurate and rapid (1–2 min) ndevices are now available based on immobilized glucose oxidase electrodes. Hexokinase and nglucose dehydrogenase methods are used for nreference. Whole blood samples preserved with fluoride show an initial rapid fall iglucose of up to 10 % at room temperature, but subsequent decline is nslow; centrifugation prevents the initial fall. Whole blood glucose nvalues are 15 % lower than corresponding plasma values in patients with a normal haematocrit reading, and arterial values are about 7 n% higher than corresponding venous values. The use of reagent–strip nglucose oxidase methods has made bedside nestimation of blood glucose very popular. However, the cost of the reagent–strips remains nhigh. Some methods still require punctilious technique, accurate timing, and storage of nstrips in airtight containers. Reasonably quantitative results can be obtained even with nvisual colour–matching techniques. Electrochemical and reflectance meters can give ncoefficients of variation of well under 5 %. Reagent–strip methods have nbeen validated under tropical conditions, but are sensitive to extreme climatic nconditions. Diabetes may be strongly suspected from the results of reagent– strip nglucose estimation, but the diagnosis cannot be confidently excluded by nthe use of this method. Confirmation of diagnosis requires estimation by nlaboratory methods. Patients can easily collect small blood samples themselves (either ispecially prepared plastic or glass capillary tubes or on filter–paper), nand self–monitoring using glucose reagent–strips with direct colour–matching or nmeters is now widely practised. Patients should be properly trained in the appropriate ntechniques to avoid inaccurate or misleading results. The insulin–treated patient is ncommonly requested to build up a “glycaemic profile” by nself–measurement of blood glucose at specific times of the day (and night). A “7–point nprofile” is useful, with samples taken before and 90 min after breakfast, before and 90 miafter lunch, before and 90 min after an evening meal, and just before going to nbed. Occasionally patients may arrange to wake at 0300 h to collect and measure a nnocturnal sample. The complete profile rarely needs to be collected within a single n24–hour period, and it may be compiled from samples collected at different times nover several days. Measurement of glucose in urine Insulin–treated patients who do not have access to nfacilities for self–measurement of blood glucose should test urine samples passed nafter rising, before main meals, and before going to bed. Non–insulin–dependent npatients do not need to monitor their urine so frequently. Urine tests are of somewhat nlimited value, however, because of the great variation in urine glucose concentration for givelevels of blood glucose. The correlation between blood and urine nglucose may be improved a little by collecting short–term fractions (15–30 min) of the nurine output. Benedict’s quantitative solution or self–boiling, caustic soda/copper nsulphate tablets may be used or the more convenient, but costly, nsemi–quantitative enzyme–based test– strips. Ketone bodies in urine and blood The appearance of persistent ketonuria nassociated with hyperglycaemia or high levels of glycosuria ithe diabetic patient points to an unacceptably severe level of metabolic disturbance nand indicates an urgent need for corrective action. The patient should be advised nto test for ketone bodies (acetone and aceto–acetic acid) when tests for glucose are repeatedly positive, nor when there issubstantial disturbance of health, nparticularly with infections. Rothera’s sodium nitroprusside test may be used or, alternatively, reagent–strips nthat are sensitive to ketones. In emergency situations such as ndiabetic ketoacidosis, a greatly raised concentratioof plasma ketones can be detected with a nreagent–strip and roughly quantified by serial 1 in 2 dilution of plasma nwith water.

Annex 1

The Oral nGlucose Tolerance Test

The oral glucose tolerance test (OGTT) is principally used for diagnosis nwhen blood glucose levels are equivocal, during pregnancy, or iepidemiological studies. The OGTT should be administered in the morning after nat least three days of unrestricted diet (greater than 150 g of carbohydrate daily) and nusual physical activity. Recent evidence suggests that a reasonable n(30–50g) carbohydrate containing meal should be consumed on the evening before nthe test. The test should be preceded by an overnight fast of 8–14 hours, during nwhich water may be drunk. Smoking is not permitted during the test. The presence of nfactors that influence interpretation of the results of the test must nbe recorded (e.g. medications, inactivity, infection, etc.). After ncollection of the fasting blood sample, the subject should drink 75 g of anhydrous glucose or 82.5 g of glucose nmonohydrate (or partial hydrolysates of starch of the nequivalent carbohydrate content) in 250–300 ml of water over the course of 5 nminutes. For children, the test load should be 1.75 g of glucose per kg body weight up nto a total of 75 g nof glucose. Timing of the test is from the beginning of the drink. Blood nsamples must be collected 2 hours after the test load. Unless the glucose nconcentration can be determined immediately, the blood sample should be ncollected in a tube containing sodium fluoride (6 mg per ml whole blood) and immediately ncentrifuged to separate the plasma; the plasma should be frozen until the glucose concentratiocan be estimated. For interpretation of results, refer to Table n1.

Age

Insulin dose n(Units/kg)

 

Infants n(< 1 year) 

0,1 – 0,125

 

Toddlers n(1-3 years) 

0,15 – 0,17

 

3-9 nyears 

0,2 – 0,5

 

9-12 nyears 

0,5 – 0,8

 

> n12 years 

1,0 and more

Insulin has 3 basic formulations:

 

• short-acting (regular, soluble, lispro)

 

•medium- or intermediate-acting (isophane, nlente)

 

• and long-acting (ultralente). n

Periods of action of different types of insulin you ncan see on Fig. 3.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Fig. 3. Periods nof action of different types of insulin.

 

Complications of DM.

Nephropathy:

n

GLOMERULAR SCLEROSIS	ISCHAEMIC LESIONS	INFECTIVE LESIONS
thickening of glomerular basement membrane membrane becomes less effective filter so protein is able to leave the blood = albuminuria may develop nephrotic syndrome with oedema and low blood albumin anaemia develops hypertension may develop and this further damages the kidney renal failure ensues	afferent and efferent arterioles become hypertrophies and hyalinized look like hypertensive disease	these ascend from the urinary tract

Microangiopathy:

• capillary basement membrane is thickened – this affects:

• retina

• renal glomerulus

• nerve sheaths

n

Macroangiopathy:

• atherosclerosis occurs at an accelerated rate

• thus diabetics are more at risk of:

• strokes

• MI

• gangrene leading to amputation

n

Retinopathy:

n

BACKGROUND RETINOPATHY	DIABETIC MACULOPATHY	PREPROLIFERATIVE RETINOPATHY	PROLIFERATIVE  RETINOPATHY
haemorrhages are the first thing to appear ‘hard ‘ exudates of lipids and proteins appear yellow-white with a clear margin	can lead to blindness macular oedema hard exudates and haemorrhages encroach on the macular area	‘cotton-wool spots’ oedema from retinal infarcts grey-white with indistinct margin venous beading	due to hypoxia ·                     new vessels formed – many branches ·                     new vessels bleed easily

Nonretinal visual problems:

• lens affected by changes in osmolality – leads to cataracts

• new vessel formation in the iris

• ocular palsies eg. of sixth cranial nerve

n

Frequent infections:

• with poor diabetic control

• white blood cells are impaired with high blood glucose levels

• important as infections then lead to poor control of diabetes

n

 

Differential diagnosis among the various obesity forms nin children.

Definition. Obesity nis defined as weight/height greater than 120% of standards for age and sex. nAlthough BMI is widly used for obesity diagnostic.

Etiology and pathogenesis. Several nfactors may contribute to the development of obesity (Tabl.4). Exogenous-constitutive, the most ncommon reason for obesity, typically is viewed as the consequence of increased ncaloric intake and genetic predisposition.

ü     nGenetic predisposition is suggested nby twin studies. Individuals with a propensity toward obesity may require fewer ncalories to maintain a normal weight.

ü     nIncreased caloric intake may be nsecondary to a variety of psychosocial causes, such as anxiety and family nmodeling.

ü     nGenetic disorders. For example, Prader-Willi syndrome and Laurence-Moon-Biedl nsyndrome are associated with obesity.

ü     nNeuroendocrine, ncerebral and endocrine obesity are appearing because of compromised perinatal life, old severe viral (bacterial) infections or nhormonal abnormalities.

 

Table 4. nClassification of obesity.

n

Form	Severity
Primary: – Exogenous-constitutive – Alimentary Secondary: – Neuroendocrine – Cerebral – Endocrine	I degree – weight excess less then 15-24 % II degree – 25-49 % III degree – 50-99 % IV degree – more than 100 %
Course
Stable Progressive: fast, slow progressive Regressive

 

Diagnosis.

ü     History. Essential elements include: 1) family history n(parental obesity is a strong predictor of childhood obesity); 2) history of nthe child’s weight height gain over time; 3) a dietary diary to document eating npatterns and caloric intake.

ü     nPhysical nexamination. 1) normal stature, sexual development and intelligence rule out nmost genetic disorders associated with obesity and strongly suggest exogenous nobesity; 2) triceps skin fold thickness measurement may be helpful; 3) blood npressure should be obtained.

Laboratory studies. Total cholesterol, ntriglycerides and high density lipoprotein should be measured.

Therapy. A reduced ncalorie diet should be devised, nutritionist often is helpful. Anorectic drugs nare useful sometimes. A formal exercise program should be encouraged. Specific nweight goals should be determined. Treatment of the base disease in a case of nsecondary obesity.

 

Practice Essentials

Type 1 diabetes is a chronic illness characterized by the nbody’s inability to produce insulin due to the autoimmune destruction of the beta ncells in the pancreas. Most pediatric patients with diabetes have type 1 and a nlifetime dependence on exogenous insulin.

Essential update: Disordered eating ncommon in pediatric patients with type 1 diabetes

In a survey of 770 Norwegian children and adolescents nwith type 1 diabetes, nearly 1in 5 (and 1in 4 females) was found to have disturbed eating nbehavior (DEB). Mean age of the subjects was 14.6 years, and mean diabetes nduration was 5.3 years. Most respondents used insulin pumps (56%) or took at least n4 insulin shots per day.

Using a predetermined cutoff of 20 or higher on the newly ndeveloped 16-item Diabetes Eating Problem Survey-Revised (DEPS-R), DEB was nidentified in 18.3% of the entire group, 27.7% of the females, and 8.6% of the nmales.

The proportions were dramatically higher among the older ngroup of 153 patients aged 17 to 19 years, in whom DEB was identified in 32.7% noverall and in 49.4% of the females and 14.5% of the males. In contrast, all of nthose rates were less than 10% among the 11- to 13-year-olds.

Signs and symptoms

Signs and symptoms of type 1 diabetes in children include nthe following:

·                                 nHyperglycemia

·                                 nGlycosuria

·                                 nPolydipsia

·                                 nUnexplained weight loss

·                                 nNonspecific malaise

·                                 nSymptoms of ketoacidosis

See Clinical Presentation for more detail.

Diagnosis

Blood glucose

Blood glucose tests using capillary blood samples, nreagent sticks, and blood glucose meters are the usual methods for monitoring nday-to-day diabetes control.

Diagnostic criteria by the American Diabetes Associatio(ADA) include the following ⁿ:

·                                 nA fasting plasma glucose (FPG) level ≥126 nmg/dL (7.0 mmol/L), or

·                                 nA 2-hour plasma glucose level ≥200 nmg/dL (11.1 mmol/L) during a 75-g oral glucose tolerance test (OGTT), or

·                                 nA random plasma glucose ≥200 mg/dL n(11.1 mmol/L) in a patient with classic symptoms of hyperglycemia or nhyperglycemic crisis

Glycated hemoglobin

Measurement of HbA1c levels is the best method for nmedium-term to long-term diabetic control monitoring. An international expert ncommittee composed of appointed representatives of the American Diabetes nAssociation, the European Association for the Study of Diabetes, and others nrecommended HbA1c assay for diagnosing diabetes mellitus.

See Workup for more detail.

Management

Glycemic control

The ADA recommends using patient age as one consideratioin the establishment of glycemic goals, with different targets for preprandial, nbedtime/overnight, and hemoglobin A_1c (HbA_1c) levels ipatients aged 0-6, 6-12, and 13-19 years. Benefits of tight glycemic control ninclude not only continued reductions in the rates of microvascular ncomplications but also significant differences in cardiovascular events and noverall mortality.

Insulin therapy

All children with type 1 diabetes mellitus require ninsulin therapy. Most require 2 or more injections of insulin daily, with doses nadjusted on the basis of self-monitoring of blood glucose levels. Insulireplacement is accomplished by giving a basal insulin and a preprandial n(premeal) insulin. The basal insulin is either long-acting (glargine or ndetemir) or intermediate-acting (NPH). The preprandial insulin is either nrapid-acting (lispro, aspart, or glulisine) or short-acting (regular).

Diet and activity

The aim of dietary management is to balance the child’s nfood intake with insulin dose and activity and to keep blood glucose nconcentrations as close as possible to reference ranges, avoiding extremes of nhyperglycemia and hypoglycemia.

The following are among the most recent dietary consensus nrecommendations (although they should be viewed in the context of the patient’s nculture):

·                                 nCarbohydrates – Should provide 50-55% of ndaily energy intake; no more than 10% of carbohydrates should be from sucrose nor other refined carbohydrates

·                                 nFat – Should provide 30-35% of daily nenergy intake

·                                 nProtein – Should provide 10-15% of daily nenergy intake

Exercise is also an important aspect of diabetes nmanagement. It has real benefits for a child with diabetes. Patients should be nencouraged to exercise regularly.

Possible mechanism for development of type 1 diabetes.

 

Background

Most pediatric patients with diabetes have type 1 ndiabetes mellitus (T1DM) and a lifetime dependence on exogenous insulin. nDiabetes mellitus (DM) is a chronic metabolic disorder caused by an absolute or nrelative deficiency of insulin, an anabolic hormone. Insulin is produced by the nbeta cells of the islets of Langerhans located in the pancreas, and the nabsence, destruction, or other loss of these cells results in type 1 diabetes n(insulin-dependent diabetes mellitus [IDDM]). A possible mechanism for the ndevelopment of type 1 diabetes is shown in the image below.

Type 2 diabetes mellitus n(non–insulin-dependent diabetes mellitus [NIDDM]) is a heterogeneous disorder. nMost patients with type 2 diabetes mellitus have insulin resistance, and their nbeta cells lack the ability to overcome this resistance. Although nthis form of diabetes was previously uncommon in children, in some countries, 20% nor more of new patients with diabetes in childhood and adolescence have type 2 ndiabetes mellitus, a change associated with increased rates of obesity. Other npatients may have inherited disorders of insulin release, leading to maturity nonset diabetes of the young (MODY) or congenital diabetes. This topic addresses nonly type 1 diabetes mellitus. (See Etiology and Epidemiology.)

Hypoglycemia

Hypoglycemia is probably the most disliked and feared ncomplication of diabetes, from the point of view of the child and the family. nChildren hate the symptoms of a hypoglycemic episode and the loss of personal ncontrol it may cause. (See Pathophysiology and Clinical.)

Manage mild hypoglycemia by giving rapidly absorbed oral ncarbohydrate or glucose; for a comatose patient, administer an intramuscular ninjection of the hormone glucagon, which stimulates the release of liver nglycogen and releases glucose into the circulation. Where appropriate, aalternative therapy is intravenous glucose (preferably no more than a 10% glucose nsolution). All treatments for hypoglycemia provide recovery in approximately 10 nminutes. (See Treatment.)

Occasionally, a child with hypoglycemic coma may not nrecover within 10 minutes, despite appropriate therapy. Under no circumstances nshould further treatment be given, especially intravenous glucose, until the nblood glucose level is checked and still found to be subnormal. Overtreatment nof hypoglycemia can lead to cerebral edema and death. If coma persists, seek nother causes.

Hypoglycemia was a particular concern in children younger nthan 4 years because the condition was thought to lead to possible intellectual nimpairment later in life. Persistent hyperglycemia is now believed to be more ndamaging.

Hyperglycemia

In an otherwise healthy individual, blood glucose levels nusually do not rise above 180 mg/dL (9 mmol/L). In a child with diabetes, blood nsugar levels rise if insulin is insufficient for a given glucose load. The nrenal threshold for glucose reabsorption is exceeded when blood glucose levels nexceed 180 mg/dL (10 mmol/L), causing glycosuria with the typical symptoms of npolyuria and polydipsia. (See Pathophysiology, Clinical, and Treatment.)

All children with diabetes experience episodes of nhyperglycemia, but persistent hyperglycemia in very young children (age < 4 ny) may lead to later intellectual impairment.

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is much less ncommon than hypoglycemia but is potentially far more serious, creating a nlife-threatening medical emergency. Ketosis usually does not occur when insuliis present. In the absence of insulin, however, severe hyperglycemia, ndehydration, and ketone production contribute to the development of DKA. The most nserious complication of DKA is the development of cerebral edema, which nincreases the risk of death and long-term morbidity. Very young children at the ntime of first diagnosis are most likely to develop cerebral edema.

DKA usually follows increasing hyperglycemia and symptoms nof osmotic diuresis. Users of insulin pumps, by virtue of absent reservoirs of nsubcutaneous insulin, may present with ketosis and more normal blood glucose nlevels. They are more likely to present with nausea, vomiting, and abdominal npain, symptoms similar to food poisoning. DKA may manifest as respiratory ndistress.

Injection-site hypertrophy

If children persistently inject their insulin into the nsame area, subcutaneous tissue swelling may develop, causing unsightly lumps nand adversely affecting insulin absorption. Rotating the injection sites nresolves the condition.

Fat atrophy can also occur, possibly in association with ninsulin antibodies. This condition is much less common but is more disfiguring. n

Diabetic retinopathy

The most common cause of acquired blindness in many ndeveloped nations, diabetic retinopathy is rare in the prepubertal child or nwithin 5 years of onset of diabetes. The prevalence and severity of retinopathy nincrease with age and are greatest in patients whose diabetic control is poor. nPrevalence rates seem to be declining, yet an estimated 80% of people with type n1 diabetes mellitus develop retinopathy.

Diabetic nephropathy and nhypertension

The exact mechanism of diabetic nephropathy is unknown. nPeak incidence is in postadolescents, 10-15 years after diagnosis, and it may noccur in as many as 30% of people with type 1 diabetes mellitus.

In a patient with nephropathy, the albumin excretion rate n(AER) increases until frank proteinuria develops, and this may progress to nrenal failure. Blood pressure rises with increased AER, and hypertensioaccelerates the progression to renal failure. Having diabetic nephropathy also nincreases the risk of significant diabetic retinopathy.

Progression may be delayed or halted by improved diabetes ncontrol, administration of angiotensin-converting enzyme inhibitors (ACE ninhibitors), and aggressive blood pressure control. Regular urine screening for nmicroalbuminuria provides opportunities for early identification and treatment nto prevent renal failure.

A child younger than 15 years with persistent proteinuria nmay have a nondiabetic cause and should be referred to a pediatric nephrologist nfor further assessment.

Peripheral and autonomic nneuropathy

The peripheral and autonomic nerves are affected in type n1 diabetes mellitus. Hyperglycemic effects on axons and microvascular changes nin endoneural capillaries are amongst the proposed mechanisms.

Autonomic changes involving cardiovascular control (eg, nheart rate, postural responses) have been described in as many as 40% of nchildren with diabetes. Cardiovascular control changes become more likely with nincreasing duration and worsening control.^{[16] n}In adults, peripheral neuropathy usually occurs as a distal nsensory loss.

Gastroparesis is another complication, and it which may nbe caused by autonomic dysfunction. Gastric emptying is significantly delayed, nleading to problems of bloating and unpredictable excursions of blood glucose nlevels.

Macrovascular disease

Although this complication is not seen in pediatric npatients, it is a significant cause of morbidity and premature mortality iadults with diabetes. People with type 1 diabetes mellitus have twice the risk nof fatal myocardial infarction (MI) and stroke that people unaffected with ndiabetes do; in women, the MI risk is 4 times greater. People with type 1 ndiabetes mellitus also have 4 times greater risk for atherosclerosis.

The combination of peripheral vascular disease and nperipheral neuropathy can cause serious foot pathology. Smoking, hypertension, nhyperlipidemia, and poor diabetic control greatly increase the risk of vascular ndisease. Smoking, in particular, may increase the risk of myocardial infarctioby a factor of 10.

Autoimmune diseases

Hypothyroidism affects 2-5% of children with diabetes. ⁿHyperthyroidism affects 1% of children with diabetes; the condition is nusually discovered at the time of diabetes diagnosis.

Although Addison disease is uncommon, affecting less tha1% of children with diabetes, it is a life-threatening condition that is easily nmissed. Addison disease may reduce the insulin requirement and increase the nfrequency of hypoglycemia. (These effects may also be the result of nunrecognized hypothyroidism.)

Celiac disease, associated with an abnormal sensitivity nto gluten in wheat products, is probably a form of autoimmune disease and may noccur in as many as 5% of children with type 1 diabetes mellitus.

Necrobiosis lipoidica is probably another form of nautoimmune disease. This condition is usually, but not exclusively, found ipatients with type 1 diabetes. Necrobiosis lipoidica affects 1-2% of childreand may be more common in children with poor diabetic control.

Limited joint mobility

Limited joint mobility (primarily affecting the hands and nfeet) is believed to be associated with poor diabetic control.

Originally described in approximately 30% of patients nwith type 1 diabetes mellitus, limited joint mobility occurs in 50% of patients nolder than age 10 years who have had diabetes for longer than 5 years. The ncondition restricts joint extension, making it difficult to press the hands nflat against each other. The skin of patients with severe joint involvement has na thickened and waxy appearance.

Limited joint mobility is associated with increased risks nfor diabetic retinopathy and nephropathy. Improved diabetes control over the npast several years appears to have reduced the frequency of these additional ncomplications by a factor of approximately 4. Patients have also markedly fewer nsevere joint mobility limitations.

Pathophysiology

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

Hyperglycemia

Hyperglycemia (ie, random blood glucose concentration of nmore than 200 mg/dL or 11 mmol/L) results when insulin deficiency leads to nuninhibited gluconeogenesis and prevents the use and storage of circulating nglucose. The kidneys cannot reabsorb the excess glucose load, causing nglycosuria, osmotic diuresis, thirst, and dehydration. Increased fat and nprotein breakdown leads to ketone production and weight loss. Without insulin, na child with type 1 diabetes mellitus wastes away and eventually dies due to nDKA. The effects of insulin deficiency are shown in the image below.

The effects of insulin deficiency

 

Hypoglycemia

Insulin inhibits glucogenesis and glycogenolysis, while nstimulating glucose uptake. Iondiabetic individuals, insulin production by nthe pancreatic islet cells is suppressed when blood glucose levels fall below n83 mg/dL (4.6 mmol/L). If insulin is injected into a treated child with ndiabetes who has not eaten adequate amounts of carbohydrates, blood glucose nlevels progressively fall.

The brain depends on glucose as a fuel. As glucose levels ndrop below 65 mg/dL (3.2 mmol/L) counterregulatory hormones (eg, glucagon, ncortisol, epinephrine) are released, and symptoms of hypoglycemia develop. These symptoms ninclude sweatiness, shaking, confusion, behavioral changes, and, eventually, ncoma when blood glucose levels fall below 30-40 mg/dL.

The glucose level at which symptoms develop varies ngreatly from individual to individual (and from time to time in the same nindividual), depending in part on the duration of diabetes, the frequency of nhypoglycemic episodes, the rate of fall of glycemia, and overall control. n(Glucose is also the sole energy source for erythrocytes and the kidney nmedulla.)

Etiology

Most cases (95%) of type 1 diabetes mellitus are the nresult of environmental factors interacting with a genetically susceptible nperson. This interaction leads to the development of autoimmune disease ndirected at the insulin-producing cells of the pancreatic islets of Langerhans. nThese cells are progressively destroyed, with insulin deficiency usually ndeveloping after the destruction of 90% of islet cells.

Genetic issues

Clear evidence suggests a genetic component in type 1 ndiabetes mellitus. Monozygotic twins have a 60% lifetime concordance for ndeveloping type 1 diabetes mellitus, although only 30% do so within 10 years nafter the first twin is diagnosed. In contrast, dizygotic twins have only an 8% nrisk of concordance, which is similar to the risk among other siblings.

The frequency of diabetes development in children with a nmother who has diabetes is 2-3%; this figure increases to 5-6% for childrewith a father who has type 1 diabetes mellitus. The risk to children rises to nalmost 30% if both parents are diabetic.

Human leukocyte antigen (HLA) class II molecules DR3 and nDR4 are associated strongly with type 1 diabetes mellitus. More than 90% of nwhites with type 1 diabetes mellitus express 1 or both of these molecules, ncompared with 50-60% of the general population.

Patients expressing DR3 are also at risk for developing nother autoimmune endocrinopathies and celiac disease. These patients are more likely nto develop diabetes at a later age, to have positive islet cell antibodies, and nto appear to have a longer period of residual islet cell function.

Patients expressing DR4 are usually younger at diagnosis nand more likely to have positive insulin antibodies, yet they are unlikely to nhave other autoimmune endocrinopathies. The expression of both DR3 and DR4 ncarries the greatest risk of type 1 diabetes mellitus; these patients have ncharacteristics of both the DR3 and DR4 groups.

Neonatal diabetes, including diagnosis in infants younger nthan age 6 months, is most likely due to an inherited defect of the iKir6.2 nsubunit potassium channel of the islet beta cells, and genetic screening is nindicated. This is particularly important, because these children respond well nto sulphonylurea therapy.

Environmental factors

Environmental factors are important, because eveidentical twins have only a 30-60% concordance for type 1 diabetes mellitus and nbecause incidence rates vary in genetically similar populations under different nliving conditions. No single factor has been identified, but ninfections and diet are considered the 2 most likely environmental candidates.

Viral infections may be the most important environmental nfactor in the development of type 1 diabetes mellitus, probably by initiating nor modifying an autoimmune process. Instances have been reported of a direct ntoxic effect of infection in congenital rubella. One survey suggests nenteroviral infection during pregnancy carries an increased risk of type 1 diabetes nmellitus in the offspring. Paradoxically, type 1 diabetes mellitus incidence is nhigher in areas where the overall burden of infectious disease is lower.

Dietary factors are also relevant. Breastfed infants have na lower risk for type 1 diabetes, and a direct relationship is observed betweeper capita cow’s milk consumption and the incidence of diabetes. Some cow’s nmilk proteins (eg, bovine serum albumin) have antigenic similarities to aislet cell antigen.

Nitrosamines, chemicals found in smoked foods and some nwater supplies, are known to cause type 1 diabetes mellitus in animal models; nhowever, no definite link has been made with humans.

The known association of increasing incidence of type 1 ndiabetes mellitus with distance from the equator may now have an explanation. nReduced exposure to ultraviolet (UV) light and lower vitamin D levels, both of nwhich are more likely found in the higher latitudes, are associated with aincreased risk of type 1 diabetes mellitus.

Chemical causes

Streptozotocin and RH-787, a rat poison, nselectively damages islet cells and can cause type 1 diabetes mellitus.

Other causes

Additional factors in the development of type 1 diabetes nmellitus include the following:

·                                 nCongenital absence of the pancreas or nislet cells

·                                 nPancreatectomy

·                                 nPancreatic damage (ie, cystic fibrosis, chronic pancreatitis, thalassemia major, hemochromatosis, hemolytic-uremic syndrome)

·                                 nWolfram syndrome (diabetes insipidus, diabetes mellitus, noptic atrophy, deafness [DIDMOAD])

·                                 nChromosomal disorders such as Down syndrome, Turner syndrome, Klinefelter syndrome, or Prader-Willi syndrome (the risk is said to nbe around 1% in Down and Turner syndromes)

Epidemiology

Occurrence in the United States

The overall annual incidence of diabetes mellitus is nabout 24.3 cases per 100,000 person-years. Although most new diabetes cases are ntype 1 (approximately 15,000 annually), increasing numbers of older childreare being diagnosed with type 2 diabetes mellitus, especially among minority ngroups (3700 annually).

International occurrence

Type 1 diabetes mellitus has wide geographic variation iincidence and prevalence. Annual incidence varies from 0.61 cases per 100,000 npopulation in China to 41.4 cases per 100,000 population in Finland. nSubstantial variations are observed betweeearby countries with differing nlifestyles, such as Estonia and Finland, and between genetically similar npopulations, such as those in Iceland and Norway.

A population-based, nationwide cohort study in Finland nexamined the short -and long-term time trends in mortality among patients with nearly-onset and late-onset type 1 diabetes. The results suggest that in those nwith early-onset type 1 diabetes (age 0-14 y), survival has improved over time. nSurvival of those with late-onset type 1 diabetes (15-29 y) has deteriorated nsince the 1980s, and the ratio of deaths caused by acute complications has nincreased in this group. Overall, alcohol was noted as an important cause of ndeath in patients with type 1 diabetes; women had higher standardized mortality nratios than did men in both groups.

Even more striking are the differences in incidence nbetween mainland Italy (8.4 cases per 100,000 population) and the Island of nSardinia (36.9 cases per 100,000 population). These variations strongly support nthe importance of environmental factors in the development of type 1 diabetes nmellitus. Most countries report that incidence rates have at least doubled ithe last 20 years. Incidence appears to increase with distance from the nequator.

Race-related demographics

Different environmental effects on type 1 diabetes nmellitus development complicate the influence of race, but racial differences nare evident. Whites have the highest reported incidence, whereas Chinese nindividuals have the lowest. Type 1 diabetes mellitus is 1.5 times more likely nto develop in American whites than in American blacks or Hispanics. Current nevidence suggests that when immigrants from an area with low incidence move to nan area with higher incidence, their rates of type 1 diabetes mellitus tend to nincrease toward the higher level.

Sex-related demographics

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

Age-related demographics

Type 1 diabetes mellitus can occur at any age, but nincidence rates generally increase with age until midpuberty and then decline. nOnset in the first year of life, although unusual, can occur, so type 1 ndiabetes mellitus must be considered in any infant or toddler, because these nchildren have the greatest risk for mortality if diagnosis is delayed. (Because ndiabetes is easily missed in an infant or preschool-aged child, if in doubt, ncheck the urine for glucose.) Symptoms in infants and toddlers may include the nfollowing:

·                                 nSevere monilial diaper/napkin rash

·                                 nUnexplained malaise

·                                 nPoor weight gain or weight loss

·                                 nIncreased thirst

·                                 nVomiting and dehydration, with a nconstantly wet napkin/diaper

In areas with high prevalence rates, a bimodal variatioof incidence has been reported that shows a definite peak in early childhood n(ie, ages 4-6 y) and a second, much greater peak of incidence during early npuberty (ie, ages 10-14 y).

Prognosis

Apart from severe DKA or hypoglycemia, type 1 diabetes nmellitus has little immediate morbidity. The risk of complications relates to diabetic ncontrol. With good management, patients can expect to lead full, normal, and nhealthy lives. Nevertheless, the average life expectancy of a child diagnosed nwith type 1 diabetes mellitus has been variously suggested to be reduced by n13-19 years, compared with their nondiabetic peers.

Morbidity and mortality

Information on mortality rates for type 1 diabetes nmellitus is difficult to ascertain without complete national registers of nchildhood diabetes, although age-specific mortality is probably double that of nthe general population. Children aged 1-4 years are particularly at risk and nmay die due to DKA at the time of diagnosis. Adolescents are also a high-risk ngroup. Most deaths result from delayed diagnosis or neglected treatment and nsubsequent cerebral edema during treatment for DKA, although untreated nhypoglycemia also causes some deaths. Unexplained death during sleep may also noccur and appears more likely to affect young males.

A population-based, nationwide cohort study in Finland nexamined the short -and long-term time trends in mortality among patients with nearly-onset and late-onset type 1 diabetes. The results suggest that in those nwith early-onset type 1 diabetes (age 0-14 y), survival has improved over time. nSurvival of those with late-onset type 1 diabetes (15-29 y) has deteriorated nsince the 1980s, and the ratio of deaths caused by acute complications has nincreased in this group. Overall, alcohol was noted as an important cause of ndeath in patients with type 1 diabetes; women had higher standardized mortality nratios than did men in both groups.

The complications of type 1 diabetes mellitus can be ndivided into 3 major categories: acute complications, long-term complications, nand complications caused by associated autoimmune diseases.

Acute complications, which include hypoglycemia, nhyperglycemia, and DKA, reflect the difficulties of maintaining a balance nbetween insulin therapy, dietary intake, and exercise.

Long-term complications arise from the damaging effects nof prolonged hyperglycemia and other metabolic consequences of insulideficiency on various tissues. Although long-term complications are rare ichildhood, maintaining good control of diabetes is important to prevent ncomplications from developing in later life. The likelihood of developing ncomplications appears to depend on the interaction of factors such as metabolic ncontrol, genetic susceptibility, lifestyle (eg, smoking, diet, exercise), npubertal status, and gender. Long-term complications include the following:

·                                 nRetinopathy

·                                 nCataracts

·                                 nGastroparesis

·                                 nHypertension

·                                 nProgressive renal failure

·                                 nEarly coronary artery disease

·                                 nPeripheral vascular disease

·                                 nPeripheral and autonomic neuropathy

·                                 nIncreased risk of infection

Associated autoimmune diseases are common in type 1 ndiabetes mellitus, particularly in children who have HLA-DR3. Some conditions nmay precede the development of diabetes, and others may develop later. As many nas 20% of children with diabetes have thyroid autoantibodies.

Patient Education

Education is a continuing process involving the child, nfamily, and all members of the diabetes team. (See the videos below.) The nfollowing strategies may be used:

·                                 nFormal education sessions in a clinic nsetting

·                                 nOpportunistic teaching at clinics or at nhome in response to crises or difficulties such as acute illness

·                                 nTherapeutic camping or other organized nevents

·                                 nPatient-organized meetings

 

Diabetes-related organizations nand patient groups include the following: ⁿ

·                                 nChildren with Diabetes – This “online ncommunity for kids, families, and adults with diabetes” is an excellent resource nwith good links

·                                 nInternational Society for nPediatric and Adolescent Diabetes

·                                 nInternational Diabetes nFederation

·                                 nDiabetes UK

·                                 nAmerican Diabetes Association

·                                 nJuvenile Diabetes Research nFoundation International

·                                 nRunsweet – This is a nWeb site devoted to giving advice on exercise management and diabetes

History

The most easily recognized symptoms of type 1 diabetes nmellitus (T1DM) are secondary to hyperglycemia, glycosuria, and DKA.

Hyperglycemia

Hyperglycemia alone may not cause obvious symptoms, nalthough some children report general malaise, headache, and weakness. Childremay also appear irritable and become ill-tempered. The main symptoms of nhyperglycemia are secondary to osmotic diuresis and glycosuria.

Glycosuria

This condition leads to increased urinary frequency and nvolume (eg, polyuria), which is particularly troublesome at night (eg, nnocturia) and often leads to enuresis in a previously continent child. These nsymptoms are easy to overlook in infants because of their naturally high fluid nintake and diaper/napkin use.

Polydipsia

Increased thirst, which may be insatiable, is secondary nto the osmotic diuresis causing dehydration.

Weight loss

Insulin deficiency leads to uninhibited gluconeogenesis, ncausing breakdown of protein and fat. Weight loss may be dramatic, although the nchild’s appetite usually remains good. Failure to thrive and wasting may be the nfirst symptoms noted in an infant or toddler and may precede frank nhyperglycemia.

Nonspecific malaise

Although this condition may be present before symptoms of nhyperglycemia or as a separate symptom of hyperglycemia, it is often only nretrospectively recognized.

Symptoms of ketoacidosis

These symptoms include the following:

·                                 nSevere dehydration

·                                 nSmell of ketones

·                                 nAcidotic breathing (ie, Kussmaul nrespiration), masquerading as respiratory distress

·                                 nAbdominal pain

·                                 nVomiting

·                                 nDrowsiness and coma

Additional symptoms

Hyperglycemia impairs immunity and renders a child more susceptible nto recurrent infection, particularly of the urinary tract, skin, and nrespiratory tract. Candidiasis may develop, especially in the groin and iflexural areas.

Physical Examination

Apart from wasting and mild dehydration, children with nearly diabetes have no specific clinical findings. A physical examination may nreveal findings associated with other autoimmune endocrinopathies, which have a nhigher incidence in children with type 1 diabetes mellitus (eg, thyroid disease nwith symptoms of overactivity or underactivity and possibly a palpable goiter). n

Cataracts are rarely presenting problems ; they typically noccur in girls with a long prodrome of mild hyperglycemia.

Necrobiosis lipoidica usually, but not exclusively, noccurs in people with diabetes. Necrobiosis most often develops on the front of nthe lower leg as a well-demarcated, red, atrophic area. The condition is nassociated with injury to dermal collagen, granulomatous inflammation, and nulceration. The cause of necrobiosis is unknown, and the condition is difficult nto manage. It is also associated with poor metabolic control and a greater risk nof developing other diabetes-related complications.

Diabetic retinopathy

The first symptoms of diabetic retinopathy are dilated nretinal venules and the appearance of capillary microaneurysms, a conditioknown as background retinopathy. These changes may be reversible or their nprogression may be halted with improved diabetic control, although in some npatients the condition initially worsens.

Subsequent changes in background retinopathy are ncharacterized by increased vessel permeability and leaking plasma that forms nhard exudates, followed by capillary occlusion and flame-shaped hemorrhages. nThe patient may not notice these changes unless the macula is involved. Laser ntherapy may be required at this stage to prevent further vision loss.

Proliferative retinopathy follows, with further vascular nocclusion, retinal ischemia, and proliferation of new retinal blood vessels and nfibrous tissue; the condition then progresses to hemorrhage, scarring, retinal ndetachment, and blindness. Prompt retinal laser therapy may prevent blindness nin the later stages, so regular screening is vital.

Diagnostic Considerations

Children with MODY may present as having type 1 diabetes. nAs they may respond better to oral hypoglycemic agents, recognizing MODY as a npossibility is important. Always consider the diagnosis of MODY in the nfollowing circumstances:

·                                 nA strong family history of diabetes nacross 2 or more generations – The age of diagnosis usually falls with each nsuccessive generation

·                                 nPersistently low insulin requirements, nparticularly with good blood glucose control

·                                 nDevelopment of diabetes from birth or nwithin the first 9 months of life

Conditions to consider in the differential diagnosis of ntype 1 diabetes include the following:

·                                 nType 2 diabetes mellitus

·                                 nMODY

·                                 nPsychogenic polydipsia

·                                 nNephrogenic diabetes insipidus

·                                 nHigh-output renal failure

·                                 nTransient hyperglycemia with illness and nother stress

·                                 nSteroid therapy

·                                 nFactitious illness (Münchhausesyndrome by proxy)

Differential Diagnoses

·                                 nDiabetes Insipidus

·                                 nHyperthyroidism

·                                 nPheochromocytoma

·                                 nRenal Glucosuria

·                                 nToxicity, Salicylate

Approach Considerations

The need for and extent of laboratory studies vary, ndepending on the general state of the child’s health. For most children, only nurine testing for glucose and blood glucose measurement are required for a ndiagnosis of diabetes. Other conditions associated with diabetes require nseveral tests at diagnosis and at later review.

Urine glucose

A positive urine glucose test suggests, but is not diagnostic nfor, type 1 diabetes mellitus (T1DM). Diagnosis must be confirmed by test nresults showing elevated blood glucose levels. Test urine of ambulatory npatients for ketones at the time of diagnosis.

Urine ketones

Ketones in the urine confirm lipolysis and ngluconeogenesis, which are normal during periods of starvation. With nhyperglycemia and heavy glycosuria, ketonuria is a marker of insulin deficiency nand potential DKA.

Islet cell antibodies

Islet cell antibodies may be present at diagnosis but are nnot needed to diagnose type 1 diabetes mellitus. Islet cell antibodies are nnonspecific markers of autoimmune disease of the pancreas and have been found nin as many as 5% of unaffected children. Other autoantibody markers of type 1 ndiabetes are known, including insulin antibodies. Additional antibodies against nislet cells are recognized (eg, those against glutamate decarboxylase [GAD nantibodies]), but these may not be available for routine testing.

Thyroid function tests and antithyroid nantibodies

Because early hypothyroidism has few easily identifiable nclinical signs in children, children with type 1 diabetes mellitus may have nundiagnosed thyroid disease. Untreated thyroid disease may interfere with ndiabetes management. Typically, hypothyroid children present with reduced ninsulin requirements and increased episodes of hypoglycemia; hyperthyroid nchildren have increased insulieeds and a tendency toward hyperglycemia. nCaution, therefore, is needed when initiating treatment as insulin requirements ncan change quite quickly. Check thyroid function regularly (every 2-5 years or nannually if thyroid antibodies are present). Antithyroid antibody tests nindicate the risk of present or potential thyroid disease.

Antigliadin antibodies

Some children with type 1 diabetes mellitus may have or nmay develop celiac disease. Positive antigliadin antibodies, especially nspecific antibodies (eg, antiendomysial, antitransglutaminase) are important nrisk markers. If antibody tests are positive, a jejunal biopsy is required to nconfirm or refute a diagnosis of celiac disease. Once celiac disease is nconfirmed, the individual should remain on a gluten-free diet for life.

Lipid profile

Lipid profiles are usually abnormal at diagnosis because nof increased circulating triglycerides caused by gluconeogenesis. Apart from nhypertriglyceridemia, primary lipid disorders rarely result in diabetes. nHyperlipidemia with poor metabolic control is common but returns to normal as nmetabolic control improves.

Urinary albumin

Beginning at age 12 years, perform an annual urinalysis nto test for a slightly increased AER, referred to as microalbuminuria, which is nan indicator of risk for diabetic nephropathy.

Renal function tests

If the child is otherwise healthy, renal function tests nare typically not required.

Blood Glucose

Apart from transient illness-induced or stress-induced nhyperglycemia, a random whole-blood glucose concentration of more than 200 nmg/dL (11 mmol/L) is diagnostic for diabetes, as is a fasting whole-blood nglucose concentration that exceeds 120 mg/dL (7 mmol/L). In the absence of nsymptoms, the physician must confirm these results on a different day. Most nchildren with diabetes detected because of symptoms have a blood glucose level nof at least 250 mg/dL (14 mmol/L).

Blood glucose tests using capillary blood samples, nreagent sticks, and blood glucose meters are the usual methods for monitoring nday-to-day diabetes control.

Glycated Hemoglobin

Glycosylated hemoglobin derivatives (HbA1a, HbA1b, HbA1c) nare the result of a nonenzymatic reaction between glucose and hemoglobin. A nstrong correlation exists between average blood glucose concentrations over a8- to 10-week period and the proportion of glycated hemoglobin. The percentage nof HbA1c is more commonly measured. (Measurement of HbA1c levels is the best nmethod for medium-term to long-term diabetic control monitoring.)

An international expert committee composed of appointed nrepresentatives of the American Diabetes Association, the European Associatiofor the Study of Diabetes, and others recommended HbA1c assay for diagnosing ndiabetes mellitus. The committee recommended that an HbA1c level of 6.5% or nhigher be considered indicative of diabetes, with diagnostic confirmation being nprovided through repeat testing (unless clinical symptoms are present and the nglucose level is >200 mg/dL). Glucose measurement should remain the choice nfor diagnosing pregnant women or be used if HbA1c assay is unavailable. The ncommittee cited the following advantages of HbA1c testing over glucose nmeasurement:

·                                 nCaptures long-term glucose exposure

·                                 nHas less biologic variability

·                                 nDoes not require fasting or timed nsamples

·                                 nIs currently used to guide management ndecisions

The Diabetes Control and Complications Trial (DCCT) found nthat patients with HbA1c levels of around 7% had the best outcomes relative to nlong-term complications. Most clinicians aim for HbA1c values of 7-9%. Values nof less than 7% are associated with an increased risk of severe hypoglycemia; nvalues of more than 9% carry an increased risk of long-term complications. The nInternational Society for Pediatric and Adolescent Diabetes (ISPAD) recommends na target level of 7.5% (58 mmol/mol) or less for all children.

Normal HbA1c values vary according to the laboratory method nused, but nondiabetic children generally have values in the low-normal range. nAt diagnosis, diabetic children unmistakably have results above the upper limit nof the reference range. Check HbA1c levels every 3 months.

Many different methods of measuring HbA1c are available, nand the variations between the different assays can be considerable and nunpredictable.

A working group was established in 1995 by the nInternational Federation of Clinical Chemists (IFCC) to find a better method of nstandardizing the various assays. This resulted in a global standard nthat is gradually being implemented. As a result, HbA1c will be reported as nmillimole per mole (mmol/mol) instead of as a percentage. The current target nrange of 7-9% is set to be replaced with values of 53-75 mmol/mol.

Microalbuminuria

Microalbuminuria is the first evidence of nephropathy. nThe exact definition varies slightly betweeations, but an increased AER is ncommonly defined as a ratio of first morning-void urinary albumin levels to ncreatinine levels that exceeds 10 mg/mmol, or as a timed, overnight AER of more nthan 20 mcg/min but less than 200 mcg/min. Early microalbuminuria may resolve. nGlomerular hyperfiltration occurs, as do abnormalities of the glomerular nbasement membrane and glomeruli. Regular urine screening for microalbuminuria nprovides opportunities for early identification and treatment to prevent renal nfailure.

Oral Glucose Tolerance Test

Although unnecessary in the diagnosis of type 1 diabetes nmellitus, an oral glucose tolerance test (OGTT) can exclude the diagnosis of ndiabetes when hyperglycemia or glycosuria are recognized in the absence of ntypical causes (eg, intercurrent illness, steroid therapy) or when the npatient’s condition includes renal glucosuria.

Obtain a fasting blood sugar level, then administer aoral glucose load (2 g/kg for children aged < 3 y, 1.75 g/kg for childreaged 3-10 y [max 50 g], or 75 g nfor children aged >10 y). Check the blood glucose concentration again after n2 hours. A fasting whole-blood glucose level higher than 120 mg/dL (6.7 mmol/L) nor a 2-hour value higher than 200 mg/dL (11 mmol/L) indicates diabetes. nHowever, mild elevations may not indicate diabetes when the patient has no nsymptoms and no diabetes-related antibodies.

A modified OGTT can also be used to identify cases of nMODY (which often present as type 1 diabetes) if, in addition to blood glucose nlevels, insulin or c-peptide (insulin precursor) levels are measured at nfasting, 30 minutes, and 2 hours. Individuals with type 1 diabetes mellitus cannot nproduce more than tiny amounts of insulin. People with MODY or type 2 diabetes nmellitus show variable and substantial insulin production in the presence of nhyperglycemia.

Approach Considerations

All children with type 1 diabetes mellitus require insulitherapy. The following are also required in treatment:

·                                 nBlood glucose testing strips

·                                 nUrine ketone testing tablets or strips

·                                 nBlood ketone testing strips

Strategies to help patients and their parents achieve the nbest possible glycemic management are crucial. A 2-year randomized clinical ntrial found that a practical, low-intensity behavioral intervention delivered nduring routine care improved glycemic outcomes.

A well-organized diabetes care team can provide all nnecessary instruction and support in an outpatient setting. The only immediate nrequirement is to train the child or family to check blood glucose levels, to nadminister insulin injections, and to recognize and treat hypoglycemia. The npatient and/or family should have 24-hour access to advice and know how to ncontact the team. Children should wear some form of medical identification, nsuch as a medic alert bracelet or necklace.

Awareness of hypoglycemia becomes impaired over time, and nsevere hypoglycemia can occur without warning. Hypoglycemia is more likely to naffect people who maintain low blood sugar levels and who already suffer nfrequent hypoglycemic attacks. Overzealous or inadequate treatment of nhypoglycemia can lead to serious consequences.

Failure to regularly examine for diabetic complications ipatients with type 1 diabetes mellitus, especially renal and ophthalmic ones, ncan be detrimental.

Inpatient care

Where a diabetes care team is available, admission is nusually required only for children with DKA. In addition, children with nsignificant dehydration, persistent vomiting, metabolic derangement, or serious nintercurrent illness require inpatient management and intravenous rehydration.

Diabetes in pregnancy

Pregnancies should be planned and carefully managed to nachieve healthy outcomes for mother and infant. Preconceptual normalization of nblood sugars and folic acid supplements (at least 5 mg/d) reduce the otherwise nincreased risk of congenital heart disease and neural tube defects. Blood sugar ncontrol during pregnancy must be strict to avoid hypoglycemia, which may damage nthe fetus, and persistent hyperglycemia, which leads to fetal gigantism, npremature delivery, and increased infant morbidity and mortality. DKA during npregnancy may result in fetal death.

Diet

Dietary management is an essential component of diabetes ncare. Diabetes is an energy metabolism disorder, and consequently, before ninsulin was discovered, children with diabetes were kept alive by a diet nseverely restricted in carbohydrate and energy intake. These measures led to a nlong tradition of strict carbohydrate control and unbalanced diets. Current ndietary management of diabetes emphasizes a healthy, balanced diet that is high nin carbohydrates and fiber and low in fat.

The following are among the most recent dietary consensus nrecommendations (although they should be viewed in the context of the patient’s nculture):

·                                 nCarbohydrates – Should provide 50-55% of ndaily energy intake; no more than 10% of carbohydrates should be from sucrose nor other refined carbohydrates

·                                 nFat – Should provide 30-35% of daily nenergy intake

·                                 nProtein – Should provide 10-15% of daily nenergy intake

The aim of dietary management is to balance the child’s nfood intake with insulin dose and activity and to keep blood glucose nconcentrations as close as possible to reference ranges, avoiding extremes of nhyperglycemia and hypoglycemia.

The ability to estimate the carbohydrate content of food n(carbohydrate counting) is particularly useful for children who receive nfast-acting insulin at mealtimes either by injection or insulin pump, as it nallows for a more precise matching of food and insulin. Adequate intake of ncomplex carbohydrates (eg, cereals) is important before bedtime to avoid nnocturnal hypoglycemia, especially for children getting twice-daily injections nof mixed insulin.

The dietitian should develop a diet plan for each child nto suit individual needs and circumstances. Regularly review and adjust the nplan to accommodate the patient’s growth and lifestyle changes.

Low-carbohydrate diets as a management option for diabetes ncontrol have regained popularity. Logic dictates that the lower the ncarbohydrate intake, the less insulin is required. No trials of nlow-carbohydrate diets in children with type 1 diabetes mellitus have beereported, and such diets cannot be recommended at the present.

Activity

Type 1 diabetes mellitus requires no restrictions oactivity; exercise has real benefits for a child with diabetes. Current nguidelines are increasingly sophisticated and allow children to compete at the nhighest levels in sports. Moreover, most children can adjust their insulidosage and diet to cope with all forms of exercise.

Children and their caretakers must be able to recognize nand treat symptoms of hypoglycemia. Hypoglycemia following exercise is most nlikely after prolonged exercise involving the legs, such as walking, running or ncycling. It may occur many hours after exercise has finished and even affect ninsulin requirements the following day. A large, presleep snack is advisable nfollowing intensive exercise.

Long-Term Monitoring

Regular outpatient review with a specialized diabetes nteam improves short- and long-term outcomes. Most teams have a nurse specialist nor educator, a dietitian, and a pediatrician with training in diabetes care. nOther members can include a psychologist, a social worker, and an exercise nspecialist. Involvement with the team is intense over the first few weeks after ndiagnosis while family members learn about diabetes management.

Conduct a structured examination and review at least once nannually to examine the patient for possible complications. Examination and nreview should include the following:

·                                 nGrowth assessment

·                                 nInjection site examination

·                                 nExamination of the hands, feet, and peripheral npulses for signs of limited joint mobility, peripheral neuropathy, and vascular ndisease

·                                 nEvaluation for signs of associated nautoimmune disease

·                                 nBlood pressure

In individuals aged 11 years or older, further nexamination should include the following:

·                                 nRetinoscopy or other retinal screening, nsuch as photography

·                                 nUrine examination for microalbuminuria

Medication Summary

Insulin is always required to treat type 1 diabetes nmellitus. Originally, all insulin was derived from the highly purified npancreatic extracts of pigs and cattle, and this form of insulin is still navailable. Human insulin was later manufactured using recombinant ndeoxyribonucleic acid (DNA) technology. “Designer” insulins are also nnow being produced; they are based on the human molecule and are tailored to nmeet specific pharmacologic targets, particularly duration of action. Insulimust be given parenterally, and this effectively means subcutaneous injection.

Alternatives to injecting insulin have been constantly nsought, including an inhaled form of insulin. Several products were idevelopment, and one (Exubera) was licensed for use but failed to generate nsufficient market penetration to justify continued production. The search for nalternatives continues, including oral sprays, sublingual lozenges, and ndelayed-absorption capsules.

Insulin has 4 basic formulations: ultra ̶ short-acting (eg, lispro, naspart, glulisine), traditional short-acting (eg, regular, soluble), medium- or nintermediate-acting (eg, isophane, lente, detemir), and long-acting (eg, nultralente, glargine).

Regular or soluble insulin is bound to either protamine n(eg, isophane) or zinc (eg, lente, ultralente) in order to prolong the duratioof action. Combinations of isophane and regular, lispro, or aspart insulins are nalso available in a limited number of concentrations that vary around the nworld, ranging from 25:75 mixtures (ie, 25% lispro, 90% isophane) to 50:50 nmixtures. The following image illustrates the activity profile of various ninsulins.

Representation of nactivity profile of some available insulins.

 

The development of insulin analogues has attempted to address some of the nshortcomings of traditional insulin. Insulins lispro, glulisine, and aspart nhave a more rapid onset of action and shorter duration, making them more nsuitable for bolusing at mealtimes and for short-term correction of nhyperglycemia. (See the graph below.) They are also more suitable for use with ninsulin pumps. An intermediate-acting insulin (detemir) has a similar profile nof action to isophane but is more pharmacologically predictable and is less nlikely to cause weight gain, whereas glargine has a relatively flat profile of naction, lasting some 18-26 hours. Despite their apparent advantages over ntraditional insulins, no evidence suggests a long-term advantage of the nanalogue insulins in terms of metabolic control or complication rates.

Representatioof activity profile of some available insulins.

 

The FDA issued an early ncommunication to health care practitioners regarding 4 published observational nstudies that described the possible association of insulin glargine (Lantus) nwith an increased risk of cancer.Insulin glargine is a long-acting humainsulin analogue approved for once-daily dosing.

The observational studies nevaluated large patient databases, and all reported some association betweeinsulin glargine and other insulin products with various types of cancer. The nduration of the observational studies was shorter than that which is considered nnecessary to evaluate for drug-related cancers. Additionally, findings were ninconsistent within and across the studies, and patient characteristics ndiffered across treatment groups. These issues raised further questions about nthe actual risk and, therefore, further evaluation is warranted.

The FDA states that patients nshould not stop taking their insulin without consulting their physician. Aongoing review by the FDA will continue to update the medical community and nconsumers with additional information as it emerges. Statements from the nAmerican Diabetes Association and the European Association for the Study of nDiabetes called the findings conflicting and inconclusive and cautioned against noverreaction.

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

·                                 nTwice-daily combinations of short- and nintermediate-acting insulin.

·                                 nMultiple injection regimens using nonce-daily or twice-daily injections of long-acting or intermediate-acting ninsulin and short-acting insulins given at each meal

·                                 nA combination of the above 2 regimens, nwith a morning injection of mixed insulin, an afternoon premeal injection of nshort-acting insulin and an evening injection of intermediate- or long-acting ninsulin

·                                 nContinuous subcutaneous insulin infusio(CSII) using an insulin pump

Although controlled clinical ntrials suggest improved short-term metabolic control in children using multiple ninjections or CSII, international comparisons do not support any particular ninsulin regimen, and all have their advantages and disadvantages.

A wide variety of ninsulin-injection devices are available, including a simple syringe and needle, nsemiautomatic pen injector devices, and needle-free jet injectors. Increasing nnumbers of young people use insulin pumps to deliver continuous subcutaneous ninsulin, with bolus doses at meal times.

When prescribing, tailor the ninsulin dose to the individual child’s needs. For instance, if using a ntwice-daily regimen, then, as a rule of thumb, prepubertal children require nbetween 0.5 and 1 U/kg/d, with between 60-70% administered in the morning and n30-40% in the evening. Insulin resistance is a feature of puberty, and some nadolescents may require as much as 2 U/kg/d. About one third of the nadministered insulin is a short-acting formulation and the remainder is a nmedium- to long-acting formulation. Basal bolus regimens have a higher nproportion of short-acting insulin. Typically, 50% of the total daily dose is ngiven as long- or intermediate-acting insulin. CSII uses only short-acting ninsulins, most often the analogues lispro or aspart. Typically, they also have naround 50% of the insulin given at a basal rate; the remainder is given as nfood-related boluses.

ntidiabetic Agents

Class Summary

These agents are used for the treatment of type 1 ndiabetes mellitus, as well as for type 2 diabetes mellitus that is unresponsive nto treatment with diet and/or oral hypoglycemics.

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Insulin detemir (Levemir)

 

This agent is indicated for daily or twice-daily nsubcutaneous administration for adults and pediatric patients with type 1 ndiabetes mellitus; it is also indicated for adults with type 2 diabetes nmellitus who require long-acting basal insulin for hyperglycemic control. The nduration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). nProlonged action is a result of the slow systemic absorption of detemir nmolecules from the injection site.

Insulin detemir’s primary activity is regulation of nglucose metabolism. It binds to insulin receptors and lowers blood glucose by nfacilitating cellular uptake of glucose into skeletal muscle and fat. The drug nalso inhibits glucose output from the liver. It inhibits lipolysis iadipocytes, inhibits proteolysis, and enhances protein synthesis.

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Insulin lispro (Humalog)

 

Onset of action for insulin lispro is 10-30 minutes, peak nactivity is 1-2 hours, and duration of action is 2-4 hours.

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Regular insulin (Humulin R, Novolin R)

 

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

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Insulin NPH (Humulin N, Novolin N)

 

Onset of action is 3-4 hours, peak effect is in 8-14 hours, nand usual duration of action is 16-24 hours.

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Insulin aspart (NovoLog)

 

Onset of action is 10-30 minutes, peak activity is 1-2 nhours, and duration of action is 3-6 hours. Insulin aspart is homologous with nregular human insulin, with the exception of the single substitution of the namino acid proline with aspartic acid in position B28. The drug is produced by nrecombinant DNA technology. Insulin lowers blood glucose levels by stimulating nperipheral glucose uptake, especially by skeletal muscle and fat, and by ninhibiting hepatic glucose production. It inhibits lipolysis in the adipocyte, ninhibits proteolysis, and enhances protein synthesis. Insulin is the principal nhormone required for proper glucose use iormal metabolic processes.

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Insulin glargine (Lantus)

 

This is a long-acting insulin analogue. Its typical onset nof action is 1-2 hours, and its duration is 20-26 hours.

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Insulin glulisine (Apidra)

 

Insulin glulisine is a human insulin analog produced by nrecombinant DNA technology using a nonpathogenic laboratory strain of nEscherichia coli (K12). It differs from human insulin by replacement of nasparagine at the B3 position with lysine, and the replacement of lysine at the nB29 position with glutamic acid. Insulin regulates glucose metabolism by nstimulating peripheral glucose uptake by skeletal muscle and fat, and inhibits nhepatic glucose production.

Glucose lowering with insulin glulisine is equipotent to nthat of regular human insulin when it is administered intravenously. After nsubcutaneous administration, insulin glulisine has a more rapid onset and a nshorter duration of action than does regular human insulin. It is useful for nthe regulation of mealtime blood glucose elevation.

 

Pediatric nType 2 Diabetes Mellitus

Practice Essentials

Although type 2 diabetes is widely diagnosed in adults, nits frequency has markedly increased in the pediatric age group since the end nof the 20th century. Most pediatric patients with type 2 diabetes belong to nminority communities.

Essential update: Antipsychotics nincrease risk of type 2 diabetes in children and young adults

In a retrospective cohort study of more than 43,000 nindividuals, study participants who were prescribed antipsychotics were nsignificantly more likely to develop type 2 diabetes within the first year of nuse compared with matched controls who were not prescribed these medications. nThe risk increased with higher medication doses and remained elevated for up to n1 year after the medications were discontinued. The association betweeantipsychotic use and type 2 diabetes remained highly significant when only nparticipants younger than 18 years were assessed.

The study included 28,858 first-time users of antipsychotic nmedications and 14,429 matched control individuals who had recently initiated nuse of a psychotropic other than an antipsychotic, all from the Tennessee nMedicaid program. All participants were 6 to 24 years of age. Antipsychotics nused included risperidone, quetiapine, aripiprazole, and olanzapine. nMedications used by the control group included mood stabilizers such as nlithium, as well as antidepressants, psychostimulants, α-agonists, and nbenzodiazepines.

A total of106 study subjects receiving antipsychotics nwere diagnosed and treated for type 2 diabetes (mean age, 16.7 years; 63% ngirls), translating into 18.9 cases per 10,000 person-years. Antipsychotic nusers had a 3-fold increased risk of developing type 2 diabetes by the end of nthe study compared with the group of nonusers. This risk was significant withithe first year of follow-up.

Signs and symptoms

Distinguishing between type 1 and type 2 diabetes at ndiagnosis is important. Typical characteristics of type 2 diabetes include the nfollowing:

·                                 nSlow and insidious onset

·                                 nMost common in overweight or obese npatients from a minority group (Native Americans, blacks, and Pacific nIslanders)

·                                 nSigns of insulin resistance

·                                 nStrong family history of type 2 ndiabetes: Familial lifestyle risk factors leading to obesity may be present, as nmay a family history of cardiovascular disease or metabolic syndrome

Physical findings may include the following:

·                                 nObesity (strongly associated with type 2 in children and adolescents)

·                                 nAcanthosis nigricans

·                                 nPolycystic ovary syndrome

·                                 nHypertension

·                                 nRetinopathy

See Clinical Presentation for more detail.

Diagnosis

Testing for type 2 diabetes should be considered when a npatient is overweight and has any 2 of the following :

·                                 nFamily history of type 2 diabetes ifirst-degree or second-degree relative

·                                 nMinority race or ethnicity (eg, AmericaIndian, black, Hispanic, Asian or Pacific Islander)

·                                 nSigns of insulin resistance or conditions nassociated with insulin resistance (eg, acanthosis nigricans, hypertensiodyslipidemia, PCOS)

Recommendations for screening are as follows:

·                                 nInitial screening may begin at age 10 nyears or at onset of puberty if puberty occurs at a young age

·                                 nScreening should be performed every 2 nyears

·                                 nA fasting plasma glucose test is the npreferred screening study; if clinical suspicion is high but fasting blood nglucose is normal (< 100 mg/dL), an oral glucose tolerance test should be nconsidered

Glucose values may be interpreted as follows:

·                                 nA random plasma glucose concentration of n200 mg/dL or greater in association with polyuria, polydipsia, or unexplained nweight loss is diagnostic of diabetes

·                                 nIn an asymptomatic patient, a fasting nplasma glucose value of 126 mg/dL or greater or a 2-hour plasma glucose value nof 200 mg/dL or greater during an oral glucose tolerance test is also ndiagnostic of diabetes

Other laboratory results that usually suggest type 2 ndiabetes are as follows:

·                                 nElevated fasting C-peptide level

·                                 nElevated fasting insulin level

·                                 nAbsence of autoimmune markers (glutamic nacid decarboxylase [GAD] and islet cell antibodies)

Testing for albuminuria can be done by means of 1 of the nfollowing 3 methods:

·                                 nMeasurement of the albumin-creatinine nratio in a random spot collection

·                                 nA 24-hour collection for albumin and ncreatinine determinations, which allows simultaneous measurement of creatinine nclearance

·                                 nTimed (eg, 4-hour or overnight) ncollection

Fasting lipid profiles should be obtained after stable glycemia nis achieved and every 2 years thereafter if normal. Optimal values for childrewith type 2 diabetes are as follows:

·                                 nTriglycerides < 150 mg/dL

·                                 nLow-density lipoprotein (LDL) < 100 nmg/dL

·                                 nHigh-density lipoprotein (HDL) >35 nmg/dL

See Workup for more detail.

Management

The goal of therapy is to achieve and maintain euglycemia nand near-normal hemoglobin A_1c (HbA_1c) levels (< 7%). More nspecifically, glycemic and nonglycemic goals may include the following:

·                                 nFasting glycemia of less than 126 mg/dL

·                                 nResolution of polyuria, nocturia, and npolydipsia

·                                 nHealthy body weight

·                                 nMaintenance of cardioprotective levels nof lipids and blood pressure (LDL level < 100 mg/dL, triglyceride < 150 nmg/dL, HDL level >35 mg/dL; blood pressure < 95th percentile for age, nsex, and height)

·                                 nParticipation of the whole family as a nunit

Treatments for pediatric type 2 diabetes include the nfollowing:

·                                 nDiabetes education and lifestyle changes n(diet, exercise, weight control)

·                                 nPharmacologic therapy with metformin, ninsulin, a sulfonylurea, or another hypoglycemic agent

·                                 nLipid-lowering agents and blood pressure nmedications to achieve cardioprotection, if necessary

To protect these patients from future cardiovascular ndisease, treatment should emphasize the following:

·                                 nImprovement of glycemia, dyslipidemia, nand hypertension

·                                 nWeight management

·                                 nPrevention of short- and long-term ncomplications

·                                 nBlood glucose monitoring 2-3 times daily n(more often when insulin treatment is being adjusted)

·                                 nEvaluation every 3 months at the ndiabetes clinic (more often, as necessary, when treatment is being adjusted)

HbA_1c values should be monitored at each nquarterly visit. HbA_1c testing has the following advantages over nglucose measurement:

·                                 nIt captures long-term glucose exposure

·                                 nIt has less biologic variability

·                                 nIt does not require fasting or timed nsamples

·                                 nIt is currently used to guide management ndecisions

Additional monitoring should be performed as follows:

·                                 nMicroalbuminuria and fasting lipid nprofile (annually)

·                                 nDilated eye examination (annually)

·                                 nBlood pressure evaluation and careful nneurologic examination (at each clinic visit)

In the past, type 2 diabetes mellitus was very rare in pediatric npatients. However, coinciding with the increasing prevalence of obesity among American children, the nincidence of type 2 diabetes in children and adolescents has markedly nincreased, to the extent that it now accounts for as many as one third of all nnew cases of diabetes diagnosed in adolescents. This trend is particularly npronounced in minority racial and ethnic groups. (See Epidemiology.)

Complications

Although the natural history of type 2 diabetes mellitus nin children is not well studied, the experience accumulated over years of ntreating adults may help to minimize the occurrence of complications ichildren. (See Prognosis and Clinical.)

Acute complications of type 2 diabetes include nhyperglycemia, diabetic ketoacidosis, hyperglycemic-hyperosmolar state, and nhypoglycemia. Complications from insulin resistance include hypertension, ndyslipidemia, and polycystic ovarian syndrome (PCOS).

As many as 4% of patients with type 2 diabetes initially npresent in a hyperglycemic-hyperosmolar coma, which can lead to cerebral edema nand death if not promptly recognized and treated.

Long-term complications of type 2 diabetes mellitus ninclude the following:

·                                 nNephropathy

·                                 nNeuropathy

·                                 nRetinopathy

·                                 nCoronary artery disease

A retrospective study found that adults diagnosed with ntype 2 diabetes before age 45 years have a much higher risk of cardiovascular ndisease relative to age-matched control subjects. The investigators concluded nthat early onset type 2 diabetes appears to be a more aggressive disease from a ncardiovascular standpoint. (See Prognosis, Clinical, and Treatment.) ⁿ

Etiology

In individuals without diabetes, approximately 50% of ntheir total daily insulin is secreted during basal periods to suppress nlipolysis, proteolysis, and glycogenolysis. In response to a meal, rapid insulisecretion (also called first-phase insulin secretion) ensues. This secretiofacilitates the peripheral use of the prandial nutrient load, suppresses nhepatic glucose production, and limits postprandial elevations in glucose nlevels. The second phase of insulin secretion follows and is sustained until nnormoglycemia is restored. A simplified scheme for the etiology of type 2 ndiabetes mellitus is shown in the image below.

Type 2 diabetes spans a continuum from impaired glucose ntolerance and impaired fasting glucose to frank diabetes that results from nprogressive deterioration of insulin secretion and action. Although the first nphase of insulin response is markedly reduced early in the course of the ndisease, ongoing disorganized basal insulin secretion associated with ndeterioration of peripheral insulin action occurs during the progression from nnormal to impaired glucose tolerance to frank diabetes.

In parallel, as a result of decreased insulin sensitivity nin the liver, endogenous glucose output increase adds to the already nhyperglycemic milieu, worsening peripheral insulin resistance and beta cell nfunction. Failure of the beta cell to keep up with the peripheral insuliresistance is the basis for the progression from impaired glucose tolerance to novert clinical type 2 diabetes. Longitudinal studies have demonstrated that nduring the transition betweeormal glucose tolerance to diabetes, 31% of a nperson’s insulin-mediated glucose disposal capacity, as well as 78% of his or nher acute insulin response, is lost.

The UK Prospective Diabetes Study found that beta cell nfunction was 50% of normal at the time of diagnosis of type 2 diabetes iadults. A case study of the progression of diabetes in an adolescent female nfound an almost 15% decline in beta cell function per year over the 6-year nduration of diabetes, with no substantial changes in insulin sensitivity. Further nprospective studies in young persons with type 2 diabetes are needed in order nto clarify the mechanism of disease in this population.

Risk factors

The major risk factors for type 2 diabetes in young npersons are as follows:

·                                 nObesity and inactivity, which are nimportant contributors to insulin resistance

·                                 nNative American, black, Hispanic, Asian, nor Pacific Islander descent

·                                 nFamily history of type 2 diabetes ifirst- and second-degree relatives

·                                 nAge of 12-16 years, the mean age range nof onset of type 2 diabetes in youths – These ages coincide with the relative ninsulin resistance that occurs during pubertal development

·                                 nLow birth weight and high birth weight

·                                 nMaternal gestational diabetes or type 2 ndiabetes

·                                 nNot breastfed during infancy

Epidemiology

Occurrence in the United States

Although type 2 diabetes is widely diagnosed in adults, nits frequency has markedly increased in the pediatric age group since the end nof the 20th century. Depending on the population studied, type 2 diabetes now nrepresents 8-45% of all new cases of diabetes reported among children and nadolescents. Most pediatric patients with type 2 diabetes belong to minority ncommunities.

The SEARCH for Diabetes in Youth Study (a US multicenter, nobservational study conducting population-based ascertainment of cases of ndiabetes mellitus in individuals over age 20 y) found that the incidence of ntype 2 diabetes was highest among American Indians aged 15-19 years (49.4 cases nper 100,000 person-years). Second and third highest incidence belonged to nAsian-Pacific Islanders and blacks, aged 15-19 years, with 22.7 cases per n100,000 person-years and 19.4 cases per 100,000 person-years, respectively.

International occurrence

An increased prevalence of type 2 diabetes has also beerecognized in countries other than the United States, including Japan, where nthe incidence of type 2 diabetes in school children after 1981 was found to be nstrongly related to an increasing prevalence of obesity. Studies among the nIndian, British, Chinese, Taiwanese, Libyan, Bangladeshi, Australian, and Maori npopulations also have shown increasing incidence of youth-onset type 2 ndiabetes.

Race-, sex-, and age-related demographics

Type 2 diabetes primarily affects minority populations. nFrom 1967-1976 to 1987-1996, the prevalence of type 2 diabetes increased 6-fold nin Pima Indian adolescents and appeared for the first time in children and nadolescents younger than age 15 years. Similar increases in prevalence were nobserved among Japanese, Asian-American, and black children. In several clinics nacross the United States, pediatric patients with a diagnosis of type 2 ndiabetes were from minority ethnic groups (black, Asian, and Hispanic groups).

The prevalence of type 2 diabetes in the pediatric npopulation is higher among girls than boys, just as the prevalence is higher namong adult females than it is in adult males.

The mean age range of onset of type 2 diabetes is 12-16 nyears; this period coincides with puberty, when a physiologic state of insuliresistance develops. In this physiologic state, type 2 diabetes develops only nif inadequate beta cell function is associated with other risk factors (eg, nobesity).

Prognosis

After 30 years of postpubertal diabetes, 44.4% of people nwith type 2 diabetes and 20.2% of people with type 1 diabetes develop diabetic nnephropathy. Overall, the incidence of nephropathy has declined among patients nwith type 1 diabetes since the end of the 20th century; however, it has not for npersons with type 2 diabetes.

So far, no population-based follow-up study has beeconducted to determine the long-term prognosis of type 2 diabetes among nchildren and adolescents. Mortality rates and standardized mortality ratios itype 2 diabetes are likely higher than those in type 1 diabetes, given that the nmajor cause of death in type 1 diabetes is end-stage renal disease.

Morbidity and mortality

Overall, morbidity and mortality associated with type 2 ndiabetes are related to short-term and long-term complications. A longitudinal, npopulation-based study conducted from 1965-2002 in the Arizona Pima nIndian population found that youth-onset type 2 diabetes is associated with nsubstantially increased incidence of end-stage renal disease and mortality imiddle age.

In a comparative study among Japanese youths with type 1 nand type 2 diabetes, the cumulative incidence of nephropathy among patients nwith type 2 diabetes was higher than it was in those with type 1 diabetes. nNephropathy also appeared earlier in type 2 diabetes than it did in type 1 diabetes.

The SEARCH for Diabetes in Youth Study found that nAmerican youth with type 2 diabetes have a higher prevalence of elevated nalbumin-to-creatinine ratio (ACR) than do young persons with type 1 diabetes. nThe study also found that high blood pressure, hyperglycemia, and high ntriglyceride concentrations are associated with elevated ACR, independent of nthe type of diabetes. Albuminuria is a risk factor for renal failure ipediatric type 2 diabetics. Youth with type 2 diabetes are at a fourfold nincreased risk of renal failure compared to pediatric patients with type 1 ndiabetes.

Among the Pima Indians of Arizona, the risk of nretinopathy is lower in patients with youth-onset type 2 diabetes than in those nwith adult-onset diabetes.

Patient Education

Education is an essential component of the treatment plain type 2 diabetes; it is a continuing process involving the child, family, and nall members of the diabetes team. The following strategies may be used:

·                                 nAppropriate teaching of survival skills nat diagnosis

·                                 nExplanation and discussion about the npossible causes of type 2 diabetes

·                                 nDiscussion about the need for blood glucose monitoring and the importance nof compliance with the drug regimen

Practical skills training includes the following:

·                                 nInsulin injections (if insulin is part nof the treatment plan)

·                                 nBlood and/or urine testing for ketone nbodies

·                                 nHypoglycemia recognition and treatment

·                                 nEmergency telephone contact procedure

·                                 nPsychosocial adjustment to the diagnosis

·                                 nImportance of regular follow-up

·                                 nBasic dietary advice

Diabetes education is an ongoing process and should naddress the following issues:

·                                 nFormal education during clinic visits or nduring diabetes classes

·                                 nEducational holidays and camps

·                                 nSupport groups

·                                 nComplications – Use times of crisis or nacute complications as opportunities to reinforce the importance of some naspects of self ̶ diabetes nmanagement that may have beeeglected

Educate the patient about the potential side effects of noral hypoglycemic agents (eg, the presence of ketonuria or of any conditiopredisposing to the accumulation of lactate in patients on metformin).

With regard to the patient’s sexual health, provide nadvice about contraception, genital hygiene, sexually transmitted diseases, and nfungal infections. In pregnant patients with type 2 diabetes, emphasize the nimportance of good glycemic control before and during pregnancy and discuss the neffect of maternal diabetes on the fetus.

History

At the time of diagnosis, determining whether a patient nhas type 1 or type 2 diabetes is important, because patients with type 1 ndiabetes are totally dependent on exogenous insulin administration for nsurvival, whereas patients with type 2 diabetes do not necessarily require nexogenous insulin to survive.

Because of the increasing prevalence of obesity in the npediatric population, the percentage of immune-mediated diabetes in overweight nor obese patients is increasing, rendering the distinction between type 1 and ntype 2 diabetes difficult at times. Blood glucose monitoring is required nregardless of the type of diabetes, and treatment with insulin should be nstarted when indicated.

The onset of type 2 diabetes is usually slow and insidious; nit most often occurs in overweight or obese patients from a minority group n(Native Americans, blacks, and Pacific Islanders). Patients with type 2 ndiabetes often have signs of insulin resistance, such as hypertension, PCOS, or nacanthosis nigricans.

A strong family history of type 2 diabetes is usually nreported among affected youth. The families of adolescents with type 2 diabetes noften have lifestyle risk factors leading to obesity. In addition, childrewith type 2 diabetes are more likely to report a family history of ncardiovascular disease and/or metabolic syndrome.

Type 1 diabetes occurs in people of all races; its onset nis typically acute and severe. Patients with type 1 diabetes are often lean and ndo not show manifestations of insulin resistance.

Physical Examination

Obesity is strongly associated with type 2 diabetes ichildren and adolescents. Eighty-five percent of children with type 2 diabetes nare either overweight or obese (defined as at or above the 85th percentile of the nsex-specific body mass index [BMI] for age-based growth charts).

Acanthosis nigricans, a marker of insulin resistance, is na velvety, hyperpigmented thickening of the skin; it is frequently seen on the nnape of the neck and in intertriginous areas; it is found in as many as 90% of nchildren with type 2 diabetes.

PCOS is a reproductive disorder commonly seen in young nwomen with acanthosis nigricans. It is characterized by hyperandrogenism and nchronic anovulation. The role of insulin resistance in the etiology of PCOS has nbeen extensively studied, and medications that decrease insulin resistance nand/or hyperinsulinemia in women with this syndrome often attenuate the nhyperandrogenism and metabolic abnormalities.

Hypertension may occur in children with ntype 2 diabetes. The risk of macrovascular and microvascular diabetic ncomplications is positively associated with elevated systolic blood pressure.

Ophthalmologic examination should be performed at or nshortly after diagnosis to detect incipient retinopathy.

Diagnostic Considerations

Conditions to consider in the differential diagnosis of ntype 2 diabetes include the following:

·                                 nAtypical diabetes mellitus (ADM)

·                                 nMaturity-onset diabetes of the young n(MODY)

·                                 nDiabetes secondary to mutations imitochondrial deoxyribonucleic acid (DNA)

·                                 nGenetic defects of the beta cell

·                                 nGenetic defects in insulin action

·                                 nDiseases of the exocrine pancreas

·                                 nEndocrinopathies

·                                 nDrug- or chemical-induced diabetes

Differential Diagnoses

·                                 nDiabetes Mellitus, Type 1

·                                 nDiabetic Ketoacidosis

Approach Considerations

According to criteria established by the AmericaDiabetes Association, testing for type 2 diabetes should be considered when a npatient is overweight (eg, body mass index [BMI] at the 85th percentile for age nand sex, weight at the 85th percentile, weight 120% of ideal for height) and nany 2 of the following factors exist :

·                                 nFamily history of type 2 diabetes ifirst-degree or second-degree relative

·                                 nMinority race or ethnicity (eg, AmericaIndian, black, Hispanic, Asian or Pacific Islander)

·                                 nSigns of insulin resistance or nconditions associated with insulin resistance (eg, acanthosis nigricans, nhypertension dyslipidemia, PCOS)

Recommendations for screening are as follows:

·                                 nInitial screening may begin at age 10 nyears or at onset of puberty if puberty occurs at a young age

·                                 nScreening should be performed every 2 nyears.

·                                 nA fasting plasma glucose test is the npreferred screening study

In children who do not meet the criteria described above nbut in whom diabetes is highly suspected, clinical judgment should be applied. nIf clinical suspicion for diabetes is high but a fasting blood glucose level is nnormal (< 100 mg/dL), an oral glucose tolerance test should be considered as na more sensitive screening tool.

Because the onset of type 2 diabetes frequently precedes nthe diagnosis by several years, testing for end-organ effects of the disease is nimportant. In addition, perform dilated eye examination for retinopathy shortly nafter diagnosis and yearly thereafter.

Plasma Glucose and Other Tests

A random plasma glucose concentration of 200 mg/dL or ngreater in association with polyuria, polydipsia, or unexplained weight loss is ndiagnostic of diabetes.

In an asymptomatic patient, a fasting (ie, no caloric nintake for at least 8 h) plasma glucose value of 126 mg/dL or greater or a 2-hour nplasma glucose value of 200 mg/dL or greater during an oral glucose tolerance ntest is also diagnostic of diabetes.

Fasting C-peptide and insulin levels are usually elevated nin type 2 diabetes. Autoimmune markers (glutamic acid decarboxylase [GAD] and islet ncell antibodies) are usually negative in type 2 diabetes but are frequently npresent in type 1 diabetes.

Evaluation for Diabetic Nephropathy

Microalbuminuria is said to be present if urinary albumiexcretion is 30 mg/24 h (equivalent to 20 µg/min with a timed specimen or 30 mg nof albumin per gram creatinine with a random sample). Testing for albuminuria ncan be performed using 1 of 3 methods, as follows:

·                                 nMeasurement of the ACR in a random spot ncollection

·                                 nA 24–hour collection for albumin and creatinine ndeterminations, which allows for simultaneous measurement of creatinine nclearance

·                                 nTimed (eg, 4-h or overnight) collection

Evaluation for Dyslipidemia

Obtain fasting lipid profile after stable glycemia has nbeen achieved and every 2 years thereafter if normal. Optimal lipid levels for nchildren with type 2 diabetes are as follows:

·                                 nTriglycerides optimal level – Less tha150 mg/dL

·                                 nLow-density lipoprotein (LDL) optimal nlevel – Less than 100 mg/dL

·                                 nHigh-density lipoprotein (HDL) optimal nlevel – More than 35 mg/dL

Approach Considerations

Ideally, management of diabetes should involve a npediatric endocrinologist, a diabetes nurse educator, a nutritionist, and a nbehavioral specialist.

In January 2013, the American Academy of Pediatrics (AAP) nissued clinical practice guidelines on the management of type 2 diabetes ichildren and adolescents. The guidelines recommend insulin treatment in all npatients who present with ketosis or extremely high blood glucose levels nbecause it may not be clear initially whether these patients have type 2 or ntype 1 diabetes. Once a diagnosis of type 2 diabetes is confirmed, lifestyle nmodification and metformin treatment should be initiated.

The goal of therapy is to achieve and maintaieuglycemia, as well as near-normal hemoglobin A_1c (HbA_1c) nlevels (≤7%). Patients who are not ill at diagnosis can be treated ninitially with lifestyle changes (eg, diet, exercise, weight control). However, nbecause few patients can maintain euglycemia with lifestyle changes alone, most nchildren and adolescents require medication. ⁿ

Hemoglobin A1c (HbA_1c) levels should be nmeasured every 3 months and treatment adjusted if goals for both HbA_1c nand blood glucose are not met. Fingerstick self-glucose monitoring is nrecommended for all patients receiving insulin or sulfonylureas, those starting nor changing therapy, and those who have not met treatment goals or who have nintercurrent illness.

Insulin therapy is indicated in symptomatic patients with npersistent hyperglycemia, the presence of an HbA1c of more than 9%, or nketoacidosis. After blood glucose levels are normalized, efforts to taper ninsulin with progressive substitution of an oral agent are undertaken.

Glycemic and nonglycemic goals should be clearly stated nand may include the following:

·                                 nFasting glycemia of less than 126 mg/dL

·                                 nResolution of polyuria, nocturia, and npolydipsia

·                                 nHealthy body weight

·                                 nMaintenance of cardioprotective levels nof lipids and blood pressure – Ie, LDL level of less than 100 mg/dL, ntriglyceride level of less than 150 mg/dL, HDL level of greater than 35 mg/dL, nblood pressure of less than the 95th percentile for age, sex, and height

·                                 nParticipation of the whole family as a unit

Unless an acute complication (eg, recurrent hypoglycemia, npersistent ketosis, hyperglycemic hyperosmolar state) occurs or there is poor npatient compliance with treatment, type 2 diabetes is usually managed in aoutpatient setting.

Recognize that, in patients with PCOS who are receiving nmetformin, possible resumption of normal ovulation and menstrual cycles nincreases the risk of pregnancy. Transfer care to an obstetrician whepregnancy is established.

Diet

Referral to a nutritionist with experience in pediatric ndiabetes is necessary. Dietary recommendations should be culturally nappropriate, sensitive to family resources, and provided to all caregivers, nespecially those in charge of cooking the family’s meals.

The entire family should be encouraged to adopt healthier nlifestyle habits such as participation in daily exercise and decreasing the nintake of high-calorie, high-fat foods.

Activity

A study by Loimaala et al study showed that long-term nendurance and strength training resulted in improved metabolic control of type n2 diabetes compared with standard treatment. However, significant ncardiovascular risk reduction and conduit arterial elasticity did not improve.

Prevention

Because type 2 diabetes in children and adolescents is nstrongly associated with obesity and sedentary lifestyle, any interventiodesigned to increase physical activity and improve dietary habits should be nencouraged.

Pharmacologic Therapy

Pharmacologic therapy is indicated when the disease is nnot well controlled with diet and exercise. Metformin should be the first oral nagent used in children and teenagers with an HbA1c level of less than 9%. If nmetformin is unsuccessful as monotherapy, the addition of insulin, a nsulfonylurea, or another hypoglycemic agent may be appropriate.

Lipid-lowering agents, such as n3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase inhibitors n(statins), and blood pressure medications (ideally, angiotensin-converting nenzyme [ACE] inhibitors) should be used if lifestyle modifications are ninsufficient in achieving cardioprotective levels of lipids and blood pressure. nFor example, statins may be needed to treat hyperlipidemia patients with type 2 ndiabetes if their fasting LDL ̶ level goals are not met after 3-6 months of lifestyle nmodification. ACE inhibitors are the agents of choice to treat hypertension and nmicroalbuminuria.

Proposed Management Algorithm

Diabetes education is indicated, including lifestyle nchanges to achieve healthy weight goals. First-line therapy is metformin at n1000-2000 mg/d. Goals include a fasting glucose level goal of less than 126 nmg/dL and/or an HbA1c level of less than 7%.If goals in step 1 are achieved, ncontinue therapy.

If goals in step 1 not achieved after 3 months (fasting nglucose level >126 mg/dL or HbA1c level >7%), add 0.4-0.6 U/kg of 24-hour ninsulin at bedtime (Glargine or Levemir). If combination therapy is adequate, ncontinue therapy. If combination therapy is inadequate after 3 months, nintensify insulin therapy until the fasting plasma glucose level is less tha126 mg/dL and the HbA1c level is less than 7%.

Stroke Prevention

In 2010, the American Heart Association-American Stroke nAssociation released updated guidelines for the primary prevention of stroke. nSpecific recommendations for patients with diabetes are incorporated in these.

Hypertension

Regular blood pressure screening, lifestyle modification, nand drug therapy are recommended. A lower risk of stroke and cardiovascular nevents are seen when systolic blood pressure levels are less than 140 mm Hg and diastolic nblood pressure is less than 90mm Hg. In patients who have hypertension with diabetes nor renal disease, the blood pressure goal is less than 130/80 mm Hg.

Diabetes

Blood pressure control is recommended in type 1 and 2 ndiabetes. Hypertensives agents that are useful in the diabetic populatioinclude ACE inhibitors and angiotensin receptor blockers (ARBs). Treating nadults with diabetes with statin therapy, especially patients with other risk nfactors, is recommended, and monotherapy with fibrates may also be considered nto lower stroke risk. Taking aspirin is reasonable in patients who are at high ncardiovascular disease risk; however, the benefit of taking aspirin in diabetic npatients for the reduction of stroke risk has not been fully demonstrated.

Dyslipidemia

Treating patients with statins is recommended in patients nwith coronary heart disease or certain high-risk conditions, for the primary preventioof ischemic stroke. In addition to statin therapy, therapeutic lifestyle nchanges and LDL-cholesterol goals are recommended. Niacin may be used ipatients with low HDL cholesterol or elevated lipoprotein (a), but its efficacy nin preventing ischemic stroke is not established.

Fibric-acid derivatives, niacin, bile acid sequestrants, nand ezetimibe may be useful in patients who have not achieved target LDL levels nwith statin therapy or who cannot tolerate statins. However, their neffectiveness in reducing the risk of stroke has not been established.

Diet

A diet that is low in sodium and high in potassium is nrecommended to reduce blood pressure. Diets that promote the consumption of nfruits, vegetables, and low-fat dairy products, such as the DASH (Dietary nApproaches to Stop Hypertension)-style diet, help to lower blood pressure and nmay lower risk of stroke.

Physical activity

Increasing physical activity is associated with a nreduction in the risk of stroke. The goal is to engage in at least 30 minutes of nmoderate intensity activity on a daily basis.

Long-Term Monitoring

Prevention and treatment of hyperlipidemia and nhypertension in individuals with type 2 diabetes are necessary in order to nprotect these patients from future cardiovascular disease. (The risk for nvascular complications and cardiovascular mortality in patients with diabetes nmellitus is increased by poor glucose control.) Treatment of type 2 diabetes nshould target the improvement of glycemia, dyslipidemia, and hypertension, as nwell as weight management and the prevention of short- and long-term ncomplications. Blood sugar monitoring should be performed 2-3 times daily, and nmore often than this when insulin treatment is being adjusted.

The patient should be seen every 3 months at the diabetes nclinic, and more often, as necessary, when treatment is being adjusted.

Hemoglobin monitoring

HbA_1c values should be monitored at each nquarterly visit. An international expert committee composed of appointed nrepresentatives of the American Diabetes Association, the European Associatiofor the Study of Diabetes, and others, recommended HbA_1c assay for nthe diagnosis of diabetes mellitus ionpregnant adults. The committee’s nrecommendation to diagnose diabetes is an HbA_1c level of 6.5% or nhigher, with confirmation from repeat testing (unless clinical symptoms are npresent and the glucose level is >200 mg/dL). Glucose measurement should nremain the choice for diagnosing pregnant women or should be used if HbA_1c nassay is unavailable. The committee listed the following advantages of HbA_1c ntesting over glucose measurement:

·                                 nCaptures long-term glucose exposure

·                                 nHas less biologic variability

·                                 nDoes not require fasting or timed nsamples

·                                 nIs currently used to guide management ndecisions

Additional concerns

Additional monitoring should be performed as follows:

·                                 nMicroalbuminuria and fasting lipid nprofile – Should be checked yearly

·                                 nDilated eye examination – Should be done nannually

·                                 nBlood pressure evaluation and careful neurologic n- Should be performed at each clinic visit

Weight loss, increased physical activity, and better food nchoices should be encouraged because they improve fasting lipid profile. Growth nassessment is important.

Medication Summary

In general, the treatment of type 2 diabetes in childrefollows the same rationale as does treatment for the disease in adults. The nsafety and efficacy of oral hypoglycemic therapy in children and adolescents nwith type 2 diabetes have not been established; however, physicians have nprescribed drugs typically used in adults to treat children and adolescents. nAmong all of the drugs currently in use to treat type 2 diabetes in adults, the nUS Food and Drug Administration (FDA) has approved only metformin and insulifor use in children.

The FDA has issued an early communication to health care npractitioners regarding 4 published observational studies that describe the npossible association of insulin glargine (Lantus) with an increased risk of ncancer. Insulin glargine is a long-acting human insulin analogue approved for nonce-daily dosing.

The observational studies evaluated large patient ndatabases, and all reported some association between insulin glargine and other ninsulin products with various types of cancer. The duration of the nobservational studies was shorter than that which is considered necessary to nevaluate for drug-related cancers. Additionally, findings were inconsistent nwithin and across the studies, and patient characteristics differed across ntreatment groups. These issues raise further questions about the actual risk of nusing insulin glargine and, therefore, concerns about the drug warrant further nevaluation.

The FDA states that patients should not stop taking ninsulin without consulting their physician. An ongoing review by the FDA will ncontinue to update the medical community and consumers with additional ninformation as it emerges. Statements from the American Diabetes Associatioand the European Association for the Study of Diabetes called the findings nconflicting and inconclusive and cautioned against overreaction.

Biguanides

Class Summary

These agents reduce hepatic glucose production; they also nincrease peripheral insulin sensitivity. Metformin rarely induces hypoglycemia. nBecause of its anorexigenic effects, many treated children maintain or lose nweight. Since metformin can lead to ovulatory cycles and resumption of regular nmenses in patients with PCOS, appropriate counseling should be provided to nsexually active adolescents.

Kooy et al found improved body weight, glycemic control, nand insulin requirements when metformin was added to insulin in type 2 diabetes nmellitus. No improvement of an aggregate of microvascular and macrovascular nmorbidity and mortality was observed; however, risk reduction of macrovascular ndisease was evident after a follow-up period of 4.3 years. Because of these nsustained beneficial effects, the policy to continue metformin treatment after nthe introduction of insulin in type 2 diabetes mellitus should be followed nunless contraindicated.

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Metformin (Glucophage, Glumetza, Riomet, Fortamet)

 

Metformin use frequently results in weight loss and mild nimprovement of all aspects of the lipid profile. It cannot be used in renal or nhepatic insufficiency or decompensated congestive heart failure requiring npharmacologic therapy (due to an increased risk for lactic acidosis).

Metformin can be used as monotherapy or with nsulfonylureas, glitazones, or insulin. It reduces hepatic glucose output, may ndecrease intestinal absorption of glucose, and may increase glucose uptake iperipheral tissues. It is a major drug used in obese patients with type 2 ndiabetes.

Because of adverse gastrointestinal (GI) effects from nmetformin, titrate the drug slowly and have patients take the medication during n(rather than before) meals. Many patients tolerate metformin best if it is administered nin the middle or at the end of the meal. The drug is available iimmediate-release (IR) or extended-release (ER) form. Only the IR form has beeapproved for children.

Sulfonylureas

Class Summary

These agents promote insulin release from the pancreas.

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Chlorpropamide

 

Chlorpropamide may increase insulin secretion from npancreatic beta cells.

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Glipizide (Glucotrol, Glucotrol XL)

 

Glipizide is a second-generation sulfonylurea that nstimulates the release of insulin from pancreatic beta cells.

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Glyburide (DiaBeta, Glynase, PresTab)

 

Glyburide is a second-generation sulfonylurea. It may be started nat a high dose in patients with severe hyperglycemia and in those with nsymptoms, if home glucose monitoring and close follow-up can be arranged.

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Tolbutamide

 

Tolbutamide increases insulin secretion from pancreatic nbeta cells.

Meglitinides

Class Summary

These agents promote short-term insulin secretion from nthe pancreas and are designed to be taken immediately before meals.

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Repaglinide (Prandin)

 

Stimulates insulin release from pancreatic beta cells.

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Nateglinide (Starlix)

 

Nateglinide is an amino acid derivative that stimulates ninsulin secretion from the pancreas (within 20 minutes of oral administration), nwhich, in turn, reduces blood glucose levels. The drug’s action depends ofunctional beta cells in pancreatic islets. Nateglinide interacts with the nadenosine triphosphate (ATP) ̶ sensitive potassium channel on pancreatic beta cells.

Alpha-glucosidase inhibitors

Class Summary

These agents lower postprandial glucose by slowing glucose nabsorption and delaying the hydrolysis of ingested complex carbohydrates and ndisaccharide. They must be taken immediately before meals.

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Acarbose (Precose)

 

Acarbose delays the hydrolysis of ingested complex ncarbohydrates and disaccharides and the absorption of glucose. It inhibits the nmetabolism of sucrose to glucose and fructose.

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Miglitol (Glyset)

 

Miglitol delays glucose absorption in the small intestine nand lowers postprandial hyperglycemia.

Thiazolinediones (glitazones)

Class Summary

The first of this class, troglitazone, was removed from nthe US market due to fatal hepatic necrosis. Rosiglitazone is an antidiabetic nagent (thiazolidinedione derivative) that improves glycemic control by nenhancing insulin sensitivity. The drug is a potent, highly selective agonist nfor the peroxisome proliferator-activated receptor-gamma (PPAR-gamma). nActivation of PPAR-gamma receptors regulates insulin-responsive gene ntranscription involved in glucose production, transport, and use, thereby nreducing blood glucose concentrations and reducing hyperinsulinemia. Potent nPPAR-gamma agonists have been shown to increase the incidence of edema.

A meta-analysis reported an increased risk of myocardial ninfarction and heart-related death in patients treated with rosiglitazone. The nreport prompted the FDA to issue an alert on May 21, 2007, to patients and nhealthcare professionals, enjoining patients to discuss the issue with their nphysician in order to make individualized decisions regarding their care. A nlarge-scale phase IV trial specifically designed to study cardiovascular noutcomes of rosiglitazone is under way. Whether this warning also applies to the nother thiazolidinediones (eg, pioglitazone) is unknown.

As of September 2010, the FDA was requiring a restricted naccess program to be developed for rosiglitazone under a risk evaluation and nmitigation strategy (REMS). Patients currently taking rosiglitazone and nbenefiting from the drug will be able to continue if they choose to do so. nRosiglitazone will only be available to new patients if they are unable to nachieve glucose control on other medications and are unable to take npioglitazone, the only other thiazolidinedione.

Results from the RECORD (Rosiglitazone Evaluated for nCardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes) ntrial indicated that the use of rosiglitazone for type 2 diabetes mellitus nincreases the risk of heart failure. In the study, cardiovascular outcomes were nassessed after adding rosiglitazone to metformin or sulfonylurea regimens for ntype 2 diabetes mellitus. The study was a multicenter, open-label trial that nincluded 4447 patients with mean HbA1c of 7.9%. Follow-up of the 2 combinations ntook place over 5-7 years.

No difference was observed between the 2 groups for ncardiovascular death, myocardial infarction, and stroke; 61 patients who nreceived rosiglitazone experienced heart failure that caused either hospital nadmission or death compared with 29 patients in the active control group.

Noncardiovascular adverse effects in the study included nincreased upper and distal lower limb fracture rates, particularly in women. At n5 years, mean HbA1c was lower in the rosiglitazone group compared with the nactive control group. In addition to finding that the use of rosiglitazone for ntype 2 diabetes mellitus increases the risk of heart failure, the study found nthat the drug increases the risk for select fractures, particularly in women.

For more information, see the FDA’s Safety Alert on Avandia. nThe online meta-analysis is titled ” Effect of Rosiglitazone on the Risk of Myocardial nInfarction and Death from Cardiovascular Causes. ” nAdditionally, responses to the controversy can be viewed at the Heartwire news n(theheart.org nfrom WebMD) including the following articles:

·                                 n” Rosiglitazone increases MI and CV death imeta-analysis. “

·                                 n” The rosiglitazone aftermath: Legitimate concerns or nhype? “

·                                 n” RECORD interim analysis of rosiglitazone safety: No nclear-cut answers. “

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Rosiglitazone (Avandia)

 

Rosiglitazone is available only via a restricted access nprogram. It is an insulin sensitizer with a major effect in the stimulation of nglucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulilevels and is used to treat type 2 diabetes associated with insulin resistance.^{[49, n50]}

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Pioglitazone (Actos)

 

Pioglitazone improves target cell response to insuliwithout increasing insulin secretion from the pancreas. It decreases hepatic nglucose output and increases insulin-dependent glucose use in skeletal muscle nand, possibly, in liver and adipose tissue.

Glucagon-like Peptide-1 (GlP-1) Receptor Agonists

Class Summary

Exenatide enhances glucose-dependent insulin secretion by nthe pancreatic beta-cell, suppresses inappropriately elevated glucagosecretion, and slows gastric emptying.

Exenatide (Byetta)

 

Exenatide is an incretin mimetic agent that mimics nglucose-dependent insulin secretion and several other antihyperglycemic actions nof incretins. It improves glycemic control in patients with type 2 diabetes nmellitus by enhancing glucose-dependent insulin secretion by pancreatic beta ncells. It also suppresses inappropriately elevated glucagon secretion and slows ngastric emptying. The drug’s 39–amino acid sequence partially overlaps that of nthe human incretin, glucagonlike peptide-1. Exenatide is indicated as nadjunctive therapy to improve glycemic control in patients with type 2 diabetes nwho are taking metformin or a sulfonylurea but who have not achieved glycemic ncontrol.

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Liraglutide (Victoza)

 

Liraglutide is an incretin mimetic agent that elicits glucagonlike npeptide-1 (GLP-1) receptor agonist activity. It activates the GLP-1 receptor by nstimulating G-protein in pancreatic beta cells. Liraglutide increases nintracellular cyclic adenosine monophosphate (AMP), leading to insulin release nin the presence of elevated glucose concentrations. It is indicated as aadjunct to diet and exercise to improve glycemic control in adults with type 2 ndiabetes. The drug has not been studied in combination with insulin.

Amylin analogue

Class Summary

This agent is a synthetic analogue of human amylin, a nnaturally occurring hormone made in pancreatic beta cells. It slows gastric nemptying, suppresses postprandial glucagon secretion, and regulates food intake nthrough centrally mediated appetite modulation. It is indicated to treat type 1 nand type 2 diabetes in combination with insulin. This agent is administered nbefore mealtime for patients who have not achieved desired glucose control ndespite optimal insulin therapy. It helps to achieve lower blood glucose levels nafter meals, less fluctuation of blood glucose levels during the day, and nimprovement of long-term control of glucose levels (ie, HbA_1C nlevels), compared with insulin alone. Less insulin use and a reduction in body nweight are also observed.

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Pramlintide (Symlin)

 

Pramlintide is a synthetic analogue of human amylin, a nnaturally occurring hormone made in pancreatic beta cells. It slows gastric nemptying, suppresses postprandial glucagon secretion, and regulates food intake nthrough centrally mediated appetite modulation. The drug is indicated to treat ntype 1 and type 2 diabetes in combination with insulin. It is administered nbefore mealtime for patients who have not achieved desired glucose control ndespite optimal insulin therapy. Pramlintide helps to achieve lower blood nglucose levels after meals, less fluctuation of blood glucose levels during the nday, and improvement of long-term control of glucose levels (ie, HbA1C levels), ncompared with insulin alone. Less insulin use and a reduction in body weight nare also observed.

Dipeptidyl peptidase IV (DPP-4) inhibitors

Class Summary

These agents block the action of DDP-4, which is known to ndegrade incretin. DDP-4 inhibitors have not yet gained FDA approval for use ichildren.

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Linagliptin (Tradjenta)

 

Linagliptin increases and prolongs incretin hormone nactivity, which is inactivated by the DPP-4 enzyme. It is indicated, along with ndiet and exercise, for adults with type 2 diabetes mellitus, to lower blood nsugar. Linagliptin may be used as monotherapy or in combination with other ncommon antidiabetic medications, including metformin, sulfonylurea, and npioglitazone. It has not been studied in combination with insulin.

Sitagliptin (Januvia)

 

Sitagliptin blocks the enzyme DPP-4, which is known to ndegrade incretin hormones. It increases concentrations of active intact nincretin hormones (GLP-1, GIP). The hormones stimulate insulin release iresponse to increased blood glucose levels following meals. This actioenhances glycemic control. Sitagliptin is indicated for type 2 diabetes as nmonotherapy or is combined with metformin or with a PPAR-gamma agonist (eg, nthiazolidinediones).

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Saxagliptin (Onglyza)

 

Saxagliptin blocks DPP-4, which is known to degrade nincretin hormones, increasing concentrations of active intact incretin hormones n(GLP-1 and GIP). The hormones stimulate insulin release in response to nincreased blood glucose levels following meals. This action enhances glycemic ncontrol. Saxagliptin is indicated as an adjunct to diet and exercise to improve nglycemic control in adults with type 2 diabetes.

 

References

 

Basic:

1.     nNelson Textbook of Pediatrics, 19th Edition. – nExpert Consult Premium Edition – Enhanced Online Features and Print / by Robert nM. Kliegman, MD, Bonita M.D. Stanton, MD, Joseph St. Geme, Nina Schor, MD, PhD nand Richard E. Behrman, MD. – 2011. – 2680 p.

2.     Pediatrics n/ Edited by O.V. Tiazhka, T.V. Pochinok, A.M. Antoshkina/ – Vinnytsa: Nova nKnyha Publishers, 2011. – 584 p.

3.     Charles nG. D. Brook, Mehul T. Dattani. Handbook nof Clinical Pediatric Endocrinology, n2012.

4.     nFima nLifshitz. Pediatric Endocrinology, Fifth Edition, Volume One: Obesity, Diabetes Mellitus, nInsulin Resistance, and Hypoglycemia, 2006.

 

Additional:

5.     nSally nRadovick, Margaret H. MacGillivray. Pediatric Endocrinology: A Practical nClinical Guide, 2003.

6.     nDennis M. Styne. nPediatric Endocrinology, 2004.

7.     nCharles G. D. Brook, Peter Clayton, nRosalind Brown. Brook’s Clinical Pediatric Endocrinology, 2005.