Type 1  Diabetes Mellitus (DM)

• Occurs in children usually between 7-15 years old, but may present at any age

Immune-mediated

• Caused by absolute deficiency of insulin secretion due to autoimmune destruction of pancreatic islet beta cells
• Both genetic susceptibility & environmental factors contribute to the pathogenesis of this type
• Associated w/ other autoimmune diseases (eg Graves’ disease, thyroiditis, celiac disease, multiple sclerosis & Addison’s disease)

Idiopathic

• Manifests as alternating episodic ketoacidosis & insulin deficiency
• No β-cell autoimmunity & human leukocyte antigen (HLA) association present
• Treatment w/ Insulin replacement is flexible

Diagnosis

• Clinical presentation can vary from polyuria, polydipsia, polyphagia, weight loss to severe dehydration, shock & diabetic ketoacidosis (DKA)
• Most important clue is an inappropriate polyuria in any child w/ dehydration, poor weight, or “the flu”
• Hyperglycemia, glycosuria, ketonemia & ketonuria occurs w/ the classic symptoms
• Can be diagnosed if polyuria, polydipsia, polyphagia, weight loss are present & fasting plasma glucose (FPG) concentration is ≥126 mg/dL (7.0 mmol/L) &/or random plasma glucose is ≥200 mg/dL (11.1 mmol/L)
• Once hyperglycemia is confirmed, evaluate for presence of DKA & manage accordingly

Type 2  Diabetes Mellitus (DM)

• Patients who have insulin resistance & relative insulin deficiency
• Many causes including genetic defects
• Aggravated by environmental factors (eg low physical activity or hypercaloric lipid-rich diet)
• Insulin treatment is not usually needed until disease progresses
• Usually seen in obese children, not insulin dependent & infrequently develop ketosis
• History of polyuria & polydipsia is relatively uncommon
• When DKA occurs, it is associated w/ the stress of another illness eg severe infection & may resolve when the stressful illness resolves
• Most patients remain asymptomatic for month to year as symptoms of hyperglycemia are not as dramatic as the polyuria & weight loss accompanying Type 1 DM
• Often seek medical care because of excessive weight gain & fatigue as a result of insulin resistance &/or incidental finding of glycosuria during routine physical exam
• Prolonged hyperglycemia may be accompanied, in time, by microvascular & macrovascular complications

Screening guidelines adapted from the American Diabetes Association 2016

• Age of 10 years or at onset of puberty if puberty occurs at a younger age
• Overweight, defined by body mass index (BMI) >85th percentile for age & gender, weight for age >85th percentile, or weight >120% of ideal for height plus any 2 of the following risk factors:
  • Family history of Type 2 DM in 1st- or 2nd-degree relative
  • Race/ethnicity (Native American, Asian American, Black, Hispanic, or Asian/Pacific Islander)
  • Signs of insulin resistance or conditions associated w/ insulin resistance [eg acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome (PCOS), or small-for-gestational-age birth weight]
  • Maternal DM/gestational DM
• Frequency of testing: every 3 years
• FPG is recommended as the primary screening test for Type 2 DM because of decreased cost & greater convenience
• 2-hour oral glucose tolerance test (OGTT) is recommended as a secondary test
• Clinical judgment should be used to test for Type 2 DM in high-risk patients who do not meet these guidelines

Diagnosis

• Can be diagnosed if polyuria, polydipsia, polyphagia, wt loss are present & FPG concentration is ≥126 mg/dL (7.0 mmol/L) &/or casual plasma glucose is ≥200 mg/dL (11.1 mmol/L)
• Clinical manifestations of Type 2 DM:
  • Obese (BMI >95th percentile for age & gender) or overweight (BMI ≥85th-94th percentile for age & gender)
  • Normal - elevated C-peptide & insulin levels
  • Absence of autoantibodies to insulin, islet cell, &/or glutamic acid decarboxylase
  • Signs of insulin resistance
    • Acanthosis nigricans
    • Dyslipidemia
    • Hypertension
    • PCOS

Other Specific Types of Diabetes Mellitus (DM)

Diabetes secondary to genetic defects of beta-cell function

• Neonatal DM
  • Hyperglycemia that occurs in the first 6 months of life
  • Insulin is required for initial treatment
  • May be transient w/o recurrence, transient w/ recurrence after 7-20 years or permanent

Transient Neonatal DM

• Onset in the 1st week of life & persists for several weeks to months before spontaneous resolution
• Occurs most often in infants who are small for gestational age
• Characterized by hyperglycemia & pronounced glycosuria, resulting in severe dehydration & sometimes, metabolic acidosis but w/ minimal or no ketonemia or ketonuria
• Insulin responses to glucose or Tolbutamide are low to absent; basal plasma insulin concentrations are normal
  • After spontaneous recovery, the insulin responses to these same stimuli are brisk & normal, implying a functional delay in beta-cell maturation w/ spontaneous resolution
• Occurrence of the syndrome in consecutive siblings has been reported
• Abnormalities of chromosome 6 are common in transient neonatal DM
• Administration of insulin is mandatory during the active phase of neonatal DM
  • 1-2 U/kg/day of an intermediate-acting insulin in 2 divided doses results in dramatic improvement, accelerated growth & weight gain
  • May attempt reducing the dose as soon as recurrent hypoglycemia manifests

Permanent Neonatal DM

• DM in the newborn period may be permanent if associated w/ pancreatic agenesis
• Studies revealed that almost one-half of neonatal DM patients had permanent diabetes, one third had transient diabetes & about one fourth had transient diabetes that recurred when they were 7-20 years old
• Affected twin & families w/ >1 affected infant have been reported
• May initially present as euglycemic & w/in the 1st month of life

• Maturity-onset diabetes of the young (MODY)
  • A primary defect in insulin secretion characterized by early onset between 9 & 25 years of age, absence of ketosis & autosomal dominant inheritance
  • Should be considered if:
    • Diagnosed w/ diabetes in the first 6 months of life
    • Family members w/ type 2 DM but w/ uncommon presentation
    • Mild fasting hyperglycemia (100-150 mg/dL or 5.5-8.5 mmol/L) but young & nonobese
    • Absent diabetes-associated autoantibodies & w/ atypical presentation of type 2 DM
    • Some patients respond to diet therapy, exercise &/or oral antidiabetic agents; others may require insulin therapy
• Mitochondrial DNA mutation

Genetic defects in insulin action

• Type A insulin resistance
• Leprechaunism
• Rabson-Mendenhall syndrome
• Lipoatrophic diabetes

Exocrine pancreatic diseases

• Pancreatitis
• Pancreatic trauma that may require pancreatectomy
• Neoplasia
• Cystic fibrosis
• Hemochromatosis
• Fibrocalculous pancreatopathy
• Pancreatic resection

Endocrinopathies

• Acromegaly
• Cushing’s syndrome
• Glucagonoma
• Pheochromocytoma
• Hyperthyroidism
• Somatostatinoma
• Aldosteronoma

Uncommon forms of immune-mediated diabetes mellitus (DM)

• “Stiff-man” syndrome
• Anti-insulin receptor antibodies
• Autoimmune polyendocrine syndrome deficiencies I & II

Drug- or chemical-induced

• Glucocorticoids
• Thyroid hormones
• Diazoxide
• Beta-adrenergic agonists
• Nicotinic acid
• Thiazides
• Dilantin
• Alpha-interferon
• Pentamidine
• Rodenticide (eg Vacor)

Genetic syndromes

• Down syndrome
• Klinefelter’s syndrome
• Turner syndrome
• Wolfram syndrome
• Friedreich’s ataxia
• Huntington’s chorea
• Laurence-Moon-Biedl syndrome
• Myotonic dystrophy
• Porphyria
• Prader-Willi syndrome

Infections

• Congenital rubella
• Cytomegalovirus

Type 1 Diabetes Mellitus (DM) 

• Beta-cell destruction which leads to complete insulin deficiency
• May be immune-mediated or idiopathic
• Most common endocrine metabolic disorder of childhood & adolescence
• Occurs more commonly in children 7-15 years, but may occur at any age

Type 2 Diabetes Mellitus (DM)

• Patients who have insulin resistance & relative insulin deficiency
• Insulin treatment is not usually needed until disease progresses
• Many causes including genetic defects

Other specific types of Diabetes Mellitus (DM)

• Uncommon causes; underlying cause or disease is identified
• Eg genetic defects, drug use, pancreatic disease, chemical exposure, other diseases, etc

Neonatal Dibaetes Mellitus (DM)

• Hyperglycemia that occurs in the first 6 months of life
• Insulin is required for initial treatment
• May be transient w/o recurrence, transient w/ recurrence after 7-20 years or permanent

Should include but is not limited to the following: 

• Exclusion of secondary causes

Growth impairment

• Evaluate height & weight based on growth chart every clinic visit.
  • See Growth Charts in MIMS Pediatrics
• Monitor thyroid-stimualting hormone (TSH) levels at diagnosis, every 1-2 years & w/ occurrence of abnormal growth rate
• Evaluate for celiac disease w/ unsatisfactory weight gain

Diabetic ketoacidosis (DKA)

• Hyperglycemia, accumulation of ketone bodies & metabolic disease due to insulin deficiency
• Type 1 DM patients may initially present w/ DKA at diagnosis
  • Obtain capillary glucose in children w/ excessive thirst, polyuria, abrupt unexplained weight loss, excessive tiredness, reduced level of consciousness, N/V, abdominal pain, hyperventilation, & appears dehydrated
• May also be caused by missed Insulin doses
• Monitor venous pH, central venous & intra-arterial pressure
  • Mild DKA: Venous pH 7.2-7.3 & <15-18 mmoL/L bicarbonate
  • Moderate DKA: Venous pH 7.1-7.2 & <10-15 mmoL/L bicarbonate
  • Severe DKA: Venous pH <7.1 & <10 mmoL/L bicarbonate
• Monitor heart rate (HR), respiratory rate (RR), blood pressure (BP), neurologic status, fluid input & output, evidence of hyper- or hypokalemia
• Monitor capillary glucose hourly
• Perform laboratory tests on electrolytes, blood glucose & blood gases every 2-4 hours

Hypoglycemia

• Blood glucose <3.9 mmol/L (70 mg/dL) causing cognitive impairment
  • Cognitive impairment may be more pronounced in patients <5 years
• May occur more frequently in those w/ lower HbA_1C levels, history of hypoglycemia, use of high Insulin doses, younger children, male gender
• May be mild, moderate or severe
  • Mild hypoglycemia: Sweating, pallor, palpitations, tremors, mild symptoms of neutropenia
  • Moderate hypoglycemia: Aggressiveness, drowsiness, confusion associated w/ neuroglycopenia; autonomic symptoms
  • Severe hypoglycemia: Altered states of consciousness, coma, seizures
• Determine frequency of hypoglycemia every clinic visit
  • Assess for unawareness of hypoglycemia & assess blood glucose

Nephropathy

• Microalbuminuria is the primary manifestation of diabetic nephropathy
  • At the development of microalbuminuria, nephropathy may still be reversible
• Poor glycemic control, smoking, family history of essential hypertension & cardiovascular disease (CVD) are associated w/ the development of nephropathy
• Screen for microalbuminuria annually once the patient starts puberty or is ≥10 years & had DM for 5 years
  • More frequent testing is indicated w/ increased values
• Confirmed elevated albumin-to-creatinine ratio (ACR) (>30 mg/g) consists of 2 out of 3 specimens obtained from separate days over a 6-months interval after treatment initiation for hypo/hyperglycemia & BP for age
  • Timed overnight or a 24-hours analysis w/ elevated albumin excretion rate (AER) of 20-199 mcg/minute may also be used
  • Exercise, smoking & menstruation may affect results, confirm on another day
• Obtain baseline estimated glomerular filtration rate (eGFR) measurement & repeat based on patient’s age, clinical status, duration of disease & treatment history
• Exclude non-DM related causes upon confirmation of diagnosis
• Monitor microalbumin excretion every 3-6 months

Hypertension

• Common comorbidity of DM
• Determine BP every clinic visit & evaluate for parental hypertension which is a major risk
  • ≥95th percentile of systolic or diastolic BP for age, gender & height percentile measured on at least 3 separate days is definitive of hypertension
  • “High-normal” BP is >90th but <95th percentile of systolic or diastolic BP for age, gender & height percentile measured on at least 3 separate days
• Exclude non-DM related causes upon confirmation of diagnosis
• Evaluate renal functional status by urinalysis, serum creatinine (Cr) & blood urea nitrogen (BUN)
• Obtain urinary albumin excretion if not obtained w/in previous 6 months

Dyslipidemia

• Elevated plasma lipid concentration, smoking, hypertension, obesity, family history of heart disease & DM contribute to the development of atherosclerosis
• Perform fasting lipid profile on >2 years prepubertal patients w/ Type 1 DM if w/ family history of hypercholesterolemia, CVD before 55 years
• Screen at puberty (≥10 years) if w/o mentioned family history
• Obtain fasting lipid profile in patients ≥10 years of age after glucose control has been achieved
• Repeat screening if low-density lipoprotein cholesterol (LDL-C) is borderline (100-129 mg/dL) or abnormal (≥130 mg/dL)

Retinopathy

• Has been reported w/ DM of 1-2 years duration
• Identify early & treat appropriately
• Hypertension, poor metabolic control, presence of albuminuria, dyslipidemia, smoking, longer duration of DM & pregnancy are associated w/ increased risk for retinopathy
• Refer patient to ophthalmologist w/ expertise in diabetic retinopathy & its risks in the pediatric patient
  • Schedule regular ophthalmological screening w/ initial exam when the patient is ≥10 years or post-puberty onset & had DM for 3-5 years & annually from then on
  • Patient planning pregnancy should have an ophthalmological exam prior to conception during the 1st trimester & at the recommendation of the ophthalmologist

Neuropathy

• Initial foot examination at the beginning of puberty & at least annually for protective sensation, pulses, skin integrity & treatable nail problems (eg ingrown toenails)
• Comprehensive foot exam should include inspection, dorsalis pedis & posterior tibial pulse palpation, patellar/ Achilles tendon reflex testing, & proprioception/vibration/monofilament sensation assessment

Thyroid disease

• Most common autoimmune disorder in Type 1 DM patients
• May be euthyroid, hypothyroid or hyperthyroid
• Screen for autoimmune thyroid disease at diagnosis & recheck TSH levels every 1-2 years for patients w/ normal TSH or if growth rate is abnormal
  • See Growth Charts in MIMS Pediatrics
• Monitor for thyroid control after establishing metabolic control
• Measure thyroid autoantibodies & TSH
  • Identify patients at increased risk of autoimmune thyroid disease w/ the presence of thyroid autoantibodies [antithyroid peroxidase (APO), & antithyroglobulin (TG)]
  • Treat patients w/ elevated TSH levels
  • Measure free T4 if TSH is abnormal
  • Perform thyroid function test whenever thyroid dysfunction is suspected & if patient has thyromegaly
• Evaluate for hypothyroidism thoroughly & treat appropriately

Celiac disease

• Type 1 DM patients have high risk for celiac disease
  • Immune-mediated damage to the mucosa of the small intestine due to ingestion of food w/ gluten (eg wheat, rye, barley & oats)
• Symptoms include diarrhea, weight loss or poor wt gain, growth failure, abdominal pain, chronic fatigue, irritability, inability to concentrate, malnutrition due to malabsorption & other GI problems
• Symptoms of DM patient w/ celiac disease include unpredictable blood glucose levels, unexplained hypoglycemia & deterioration in glycemic control
• Screen for celiac disease by testing for the presence of IgA autoantibodies to tissue transglutaminase (tTG) or deaminated gliadin antibodies, or endomysial autoantibody (EMA) assay
  • Perform test upon diagnosis of type I DM & in children w/ 1st-degree relatives w/ celiac disease, growth failure, failure to gain weaight & gastroenterologic symptoms (diarrhea, flatulence, abdominal pain, signs of malabsorption), & those w/ frequent unexplained hypoglycemia or deteriorating glycemic control
  • Confirm elevated tTG antibodies
  • Interpret low to moderate tTG antibodies along w/ symptoms & repeat screening after 6-12 months
• Confirm positive Ab levels
  • Recommend small bowel biopsy if patient has elevated tTG antibodies
• Refer patient to gastroenterologist once celiac disease is confirmed
  • Recommend consultation w/ registered dietitian experienced w/ DM & celiac disease in pediatric patients
• Screen periodically in patients negative for celiac disease

Psychiatric disorders

• DM is a risk factor for psychiatric disorders (eg depression, generalized anxiety disorders) in adolescent patients
• An increasing number of adolescents newly diagnosed w/ DM considers suicide
• Screen patients ≥10 years annually for depression
• Screen for psychiatric disorders in patients w/ difficulties in achieving treatment goals & w/ recurrent DKA
  • Patients w/ DKA are more likely to develop psychiatric disorders

Eating disorders

• Associated w/ DM in adolescent patients
• Patients w/ eating disorders are at risk for poor metabolic control & recurrent hospitalization
• Mental health professional should screen for eating disorders w/ failure in treatment goals especially if patient is underweight

Early in the evaluation of a new patient w/ diabetes mellitus (DM), it is important to distinguish between Type 1 & Type 2 DM to optimize therapy

• Past &/or current DM characteristics including age of onset, diagnosis, management & treatment
• Previous or ongoing infection(s)
• Growth records
• Family history of DM & cardiovascular disease (CVD)
• History of DM-related complications
• Medications, nutritional status, eating patterns & exercise history
• Tobacco, alcohol use & drug history
• Sexual activity & contraceptive use
• Risk factors for atherosclerosis
• Glycosylated hemoglobin (HbA_1c) history
• History of hypoglycemia
• History of diabetic ketoacidosis (DKA)
• History of gestational diabetes or macrosomia
• History of other disorders (eg endocrine, eating & mood disorders)

• Height & weight, calculate body mass index (BMI), measure waist circumference
• Blood pressure (BP) measurement
• Hand & foot examination, & evaluation of pulses by palpation w/ auscultation
• Funduscopic, oral, abdominal examination
• Cardiac & thyroid examination
• Skin examination for acanthosis nigricans
• Neurological examination
• Evaluate signs of puberty/physical development

• If there is suspicion or any evidence of diabetes ketoacidosis (DKA), include:
  • Serum glucose
  • Electrolytes
  • Arterial or venous pH
  • Serum or urine ketones
• HbA_1c
•  Fasting lipid profile [total cholesterol, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) & triglycerides (TG)]
• Test for microalbuminuria
• Thyroid antibodies
• Liver function test
• Genetic testing - if presentation is atypical & w/ family history of monogenic diabetes

Diagnostic criteria for diabetes mellitus (DM) adapted from the American Diabetes Association 2016

Any of the following:

• HbA_1c >6.5% (48 mmol/mol)
• Done in a National Glycohemoglobin Standardization Program (NGSP)-certified method traceable to the Diabetes Control & Complications Trial (DCCT) reference assay
• Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L)
  • Fasting is defined as no caloric intake for at least 8 hours
• 2-hours plasma glucose of ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT)
  • Perform test as described by the World Health Organization (WHO), using a glucose load of 75 g anhydrous glucose dissolved in water or 1.75 g /kg body weight if weight is <40 lbs (18 kg)
  • OGTT is not recommended for routine clinical use, but may be required in the evaluation of patients when diabetes is still suspected despite a normal FPG
• Symptoms of polyuria, polydipsia & unexplained wt loss w/ random plasma glucose ≥200 mg/dL (11.1 mmol/L)
  • Random is defined as any time of day w/o regard to time since last meal

If typical hyperglycemic symptoms are not present, a repeat test should be done on a different day to confirm diagnosis

• Confirm diagnosis if FPG ≥126 mg/dL or 2-hours plasma glucose of ≥200 mg/dL or random glucose of ≥200 mg/ dL in high-risk patient screened for DM