I. Diabetes

A. Diagnosis of Diabetes Mellitus^{1, 2, 3}
Diagnostic criteria (must meet one of four):

1. 1. Symptoms of diabetes (polyuria, polydipsia, weight loss, frequent yeast infections) and random blood glucose (BG)≥200 mg/dL
2. 2. Fasting plasma glucose (FPG = no caloric intake for at least 8 hours)≥126 mg/dL
3. 3. Oral glucose tolerance test (OGTT) with a 2-hour postload plasma glucose of≥200 mg/dL
4. 4. Hemoglobin A_1c (HbA_1c)≥6.5% obtained via laboratory testing (POCT HbA₁c is nondiagnostic)

NOTE: In the absence of symptoms of hyperglycemia, FPG or OGTT should be repeated on another day.

B. Definition of Increased Risk (Prediabetes)

1. 1. FPG 100 to 125 mg/dL
2. 2. 2-hour post-OGTT BG 140 to 199 mg/dL
3. 3. HbA_1c 5.7% to 6.4%

C. Interpreting Hemoglobin A1c^1,2

1. 1. Estimates average BG for the past 3 months
2. 2. HbA_1c of 6% approximately equals an average BG of 130 mg/dL; each additional 1% ≈ 30 mg/dL more
3. 3. Unreliable in patients with abnormal red cell life span or morphology (e.g., sickle cell disease, spherocytosis)
4. 4. Although there are limited data supporting HbA_1C for diagnosing type 2 diabetes in children and adolescents, the American Diabetes Association continues to recommend HbA_1C for diagnosis of type 2 diabetes in this population.

D. Etiology: Distinguishing Between Types of Diabetes Mellitus^1,2

1. 1. Type 1 (T1DM) versus T2DM (most common types, polygenic; Table 10.1)
2. 2. Other forms of diabetes^4,5
   1. a. Monogenic diabetes: 1% to 2% of diabetes mellitus (DM). Due to single-gene mutations, typically relating to insulin production or release. Identifying gene can have clinical significance.
      1. (1) Suspect if autosomal dominant inheritance pattern of early-onset (<25 years) DM, insulin independence, absent T2DM phenotype (nonobese), or preservation of C-peptide
      2. (2) Many well-described subtypes; some, such as MODY1 and MODY3 (due to mutations in transcription factors for insulin production) responsive to treatment with sulfonylureas
   2. b. Neonatal diabetes (NDM): Defined as DM onset <6 months of age
      1. (1) Rare: 1:160,000 to 260,000 live births, typically a de novo mutation
      2. (2) May be transient (50% recur) or permanent
      3. (3) Subset respond to sulfonylureas
   3. c. Cystic fibrosis–related diabetes (CFRD): OGTT rather than HbA_1c is the recommended screening test.
   4. d. Other causes of DM: Diseases of exocrine pancreas due to pancreatitis, trauma, infection, invasive disease (e.g., hemochromatosis)

E. Screening for Type 2 Diabetes Mellitus^1,6

1. 1. Whom to screen: Children who are overweight (body mass index [BMI] >85th percentile) and have one or more of the following risk factors:
   1. a. Maternal history of diabetes or gestational diabetes mellitus during child’s gestation
   2. b. Family history of T2DM in a first- or second-degree relative
   3. c. Race/ethnicity: African American, Native American, Hispanic, Asian, or Pacific Islander
   4. d. Signs associated with insulin resistance (acanthosis nigricans, hypertension, dyslipidemia, polycystic ovarian syndrome, or small-for-gestational-age birth weight)
2. 2. How to screen: Fasting plasma glucose, OGTT, or HbA_1c
3. 3. When to screen: Begin at the age of 10 years or at the onset of puberty (whichever occurs first) and repeat at a minimum of every 3 years or more often if BMI is increasing.

F. Additional Testing in New-Onset Diabetes

1. 1. Diabetes autoantibodies^1,2 : Recommended for all children with suspected T2DM or whose diabetes type is unclear
   1. a. Includes islet cell autoantibodies (ICAs) and antibodies to GAD (GAD65), insulin, tyrosine phosphatases IA-2, IA-2β, and β-cell–specific zinc transporter 8 (ZnT8)
   2. b. Confirmation of diagnosis of T1DM if 2 or more antibodies are present, though about 5% of T1DM will not have measurable ICAs, and some children with T2DM will have measurable ICAs
2. 2. Screening for autoimmune diseases in T1DM ⁶ :
   1. a. Thyroid disease (present in 17% to 30% of patients with T1DM): Screen with TSH when clinically well and consider screening for thyroid antibodies. If TSH normal, recheck every 1 to 2 years or sooner if symptoms develop.
   2. b. Celiac disease (present in 1.6% to 16.4% of patients with T1DM): Screen with tissue transglutaminase (TTG) IgA antibody and total IgA. Repeat within 2 years of diabetes diagnosis and again after 5 years. Repeat more frequently if there are symptoms or a first-degree relative with celiac disease.

G. Management of Diabetes^{6, 7, 8}

1. 1. Diabetes medications FDA approved for children:
   1. a. Insulin: See ^{TABLE 10.2 TABLE 10.3} for calculations. Insulin doses are subsequently adjusted based on actual blood sugars.
   2. b. Metformin: FDA approved in children ≥10 years old with type 2 diabetes, though sometimes used off label in younger children. Main side effects are gastrointestinal (GI) and are often transient. Extended-release option is available for patients with GI side effects.
   3. c. Glucagon-like peptide 1 (GLP-1) agonists (currently only liraglutide and exenatide): FDA approved in children ≥ 10 years old with T2DM. Main side effects include GI effects, pancreatitis, and hypoglycemia. Avoid if there is a family history of medullary thyroid cancer or personal history of pancreatitis.
2. 2. T1DM management: The majority of children with T1DM should be treated with intensive insulin regimens via multiple daily injections, a continuous subcutaneous infusion via insulin pump, or an automated insulin delivery system.
3. 3. T2DM management:
   1. a. Lifestyle modification therapy (nutrition and physical activity) and metformin should be initiated at time of diagnosis.
   2. b. Insulin therapy should be initiated if distinction between T1DM and T2DM is unclear, when HbA_1c ≥8.5%, when random BG ≥250, in presence of diabetic ketoacidosis (DKA), or when patient with known T2DM is not meeting glycemic target with metformin and lifestyle modification alone. NOTE: If significant hyperglycemia (BG >600) or ketosis is present, patient should be evaluated for DKA or hyperosmolar hyperglycemic state
   3. c. Consider addition of GLP-1 agonist therapy if glycemic targets are not met with metformin alone, or combined therapy with metformin and insulin.
4. 4. Goals of therapy:
   1. a. HbA1c <7% (individualized to avoid excessive hypoglycemia)
   2. b. Assessment and management of complications: hypertension, dyslipidemia, nephropathy, retinopathy, neuropathy in all types of diabetes; additionally for obstructive sleep apnea, nonalcoholic fatty liver disease, and polycystic ovarian syndrome in type 2 diabetes
5. 5. Interdisciplinary care team should include mental health provider and medical nutrition therapy with initial education and annual update. Regularly assess for eating disorders, disease-related coping, depression, and psychosocial stressors impacting diabetes management.

H. Diabetes Management Devices⁹

1. 1. Technology is rapidly changing, but general principles are described below.
2. 2. Insulin pumps: Contain rapid-acting insulin only and provide basal and bolus insulin. Doses can be programmed to vary throughout the day. Settings consist of:
   1. a. Basal rate—continuous insulin infusion
   2. b. Carbohydrate coverage—insulin-to-carbohydrate ratio
   3. c. Hyperglycemia correction—based on correction factor and target blood glucose

NOTE: There is risk for DKA with interruptions in insulin delivery (e.g., pump malfunction) given lack of long-acting insulin.

1. 3. Continuous glucose monitors (CGMs): Measure glucose concentration in interstitial fluid continuously and provide alerts for high and low glucose levels.
2. 4. Automated insulin delivery systems: Use of continuous glucose monitor data and algorithms to automate insulin delivery to reduce hyperglycemia and hypoglycemia and increase time in target range.

I. Monitoring^{6,8, 9, 10}

1. 1. Glycemic control:
   1. a. Assessment of blood glucose using glucometer or CGM
      1. (1) Multiple times daily (e.g., before meals/snacks, at bedtime, prior to exercise, with symptoms of hypoglycemia, after treating for hypoglycemia, before driving)
      2. (2) CGM metrics over most recent 14 or more days: time in range (70–180 mg/dL), time below target (<70 and <54 mg/dL) and time above target (>180 mg/dL)
   2. b. HbA_1c every 3 months
2. 2. Urine ketones should be checked with persistent hyperglycemia, any illness (regardless of blood glucose level), or with nausea/vomiting.
3. 3. Associated conditions or complications: See Table 10.4.

J. Diabetic Emergencies^11,12

1. 1. Diabetic ketoacidosis (DKA)
   1. a. Definition: Hyperglycemia (or euglycemia in a patient with known diabetes), ketonemia, ketonuria, and metabolic acidosis (pH <7.30, bicarbonate <15 mEq/L)
   2. b. BG reflects hydration status, pH reflects DKA severity
   3. c. Symptoms: Nausea, emesis, abdominal pain, fruity breath, altered mental status, Kussmaul respirations
   4. d. Precipitating factors: New-onset DM, known diabetes with missed insulin doses, insulin pump/infusion site malfunction, or physiologic stress due to acute illness
   5. e. Management: See Fig. 10.1. Because the fluid and electrolyte requirements vary greatly from patient to patient, guidelines are only a starting point, and therapy must be individualized based on patient characteristics. NOTE: Initial insulin administration may cause transient worsening of the acidosis as potassium is driven into cells in exchange for hydrogen ions.
   6. f. Cerebral edema: Most severe complication of DKA. Overly aggressive hydration and rapid correction of hyperglycemia may play a role in its development. Risk factors include severe acidosis, evidence of renal insufficiency, young age and new onset, use of bicarbonate.
   7. g. Once DKA is resolved, transition to subcutaneous (SQ) insulin. See ^{TABLE 10.2 TABLE 10.3} for calculations or resume home insulin doses.
2. 2. Hyperosmolar hyperglycemic state (HHS)
   1. a. Definition: Extreme hyperglycemia (BG >600 mg/dL) and hyperosmolarity (>320 mOsm/kg), without significant ketosis or acidosis
   2. b. Characteristics: Gradually increasing polyuria and polydipsia leading to profound dehydration, altered consciousness
   3. c. Management:
      1. (1) Fluids: Fluids alone will decrease BG due to dilution, promotion of glucosuria, and increased glucose uptake with improved circulation. Fluid replacement should be more rapid than in DKA with goal of gradual decline in serum sodium (about 0.5 mEq/dL/hr) and osmolality. Bolus ≥20 cc/kg 0.9% saline and repeat until perfusion improved. Then start maintenance fluids plus deficit replacement over 24 to 48 hours using 0.45% to 0.75% saline (if perfusion inadequate, consider isotonic fluids). Urine output should also be replaced.
      2. (2) Insulin therapy: Start insulin (0.025 to 0.05 unit/kg/hr) when BG no longer declining at least 50 mg/dL/hr with fluids alone. Titrate insulin to decrease BG by 75 to 100 mg/dL/hr.
      3. (3) Electrolytes: Potassium, phosphate, and magnesium deficits greater than in DKA; monitor every 2 to 4 hours. Start potassium replacement with 40 mEq/L once K <5 mEq/L.