Diabetes Mellitus Type 1 in Children 

Elsevier Point of Care  ()Updated August 8, 2022. Copyright Elsevier BV. All rights reserved.

Synopsis

Urgent Action

• DKA and severe treatment-related hypoglycemia are life-threatening complications and must be treated emergently
• In any child with known diabetes who presents with altered mental status, check glucose level and correct any hypoglycemia immediately
• If patient is severely hyperglycemic, correct volume deficits, electrolyte abnormalities, and administer insulin
• Identify and treat any associated infections

Key Points

• Diabetes mellitus type 1 is a chronic metabolic disease characterized by hyperglycemia and absolute insulin deficiency secondary to destruction of pancreatic β-cells
• Type 1 diabetes accounts for most cases of diabetes diagnosed in childhood
• Children with type 1 diabetes typically present abruptly with severe hyperglycemia and/or in state of DKA
• Children typically have an elevated glucose level, varying degrees of acidosis, and positive pancreatic islet autoantibodies findings
• History and physical examination can suggest diabetes, but biochemical parameters are required for diabetes diagnosis; specific testing for pancreatic islet autoantibodies and C-peptide level can help differentiate diabetes type and confirm a diagnosis of type 1 disease
• Differential diagnosis for type 1 diabetes in children includes type 2 diabetes and monogenic diabetes; children with cystic fibrosis may also have an associated form of diabetes
• Initial treatment of severe hyperglycemia includes correction of fluid deficits and electrolyte abnormalities, insulin administration, dosing adjustments, and diabetes education
• Initial treatment of severe hypoglycemia includes administration of rapidly absorbed glucose (oral), glucagon (IM or intranasal), and/or IV glucose, depending on patient's ability to use oral route
• Comprehensive chronic management for children with type 1 diabetes includes intensive insulin therapy, glucose monitoring, age-appropriate diabetes education, lifestyle management including medical nutrition therapy, and ongoing assessment and treatment of associated comorbidities and complications
• Most common acute complication associated with type 1 diabetes is DKA; in children, this may be associated with cerebral edema—the most common cause of death
• Chronic complications associated with type 1 diabetes include cardiovascular disease, nephropathy, and retinopathy
• Type 1 diabetes is associated with increased risk of mortality in children and adolescents

Pitfalls

• Failure to consider diabetes in a child with new-onset enuresis, weight loss, or poor school performance can delay diagnosis, leading to ketoacidosis
• Failure to consider cerebral edema in a child with DKA and altered mental status may result in death
• Children with overweight or obesity are at risk for type 2 diabetes, but they can also develop type 1 diabetes

Terminology

Clinical Clarification

• Diabetes mellitus type 1 is a chronic metabolic disease characterized by hyperglycemia and absolute insulin deficiency secondary to destruction of pancreatic β-cells 1
• People with diabetes mellitus type 1 have complete, lifelong dependence on exogenous insulin to regulate blood glucose levels 1

Classification

• Immune-mediated diabetes 2
  • Caused by progressive cell-mediated autoimmune destruction of pancreatic β-cells
  • Accounts for most cases of type 1 diabetes mellitus, but only 5% to 10% of all cases of diabetes 2
  • Defined by presence of autoimmune markers, including autoantibodies to the following: GAD65 (glutamate decarboxylase 2), insulin, the tyrosine phosphatases IA-2 and IA-2β, and the zinc transporter protein ZnT8 (SLC30A8, a transporter related to insulin secretion)
• Idiopathic diabetes (type 1B) 2
  • Type 1 diabetes mellitus with nonimmune basis for pancreatic β-cell destruction
  • Permanent insulinopenia without immunologic evidence of β-cell autoimmunity or HLA association
  • Mainly occurs in patients with African or Asian ancestry, and accounts for a minority of patients with type 1 diabetes
• Stages 2 3
  • Stage 1: presymptomatic; normoglycemic in the presence of β-cell autoimmunity as evidenced by development of 2 or more type 1 diabetes–associated islet autoantibodies
  • Stage 2: presymptomatic; progresses to glucose intolerance or dysglycemia (impaired fasting glucose), also in the presence of β-cell autoimmunity
  • Stage 3: onset of symptomatic disease, as defined by standard criteria

Diagnosis

Clinical Presentation

History

• Patient typically presents abruptly with severe hyperglycemia and/or in state of DKA
  • Approximately 30% to 40% of children present with DKA; rates have increased over time 4 (Related: Diabetic Ketoacidosis)
• Most common presenting symptoms 5
  • Polyuria
  • Polydipsia
  • Nocturia
  • Polyphagia
  • Unexplained weight loss
• Less common symptoms at presentation
  • Nausea or vomiting
  • Abdominal pain
  • Fatigue
  • Blurred vision
• Commonly missed scenarios in children 5
  • Onset of enuresis in a previously toilet-trained child
  • Perineal candidiasis, especially in prepubertal girls
  • Chronic weight loss or failure to gain weight in a growing child
  • Irritability and deteriorating school performance
  • Recurrent skin infections
• Rarely, type 1 diabetes is discovered presymptomatically when metabolic abnormalities are mild (incidental glucosuria), but this is more likely to occur in adults 6

Physical examination

• Findings are unremarkable, except in severe hyperglycemia with DKA
  • Kussmaul respiration: high respiratory rate and large tidal volume of each breath
  • Altered mental status: disoriented, semicomatose, or rarely comatose
  • Signs of dehydration: orthostatic hypotension, tachycardia, and poor skin turgor
  • Fruity odor to the breath, caused by ketosis

Causes and Risk Factors

Causes

• Autoimmune (most common cause in childhood)
  • T cell–mediated autoimmune disease characterized by selective destruction of pancreatic β-cells
  • Islet cell antibodies, produced in response to an environmental trigger, destroy pancreatic β-cells in genetically susceptible persons
    • Although it is commonly held that signs of diabetes occur when more than 80% of β-cells are destroyed, some studies have concluded that this is often an overestimate and that even a 40% reduction is sufficient to produce symptoms in some persons 7
• Idiopathic
  • Pancreatic β-cell failure that occurs without autoimmune destruction

Risk factors and/or associations

Age

• Type 1 diabetes accounts for most cases of diabetes diagnosed in childhood 8
• Can occur at any age; up to 25% to 50% of people with type 1 diabetes present in adulthood 8

Sex

• Approximately equal distribution between males and females overall 9

Genetics

• Risk of type 1 diabetes is conferred by 2 susceptible haplotypes in the region of the HLA complex in the class II region 10
  • Specific HLA DR/DQ alleles associated with type 1 diabetes include DRB1*03:01-DQB1*02:01 (DR3/DQ2) or DRB1*04:01-DQB1*03:02 (DR4/DQ8) 11
  • While a large proportion of people with type 1 diabetes carry a susceptible haplotype, only a small proportion of people in the general population with this susceptible haplotype actually develop the disease
    • 40% to 50% of familial clustering in type 1 diabetes is due to the susceptible haplotype in the HLA complex 12
    • Remaining proportion of familial clustering caused by genetic susceptibility is associated with variations at numerous other loci (more than 50), each of which accounts for a modest impact on risk 13
• Familial clustering 9
  • Having a first-degree relative with type 1 diabetes carries a 5% lifetime risk of developing the disease, compared with a 0.3% risk in the general population 14
    • Monozygotic twins have a cumulative concordance rate of 65%, 15 whereas dizygotic twins have a concordance rate of 6% to 10% 9
    • Offspring of affected mothers have a 2% to 3% risk, whereas offspring of affected fathers have a 7% risk 9
• Neonatal (congenital) diabetes
  • Most sequence variants that cause diabetes in the first 6 months of life are dominantly inherited 2
  • The most common of such disease-associated variants involve the Kir6.2 subunit (KCNJ11) and SUR1 subunit (ABCC8) of the β-cell ATP-sensitive potassium channel 2
  • The second most common of such disease-associated variants are in INS, the insulin gene 2

Ethnicity/race

• Incidence and prevalence are highest in non-Hispanic White people 9 16
  • In the United States, incidence is increasing at greater rate in racial/ethnic minority youth compared with White populations 17
• Incidence is highest in Finland, Sardinia, Sweden, northern Europe, North America, and Australasia; lowest incidence is in East Asia and Southeast Asia 18
• Most patients with idiopathic (type 1B) diabetes are of Asian or African descent 2

Other risk factors/associations

• Clustering with other autoimmune disorders associated with genetic susceptibility 9
  • Thyroid disease
    • Autoimmune hypothyroidism occurs in approximately 15% to 30% of children and adolescents with type 1 diabetes 19
    • Hyperthyroidism is much less common (approximately 0.5% of children with type 1 diabetes), but it occurs at higher frequency than in the general population 20
  • Celiac disease
    • Symptoms include diarrhea, weight loss, abdominal pain, bloating, chronic fatigue, malnutrition due to malabsorption, and unexplained hypoglycemia or erratic blood glucose levels
    • Occurs more frequently in children or adolescents with type 1A diabetes mellitus (4%-9%) compared with the general population (0.3%-1%) 19
    • Autoantibodies indicative of celiac disease include IgA antitissue transglutaminase and antiendomysial antibodies
  • Autoimmune polyendocrine syndrome type 1 21 (OMIM #240300) 22
    • Autosomal dominant or recessive disorder caused by sequence variants in the AIRE gene (autoimmune regulator)
    • Type 1 diabetes occurs in 4% to 18% of cases 21
    • Syndrome also includes mucocutaneous candidiasis, hypoparathyroidism, and Addison disease
  • X-linked immunodysregulation, polyendocrinopathy, and enteropathy (OMIM #304790) 23
    • X-linked recessive disease caused by sequence variants in the FOXP3 gene (encoding forkhead box P3)
    • Affects only boys, and is characterized by severe neonatal autoimmunity that leads to death in infancy
  • Autoimmune polyendocrine syndrome type 2 21 (OMIM %269200) 24
    • Rare disorder of unknown molecular basis; susceptibility is linked to class II alleles within the major histocompatibility complex
    • Approximately 60% of patients with this syndrome develop type 1 diabetes 21
    • Clinical components, which also include Addison disease and autoimmune thyroid disease, most often evolve in the third decade of life, but they can present in childhood
• Recurrent viral respiratory tract infections during the first 6 months of life are associated with slightly increased risk 25
• Season of birth 26
  • Higher prevalence among those born in April through July
  • Lower prevalence among those born in November through February
• Birth size
  • Being born large for gestational age is a risk factor for type 1 diabetes; independent of maternal BMI and diabetes status 27
• Season of onset
  • Higher incidence of onset from late autumn through early spring compared with the rest of the year
• Vitamin D deficiency and insufficiency is common at onset of type 1 diabetes in children 28

Diagnostic Procedures

• History and physical examination can suggest diabetes, but biochemical parameters are required for a diagnosis of diabetes
• Laboratory confirmation of diabetes can be achieved with either of the following: 2
  • 2 diagnostic test results from among the following 3 tests, using the same or 2 different types of tests and the same or 2 different test samples:
    • Fasting plasma glucose level of 126 mg/dL or higher (no caloric intake for at least 8 hours before blood draw)
    • Hemoglobin A1C measurement of 6.5% or higher
    • 2-hour plasma glucose measurement of 200 mg/dL or higher during an oral glucose tolerance test (rarely used for patients with type 1 diabetes mellitus)
  • One random plasma glucose measurement of 200 mg/dL or higher when classic symptoms of hyperglycemia or hyperglycemic crisis are present
• Pancreatic islet autoantibodies and C-peptide levels are useful laboratory studies for determining diabetes type classification when there is uncertainty about type 1 status 2
• Initial diagnostic assessment of comorbidities at time of diagnosis 2
  • Measure blood pressure, fasting lipid panel, and urinary albumin excretion
  • American Diabetes Association provides complete lists of comprehensive medical evaluation components to cover at initial evaluation 29 30
• Additional baseline laboratory tests recommended at diagnosis to screen for associated diseases include: 29 30
  • Lipid panel (after glucose control has been established for those aged 2 years or older)
  • Liver function tests
  • Spot urinary albumin to creatinine ratio (at puberty or after age 10 years, whichever is earlier, and diabetes duration of 5 years)
  • Estimated GFR/creatinine clearance
  • TSH, antithyroid peroxidase, and antithyroglobulin antibodies (soon after diagnosis) 29
  • Celiac antibody panel (soon after diagnosis) 29
    • Obtain IgA tissue transglutaminase antibodies in patients with documented total serum IgA levels within reference range; obtain IgG to tissue transglutaminase and deamidated gliadin antibodies in IgA-deficient patients

Differential Diagnosis

Most common

• Type 2 diabetes mellitus (Related: Diabetes Mellitus Type 2 in Children)
  • Typical features include obesity, insulin resistance, and strong family history of type 2 diabetes
  • Patients exhibit marked insulin resistance or, alternatively, insulin needs resolve
  • Differentiated from type 1 diabetes on basis of clinical course and pancreatic islet autoantibodies
    • Clinical course of type 1 diabetes is characterized by ongoing, absolute insulin requirement that is lifelong, whereas insulin dependency in type 2 diabetes is absent or develops later
    • Positive pancreatic islet autoantibodies finding usually indicates type 1 diabetes 2
    • Initial diabetes diagnosis in children favors type 1 diabetes; type 2 diabetes is more likely after age 35 years 34
    • Lower BMI, unintentional weight loss, ketoacidosis, and severe hyperglycemia at presentation also favor type 1 diabetes 34
    • Type 2 diabetes most often responds to noninsulin antihyperglycemic agents early in the course of disease (eg, metformin, glyburide)
  • C-peptide levels are helpful for distinguishing type 1 from type 2 diabetes, but the measurement is most useful several months to a year after therapy begins, allowing for the resolution of any glucotoxicity
    • Most patients with type 1 diabetes have an undetectable or low C-peptide level 37
    • Fasting C-peptide level greater than 3 nanograms/mL after several months of therapy is highly suggestive of type 2 diabetes 39
• Monogenic diabetes mellitus 40
  • Set of disorders that cause β-cell dysfunction and impaired insulin secretion, with onset of hyperglycemia in youth 41
  • Prevalence of 1% to 2% in pediatric diabetes population 42
  • Consider in children with the following findings: 40
    • Diabetes diagnosed within the first 6 months of life 2
    • Strong family history of diabetes suggesting autosomal dominant inheritance 2
    • Mild fasting hyperglycemia (100-150 mg/dL [5.5-8.5 mmol/L]), especially if young and without obesity 40
    • Diabetes with negative autoantibodies results and without signs of obesity or insulin resistance 2
  • Differentiated from type 1 or type 2 diabetes with genetic testing
• Characteristics of types of primary diabetes in children and adolescents.

  Characteristic	Immune-mediated type 1 diabetes	Idiopathic type 1 diabetes	Monogenic diabetes	Type 2 diabetes
  Prevalence
  In children with diabetes (overall)	Most cases of type 1 diabetes in children, but 5% to 10% of all diabetes	10% or higher in African-American children	1% to 6%	Approximately 12%
  Ethnicity	All, white populations at highest risk (30%-60% lower in African-American populations)	African-American and Asian	All	All, minority groups at highest risk in North America
  Onset
  Typical age at onset in children	Throughout childhood and adolescence, but may occur into 8th or 9th decade of life	Pubertal	Typically younger than 35 years	Puberty (mean age, 13.5 years)
  Onset	Acute severe	Acute severe	Gradual	Insidious to severe
  DKA at onset	Approximately 32% in United States (up to 80% globally)	Episodic	Not typical	5% to 20%
  Heredity
  Affected relative	3% to 10%	More than 75%	50% to 90%	Up to 90%
  Inheritance	Polygenic	Autosomal dominant	Autosomal dominant	Polygenic
  HLA-DR3/4 association	Present	Absent	Absent	Absent
  Insulin status
  Insulin (C-peptide) secretion	Reduced or absent	Variably reduced	Variably reduced	Varies (up 85% impairment at time of diagnosis)
  Insulin sensitivity	Normal when controlled	Normal	Normal	Reduced
  Insulin dependence	Lifelong	Intermittent	Variable	Variable
  Associated features
  Islet autoantibodies	+ (80%-90%)	−	− (less than 1%)	− (less than 10%)
  Acanthosis nigricans	−	−	− (matches general population)	+ (86%)
  Obesity	− (matches general population)	+/− (varies by population)	− (uncommon)	+ (very common, more than 90%)

  Citation: Data from Chiang JL et al: Type 1 diabetes in children and adolescents: a position statement by the American Diabetes Association. Diabetes Care. 41(9):2026-44, 2018; American Diabetes Association: 2. Classification and diagnosis of diabetes: Standards of Medical Care in Diabetes--2022. Diabetes Care. 45(suppl 1):S17-38, 2022; and Mayer-Davis EJ et al: ISPAD clinical practice consensus guidelines 2018: definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes. 19(suppl 27):7-19, 2018.

Cystic fibrosis–related diabetes 43

• Diabetes occurs in 20% of adolescents with cystic fibrosis, and it is typically discovered through screening measures 43
• Results primarily from insulin deficiency but is also marked by high degree of insulin resistance
• Hyperglycemia can be transient and dependent on any acute illness, inflammation, bowel function, or use of medication that promotes glucose intolerance
• Differentiation from type 1 diabetes is usually made on basis of patient's known history of cystic fibrosis

Treatment

Goals

• Goals of initial management 36
  • Correct fluid and electrolyte imbalances
  • Stabilize metabolic state with insulin
  • Provide basic diabetes education and self-management training for child and caregivers
• Goals of chronic management
  • Realize that all glycemic goals are individualized based on the child's current life circumstances and may change over time
  • Aim for optimal glycemic control
    • Hemoglobin A1C target level less than 7% is appropriate for most children 29
      • A goal of less than 6.5% is reasonable for selected children if it can be achieved without excessive hypoglycemia or other negative impacts on well-being, or undue burden of care
      • More relaxed glycemic targets (less than 7.5%) are suggested for children who cannot articulate hypoglycemic symptoms, experience hypoglycemia unawareness, lack advanced insulin delivery or monitoring technology, or cannot check blood glucose level regularly 44
      • Even less stringent A1C goals (such as less than 8%) may be appropriate for children who experience severe hypoglycemia or have a limited life expectancy, or where the harms of treatment are perceived to be greater than the benefits 29
    • Target goals for measurements from glucometer
      • Preprandial, bedtime and overnight goal: 70 to 126 mg/dL (3.9-7 mmol/L) 1
      • Postprandial peak: 180 mg/dL (10 mmol/L) 1
      • Before physical activity and exercise: 126 to 180 mg/dL (7-10 mmol/L) 29
    • Ambulatory glucose profile targets (continuous glucose monitoring) 45
      • Note: spending 70% time in range corresponds to hemoglobin A1C of 7%
      • Time in range (70-180 mg/dL): more than 70% or more than 16 hours and 48 minutes
      • Time below range (54-69 mg/dL): less than 4% or less than 1 hour
      • Time below range (less than 54 mg/dL): less than 1% or less than 15 minutes
      • Time above range (181-250 mg/dL): less than 25% (less than 4 hours)
      • Time above range (more than 250 mg/dL): less than 5% (less than 1 hour and 12 minutes)
      • Glycemic variability (%coefficient of variation): 36% or less
      • Percentage of time continuous glucose monitoring is active: 70% of data from 14 days
    • Minimize hypoglycemia (especially important for children younger than 6 years) 29
    • Avoid extreme fluctuations in blood glucose level
  • Maintain normal growth and development
  • Minimize risk of acute and chronic complications
• Cardiovascular goals
  • Blood pressure
    • Consistently below 90th percentile for age, sex, and height 29
      • In adolescents aged 13 years or older, below 120/80 mm Hg 29
    • Reference ranges for age, sex, and height and appropriate methods for measurement are available from the American Academy of Pediatrics 46
  • Lipids
    • Goal is an LDL-C value lower than 100 mg/dL 29

Disposition

Admission criteria

New diagnosis

• Consider the following factors when deciding to admit patient for new diagnosis of diabetes: 36
  • Severity of metabolic derangements
  • Family psychosocial circumstances
  • Resources available at the treatment center and experience in managing newly diagnosed children in an outpatient setting
• New diagnosis of diabetes usually requires inpatient admission under the following circumstances: 47
  • DKA
  • Random glucose measurement is 250 mg/dL or greater
  • Hemoglobin A1C greater than 9%
• Ongoing clinical trials are studying the ideal setting in which to deliver care of patient with newly diagnosed type 1 diabetes who is not acutely ill 48
  • Available data suggest that when adequate resources for home management are available, outcomes such as acute complications, long-term metabolic control, behavioral problems, and psychosocial issues are comparable when initial care occurs in the outpatient versus inpatient setting 49

Established diagnosis

• Failure to control diabetes as outpatient, when insulin adjustment and monitoring cannot be reliably and safely managed at home

Criteria for ICU admission

• Any patient with severe DKA or the following: 50
  • Altered mental status
  • Consider for children younger than 5 years; strongly consider for children younger 2 years
  • pH less than 7.15 or bicarbonate level less than 5 mEq/L
  • Hemodynamic instability

Recommendations for specialist referral

• A multidisciplinary treatment team of specialists with experience managing pediatric diabetes is ideal for care coordination 29
• Refer all patients to pediatric endocrinologist for guidance on initiation and modifications of insulin regimen
• Refer all patients to registered dietitian trained in the care of children and adolescents with type 1 diabetes
• Refer to ophthalmologist to evaluate for retinopathy once child is aged 10 years or older, or puberty has started (whichever is earlier), and child has had diabetes for 3 to 5 years 29
• Refer to nephrologist for management of diabetic nephropathy, as determined by development of modestly elevated urinary albumin excretion
• Refer to mental health professional (clinical psychologist or social worker) for guidance on psychosocial issues, including diabetes-related family conflict and stress 29

Treatment Options

Initial management of children with newly diagnosed type 1 diabetes

• For acutely ill children who present with severe hyperglycemia, the first priority is to treat dehydration, replace electrolytes, correct any acidemia, and administer insulin 36
• Second priority is to provide basic diabetes education and self-management training for the child (age- and developmentally appropriate) and other caregivers 36

Long-term management of chronic disease in children with type 1 diabetes consists of several components, which together constitute a comprehensive treatment plan 29

• Intensive insulin therapy 51
• Glucose monitoring 51
• Age-appropriate diabetes education 30
• Lifestyle management including medical nutrition therapy 52
• Ongoing assessment and treatment of comorbidities and complications 29

Insulin therapy

• Intensive insulin therapy to simulate a physiologic pattern of insulin secretion is standard of care 53 54
• Successful management requires balancing insulin replacement with carbohydrate intake and physical activity
• Intensive insulin therapy consists of insulin delivery using 1 of 2 methods 54
  • Multiple (3-4 per day) daily injections, which combine rapid and long-acting insulin analogues, or
  • Continuous subcutaneous insulin infusion (ie, insulin pump), which provides rapid-acting insulin through a catheter that is inserted into subcutaneous tissue of the anterior abdominal wall
• Most children with newly diagnosed disease start with a regimen of multiple daily injections; some may transition to continuous subcutaneous insulin infusion thereafter
• Both methods of insulin delivery require adjustment of the insulin dose depending on the preprandial glucose levels, dietary intake, and physical activity

Glucose monitoring 51

• Blood glucose monitoring is essential to determine basal and prandial insulin needs, to prevent hypoglycemia, and to assess response to changes in insulin dosing
• Methods for monitoring of blood glucose include capillary blood glucose testing using a glucometer or continuous glucose monitoring
• If self-monitoring with a glucometer, children and adolescents may need to check capillary blood glucose levels up to 6 to 10 times per day, including before meals and snacks, at bedtime, and periodically in situations such as exercise, driving, or hypoglycemic symptoms
• Continuous glucose monitoring should be considered for all children and adolescents with type 1 diabetes who are capable of using the device safely, either independently or with caregiver assistance 29 51
  • Real-time continuous glucose monitors are a useful tool to lower and/or maintain hemoglobin A1C and/or reduce hypoglycemia in children with diabetes who are treated with insulin (eg, multiple daily injections, continuous subcutaneous insulin infusion); daily use is recommended 55
  • Intermittently scanned continuous glucose monitors may lower hemoglobin A1C and/or reduce hypoglycemia in children with diabetes who are treated with insulin; recommended frequency of scanning is at a minimum of once every 8 hours 55

Diabetes education 29 52

• Purpose is to enable the patient to acquire the knowledge and skills necessary to make informed day-to-day management decisions and perform diabetes self-care
• Begins at diagnosis with a series of formal sessions with a certified diabetes educator and continues longitudinally with periodic reassessment
• Should be individualized, culturally sensitive, and developmentally appropriate

Medical nutrition therapy

• Individualized nutrition counseling, provided by a registered dietitian, is recommended for all patients 29
• Monitoring carbohydrate intake (ie, carbohydrate counting or experience-based estimation) is an important aspect in achieving optimal glycemic control 29
• Nutrition counseling occurs as part of initial education and generally requires a series of sessions in the first several months after the diagnosis
• Annually scheduled reorientations are ideal, with young children requiring more frequent reevaluations 29

Drug therapy

• Insulin
  • General principles 56
    • Initial insulin therapy with either multiple daily injections or continuous subcutaneous insulin infusion requires comprehensive education
      • Multiple daily injections 56
        • Basal insulin is given as an injection of long- or intermediate-acting insulin analogues, while meal-related glucose excursions are treated with bolus injections of rapid-acting insulin analogues
        • Injected insulin may be given via syringes or insulin pens
          • Modern insulin pens labeled as smart pens are linked to mobile apps that record the concurrent glucose level from a continuous glucose monitor. Use of smart pens has been associated with better glycemic control and reduce hypoglycemic events 57 58 59
      • Continuous subcutaneous insulin infusion 56
        • Rapid-acting insulin analogue is typically used in the device
        • Provides a 24-hour preselected but adjustable basal rate of rapid-acting insulin, along with patient-activated mealtime bolus doses
        • Modern day insulin pump advances include sensor-augmentation, automated suspension of insulin delivery at low glucose thresholds, predictive low-glucose suspension which reduces or stops insulin delivery based on input from linked continuous glucose monitors, and automated insulin delivery systems that assess the rate of change and increase or decrease insulin delivery without patient input (the latter are also known as hybrid closed-loop systems) 1 58
      • Insulin analogues are preferred for both multiple daily injections and continuous subcutaneous insulin infusion; no clinically significant differences have been found among the various analogues available in the pediatric population 60
    • For either mode of insulin delivery, at meals, a dose of rapid insulin is estimated based on preprandial blood glucose level and anticipated carbohydrate intake using individualized ratios of carbohydrate to insulin
    • Safety and effectiveness of a prescribed insulin regimen depend on frequent blood glucose monitoring and/or a continuous glucose monitoring system to avoid hypoglycemia and glucose variability
    • Regardless of the mode of insulin delivery, regularly review and modify insulin doses based on consideration of individual factors (eg, exercise, pubertal status) and daily pattern of blood glucose
  • Initial strategy at the time of a new diagnosis in insulin-naive patients is as follows:
    • Starting doses vary widely, with higher doses usually necessary after a patient has stabilized from DKA
    • Suggested starting total daily doses 8
      • Prepubertal children: 0.25 to 0.5 units/kg/day
      • Pubertal children: 0.5 to 0.75 units/kg/day
      • Postpubertal children: 0.25 to 0.5 units/kg/day
    • Divide total daily insulin into bolus and prandial portions 8
      • Basal insulin glargine should be 25% to 30% of the total dose in toddlers and 40% to 50% in older children
      • Remaining portion of the total daily dose is provided as bolus insulin
    • Typical maintenance total daily doses 53
      • During the partial remission "honeymoon" phase, the total daily insulin dose is usually less than 0.5 units/kg/day
      • Prepubertal children (outside the partial remission phase) usually require a total daily insulin dose of 0.7 to 1 units/kg/day
      • During puberty, total daily insulin requirements can reach as high as 1 to 2 units/kg/day
    • Optimal dose of insulin maximizes glycemic control without causing frequent or severe hypoglycemia, and on a practical level, it can be determined empirically only with frequent blood glucose monitoring and insulin adjustments
• Basal insulins
  • Basal insulin is designed to ideally provide enough insulin to maintain euglycemia between meals and overnight 61
  • Premixed insulin products are not recommended except in limited situations, such as when an adolescent refuses injections, a caregiver has limited math abilities, or a caregiver cannot mix insulin products 62
  • Detemir insulin
    • Insulin Detemir (Recombinant) Solution for injection; Children and Adolescents 2 to 17 years: Insulin requirements highly variable and must be individualized based on patient factors and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement is often between 1 to 2 units/kg/day. Use insulin detemir in combination with rapid-acting insulin as part of a basal-bolus regimen; approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, the rest should be adjusted doses for prandial insulin. Alternatively, administer one-third to one-half of total daily insulin requirements subcutaneously 1 to 2 times/day as insulin detemir. Titrate dosage to achieve blood glucose and A1C goals. For once daily dosing, give dose with evening meal or at bedtime. For twice daily dosing, give 1 dose in the morning; give the second dose 12 hours after the morning dose, with the evening meal, or at bedtime. Conversion of insulin glargine or NPH insulin to insulin detemir is 1:1. Adjust to response; concurrent rapid- or short-acting insulin dosages or timing may need adjusted.
  • Glargine insulin
    • Insulin Glargine Solution for injection; Children and Adolescents 6 to 17 years: Insulin requirements highly variable and must be individualized based on patient factors and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement often between 1 to 2 units/kg/day. Use insulin glargine in combination with rapid-acting insulin as part of a basal-bolus regimen; approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, the rest should be adjusted doses for prandial insulin. Alternatively, initially administer one-third of the total daily insulin requirements/dose subcutaneously once daily. Titrate to blood glucose control and A1C goals in conjunction with a rapid- or short-acting insulin. Give the dose at the same time every day, at any time. No dose chage is necessary for conversion from once daily NPH insulin. For conversion from twice-daily NPH, reduce the total daily dose of NPH insulin (or other twice daily basal insulin) by 20% and give once daily. When transferring from once-daily Toujeo to once-daily Lantus, Basaglar, or Semglee, the recommended initial Lantus, Basaglar, or Semglee dose is 80% of the Toujeo dose that is being discontinued. Adjust to patient response; concurrent rapid- or short-acting insulin dosages or timing may need to be adjusted.
  • NPH insulin (isophane insulin suspension)
    • Insulin Suspension Isophane (NPH) (Recombinant) Suspension for injection; Infants, Children, and Adolescents: Insulin requirements highly variable and must be individualized based on patient factors and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement is often between 1 to 2 units/kg/day. Use isophane insulin in combination with rapid-acting insulin as part of a basal-bolus regimen; approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, the rest should be adjusted doses for prandial insulin. Isophane insulin is given once daily before bed or divided into a twice daily regimen given 30 to 60 minutes before a meal.
• Prandial insulins 63
  • Prandial doses (rapid-acting analogues or regular insulin) are used to limit glucose excursions that occur after meals or snacks
  • Regular insulin
    • Insulin Regular (Recombinant) Solution for injection; Infants, Children, and Adolescents: Insulin requirements highly variable; must be individualized based on patient and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement often between 1 and 2 units/kg/day. Use regular insulin in combination with intermediate- or long-acting insulin. Depending on the type of insulin used as the basal insulin, approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, with the remainder divided into 3 to 4 prandial regular insulin boluses. Administer pre-meal doses of regular insulin approximately 20 to 30 minutes prior to a meal.
  • Aspart insulin
    • Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents 2 to 17 years: Insulin requirements highly variable; must be individualized based on patient and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement often between 1 to 2 units/kg/day. Use insulin aspart in combination with intermediate- or long-acting insulin. Depending on the type of insulin used as the basal insulin, approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, with the remainder divided into 3 to 4 prandial rapid-acting insulin boluses. Administer insulin aspart immediately before a meal (i.e., meal starts within 5 to 10 minutes after injection).
  • Lispro insulin
    • Insulin Lispro Solution for injection; Children and Adolescents 3 to 17 years: Insulin requirements highly variable; must be individualized based on patient and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement often between 1 to 2 units/kg/day. Use insulin lispro in combination with intermediate- or long-acting insulin. Depending on the type of insulin used as the basal insulin, approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, with the remainder divided into 3 to 4 prandial rapid-acting insulin boluses. Administer insulin lispro 15 minutes before or immediately after a meal.
  • Glulisine insulin
    • Insulin Glulisine Solution for injection; Children and Adolescents 4 to 17 years: Insulin requirements highly variable; must be individualized based on patient and insulin regimen. During partial remission phase, total combined daily insulin requirement often less than 0.5 units/kg/day. Prepubertal children (outside the partial remission phase) usually require 0.7 to 1 unit/kg/day. During puberty, insulin requirement often between 1 to 2 units/kg/day. Use insulin glulisine in combination with intermediate- or long-acting insulin. Depending on the type of insulin used as the basal insulin, approximately 30% to 45% (sometimes 50% when insulin analogs are used) should be basal insulin, with the remainder divided into 3 to 4 prandial rapid-acting insulin boluses. Administer insulin glulisine within 15 minutes before or 20 minutes after starting a meal.
• Rapid-acting insulin analogues for continuous subcutaneous insulin infusion devices 63
  • Aspart insulin
    • Insulin Aspart (Recombinant) Solution for injection; Children and Adolescents 2 to 17 years: When used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), individualize dosing to the patient's age and metabolic needs. Therapy is provided by a professional team trained in CSII therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week).
  • Lispro insulin
    • Insulin Lispro Solution for injection; Children and Adolescents 3 to 17 years: When used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), individualize dosing to the patient's age and metabolic needs. Use Admelog or Humalog 100 units/mL only. Do NOT administer Humalog 200 units/mL using a continuous subcutaneous infusion pump. Therapy is provided by a professional team trained in CSII therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week).
  • Glulisine insulin
    • Insulin Glulisine Solution for injection; Children and Adolescents 4 to 17 years: When used in an external insulin pump via continuous subcutaneous insulin infusion (CSII), individualize dosing to the patient's age and metabolic needs. Therapy is provided by a professional team trained in CSII therapy and capable of supporting patient care continuously (i.e., 24-hours/7 days-a-week).
• Glucagon for severe hypoglycemia
  • Glucagon Hydrochloride Solution for injection; Infants and Children weighing less than 25 kg and Children younger than 6 years with unknown weight: 0.5 mg IM, IV, or subcutaneously once. May repeat dose if there has been no response after 15 minutes.
  • Glucagon Hydrochloride Solution for injection; Children and Adolescents weighing 25 kg or more and Children 6 years and older with unknown weight: 1 mg IM, IV, or subcutaneously. May repeat dose if there has been no response after 15 minutes.
• Common insulin preparations and approximate action profiles.

  Type of insulin	Onset	Peak	Duration
  Ultra-rapid-acting
  Aspart (Fiasp)	15 to 20 minutes	1 to 3 hours	3 to 5 hours
  Rapid-acting
  Aspart (Novolog)	15 to 30 minutes	1 to 3 hours	3 to 5 hours
  Lispro (Humalog)	15 to 30 minutes	1 to 3 hours	3 to 5 hours
  Glulisine (Apidra)	15 to 30 minutes	1 to 3 hours	3 to 5 hours
  Short-acting
  Regular Insulin	30 to 60 minutes	2 to 4 hours	5 to 8 hours
  Intermediate-acting
  NPH	2 to 4 hours	4 to 8 hours	12 to 18 hours
  Long-acting
  Detemir (Levemir)	2 to 4 hours	None	12 to 24 hours
  Glargine (Lantus)	2 to 4 hours	None	Up to 24 hours
  Degludec (Tresiba)	2 to 4 hours	None	More than 24 hours

  Citation: Data from European Medicines Agency: Fiasp, INN-insulin aspart. Annex 1: summary of product characteristics. European Medicines Agency website. Published February 3, 2017. Updated September 23, 2021. Accessed August 1, 2022. https://www.ema.europa.eu/en/documents/product-information/fiasp-epar-product-information_en.pdf ; and Chiang JL et al: Type 1 diabetes in children and adolescents: a position statement by the American Diabetes Association. Diabetes Care. 41(9):2026-44, 2018.

Nondrug and supportive care

Fluid administration to correct dehydration

• Replace volume deficits with normal saline IV fluids at a rate not to exceed 1.5 to 2 times the usual daily maintenance requirement 50

Blood glucose monitoring 64

• Point of care testing technology in which a small volume of capillary blood is placed on a test strip and inserted into a glucometer, providing a real-time digital display of blood glucose level
• Indicated for all children with type 1 diabetes; introduced at diagnosis
• Recommended testing frequency is a minimum of 4 blood glucose tests per day (before meals and at bedtime) 64
  • May be needed up to 6 to 10 times per day, including before meals and snacks, at bedtime, and as needed in specific situations such as exercise, driving, or hypoglycemic symptoms 51 65
  • Mealtime testing results are used to determine prandial doses of insulin
• School employees and caregivers should be knowledgeable about blood glucose monitoring and should be equipped with all necessary supplies
• Real-time continuous glucose monitoring
  • Testing technology in which a catheter with a glucose oxidase sensor is placed subcutaneously to measure and record interstitial glucose concentrations and provide a real-time display of glucose levels
  • Personal continuous glucose monitoring devices are available either as stand-alone devices or combined with an insulin pump
    • Combined continuous subcutaneous insulin infusion and glucose monitoring systems (ie, sensor-augmented pump) function to deliver insulin and sample interstitial fluid glucose levels but do not automatically provide bolus doses
    • Combined continuous subcutaneous insulin infusion and glucose monitoring systems with threshold suspension functionality halt insulin delivery for up to 2 hours when the sensor glucose value reaches a predetermined lower threshold; this is a safety measure against an impending hypoglycemic event
  • Glucometric data analysis by the health care professional is used to adjust insulin doses
  • Overall, use of continuous glucose monitoring has a favorable balance of benefits (improved control) against any potential harms, especially in children with frequent hypoglycemia and/or hypoglycemia unawareness
    • Benefits of continuous glucose monitoring are proportional to adherence with wearing the device and are realized when data from the devices are reviewed for patterns to make thoughtful insulin dosage adjustments on a periodic basis 54
    • Continuous glucose monitoring, when used properly in conjunction with insulin therapy, is a useful tool to lower and/or maintain hemoglobin A1C levels and/or reduce hypoglycemia 66 67 68
    • As a general rule, adolescents and young adults (aged 13-24 years) are least likely to use the devices with regularity, and thus they often do not achieve hemoglobin A1C reductions as substantial as those in either younger children or adults
  • Indications
    • American Diabetes Association recommends offering continuous glucose monitoring to all youths with type 1 diabetes who are capable of using the device safely, either independently or with caregiver assistance 29 51
    • Other professional societies recommend real-time continuous glucose monitoring systems in children with type 1 diabetes under the following circumstances: 64
      • Frequent episodes of severe hypoglycemia, particularly nocturnal
      • Hypoglycemia unawareness
  • Contraindications
    • Relative: unwillingness to use glucometer to guide insulin dosing
• Intermittently scanned (flash) continuous glucose monitoring 65 69
  • An alternative glucose-sensing device that does not require calibration (and is thus simpler and more attractive to users)
  • Displays present, 8-hour historic, and trend glucose data when scanned by the user with a near-field scanner
  • Intermittently scanned continuous glucose monitoring, when used properly with insulin therapy, may be useful to replace self-monitoring of blood glucose; 29 limited data show that the device has accuracy similar to standard continuous glucose monitor devices and lower rates of hypoglycemia 70
  • Main disadvantage is that it does not provide alarms for hypoglycemia or hyperglycemia

Diabetes education and self-management training 29

• Family education and involvement is particularly important for optimal diabetes management in children and adolescents
  • Diabetes care team should encourage developmentally appropriate parental involvement in managing the patient's diabetes care tasks
• Education is ideally provided with sensitivity to the age and developmental stage of the patient, with regard to approach and content delivered
  • For preschoolers, direct education toward the parents and primary caregivers; whereas, for most adolescents, direct education primarily toward the patient
• To be effective, educational interventions need to be ongoing, with frequent in-person and telephone contact (improves hemoglobin A1C levels and decreases hospitalization rates for acute diabetes complications)
• Counseling topics include the importance of optimizing blood glucose, lipid, and blood pressure treatment; encouragement to participate in regular exercise; and avoidance of smoking
• Educational content is based on life stages and individualized to the patient's needs

Medical nutrition therapy 52

• All patients with type 1 diabetes should receive nutrition counseling sessions that include both the patient and parents/caregivers
• No special nutritional requirements for a child with type 1 diabetes, other than those for optimal growth and development 8
• Registered dietitian constructs an individualized food plan with recommendations regarding daily caloric intake, division of calories between meals and snacks, meal composition, and macronutrient distribution 8
  • Total recommended caloric intake is based on size
  • Ideal macronutrient distribution is individualized; 52 general target includes a macronutrient distribution comprising approximately 55% carbohydrate, 30% fat, and 15% protein
  • Dietitian provides guidance on selection of type and amounts of carbohydrates, which are the primary determinants of insulin needs
    • Carbohydrate content should be approximately 70% complex, aiming for high fiber content with limited intake of sucrose or highly refined sugars
  • Ideally, dietary fats are polyunsaturated and from vegetable sources
• Dietitian also educates patients and families on how to perform carbohydrate counting, as well as the impact that different types of carbohydrates exert on blood glucose levels and how these foods interact with exercise and insulin
• Consider food preferences, as well cultural and ethnic diets
• Consistent eating patterns with regular carbohydrate intake are advisable, although rare exceptions for excesses are permissible
• Guidelines are available to guide management of diabetes in children and adolescents during fasting for Ramadan 71 and during intercurrent illness 72

Immunizations 63

• Annual influenza vaccine for children with diabetes who are aged 6 months or older
• Pneumococcal polysaccharide vaccine for children with diabetes aged 2 years or older
• Routine childhood vaccinations in accordance with recommended CDC vaccination schedules 73
  • Since mid-2022, this includes COVID-19 vaccination for ages 6 months and older

Other lifestyle issues

• Discourage smoking (including e-cigarettes) in young people who do not smoke and encourage smoking cessation in those who do 29 (Related: Tobacco Use Disorder and Smoking Cessation)
• Limit exposure to cigarette smoke in the home
• Instruct patients to wear medical alert bracelet

Physical activity

• Encourage engagement in at least 60 minutes of moderate to vigorous aerobic physical activity daily (same recommendations for physical activity for all children, independent of a diagnosis of diabetes) 52
  • Participation in physical activity with duration of at least 60 minutes significantly reduces hemoglobin A1C 74
  • Encourage muscle and bone strengthening activities at least 3 times weekly 52
• Inform patients that anaerobic exercise or high-intensity activity can result in hyperglycemia immediately after start of exercise; also, aerobic activity increases the risk of hypoglycemia during and after exercise 75
• Strategies to prevent exercise-induced hypoglycemia include: 76
  • Aim for blood glucose level of 126 to 180 mg/dL before physical activity and exercise 29
    • If initial blood glucose levels are below goal, delay physical activity and consume sufficient carbohydrates until blood glucose level is within appropriate preexercise range 29 75
  • Adjust insulin and/or carbohydrate intake
    • Reduce prandial insulin dose for meal or snack preceding exercise 29
    • Increase carbohydrate intake before exercise 29
    • Reduce basal insulin rates on continuous subcutaneous insulin infusion device by about 10% to 50% or more or suspend for 1 to 2 hours during exercise 29
    • Reduce basal insulin rate or long-acting insulin dose by approximately 20% after exercise to mitigate delayed exercise-induced hypoglycemia 29
  • Monitor glucose frequently before, during, and after exercise
    • Have blood glucose testing supplies and sources of simple carbohydrate readily available to prevent and treat hypoglycemia 29
    • For more strenuous and prolonged activities, instruct patient to consume 0.5 to 1.5 g carbohydrates/kg for each hour of strenuous activity 75
    • Monitor blood glucose during periods of continuous physical activity about every 30 minutes as well as 15 minutes after completion of exercise and at bedtime 75
    • Detailed guideline recommendations are available outlining initial recommendations for general insulin therapy, carbohydrate consumption, and glucose sensor thresholds for patients using continuous glucose monitoring systems 77
    • Consider use of remote monitor (eg, mobile application) to watch continuous glucose monitoring system in real time during exercise to assess and respond to glycemic changes during activity 77
    • If not already used, consider initiating a combined insulin pump/continuous glucose monitoring system, particularly one with a low glucose threshold–suspend feature 75
• Marked hyperglycemia (glucose level of 350 mg/dL or more) before exercise should prompt delay of physical activity; presence of insulin deficiency and ketosis should be evaluated 29
• If significant hyperglycemia occurs after exercise (usually from high-intensity exercise and increased catecholamine production), cautiously administer a small rapid-acting bolus of insulin 75

Behavioral and psychosocial aspects of care 29

• Assess for psychosocial issues and family stress that may impact diabetes management; provide referrals to trained mental health providers when indicated
• Encourage family involvement in diabetes management for children and adolescents, individualized to developmental appropriateness
• Factors like food security, housing stability, health literature, financial constraints, and social support should be considered and incorporated in treatment planning
• Consider assessing social adjustment (peer relationships) and school performance to determine if further evaluation is needed

Various diabetes advocacy position statements are available from the American Diabetes Association, including the following: 78

• Diabetes care in the school setting 79 80
• Care of young children with diabetes in the child care setting 81
• Insulin access and affordability 82
• Diabetes and driving 83
• Diabetes and employment 84
• Diabetes care in correctional institutions 85

During the COVID-19 pandemic, telehealth should be used for sick day management and routine diabetes care

Procedures

Continuous subcutaneous insulin infusion (insulin pump) therapy 86 87

General explanation

• Mechanically driven insulin delivery technology in which a catheter is placed subcutaneously to provide a continuous infusion of rapid-acting insulin
• Provided as a preset basal rate with operator-driven periodic boluses; basal delivery rate can be programmed to vary throughout the day
• A sensor-augmented pump is a continuous subcutaneous insulin infusion device combined with a continuous glucose monitoring feature
  • A pump with threshold suspension functionality temporarily halts delivery of insulin when interstitial glucose levels fall below a set threshold
  • Sensor-augmented pumps with threshold suspension functionality are ideal for patients with frequent nocturnal hypoglycemia, recurrent severe hypoglycemia, or hypoglycemia unawareness
• Automated insulin delivery systems combine an insulin pump, a continuous glucose monitor, and an algorithm that adjusts insulin delivery; 2 such hybrid closed-loop devices have been approved by FDA 55
  • Pump automatically adjusts delivery of basal insulin based on glucose values as determined by the continuous glucose monitor, without requiring intervention from the user; it automatically increases, decreases, and suspends insulin delivery in response to continuous glucose monitoring
  • Patients still must enter carbohydrate intake and periodically calibrate sensor
• Comparison of outcomes using multiple daily insulin injections versus continuous subcutaneous insulin infusion shows that the latter is associated with slightly lower hemoglobin A1C levels, 88 less DKA, 89 and improved quality of life 86
• Use of continuous subcutaneous insulin infusion is associated with reduction in all-cause and cardiovascular mortality when compared with multiple daily insulin injections 90

Indication

• Suggested indications vary among different professional societies
• American Diabetes Association 54 29 and International Society for Pediatric and Adolescent Diabetes 53 both recommend continuous subcutaneous insulin infusion as a possible alternative to multiple daily injections of insulin for all pediatric patients with type 1 diabetes
• American Association of Clinical Endocrinologists suggests consideration of continuous subcutaneous insulin infusion therapy for children with type 1 diabetes under the following circumstances: 86
  • Elevated hemoglobin A1C levels on injection therapy
  • Frequent, severe hypoglycemia
  • Widely fluctuating glucose levels
  • Microvascular complications and/or risk factors for macrovascular complications
• Hybrid closed-loop systems are intended for patients aged 14 years or older with type 1 diabetes 91

Complications 92

• Cutaneous irritation or infection
• Mechanical failures of software or hardware (eg, insulin leaking, screen fading, battery damage)
• Catheter problems (eg, occlusion, bubbles, kinking)

Contraindications

• Hybrid closed-loop system should not be used in: 93
  • Anyone younger than 7 years
  • Patients who require less than a total daily insulin dose of 8 units/day; requires a minimum of 8 units/day to operate safely

Interpretation of results

• Insulin pumps equipped with predictive threshold-suspend features appear to reduce hypoglycemia 2-fold (compared to standard sensor-augmented pumps without suspension feature) without deterioration in glycemic control 94
• Hybrid closed-loop systems have been shown to be safe during in-home use by adolescents (and adults), to provide reductions in hypoglycemia and hyperglycemia, and to result in lower hemoglobin A1C values 95
• Children and adolescents using a closed-loop system maintained glucose levels in the target range for a greater percentage of time than those using sensor-augmented insulin pumps 96 97 98
• A recent large randomized trial found that a hybrid closed-loop system significantly improved glycemic control without increasing time spent in hypoglycemia even for very young children (aged 1 to 7 years) with type 1 diabetes, indicating promise for future use in this population 99

Comorbidities

• Hypertension 29
  • Measure blood pressure at each office visit
  • Encourage adolescents with diabetes to use ambulatory blood pressure monitoring periodically 46
  • Normative blood pressure values and thresholds for diagnosing elevated blood pressure and hypertension are now lower than in previous classifications 29 46
    • Elevated blood pressure (previously termed "prehypertension") is either of the following confirmed on 3 separate visits: 46
      • Systolic or diastolic blood pressure in 90th to less than 95th percentile for age, sex, and height
      • 120 to 129 mm Hg systolic and less than 80 mm Hg diastolic in adolescents aged 13 years or older
    • Confirmed hypertension is either of the following confirmed on 3 separate visits: 46
      • Systolic or diastolic blood pressure in 95th percentile or higher for age, sex, and height
      • 130/80 mm Hg or greater in adolescents aged 13 years or older
  • Initial treatment for high-normal blood pressure is aimed at lifestyle modifications of altering diet, increasing exercise, and controlling weight 29
    • Consider pharmacologic treatment of hypertension if target blood pressure is not reached with 3 to 6 months of using lifestyle methods 29
    • Ambulatory blood pressure monitoring is strongly encouraged for these patients 29
  • Consider starting pharmacologic treatment in addition to lifestyle modification in patients with hypertension (blood pressure at 95th percentile or greater for age, sex, and height, or 130/80 mm Hg or greater in adolescents aged 13 years or older) 29
    • ACE inhibitors or angiotensin receptor blockers (alternatively) are preferred in children with diabetes and hypertension 29
    • Use of an ACE inhibitor with statin is not recommended for primary prevention of microvascular complications, because available data do not demonstrate reduction in albuminuria or progression of retinopathy 100
  • Goal blood pressure levels are those that are consistently below 90th percentile for age, sex, and height, or below 120/80 mm Hg in adolescents aged 13 years or older 29
• Dyslipidemia
  • Dyslipidemia is a risk factor for atherosclerotic cardiovascular disease in type 1 diabetes
  • Initial therapy consists of both: 29
    • Optimizing glucose control (which can improve lipid values but not normalize them), and 101
    • Medical nutrition therapy to limit the amount of calories from fat to 25% to 30%, saturated fat to less than 7%, cholesterol less than 200 mg/day, avoidance of trans fats, and about 10% calories from monounsaturated fats 29
  • Pharmacotherapy with a statin is recommended for children aged 10 years or older if, after attempting therapeutic lifestyle change, LDL-C level remains higher than 160 mg/dL or LDL-C level remains higher than 130 mg/dL when the patient has 1 or more cardiovascular disease risk factors 29
    • Goal of therapy is to achieve LDL cholesterol value less than 100 mg/dL 29
• Cardiovascular disease 102
  • Cardiovascular events generally do not occur during childhood, but atherosclerotic process begins during childhood in diabetes 103
    • Age and hemoglobin A1C level are strongest risk factors for a major atherosclerotic event or any cardiovascular disease in type 1 diabetes 104
    • Cardiovascular risk reduction involves optimizing glycemic control and managing other cardiovascular risk factors (eg, maintaining healthy body weight, physical activity, healthy diet, treating hypertension) 103
• Autoimmune conditions
  • Assess for presence of thyroid dysfunction and celiac disease soon after initial diabetes diagnosis and if symptoms develop
    • Autoimmune thyroiditis
      • Most common autoimmune disorder associated with diabetes, occurring in 15% to 30% of children and adolescents with type 1 diabetes 19
      • Assess TSH level soon after initial diabetes diagnosis and metabolic stabilization, and obtain tests for anti–thyroid peroxidase and antithyroglobulin antibodies 29 105
      • If TSH levels are within reference range, consider rechecking every 1 to 2 years or sooner if the patient has positive thyroid antibodies or develops symptoms suggestive of thyroid dysfunction, thyromegaly, abnormal growth rate, or unexplained glycemic variation 29
    • Celiac disease 106
      • Gluten-sensitive enteropathy that occurs in approximately 2% to 16% of patients with type 1 diabetes 29
      • Higher prevalence in patients with type 1 diabetes, family history of celiac disease, younger age, and associated thyroid autoimmunity 106
      • Children may be asymptomatic or may present with the following symptoms: weight loss, poor growth, anemia, dermatitis herpetiformis, bone and muscle pains, abdominal pain, diarrhea, constipation, mouth ulcers, bloating, and gas 106
      • Screen all children with type 1 diabetes at diagnosis; repeat screening within 2 years of diagnosis and then again after 5 years; consider more frequent screening in children with suggestive symptoms or first-degree relative with celiac disease 29
        • Obtain IgA tissue transglutaminase antibodies in patients with documentation of normal total serum IgA levels; obtain IgG to tissue transglutaminase and deamidated gliadin antibodies in IgA-deficient patients
      • Some experts suggest confirming celiac disease diagnosis with small-bowel biopsy, given potential challenges of recommended dietary restrictions for patients with both diabetes and celiac disease 29
      • Treat patients with confirmed celiac disease using gluten-free diet in consultation with a dietitian experienced in managing both diabetes and celiac disease 29
    • Other autoimmune conditions
      • Conditions that occur more commonly in children with type 1 diabetes include Addison disease (primary adrenal insufficiency), autoimmune hepatitis, autoimmune gastritis, dermatomyositis, and myasthenia gravis
      • A heightened awareness of the risk of such conditions is advisable, but routine screening of asymptomatic children is not recommended 29
• Overweight and obesity
  • Children with overweight or obesity are at risk for type 2 diabetes, but they can also develop type 1 diabetes
  • Approximately 15% and 25% of children with type 1 diabetes in the United States are overweight or obese, respectively 107
  • Intensive diabetes management can make weight control challenging, although most series have found that overweight or obese body habitus is associated with higher hemoglobin A1C levels 108
  • Overweight or obese body habitus in youth with type 1 diabetes has negative implications for glycemic control, insulin resistance, and cardiovascular risk factors (eg, hypertension, dyslipidemia) 109
  • Suggested strategies for limiting weight gain include avoidance of excessive caloric intake, selecting more nutritious foods, encouraging regular physical activity, advising reduced screen time, and eliminating snacks 107
• Psychosocial issues
  • Psychosocial distress is common, owing to burdens of diabetes management throughout childhood and adolescence 29
    • The term diabetes distress refers to the duress of constant behavioral demands of diabetes self-management (eg, medication dosing, frequency, and titration; monitoring blood glucose, food intake and eating patterns; physical activity) 110
    • Occurs in approximately one-third of adolescents with diabetes 111
    • Monitor for diabetes distress routinely (Diabetes Distress Scale 112) beginning at age 7 or 8 years, 29 and refer patient to diabetes education or a behavioral health provider if areas of diabetes care are impacted 110
  • Rates of depression are higher in youth with type 1 diabetes, compared with youth without the disease 113
    • Annually screen youth for depression using depression screening tools 110 114
    • Consider screening for depression with any changes in medical status, including development of new complications 110
  • Comorbid anxiety complicates management of diabetes by mimicking symptoms of hypoglycemia; patient may also have fear of hypoglycemia that leads to intentionally maintaining blood glucose above healthy target levels 113
  • Mental health comorbidities can reduce adherence to treatment, which ultimately increases risk for long-term complications and reduces quality of life
    • Refer children or adolescents to a mental health provider for evaluation and treatment, in the following situations: 110
      • Diabetes distress persists even after tailored diabetes education
      • Positive screening result for depression, eating disorder, or anxiety; suspicion for a serious mental illness; or fear of hypoglycemia
      • Repeated hospitalizations for DKA, intentionally omitting insulin, or declining to perform self-care behaviors (eg, injecting insulin, monitoring blood glucose)
  • Assess food security, housing stability/homelessness, health literacy, financial barriers, and social/community support and apply pertinent information to treatment decisions 29
• Eating disorders
  • Higher incidence in youth with type 1 diabetes, compared with youth without diabetes
  • Disturbed eating behaviors, coupled with unhealthy weight control behaviors, correlate with worse glycemic control 115
    • Insulin omission and insulin underdosing are the most common and serious weight control behaviors and are associated with increased morbidity and mortality 116
    • Consider reevaluating treatment regimen if symptoms of disordered eating behavior are evident
  • Screen for disordered eating behaviors in patients between the ages of 10 and 12 years with available screening tools, 117 particularly when hyperglycemia and weight loss are unexplained 29

Special populations

• Patients in pubertal stage
  • Puberty is a state of relative insulin resistance and therefore insulin requirements increase substantially
  • Anticipate increases in basal and prandial insulin doses
    • Basal insulin requirements typically range from 1 to 2 units/kg/day 53
    • Increase insulin to carbohydrate ratios to estimate prandial doses 63
• Older adolescents
  • Motor vehicle operation issues
    • Counsel adolescents to test blood glucose before driving, to carry a source of glucose, and to discontinue driving if symptoms of hypoglycemia occur; document this counseling in the record
  • Preconception counseling 118
    • Discuss risks of fetal malformations, maternal complications, and diabetes in offspring for female patients with reproductive potential
      • Major malformations are caused by hyperglycemia during the first 8 weeks of gestation and account for 50% of perinatal mortality 119
      • Fetal complications later in pregnancy arise from fetal hyperinsulinemia secondary to maternal hyperglycemia, leading to macrosomia 119
    • Discuss contraceptives with all female patients with childbearing potential 29
  • Transition to adulthood
    • Adolescents should gradually assume greater responsibility for diabetes management
    • Begin to prepare youth for transition in early adolescence 29
    • Start a transition plan at least 1 year in advance of transferring over to adult health care to prepare for issues related to insurance, obtaining diabetes supplies, affective disorders, reproductive health, substance use, and identifying an adult care physician 29 120
• Adolescents who are pregnant 119
  • Most pregnancies in adolescents with type 1 diabetes are unplanned; referral to a high-risk obstetrics specialist is routine
  • Glycemic goals in pregnancy are more stringent
    • American Association of Clinical Endocrinologists targets 63
      • Hemoglobin A1C less than 6% during pregnancy
      • Preprandial, bedtime, and overnight glucose levels: 60 to 99 mg/dL
      • Peak postprandial blood glucose level: 100 to 129 mg/dL
    • American Diabetes Association targets 118
      • Hemoglobin A1C level: ideal value is 6% or lower (may use target of less than 7% in patients with frequent hypoglycemia)
      • Fasting blood glucose level of less than 95 mg/dL
      • 1-hour postprandial blood glucose level less than 140 mg/dL or 2-hour postprandial blood glucose level less than 120 mg/dL
  • Pregnancy changes maternal insulin sensitivity, which results in altered insulin requirements
    • First trimester insulin requirements are typically lower, whereas second and third trimester requirements are typically higher, owing to increasing insulin resistance
    • Shift in allocation of total daily insulin
      • Increase proportion of insulin given with meals
      • Reduce dose of insulin given as basal proportion
    • Blood glucose monitoring may be required 10 or more times per day to achieve glucose targets while avoiding hypoglycemia
      • During pregnancy, both preprandial and postprandial blood glucose testing are required to achieve glycemic targets 118
    • Continuous glucose monitoring does not affect maternal or neonatal outcomes, but this technology may be useful for pregnant patients with preexisting type 1 diabetes who have unstable glucose levels and frequent hypoglycemia
  • Prescribe folic acid 5 mg daily and prenatal vitamin as soon as pregnancy is confirmed
  • Perform fetal ultrasonography in first trimester to evaluate gestational age
  • Withdraw ACE inhibitors, angiotensin receptor antagonists, diuretics, and statins
  • Refer for baseline ophthalmologic examination in first trimester, and monitor every trimester as indicated by degree of retinopathy
  • Prescribe low-dose aspirin starting at end of first trimester, to lower risk of preeclampsia 118

Monitoring

• American Diabetes Association provides a complete list of comprehensive medical evaluation components to cover at annual examination and at each follow-up visit 30
  • Periodically reassess the following:
    • Diabetes self-management and support 29
    • Educational needs and training for those providing care for child (eg, day care providers, school personnel) 29
    • Growth and development
      • Measure height and weight at each visit, or on quarterly basis 16
      • Calculate BMI percentile and corresponding BMI-for-age percentile on quarterly basis 121
      • Regularly check injection sites and technique
    • Glycemic control
      • Blood glucose monitoring is essential for optimal management
        • Inverse relationship exists between frequency of blood glucose monitoring and hemoglobin A1C levels 122
        • Recommended frequency of blood glucose monitoring is determined on an individual basis, according to blood glucose lability and likelihood of hypoglycemia
          • Minimum frequency of testing suggested is 4 times per day (premeal and at bedtime) 64
          • Testing at other times (eg, 2 hours after meals; overnight; before, during, and after exercise) can provide more information about glucose trends and aid in refining insulin doses 16 64 65
        • Blood glucose data are analyzed by treating physician to identify hyperglycemic and hypoglycemic trends, which are then used to adjust insulin dosing
        • Use of metrics obtained from a continuous glucose monitoring device may improve overall assessment of glycemic control; allows precise assessment of time with glucose in target range and frequency of hypoglycemia 51
          • Continuous glucose monitoring metrics are recommended to be used in conjunction with hemoglobin A1C values whenever possible 29
          • A 14-day continuous glucose monitoring assessment of time in range and glucose management indicator can serve as a surrogate for A1C for use in clinical management 51
          • Uncertainty exists surrounding ideal target time in range for children; general goal is a time in range greater than 70% with time below range less than 4% 29 51
          • Precise range for a given child's glucose parameters is somewhat individualized; general goal is target range of 70 to 180 mg/dL 29
      • Hemoglobin A1C serves as an indicator of long-term glycemic control
        • Also serves as correlate for risk of diabetes complications; lower hemoglobin A1C in adolescence and young adulthood is associated with a lower risk and rate of microvascular and macrovascular complications 2 123
        • Recommended measurement includes: 51
          • At least twice yearly in patients meeting treatment goals (stable glycemic control)
          • At least quarterly and as needed in patients whose therapy has recently changed and/or who are not meeting glycemic goals
        • Target goal hemoglobin A1C less than 7% is appropriate for many children; individualization of target goal may be necessary based on needs and situation of family and patient 29 44
      • Monitor blood or urine ketone levels in the setting of prolonged hyperglycemia or acute illness 16 65
        • Aids in determining whether adjustments to treatment and referral for urgent care are necessary
      • Follow-up visits with diabetes educators should occur at least every 3 to 6 months initially, individualized to the patient 30
        • Discuss self-care behaviors, physical activity, and daily routines
        • Inquire about frequency, severity, and circumstances surrounding hypoglycemic events
        • Review blood glucose monitoring data to identify patterns and trends in relation to insulin dosing and meals
        • Monitoring of carbohydrate intake (eg, carbohydrate counting, experience-based estimation) is an important aspect in achieving glycemic control 29
    • Comorbidities
      • Hypertension
        • Measure blood pressure at each routine visit 29
      • Dyslipidemia
        • Perform initial lipid testing when initial glycemic control has been achieved and patient is at least 2 years old; subsequent testing should be performed at ages 9 to 11 years if initial LDL-C is 100 mg/dL or lower 29
          • Initial testing may be done with a nonfasting, non-HDL-C level with confirmatory testing using a fasting lipid panel
          • Lipid profile may be repeated every 3 years if LDL-C values are within the accepted risk level (less than 100 mg/dL); 29 monitor annually if level is abnormal 16
      • Autoimmune thyroid disease
        • Annual thyroid examination with TSH measurement every 1 to 2 years, or sooner if patient has positive thyroid antibodies or develops symptoms suggestive of thyroid dysfunction 29
        • If patient develops autoimmune hypothyroidism and takes thyroid hormone replacement, measure periodically to maintain TSH level within reference range
      • Celiac disease
        • Repeat screening within 2 years of initial screening (at time of diagnosis); provide follow-up with screening every 5 years or more frequently in patients with symptoms concerning for celiac disease, or in patients with a first-degree relative with celiac disease 29
          • Obtain IgA tissue transglutaminase antibodies (with documentation of normal total serum IgA levels) or IgG tissue transglutaminase antibodies and deamidated gliadin antibodies in IgA deficient patients
      • Psychosocial issues
        • Monitor for psychosocial issues and family stress that may impact management (during routine follow-up care) 29
        • Monitor children and adolescents, along with their parents, for signs of diabetes distress (during routine follow-up care) 110
        • Screen for depression and anxiety quarterly
        • For teenagers, assess use of alcohol, tobacco, illicit drugs, and contraception as needed
        • Monitor for eating disorders (with a validated screening tool) in patients around age 10 to 12 years and when hyperglycemia and/or weight loss are unexplained 29
    • Complications
      • Nephropathy
        • Measure urinary albumin-creatinine ratio (from a spot urine sample, preferably a morning sample) once child has had diabetes for 5 years starting at puberty or at age 10 years, whichever is earlier, and then annually thereafter 29
        • Obtain estimated GFR as needed based on clinical status, age, duration of diabetes, and therapy 29
      • Retinopathy
        • Obtain initial dilated retinal and comprehensive eye examinations once patient is at least 11 years old or pubertal (whichever is earlier) and has had diabetes diagnosis for 3 to 5 years, then every 2 years thereafter 29 124
        • Less-frequent examinations (every 4 years) may be acceptable with the advice of an eye care professional 29
        • Other recommendations suggest initial ophthalmologic examination beginning 5 years after diagnosis and annually thereafter 125
      • Neuropathy
        • Visual foot examination at each visit with older children to educate regarding importance of foot care 29
        • Consider annual comprehensive foot examination, to assess for peripheral neuropathy, at start of puberty or at age 10 years (whichever is earlier) once diabetes has been established for 5 years 29
          • Assessment includes history and monofilament testing with pinprick, temperature, or vibration sensation tests

Complications and Prognosis

Complications

• Acute
  • DKA (diabetic ketoacidosis) 126 (Related: Diabetic Ketoacidosis)
    • Life-threatening condition marked by hyperglycemia, metabolic acidosis, and ketonemia
    • 30% of new-onset diabetes cases in children present as DKA 127
    • COVID‐19 infection may precipitate severe metabolic complications of diabetes including DKA, which may be the initial presentation of new-onset diabetes 128
    • Delays in diagnosis of diabetes and seeking care for diabetes‐related emergencies owing to fear of exposure to COVID‐19 may result in more severe DKA at presentation 128 129
    • Signs and symptoms include polyuria, polydipsia, polyphagia, weight loss, weakness, abdominal pain, nausea, vomiting, Kussmaul respirations, and acetone breath
    • Treat with fluid resuscitation, insulin, electrolyte replacement, and correction of precipitating factors
    • Cerebral edema is the major complication; it causes 20% of all deaths from DKA occurring in children 130
  • Treatment-related hypoglycemia
    • Thresholds 131
      • At a glucose level of 70 mg/dL or lower, hypoglycemia is sufficiently low to require treatment with fast-acting carbohydrate and dose adjustment of insulin
      • At a glucose level of less than 54 mg/dL, hypoglycemia is considered serious and clinically significant
      • Severe hypoglycemia associated with severe cognitive impairment does not have a specific numerical threshold, but this category is reserved for any hypoglycemic event that requires external assistance for recovery
    • Recognition is developmentally and age-dependent; limitations of infants and toddlers to detect or report symptoms may demand more frequent monitoring 29
    • Frequent, severe, and/or nocturnal hypoglycemia require adjustment in insulin doses 69
    • In young children, severe hypoglycemia may lead to cognitive deficits; thus, if hypoglycemia is frequent, blood glucose targets may need to be relaxed for this age group 29
    • Immediate treatment of severe hypoglycemia requires administration of rapidly absorbed glucose (oral), glucagon (IM or intranasal), and/or IV glucose, with treatment based on severity of hypoglycemia, level of consciousness, and ability of child to ingest oral glucose 132 133
• Chronic
  • Microvascular complications 29 124 134
    • Intensive diabetes therapy aimed at achieving near-normal glycemia reduces the development of microvascular complications in type 1 diabetes
    • Rarely occurs before puberty or in children with diabetes duration less than 2 years, but does occur after puberty or in children with diabetes duration of 5 to 10 years 16
      • Nephropathy 29 134
        • Elevated albumin excretion rate is usually first finding; persistence predicts progression to gross proteinuria within 6 to 14 years
          • Reference range: less than 30 mg/g albumin-creatinine ratio 134
          • Modestly elevated albumin excretion: 30 to 299 mg/g albumin-creatinine ratio (in a spot urine sample) 134
          • Persistent abnormal microalbumin excretion: requires documentation of 2 of 3 consecutive abnormal values obtained on different days over a 6-month period 29
          • Test confounders include exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, menstruation, and severe hypertension 134
        • In addition to strict glycemic control, blood pressure control is essential to reduce the risk or slow progression of nephropathy
        • Consider treatment with ACE inhibitor (or angiotensin receptor blocker) for nonpregnant patients with persistently abnormal microalbumin excretion (greater than 30 mg/g) 29
      • Retinopathy
        • Highly specific vascular complication of diabetes, with prevalence strongly correlated to duration of diabetes and level of glycemic control
        • Refer to ophthalmologist for an initial dilated retinal and comprehensive eye examination once the child is at least 11 years old or pubertal (whichever is earlier) and has had diagnosis of diabetes for 3 to 5 years 29
        • Measures to reduce risk or slow progression of diabetic retinopathy include optimal control of glycemia, blood pressure, and serum lipid levels 124
      • Neuropathy 124
        • Neurologic complications rarely occur during childhood
        • Measures to prevent or delay onset of diabetic neuropathy include optimizing glycemic control
  • Macrovascular complications
    • Cardiovascular disease 102
      • Coronary artery disease is main cause of death in persons with type 1 diabetes
      • Cardiovascular events generally do not occur during childhood, but the atherosclerotic process begins during childhood in patients with diabetes
        • Age and hemoglobin A1C level are the strongest risk factors for a major atherosclerotic event or for any cardiovascular disease in patients with type 1 diabetes 104
      • A period of intensive diabetes management at an early stage of the disease is associated with beneficial effects on the long-term occurrence of cardiovascular disease 104
      • Addressing other individual risk factors for atherosclerotic cardiovascular disease to reduce the likelihood of harmful events is especially important in diabetes 109
      • Lifestyle measures to reduce risk include achieving blood pressure and weight control, smoking cessation or avoidance, and consuming a balanced diet that is rich in fruits and vegetables, low in saturated fat and sodium, and enriched in whole grains
  • Abnormal growth
    • Poor growth and delay in pubertal and skeletal maturation may result from chronic undertreatment with insulin, resulting in poor diabetes control or development of comorbidity (eg, depression, thyroid disease, celiac disease) 29
    • Obesity is as common in children and adolescents with type 1 diabetes as in those without diabetes 29
    • Maintain normal physical growth to include regular gains in height and weight, as well as normal timing of the onset and magnitude of the pubertal growth spurt
      • If patient is not growing appropriately according to nomograms:
        • Alter insulin dosing and control
        • Consider coexistence or development of comorbidity (eg, hypothyroidism, celiac disease)
        • Reassess nutritional status and refine dietary counseling

Prognosis

• Type 1 diabetes is associated with increased risk of mortality
  • Excess mortality in childhood- or adolescent-diagnosed type 1 diabetes is apparent across countries worldwide 135
  • All-cause and cardiovascular-related mortality rates are at least twice as high as those for matched controls 136
  • Excess risk of death from any cause and death from cardiovascular causes appears to vary by glycemic control, with the risk for death rising as hemoglobin A1C levels increase 137
  • Over the long term, an initial period of intensive diabetes therapy (duration of 6.5 years) is associated with a modestly lower all-cause mortality rate when compared with conventional therapy 137

Screening and Prevention

Screening

At-risk populations

• First-degree relatives have an 8- to 15-fold increased risk of type 1 diabetes 138
• Second-degree relatives have a 2-fold increased risk of type 1 diabetes 138

Screening tests

• Measuring islet autoantibodies in relatives of patients with type 1 diabetes may identify those who are at risk for developing disease 3
  • General population screening of first-degree relatives of those with type 1 diabetes is not universally recommended, but it is available in clinical research trials

Prevention

• There are no known effective lifestyle measures or pharmacologic interventions that delay or prevent type 1 diabetes 139